I like Dr Ben Lomatayo’s response, hence, would like to draw your attention to his reply yesterday to my question in this thread.
At least one episode of either neutropenia or cytopenia occurs in 20-60% of KTR during their transplant.1,2 Cytopenia is more common in the initial period due to induction therapy and intense maintenance immunosuppression.2 The episodes can last for 1-4 weeks.1
The offending drugs include mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS), ganciclovir/valganciclovir, anti thymocyte globulin (ATG), tacrolimus, sirolimus, and cotrimoxazole.1,2 Unfortunately, there is no evidence-based approach to identifying the culprit agent and modifying the medications.2 In case of persistent neutropenia, autoimmune etiology should be considered.3 Finally, neutropenia may occur because of a viral (CMV) or bacterial infection.1
In Liverpool, I have seen CNI-induced neutropenia only once over the last 35 years and the most plausible explanation for this association is due to its pharmacokinetic interaction with MMF: Tacrolimus increases the availability of the active form of MMF. Induction therapy may also contribute to neutropenia, especially ATG. In our experience, IL2R blocker (such as simulect) has never been found to be causing leucopenia either due to their own effect or as an additive to other medication.
Approach to this patient with leucopenia:
My approach would, therefore, be first to ensure that the patient is not septic or have a fever, in which case they would need to be admitted for treatment with broad-spectrum antibiotics in a side room. I would advise the patient to seek medical help immediately if they develop a fever and advise them to avoid crowded places and people with ongoing infections.
In addition to MMF, other causes that would need to be considered are as follows.
1. Investigating potential causes: CMV/EBV infection can cause leucopenia so I would send off CMV and EBV PCR to exclude this as well as look at the donor status of these viruses. Additionally, the patient is immunosuppressed and is susceptible to a wide range of other viral infections that can also cause leucopenia (Adenovirus, enterovirus, influenza, etc.
2. Hematological malignancies although rare would be something that I would bear at the back of my mind. When I note leucopenia, my first step would be to reduce or stop the MMF and add prednisolone 10 mg per day just to cover for the period when the recovery from leucopenia recovers and that patient would be in a phase of higher risk of acute rejection. If leucopenia is associated with altered LFTs, then the first drug that I would stop is co-trimoxazole and replace it with dapsone 100 mg per day. The caveat is that a longer interruption (>6 days) of MMF has been linked to an increased risk of acute rejection during the recovery phase when a patient is discharged to home. Some clinicians hold off co-trimoxazole and valganciclovir as well. G-CSF has been considered a second-line of therapy after adjustment of the other medications, however, it is required only rarely.1 I do not know any transplant unit personally where MPA levels (or even more reliable IPMDH levels) are measured for routine clinical application. The reason is that there is a tremendous degree of overlap between the ‘therapeutic range’ and ‘toxic level range’.
References:
1. Bagnasco SM, Gottipati S, Kraus E, Alachkar N, Montgomery RA, Racusen LC, Arend LJ. Sarcoidosis in native and transplanted kidneys: incidence, pathologic findings, and clinical course. PLOS One. 2014; 9: e110778. 2. Knoll GA, Macdonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol. 2003; 14: 2381-2386. 3. Shigemitsu H, Patel HV, Schreiber MP. Extrapulmonary Sarcoidosis. In: Judson M. (eds) Pulmonary Sarcoidosis. Respiratory Medicine. 2014; 17. Humana Press, New York, NY 4. Leonardo Riella. Neutropenia in transplant recipients. Renal Fellow Network. Dec 2010. https://www.renalfellow.org/2010/12/22/neutropenia-in-transplant-recipients/ 5. Khalil M.A.U, Khan T.F.T, Tan J. Drug-Induced Hematological Cytopenia in Kidney Transplantation and the Challenges It Poses for Kidney Transplant Physicians. Journal of transplantation. August 2018. Volume 2018. 22 pages. 6. Olivier A, Rebecca S, Anne S, et al. Autoimmune Neutropenia After Kidney Transplantation. A Disregarded Entity of Posttransplant Neutropenia. Transplantation: April 15th, 2014;97(7):725-729.
Dear Prof
I fully agree with you. We also need to look for other etiologies of the cytopenia. Drugs are the most common cause, but due to the immunosuppression these patients have a high risk of getting opportunistic infections like CMV. The other important thing highlighted is autoimmune etiologies. It is always important to look for connective tissue disease in these patients. One of the things that we in Sub Saharan Africa have to always think of is tuberculosis as it can also cause bone marrow suppression and the diagnosis of TB can be very challenging in the background of immunosuppression
Yes, the issue of TB is quiet common in this part of the world and it requires high index of suspicion. In terms of diagnostic urine LAM may be helpful although it was not originally design for transplant population. I think it should be of evaluation of persistent unexplained pan or bi-cytopenia in transplant setting specially in Africa or endemic areas.
Dear Professor ,
Thank you so much for the informative and reasonable approach .
At my center we recently started to check the MMF level once at least (done outside in a Tx center in Spain) especially for those with persistent leucopenia or recurrent infections or weight loss -those are mostly suspected from side effects of MMF .
Reducing the dose of the MMF is done for sure along with trial to keep the FK level on the higher therapeutic level as most of those recipients are recently transplanted .
we believe that the MMF side effects of leucopenia are mostly evident in the early post transplant period , Steroids free regimen is occasionally done but its not an option for those with reduced MMF dose
Valcyte leucopenia nearly occurs in all patients ( bicytopenia too ) so close follow up is highly recommended .
Batool Butt
2 years ago
Renal transplant recipients need immunosuppression medications post –op to maintain graft survival.But they are associated with number of side effects –one of which is myelosuppression. About 20-60% of Kidney transplant recipients had an episode of cytopenia Approximately 20-60% of KTRs experience one episode of cytopenia after transplant. Most episodes of cytopenia are observed within the first 3 months post-transplant. Drugs which cause cytopenias (neutropenia and leucopenia) include: 1-Rituximab: is a monoclonal antibody that binds CD20 antigen resulting in B cell depletion.According to one study,cytopenias occur in about 48% with Rituximab.
2-Antithymocyte globulin- Cytopenias more common with ATG if high doses given and also if administered with antimetabolite that is why antimetabolite withheld when ATG administered.Dose need to be modified and reduced according to WBC and platelet count. 3-Alemtuzumab– more severe cytopenias compared to ATG and this study stated 33.4% to 42% incidence of leucopenia. 4-Interleukin receptor antagonists (basiliximab and dacliuzumab)-cytopenia rare. 5-Mycophenolic mofetil and enteric-coated mycophenolate sodium-11.8%-40% incidence of leucopenia mentioned in the literature.
For all of the above mentioned drugs-drugs need to be reduced or stopped if cytopenias occur. 6-Tacrolimus- neutropenia noticed in the first 3 months after transplant. 7-Azathioprine- usually observed in the first month after transplant with doses >1.99 mg/kg body Mammalian target of rapamycin inhibitors (sirolimus and everolimus) 8-Mammalian target of rapamycin inhibitors (sirolimus and everolimus)-dose dependent myelosuppression-Combination therapy with MMF cause severe leucopenia.In some cases , it resolves spontaneously ,however, few cases require dose reduction or cessation. 9-Valganciclovir-Several factors like co-administeratin with MMF,high doses of drug and low BMI can increase the chances of cytopenias . 10-Ganciclovir- incidence reported is 7.1% to 23.1%. Cytoenias less than valganciclovir. 11-Trimethoprim-sulfamethoxazole-dose-dependent inhibition of granulopoiesis. Folinic acid can reverse this side effect. 12-Dapsone-also causes of agranulocytosis. Posttransplant Drug-induced Thrombocytopenia-Similar drugs which cause leucopenia –also causes thrombocytopenia like Rituximab,ATG,Alemtuzumab ,Basiliximab ,etc. Differential Diagnosis of Leukopenia and Thrombocytopenia-Other causes which are responsible for causing this includes:B12, folic acid, zinc, and copper deficiencies, Infections with EBV, CMV, parvovirus B19, HHV 6, condition which causes Thrombocytic microangiopathy like renal ischemic events, ABMR, and viral infection . Therapy for Drug-induced Hematological Cytopenia: dose reduction or cessation of the offending agent
–Specific treatment: G-CSF or GM-CSF-reserved for specific cases like febrile neutropenia and those with diminished bone marrow reserves: extensive radiotherapy, patients with AIDS/human, and patients older than 65 years.Thrombopoietin receptor agonists for thrombocytopenia.
What is the level of evidence provided by this article?
This is a narrative review, level V.
Wee Leng Gan
2 years ago
Kidney transplant recipients often have hematological cytopenia due to immunosuppressant.
Common culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG.
The approach in managing myelosuppression include judicious reduction or withdrawal of suspected agents. The treating clinician should remain alert to look for opportunistic infection and early signs of acute rejection as a result of reduction of immunosuppression. The prophylactic administration of G-CSF or GM-CSF is suggested in patients with febrile neutropenia,103 those with diminished bone marrow reserves (eg, ANC <1.5 × 109/L) , patients with AIDS/human immunodeficiency virus infection, and patients older than 65 years, sepsis, neutropenic pyrexia of more than 7 days.
Some conditions constitute medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC <500/μL,94 and prolonged neutropenia of more than 7 days.
Thrombocytopenia in kidney transplant can be attributed to either bone marrow suppression or to an idiosyncratic drug reaction. if thrombocytopenia is due to idiosyncratic reaction (eg, due to trimethoprim sulfamethoxazole), then immediate withdrawal of the suspected agent is required. Occasionally, platelet transfusion may be required, such as in life-threatening bleeding risk, serious decline of platelet count (<20 000/mm3), or before an invasive procedure. The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
Before ocular and neurosurgical invasive procedures, a minimum platelet count of ≥100 000/mm3 is usually advised.
For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
Platelets count with minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
optimization of the myelopoietic function and normalization of the hematological profile, resulting in better allograft and patient survival.
Fatima AlTaher
2 years ago
Hematological complications are common after kidney transplantion affecting 20-60 % of patients in the form of uni , bi or pancytopenia as anemia , leukopenia or thrombocytopenia that increase the risk of opportunistic infection as CMV and Pneumocystis jeroviki endangering the recipient life , mean while the only effective treatment strategy is to reduce the dose of IS drugs which increase the risk of graft rejection.
Leukopenia can be classified according to severity into Mild : WBC count >2000-3000 cell /mm3, Moderate 1000-2000 cell /mm3 and Severe < 1.000 cell .Severity and duration of leukopenia increase the risk of opportunistic infection specially after withdrawal of Prophylactic against CMV and Pneumocystis jeroviki. Drugs causing leukopenia
1- Rituximab: used for desensitization, induction in ABO incompatibile kidney transplantion and treatment of ABMR , is associated with leukopenia in 36 % of cases and this leukopenia could start as late as 4 weeks from last rituximab dose
2-ATG
wide range and non specific effects on different blood cell lineages that causes cytopenia in up to 50% of cases Management of ATG induced cytopenia
1- half the ATG dose when platelets drop 50000-75000 or WBCs to 2000-3000
2- Hold ATG when platelets< 50000 or WBCs <2000
3- Alemtizumab: anti CD52 agent that’s expressed on surface of mononuclearsl cells including neutrophils . Causes leukopenia in 30% of cases.
4- Basiliximan : least common drug in inducing leukopenia compared with other agents used for induction. 5- Drugs used for maintenance therapy as
MMF, tacrolimus and azathioprine: all can cause myelosuppressive. Their dose should be Prophylactically decrease with induction with ATG or basiliximab
Non-IS drugs also may cause leukopenia including valganciclovir, ganciclovir and trimethoprim -Sulha. Management of drug induced leukopenia
1- Prophylactically, deceased the dose of MMF and tacrolimus during induction with ATG and alemtuzumab.
2- close monitoring of CBC.
3- Adjust the dose or hold it according to severity of leukopenia. Conclusion
In kidney transplantation, both immunosuppressive and non-immune suppressive drug could lead to cytopenia via different mechanisms, that requires close monitoring of the patient, adjust or stop the offending drug when needed which in turn increase the risk of graft rejection thus, we need to balance the risk and benefits of those drugs.
Level of evidence: 5
Alyaa Ali
2 years ago
Myelosupression presenting as cytopenia is common in kidney transplantation, 20 to 60 % of kidney recipients develop at least 1 episode of cytopenia after transplant.
Most episodes occurs during the first 3 months
Immunosuppressive drugs are important for allograft survival, but they carry the risk of harmatological complications as myelosuppression.
Cautions should be taken in reduction or complete withdrawal of the causative agent as there is increased risk of acute rejection and increased risk of opportunistic infections.
Cytopenia can be pancytopenia involves all 3 cells lines ( WBC,RBC and platelets) or bicytopenia involves 2 of 3 lines
Rituximab
Late onset neutropenia is a neutropenia that is occurred 4 weeks after the last dose of rituximab after exclusion of other causes
It’s incidence is about 37% to 48%.
Leucopenia after rituximab occurs in about 19 % to 24%.
Dose reduction or drug withdrawal is usually the ideal response for harmatological recovery.
Antithymocyte globulin
Leukopenia incidence with ATG is variable as a result of differences in protocols and variabilities in periods of administration 10%,38%,50%.
Thrombocytopenia in 14%.
The dose of ATG should be halved when platelet count reaches 50000 to 75000 per mm or WBC count reaches 2000 to 3000 per mm. ATG should be held when platelet count less than 50000 per mm or WBC count below 2000 per mm.
Alemtuzumab
Leukopenia incidence is 33% to 42%
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe, with the lowest WBC count observed 130 days after last given dose.
IL-2R antagonists
Their leucopenic and thrombocytopenia effects are rare compared with ATG and alemtuzumab
So they would be an optimum therapeutic option for Leukopenic KTRs with low/moderate risk of rejection.
MMF
Incidence of Leukopenia is 11.8% to 40%.
The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MMF.
Treated by dose reduction or complete withdrawal
Prevention can be done by preemptive dose reduction of MMF after ATG and alemtuzumab induction, shifting to mTOR inhibitors and halving the CMV prophylactic dose of valganciclovir.
Tacrolimus
Combined Tac and MMF cause neutropenia in 28% of KTRs.
Observed within 3 months after transplantation
Reduction dose of MMF
Azathioprine
Azathioprine induces Leukopenia and neutropenia in 50% of KTRs, which occur mainly in the first month after transplantation
Azathioprine levels should be monitored weekly, with full blood count monitoring.
mTORi
Everolimus therapy can be complicated by Leukopenia in 11 to 19%.
Observed within the first 4 to 8 weeks
Most cases resolve spontaneously, if no dose reduction
If resistant, drug cessation
Valganciclovir
10 to 28 % of KTRs are vulnerable for Leukopenia development
5 to 37% of patients develop neutropenia
This occurs with higher doses of drug 900 mg or more.
It occurs within 3 months
Resolve spontaneously or by dose reduction or cessation of drug
Ganciclovir
Cause Leukopenia in 7.1 to 23.1% , it exerts modest myelosupression compared with Valganciclovir
Trimethoprim- sulfamethoxazole
Can cause neutropenia , Leukopenia or megaloblastic anemia
Induce Leukopenia in only 2% of recipient.
Dapsone
Cause neutropenia
Drug induced lymphopenia
Is usually due to induction therapy with ATG
Drug induced thrombocytopenia
Rituximab causes thrombocytopenia in 48% of cases
ATG , incidence of thrombocytopenia 10 to 26 %
Alemtuzumab causes thrombocytopenia in 14% of KTRs
IL- 2R antagonists cause rare thrombocytopenia compared with ATG
MMF, MTORi
Ganciclovir
Trimethoprim- sulfamethoxazole
DD of drug induced neutropenia and thrombo
cytopenia
B12 , folic acid , zinc and copper deficiency
EBV
CMV
Parovirus B19
Hemophagocytic syndrome
Specific management of neutropenia
Severe neutropenia , ANC < 500 / ul
Drug reduction or complete withdrawal of the suspected agent WBC count correction with administration of colony-stimulating factors.
Thrombocytopenia
Dose reduction or complete withdrawal of causative agent
Platelet transfusion if number below 20000 per mm3
Hinda Hassan
2 years ago
pancytopenia involves all 3 cells lines: WBCs, RBCs and platelets. bicytopenia involves 2 of 3 cell lines. Rituximab
Rituximab is associated with Late-onset neutropenia which occur 4 weeks after start of rituximab therapy, usually observed after the sixth rituximab dose. The incidence ranges from 19% to 24.6% .Dose reduction or drug withdrawal is usually the ideal response for hematological recovery. Rituximab-induced thrombocytopenia rarely induces bleeding and so platelet infusion is rarely indicated. Anti-thymocyte globulin
Leukopenia incidence is variable as a result of differences in protocols and administration periods. administration. Monitoring is through CD3+ T-cell count or total lymphocyte count. The dose of ATG should be halved when any of the following occur:
-platelet count reaches 50 000 to 75 000 per mm3
-WBC count reaches 2000 to 3000 per mm3.
Treatment with ATG should be held when any of the following occur
-platelet count declines to less than 50 000 per mm3
-WBC count is less than 2000 per mm3.
Antithymocyte globulin may induce thrombocytopenia from 10% to 26.5% and lymphopenia can also result . Alemtuzumab
the myelotoxic effects are more severe when compared with ATG but the infectious episodes are usually not life-threatening. Alemtuzumab Autoimmune thrombocytopenia has been observed in 14% of KTRs with bleeding requiring surgical intervention in 12% of KTRs. interleukin receptor antagonists basiliximab and daclizumab
the incidence of leukopenia was lesser than ATG ,so they can be an option for leukopenic recipients with low/moderate risk of rejection. interleukin receptor antagonists thrombocytopenic drawbacks are currently rare . Mycophenolic mofetil and enteric-coated mycophenolate sodium
Both ATG-related and alemtuzumab related cytopenia may mask the diagnosis of MMF myelotoxicity. The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA so, dose reduction or complete withdrawal can reverse this. other alternatives are reduction of other cytotoxic medication or shifting in to mTOTi. MMF dose reduction is required for leukopenia, anemia, thrombocytopenia, andpancytopenia.
Tacrolimus
May cause anemia, neutropenia, and combined anemia/neutropenia and intensify MMF myelotoxicity. Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant. Azathioprine
may induce leukopenia and neutropenia with doses greater than 1.99 mg/kg body weight/day and present mostly in the first month after transplant. a past history of drug-induced leukopenic events would increase the risk of leukopenia by 70%. Patients with complete lack or low thiopurine S-methyl transferase activity are vulnerable to developing severe, life-threatening myelotoxicity. Monitoring can be through RBC 6-thioguanine nucleotide in RBCs. Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity. Azathioprine levels should be monitored weekly in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment. Mammalian target of rapamycin inhibitors
Severity of myelotoxicity is dose dependent and can be usually observed within the first 4 to 8 weeks. In most patients, leukopenia resolves spontaneouslybut, if persists, then a reduction of the MMF dose with simultaneous reduction of mTORi or total withdrawal can be tried. Thrombocytopenia has been reported with mTORi and it is dose dependent. valganciclovir
cytopenia may be potentiated by several factors, including doses 900 mg or more , low body mass index and concomitant MMF . Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal. Ganciclovir
exerts modest myelosuppression and a lesser incidence of leukopenia and which respond to dose reduction but some require ganciclovir cessation. Ganciclovir can induce thrombocytopenia in 23.1% of KTRs. Valacyclovir
myelotoxicity is relatively mild but increase with other cytopenic drugs Trimethoprim-sulfamethoxazole
associated with neutropenia and leukopenia , megaloblastic anemia and dosedependent inhibition of granulopoiesis ,the latter can be reversed with use of Folinic acid . Trimethoprim-sulfamethoxazole thrombocytopenia is observed. Dapsone
is associated with neutropenia and agranulocytosis
Differential diagnosis of drug-induced leukopenia and thrombocytopenia
1- Metabolic:B12, folic acid, zinc, and copper deficiencies,
2- Infections: Epstein-Barr virus-,Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis
3- Hemophagocytic Syndrome can be associated with cytopenia and several viral infections (CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
4- Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B19). Therapy for Drug-induced Hematological Cytopenia
the first step is determining the patient’s full detailed history to unravel possible culprit. if no cause was identyified, then a dose reduction or complete withdrawal of the suspected agent with correction of WBC count through administration of “colonystimulating” factors if there is no accepted response to the previous maneuvers.
level of evidence is 5
Asmaa Khudhur
2 years ago
Drug-Induced Myelosuppression in Kidney Transplant Patients
It is common for kidney transplant recipients to experience myelosuppression that manifests as cytopenia (KTRs). After transplant, at least 1 episode of cytopenia affects 20% to 60% of KTRs. The majority of cytopenia episodes are seen in the first three months.
Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole are included on the list of responsible substances.
It may be urgently necessary to carefully reduce or completely remove the problematic substance; but, as was mentioned below, possible dangers should be anticipated and managed appropriately.
Consideration must be given to the increased risk of acute rejection following the discontinuation of myelosuppressive immunosuppressive drugs. After stopping valganciclovir, there is a higher risk of infection, including opportunistic infections like cytomegalovirus (CMV), or after stopping trimethoprim-sulfamethoxazole, there is a higher risk of Pneumocystis jirovecii.
Drug-induced Leukopenia and Neutropenia:
Rituximab:
In one study, 48% of patients experienced rituximab-induced cytopenia (grade 3/4), with patients with lymphoma experiencing 40% lymphopenia, 6% neutropenia, and 4% leukopenia. Four weeks following the initiation of rituximab therapy, cytopenia may develop (late-onset neutropenia).
After the sixth rituximab, late-onset neutropenia is typically noted.
Antithymocyte globulin:
Neutropenia may be brought on by larger ATG doses as well as a general aversion to neutrophils and platelets.
When the WBC count or platelet count reaches 2000 to 3000 per mm3 or 50 000 to 75 000 per mm3, the dose of ATG should be cut in half.
36,39 When the platelet count drops to fewer than 50,000 per mm3 or the WBC count drops to less than 2,000 per mm3, ATG treatment should be stopped. When it falls below 0.05 109/L, the CD3+ T-cell count needs to be watched.
Alemtuzumab:
According to several data, the leukopenic incidence in KTRs treated with alemtuzumab ranged from 33.3% to 42%. When neutropenia is also present, the incidence is higher (47%) Alemtuzumab has more severe myelotoxic side effects than ATG,with the lowest WBC numbers seen 130 days after the last dosage. Infectious episodes, though, often do not pose a danger to life. MMF may be dosed down to 14 mg/kg in response to alemtuzumab-induced leukopenia, which is a substantially lower dose than that needed for ATG-induced leukopenia.
Mycophenolic mofetil and enteric-coated mycophenolate sodium :
ATG-related and alemtuzumab-related cytopenia may conceal the diagnosis of MMF myelotoxicity because they may require MMF dose reduction.Single-nucleotide polymorphism has its role in the development of MMF-related cytopenia.The hematological sequelae with myelosuppression are the most frequent cause requiring MMF dose reduction, accounting for 46.5% of MMF-reducing events.
The concurrent administration of valganciclovir,valacyclovir, and fenofibrate may exacerbate the leukopenia caused by MMF. The myelotoxic effect of MMF is dosage dependant and typically related to the trough levels of MPA.
An appropriate approach to MMF-induced neutropenia and leukopenia appears to be a dose reduction or complete withdrawal in order to manage cytopenia.
Tacrolimus :
The direct suppression of myeloid cells, which results in bone marrow hypoplasia in hepatic transplant recipients,altered cytokine production by T lymphocytes and monocytes, and production of antimyeloid precursors and anti-mature neutrophil antibodies are some of the mechanisms by which tacrolimus-induced neutropenia is brought on. It has been demonstrated that tacrolimus blocks MPA glucuronidation, which increases blood levels. Tacrolimus does not obstruct MMF enterohepatic circulation, in contrast to cyclosporine, resulting in elevated MPA levels. Within three months, tacrolimus and MMF together increase the area under the curve for MMF by 20% to 30%.
Within the first three months following transplant, tacrolimus-induced neutropenia can be seen.
Azathioprine :
Nearly half of KTRs may experience leukopenia and neutropenia after taking azathioprine, especially at doses higher than 1.99 mg/kg body weight/day. The first month following transplantation is when azathioprine-induced leukopenia most frequently manifests. A dose reduction or brief drug discontinuation usually suffices in this circumstance. Notably, the risk of leukopenia would rise by 70% if there was a history of drug-induced leukopenic episodes.
Mammalian target of rapamycin inhibitors:
Myelotoxicity severity is dosage dependent,with sirolimus involving 20% or less of KTRs. Although leukopenia and thrombocytopenia can frequently arise at lower drug levels, a trough level of >12 ng/dL has been demonstrated to be strongly related with their development.
valganciclovir:
Its myelotoxicity profile has been impacted by (for oral ganciclovir).
Disrupted signal transduction by mTORi through the gp130 chain and platelet activation are among the hypothesized mechanisms for mTORi-induced myelotoxicity.
Although 4.9% to 37.5% of patients may develop neutropenia, 10% to 28% of KTRs are susceptible to leukopenia development.
The development of leukopenia and neutropenia may be significantly impacted by greater doses of the drug (900 mg or more), a low body mass index, which is a substantial potentiator of leukopenia, and concurrent MMF use, which can also exacerbate valganciclovir myelotoxicity.
Ganciclovir:
Because this medication’s oral bioavailability is so low, it is usually administered intravenously. Ganciclovir causes leukopenia through the myelosuppressive effects it has, with rates ranging from 7.1% to 23.1%. 42 The myelosuppressive effects of ganciclovir are less than valganciclovir’s.
valacyclovir:
Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole:
A typical medication used for Pneumocystis jirovecii prevention is trimethoprim-sulfamethoxazole. Use of trimethoprim-sulfamethoxazole is linked to a number of cytopenias, including neutropenia, leukopenia, and megaloblastic anemia.
Dapsone:
Dapsone, a different medication for Pneumocystis jirovecii prophylaxis, has a number of hematological side effects, including neutropenia. Additionally, the emergence of agranulocytosis has the potential to exacerbate the neutropenic effects of dapsone.
Level of evidence 5.
Mohammed Sobair
2 years ago
introduction;
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number of these drugs are associated with hematological complications. Myelosuppression presenting as cytopenia is not uncommon in kidney transplant recipients.
From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
Most episodes of cytopenia are observed during the first 3 months.
The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Consequences of Hematological Cytopenia:
Leukopenia KTRs are vulnerable to the development of opportunistic infections.
Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
Neutropenic KTRs commonly experience more intra-abdominal infections, than those with normal neutrophil counts.
Both tacrolimus and MMF therapy are commonly associated with neutropenia.
In an attempt to reduce the severity of neutropenia, transplant physicians often reduce or withhold MMF. Despite the expected rise in WBC, its associated with increase risk of acute rejection.
Drug-induced Leukopenia and Neutropenia:
number of agents have been implicated in posttransplant leukopenia and neutropenia development.
Rituximab:
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen.
Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial as follows
: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma.
Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia). Late-onset neutropenia can, after 4weeks.
Late onset neutropenia is usually observed after the sixth rituximab dose. Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently implicated in its evolution.
The reported incidence of leukopenia after rituximab therapy ranges from 19% to 24.6% with an average relative risk of leukopenia of 8percdnt.
ATG:
leukopenia in 45.2% and as combined leukopenia and thrombocytopenia in 14.3% of studied KTRs38 (Figure 5).
dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm. Treatment with ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L.
Alemtuzumab :
is an anti-CD52 humanized mono – clonal immunoglobulin G1.
With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
The incidence is higher (47%) if neutropenia is also present.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe, with the lowest WBC counts observed 130 days after the last given dose.
However, infectious episodes are usually not life-threatening.
dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia.
With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required. interleukin receptor antagonists :
basiliximab, a monoclonal chimeric, Because anti-IL-2R activity is confined to activated T cells, their leukopenia and thrombocytopenic drawbacks are currently rare compared with drawbacks with ATG and alemtuzumab (10% to 15% vs 5% for basiliximab).
Moreover, leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab.
Brennan and colleagues reported leukopenia in 33.3% of their patients who received ATG induction. In comparison, the incidence of leukopenia was 10.6% for KTRs who received basiliximab.38 Another study reported a significantly higher incidence of leukopenia in KTRs who received thymoglobulin compared with those who received basiliximab (22.8% vs 11.8%; P < . 05).
Considering all these observations, the anti-IL-2R agents would be an optimum therapeutic option for leukopenia KTRs with low/moderate risk of rejection. Mycophenolic mofetil :
MMF hematotoxicity, 11.8% to 40% of KTRs can develop leukopenia .
Concomitant administration of valacyclovir, and fenofibrate may exaggerate MMF related leukopenia. To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia.
Several approaches could be added for the management of this type of leukopenia, including preemptive dose reduction of MMF after ATG and alemtuzumab induction, shifting to a suitable mammalian target of rapamycin inhibitor ,and halving the CMV prophylactic dose of valganciclovir, which could also be another preventive measure.
For resistant cases, cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal. Tacrolimus:
Tacrolimus the mainstay of clinical immunosuppression regimens.
16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia.
Tacrolimus may also intensify MMF myelotoxicity.
There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus.
A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include Everolimus, Belatacept, or eculizumab. Azathioprine
induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
Most cases of azathioprine induced leukopenia present in the first month after transplant.
In this situation, a dose reduction or transient drug withdrawal is usually sufficient.
Of note, a past history of drug-induced leukopenia events would increase the risk of leukopenia by 70%.
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine.
Patients with complete lack or low TPMT activity are vulnerable to developing severe, life-threatening myelotoxicity.
To ameliorate the risk of myelosuppression, 2 techniques have been proposed. The first is monitoring of 6-thioguanine nucleotide in RBCs, which is an efficacious and more beneficial method than monitoring of 6-mercaptopurine in plasma.
Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
Drugs that interact with azathioprine include allopurinol, Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will ensue.
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month
then twice per month during the second and third months, and then monthly or less according to dose adjustment. Mammalian target of rapamycin inhibitors
Severity of myelotoxicity is dose dependent, with involvement of about 20% of KTRs on sirolimus.
A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia, although it can commonly occur even with lower drug levels.
Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
Everolimus therapy, on the other hand, can be also complicated by leukopenia (11%-19%).
The development of cytopenia with mTor agents can be usually observed within the first 4 to 8 weeks. For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously.
valganciclovir
Although 10% to 28% of KTRs are vulnerable for leukopenia development,4.9% to 37.5% of patients may develop neutropenia.
The resultant cytopenia may be potentiated by several factors,
including higher doses of the drug (900 mg or more) having a significant impact on leukopenia and neutropenia development,
Low body mass index.
concomitant MMF administration.
Low dose is effective and less cytotoxic than high dose. Ganciclovir:
Less myelotoxic ,but need IV administration. Through its myelosuppressive effects, ganciclovir causes leukopenia, with rates of 7.1% to 23.1% . valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials.
Trimethoprim-sulfamethoxazole:
Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia.
Trimethoprim per se can cause dose dependent inhibition of granulopoiesis in vitro. Folinic acid can reverse this side effect. induce leukopenia in only 2% of recipients. However, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression. Dapsone :
is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis. Drug-induced Lymphopenia
In leukopenia KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia.. Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia. Rituximab:
Rituximab-induced thrombocytopenia (grade 3/4)
has been reported in 48% of patients in one trial, with rate of thrombocytopenia in 2% of lymphoma patients.
Because rituximab-related thrombocytopenia rarely induces bleeding, platelet infusion is rarely Antithymocyte globulin:
Cross-reaction of antibodies toward nonlymphoid tissue may result in the development of thrombotic events and thrombocytopenia.
Both higher doses of ATG and its nonspecific affinity to platelet cells may induce thrombocytopenia.
An incidence of thrombocytopenia ranging from 10% to 26.5% . Alemtuzumab
incidence ranging from 1% to 2.5%.90,91 Alemtuzumab-induced thrombocytopenia has been observed in 14% of KTRs.
Bleeding requiring surgical intervention has been observed in 12% of KTRs. interleukin receptor antagonists:
Because anti-IL-2R activity is confined to activated T cells, their thrombocytopenic drawbacks are currently rare compared with that shown with ATG and alemtuzumab (5% for basiliximab). Mycophenolic mofetil and enteric-coated mycophenolate sodium
The hematological sequelae of myelosuppression are the most common reason for reducing MMF dose. Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia. Mammalian target of rapamycin inhibitors :
The most common members of mTor :
Thrombocytopenia 20% of KTRs on sirolimus therapy. A trough level of >12 ng/dL is associated with thrombocytopenia.
Everolimus therapy is associated with thrombocytopenia in 10% to 17% patients
A suggested mechanism of mTor-induced myelotoxicity is the potential predisposition to thrombocytopenic micro – angiopathy with subsequent development of thrombocytopenia. Ganciclovir
Through its myelosuppressive effect, it can induce thrombocytopenia in 23.1% of KTRs.
Trimethoprim-sulfamethoxazole :
Several hematologic complications have been observed with this agent, including thrombocytopenia. Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia:
IB12, folic acid, zinc, and copper deficiencies.
Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia.
Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis , can lead to myelosuppression-induced cytopenia.
Hemophagocytic Syndrome :
Hemophagocytic syndrome can be associated with cytopenia.
Several viral infections (CMV, adenovir Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
thrombocytopenic microangiopathy with consequent thrombocytopenia can develop in the following situations:
renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B1.
Therapy for Drug-induced Hematological Cytopenia:
In addition to the aforementioned protocols.
Specific treatment of neutropenia
the patient’s full detailed history to unravel possible culprit(s).
a dose reduction or complete withdrawal of the suspected agent with correction of WBC count may serve as the only available technique to find a diagnosis.
administration of “colony stimulating” factors if there is no accepted response to the previous maneuvers.
Summary :
Through clinical assessments, culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG.
step is reduction or complete withdrawal of the suspected agent.
Until correction of cytopenia is accomplished, the treating clinician should remain alert to look for
(1) an opportunistic infection and (2) early signs of acute rejection as a result of reduction of immunosuppression.
Based on findings from G-CSF or GM-CSF use in oncology, these agents can be utilized in solid-organ transplant, but there is no consensus.
The prophylactic administration :
patients with febrile neutropenia.
those with diminished bone marrow reserves (eg, ANC <1.5 × 109/L) due to extensive radiotherapy, patients with AIDS/human immunodeficiency virus infection, and patients older than 65 years. On the other hand, therapeutic indications include sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infections, and adjunctive therapy along with antibiotics in the aforementioned indications.
medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC.
if bone marrow suppression is the underlying mechanism, dose reduction or complete drug cessation is required for correction of platelet decline.
Occasionally, platelet transfusion :
such as in life-threatening bleeding risk.
serious decline of platelet count (<20 000/mm3), or before an invasive procedure (eg, organ biopsy; Figure 9).107 The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy.
Before ocular and neurosurgical invasive procedures a minimum platelet count of ≥100 000/mm usually advised.
For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
Because of the high vascularity of renal tissue, a minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
The treating clinician should be aware that anemia associated with bleeding may lead to a major bleeding event, and platelet transfusion at that time may be required even if the platelet count is >100 000/μL.
Level of evidence 5.
Dalia Ali
2 years ago
Introduction
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number of these drugs are associated with hematological complications. Myelosuppression presenting as cyto penia is not uncommon in kidney transplant recipients (KTRs). From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole. Cautious reduction or complete withdrawal of the offending agent may be urgently warranted; however, as described here, potential risks should be expected and managed accordingly.
Cytopenia can be identified as follows: pancy topenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets; bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count; and leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.12 These levels are 3000 cells/mm3 (normal), 2000 to 3000 WBCs/mm3, 1000 to 2000 WBCs/mm3, and <1000 WBC/mm3 (the latter 3 levels indicating abnormal with variable severities). Leukopenia is also termed alternatively with neutropenia, although these terms are not synonymous.
Absolute neutrophil count (ANC) is used to
assess the magnitude of neutropenic severity as follows13: ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100. An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as mild, moderate, or severe. Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L, moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L, and severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L
Platelet count of 150 000/mm3 is considered the
lower limit of normal level in many laboratories. The CTCAE has also graded throm bocytopenia into 4 levels. These levels are grade I or subnormal (75 000-150,000 cells//mm3), grade II or low (50000-75000 cells/mm3, grade III or moderate (25 000-50 000 cells/mm3), and grade IV or critical (<25 000/mm3)
Drug-induced Leukopenia and Neutropenia Rituximab Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion and thus affecting phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells. Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes,in attempted treatment of chronic antibodymediated rejection, and in resolution therapy of posttransplant lymphoproliferative disorder.
Antithymocyte globulin Thymoglobulin activity is not confined to T cells; rather, a wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.Moreover, cross-reaction of antibodies toward nonlymphoid tissue may result in the development of neutropenia. Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia
Alemtuzumab Alemtuzumab is an anti-CD52 humanized mono clonal immunoglobulin G1 antibody. The former is a glycoprotein expressed on mononuclear cells (eg, T and B lymphocytes), monocytes, and natural killer cells. Alemtuzumab can be administrated as an induction agent42,43 or as antirejection medication.
interleukin receptor antagonists Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab, a monoclonal chimeric, and daclizumab, a humanized murine antibody against CD25 that can suppress IL-2mediated T-cell activation and proliferation in KTRs. The latter agent has been withdrawn from the market.
Mycophenolic mofetil and enteric-coated mycophenolate sodium These agents are inosine monophosphate dehydro genase inhibitors that can inhibit both cell-mediated and humoral immune responses through sup pression of guanosine nucleotide synthesis de novo pathways in T/B lymphocytes, arresting their differentiation.
Tacrolimus Tacrolimus is the mainstay of clinical immuno suppression regimens.63 Although much less common in renal transplant recipients, 16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia.11 Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs
Azathioprine Azathioprine is a traditional antimetabolite that was introduced in 1960 and has been greatly replaced by the more potent MMF in immunosuppression after kidney transplant. Azathioprine may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day. Most cases of azathioprineinduced leukopenia present in the first month after transplant. In this situation, a dose reduction or transient drug withdrawal is usually sufficient. Of note, a past history of drug-induced leukopenic events would increase the risk of leukopenia by 70%.
Mammalian target of rapamycin inhibitors The most common mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, have been involved in many myelotoxic side effects.77,78 Leukopenia has been reported in a meta-analysis of 8 trials that involved conversion from calcineurin inhibitor (CNI) to mTORi.79 Severity of myelotoxicity is dose dependent,80 with involvement of about 20% of KTRs on sirolimus. A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia,81 although it can commonly occur even with lower drug levels.
valganciclovir The higher bioavailability of this agent (70% vs 7% for oral ganciclovir) has also affected its myelotoxicity profile42, 43 . Although 10% to 28% of KTRs are vulnerable for
leukopenia development, 4.9% to 37.5% of patients may develop neutropenia.The resultant cytopenia may be potentiated by several factors, including higher doses of the drug (900 mg or more) having a significant impact on leukopenia and neu tropenia development, low body mass index, which is a significant potentiating factor for leukopenia, and concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
Ganciclovir Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs. The bioavailability of this drug is rather poor when given orally; therefore, it is always given intravenously. Through its myelosup pressive effects, ganciclovir causes leukopenia, with rates of 7.1% to 23.1%
valacyclovir Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild. Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials
Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis. Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia. Trimethoprim per se can cause dosedependent inhibition of granulopoiesis in vitro. Folinic acid can reverse this side effect. Similarly, folate-depleted granulocyte precursors have been observed in another in vitro report.
Dapsone Dapsone is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.69 Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Drug-induced Lymphopenia
In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia. The latter is usually complicated by augmented risk of serious infection; on the other and, lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG). Posttransplant Drug-induced Thrombocytopenia A number of medications have been implicated in the evolution of posttransplant thrombocytopenia
Rituximab Rituximab-induced thrombocytopenia (grade 3/4) has been reported in 48% of patients in one trial, with rate of thrombocytopenia in 2% of lymphoma patients. Because rituximab-related thrombocytopenia rarely induces bleeding, platelet infusion is rarely indicated.
Antithymocyte globulin Cross-reaction of antibodies toward nonlymphoid tissue may result in the development of thrombotic events and thrombocytopenia. Both higher doses of ATG and its nonspecific affinity to platelet cells may induce thrombocytopenia.An incidence of thrombocytopenia ranging from 10% to 26.5% has been reported in KTRs. Brennan and associates reported cessation or reduction in doses of ATG due to thrombocytopenia in 11.9% of KTRs.
Alemtuzumab Autoimmune thrombocytopenia has been observed in multiple sclerosis and chronic lymphocytic leukemia with an incidence ranging from 1% to 2.5%.
interleukin receptor antagonists Because anti-IL-2R activity is confined to activated T cells, their thrombocytopenic drawbacks are currently rare compared with that shown with ATG and alemtuzumab (5% for basiliximab).
Mycophenolic mofetil and enteric-coated mycophenolate sodium The hematological sequelae of myelosuppression are the most common reason for reducing MMF dose.
Summary
Through clinical assessments, culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG. The first therapeutic step is reduction or complete withdrawal of the suspected agent. Until correction of cytopenia is accomplished, the treating clinician should remain alert to look for an opportunistic infection and early signs of acute rejection as a result of reduction of immunosuppression. Based on findings from G-CSF or GM-CSF use in oncology, these agents can be utilized in solid-organ transplant, but there is no consensus
Level 5
Ahmed Omran
2 years ago
The article discusses myelosuppression induced by medications used for kidney transplantation, together with discussing the overlap caused by the use of combination of two or more drugs.
Medications may present with leukopenia ; in decreasing order r ATG, azathioprine, alemtuzumab, MMF, sulfa drugs, valganciclovir, rituximab ,everolimus, basiliximab and valaciclovir.
Some drugs can cause neutropenia, eg rituximab, alemtuzumab, valganciclovir, combination of MMF & tacrolimus, sulfa drugs, and tacrolimus alone.
Some drugs can cause thrombocytopenia, such as Ganciclovir, Sirolimus, Sulfas, everolimus, alemtuzumab and basiliximab.
Association of these drugs, in addition to the dose, duration, and clinical and metabolic conditions can increase these symptoms.
Differential diagnosis metabolic causes associated with vitamin B12, folic acid, zinc, or copper. Epstein Bar, Cytomegalovirus, Parvovirus B19, Herpesvirus 6, Influenza, and Rickettsia infections are also considered..
Level 5 study
Nasrin Esfandiar
2 years ago
Briefly summarise this article
Myelo-suppression induced by drugs in patients having kidney transplantation: Best choice for patients with end-stage kidney failure is renal transplant. An important factor in allograft survival in transplant recipients is immunosuppressive medicines. Some common immunosuppressive drugs in kidney transplant causes complications such as myelosuppression presenting as cytopenia. 20% to 60% of KTRs experience cytopenia at least once post-transplant which is associated with hematological complications. During the first 3 months, they observe most episodes of cytopenia. The list of medications can lead to enteric-coated mycophenolate sodium, cytopenia includes mycophenolate mofetil (MMF), ATG, ganciclovir and valganciclovir, Tacrolimus can strengthen the enhancement of the effect of Sirolimus, MMF, and trimethoprim-sulfamethoxazole. Making a balance between complete withdrawal of the offending agent and risk of rejection or reduction is crucial, in the direct post-transplantation period, in particular. Additionally, there is the risk of infections such as opportunistic infections like cytomegalovirus (CMV) infection, post valganciclovir cessation or the risk of Pneumocystis jirovecii, withdrawal of post trimethoprim-sulfamethoxazole. Cytopenia induced by Rituximab (grade 3/4) been reported in 48% of patients in one trial such as: 6% neutropenia, 40% lymphopenia, and 4% leukopenia. In patients with lymphoma, 4 weeks after start of rituximab therapy, Cytopenia might happen (late-onset neutropenia). We use absolute neutrophil count (ANC) for assessing the severity of neutropenia. We can grade an ANC less than1500/μL as mild, moderate, or severe and term it neutropenia. ANC level of 1000 to 1500/μL is Mild neutropenia, ANC level of 500 to 999/μL is moderate neutropenia, and ANC level of less than 500/μL is severe neutropenia (agranulocytosis). The development of opportunistic infectionsmake vulnerability for leukopenic KTRs. The sensitivity to infection increases when ANC is less than 1000 cells/μL. Magnitude of neutropenic decline and the duration of neutropenia has a correlation with severity and predisposition to frequency of infection. In neutropenic KTRs, Infection with Escherichia coli is also more prevalent. · Specific treatment of neutropenia: Measurement of ANC can be used for evaluation of the severity of neutropenia, with ANC less than 500/μL in medical emergencies, such as septic shock and severe pneumonia. Determining the patient’s history in full detail for recognizing culprit drugs with reduction of dose or complete withdrawal of the suspected agent, is the first step. Administration of “colony stimulating” factors if there is no response accepted to the prior action is the next step for WBC count correction. Three significant effects of the granulocyte colony-stimulating factor are: reduction of inflammatory cytokines, neutrophil proliferation, and production of anti-inflammatory soluble tumor necrosis factor and IL-l receptor antagonist and prostaglandin E2. There are minimal effects for Granulocyte colony-stimulating factor on lymphocytes since they are lacking specific receptors of G-CSF.
What is the level of evidence provided by this article?
The level of evidence is 5 as this is a review article.
Mohamed Fouad
2 years ago
Drug-Induced Myelosuppression in Kidney Transplant Patients
Renal transplantation is considered the best option for patients with end-stage kidney failure. Immunosuppressive drugs are important to allograft survival in transplant recipients. There are number of immunosuppressive medications are associated with hematological complications such as myelosuppression presenting as cytopenia which is so common in kidney transplant recipients from 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.
The list of medications can cause cytopenia includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, ATG, Tacrolimus can cause potentiation of the effect of MMF, Sirolimus, and trimethoprim-sulfamethoxazole. It is important to make a balance between reduction or complete withdrawal of the offending agent and risk of rejection especially in the direct post transplant period. There is also risk of infection including opportunistic infections like cytomegalovirus (CMV) infection after cessation of valganciclovir or risk of Pneumocystis jirovecii after trimethoprim-sulfamethoxazole withdrawal.
Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial as follows:40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma.24 Cytopenia can occur 4 weeks after start of rituximab therapy
(late-onset neutropenia).
Absolute neutrophil count (ANC) is used to assess the severity of neutropenia, An ANC of <1500/μL can be termed neutropenia and graded as mild, moderate, or severe. Mild neutropenia is ANC level of 1000 to 1500/μL , moderate neutropenia is ANC level of 500 to 999/μL, and severe neutropenia (agranulocytosis) is ANC level of <500/μL . Leukopenic KTRs are vulnerable to the development of opportunistic infections. When ANC is <1000 cells/μL, susceptibility to infection increases. The predisposition to frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenic decline. Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
Specific treatment of neutropenia
In medical emergencies, such as severe pneumonia and septic shock, measurement of ANC can be used to evaluate the severity of neutropenia, ANC <500/μL. The first step is determining the patient’s full detailed history to recognize culprit medications with dose reduction or complete withdrawal of the suspected agent. The next therapeutic step for WBC count correction would be administration of “colony stimulating” factors if there is no accepted response to the previous action.
Granulocyte colony-stimulating factor has 3 major effects: neutrophil proliferation, reduction of inflammatory cytokines, and production of anti-inflammatory soluble tumor necrosis factor and IL-l receptor antagonist and prostaglandin E2. Granulocyte colony-stimulating factor has minimal effects on lymphocytes as they are devoid of specific G-CSF receptors.
Jamila Elamouri
2 years ago
Immunosuppression drugs are a crucial for allograft survival. However, these medications are associated with many complications from which hematological complicationsm cytopenia. This increases risk of infection, including opportunistic infection which is life-threatening in the presence of leukopenia and neutropenia. In addition, thrombocytopenia can lead to bleeding. Drug withdrawal or dose reduction may be the only way to recognize the offending medication or medications.
Severe neutropenia (agranulocytosis) is associated with grave outcoe, particularly in patients with febrile neutropenia. Many drugs have been introduced to manage serious cytopenia such as CSF, GM-CSF, and thrombopoietic agents. However, there is dearth of safety and efficacy profiles for these noval agents.
Level 5
Ahmed Fouad Omar
2 years ago
Introduction
Immunosuppressive medications are mandatory for the graft survival but it can lead to myelo-suppression particularly during the first 3 months post-transplant. About 20-60% of KTR have at least I episode of myelo-suppression.
Myelo-suppression is categorized into:
· Leukopenia is either mild (≺3000), moderate (≺2000), severe (≺1000).
· Neutropenia is either mild (≺1500), moderate (≺1000), severe (≺500).
· Thrombocytopenia is divided into low (≺75000), moderate (≺50000), critical (≺25000).
Drugs that cause myelotoxicity:
1. ATG: its use is associated with leukopenia, neutropenia and thrombocytopenia. It is dose related, and increase with the use of other myelosuppressive drugs especially azathioprine.
2. Alemtuzumab: leucopenia occur in 33-42% of KTR. It causes more myelotoxicity than ATG.
Rituximab: . causes cytopenia in 48% of KTR. Reduce the dose or stop it is the best treatment option. Usually it is self-limited and respond well to dose reduction or stopping treatment.
IL-2 receptors antagonist: rarely causes leukopenia or thrombocytopenia. may induce neutropenia if used with MMF
MMF: Myelosuppression is dose dependent. leukopenia occur in 10-40% , thrombocytopenia in 46% of KTR. MMF dose reduction but need to be weighed against increase risk of rejection.
Azathioprine: cause neutropenia & leukopenia in 50% of cases. Its effects are dose dependent. Patients with TPMT deficiency develop severe life threatening leucopenia and infections.
mTOR-I: myelotoxicity is dose dependent occur in 20% of KTR on sirolimus. Respond to dose reduction. Myelosuppression risk increases when combined with MMF.
– Valganciclovir cause leucopenia in 10-28% of KTR. Risk factors are high doses, combination with MMF and low BMI. leukopenia usually resolve spontaneously, but prophylaxis with G-CSF may be needed if the effect is prolonged.
– Ganciclovir is less toxic and Valacyclovir is the least myelotoxic.
9. Trimethoprim-sulfamethoxazole: leukopenia occur in only 2% of cases especially when combined with azathioprine 10. DD of Drug-induced Leukopenia and Thrombocytopenia:
– deficits in B12, folic acid, zinc, and copper
Infections: EBV, CMV, parvovirus B19, human herpes virus 6, and influenza viruses.
Management:
There is no evidence-based approach to identifying the culprit agent and modifying the medications in case of persistent neutropenia is required. However, infections should be excluded Therapy for Drug-induced Hematological Cytopenia:
– Drug withdrawal or dose reduction may be the only way to recognize the culprit medication. Specific treatment:
– Neutropenia: G-CSF or GM-CSF agents can be utilized in solid-organ transplants with no consensus. Used in patients with febrile neutropenia and those with diminished bone marrow reserves, patients with AIDS and those >65 years
-Thrombocytopenia: thrombopoietin receptor agonists.
What is the level of evidence provided by this article?
Narrative review, level of V evidence
Abdullah Raoof
2 years ago
Drug-Induced Myelosuppression in Kidney Transplant Patients
Introduction:
Anumber of immunosuppression drug are associated with hematological complications.
20% to 60% of KTRs may develop cytopenia posttransplant.
The cytopenia are commonly seen during the first 3 months.
Causes may includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy – mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
The higher risk of acute rejection and increased risk of infection, should be considered if cytopenia induced drug has to be reduced or withdrawn.
Cytopenia could be as : pancy topenia involves all 3 cells lines,
bicytopenia involves 2 of 3 cell lines; thrombocytopenia and leukopenia. Definitions:
Leukopenia
– <3000 cells/mm3 (normal),
– 2000 to 3000 WBCs/mm3,
– 1000 to 2000 WBCs/mm3,
– <1000 WBC/mm3
(the latter 3 levels indicating abnormal with variable severities).
severity of granulocytopenia.
Absolute neutrophil count (ANC) is used to assess the magnitude of neutropenic severity as follows:
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as mild, moderate, or severe.
– Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to1.5 × 109/L,
– moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L,
– severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L.
thrombocytopenia:
Above 150,000 is normal.
– grade I or subnormal (75 000-150,000 cells//mm3),
– grade II or low (50000-75000 cells/mm3,
– grade III or moderate (25 000-50 000 cells/mm3),
– grade IV or critical (<25 000/mm3) .
Leukopenic patient are vulnerable to opportunistic infections.
On the other hand there is high risk of acute allograft rejection with more than 50% reduction in medication dose. Drug-induced Leukopenia and Neutropenia: Rituximab:
Rituximab-induced cytopenia has
been reported in 48% of patients .40% lymphopenia, 6% neutropenia, and 4% leukopenia . Cytopenia can occur 4 weeks after start of rituximab therapy.
Dose reduction or drug withdrawal is usually the ideal response for hematological recovery. Antithymocyte globulin:
wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.
Leukopenia incidence with ATG is variable, with studies showing 10%, 38%, 33.5%, and 50%.
The dose of ATG should be halved when platelet
count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm.
Treatment should be stopped when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3.
CD3+ T-cell count should be monitored when less than 0.05 × 109/L (<50/µL; normal range, 128-131/µL) to avoid unnecessary higher doses. This approach is successful in reducing the incidence of acute rejection episodes, infections, and cytopenia.
Total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available. Alemtuzumab:
Alemtuzumab is an anti-CD52 humanized mono –
clonal immunoglobulin G1 antibody.
With alemtuzumab, the leukopenic incidence in
KTRs ranges from 33.3% to 42% in various reports.34,46
The incidence is higher (47%) if neutropenia is also
present. Compared with ATG, the myelotoxic effects of alemtuzumab are more severe. interleukin receptor antagonists:
the leukopenic and thrombocytopenic drawbacks are currently rare compared with drawbacks with ATG and alemtuzumab.
The anti-IL-2R agent is the optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection. Mycophenolic mofetil and enteric-coated mycophenolate sodium:
These agents are inosine monophosphate dehydro -genase inhibitors.
With regard to MMF hematotoxicity, 11.8% to 40%
These drug users develop leukopenia .
46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia. The myelotoxic effect of MMF is dose dependent.
Treatment :
– preemptive dose reduction of MMF after ATG and alemtuzumab induction,
– shifting to a suitable mammalian target of rapamycin inhibitor (eg, sirolimus or everolimus may reverse cytopenia)
– halving the CMV prophylactic dose of valganciclovir,
Efficacy of valganciclovir 450 mg daily has been proven to be equal to a dose of 900 mg daily for CMV prophylaxis. For resistant cases, cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal. Tacrolimus:
Present as anemia, neutropenia, and combined anemia/neutropenia.
tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs. contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels. A combination of tacrolimus and MMF expands the area under the curve for MMF within 3 months by approximately 20% to 30%. Azathioprine:
Azathioprine is antimetabolite.
Azathioprine may induce leukopenia and neutropenia in almost half of KTRs.
As a treatment a dose reduction or transient drug withdrawal is usually sufficient.
To ameliorate the risk of myelosuppression techniques have been proposed.
The first is
monitoring of 6-thioguanine nucleotide in RBCs,
which is an efficacious and more beneficial method
than monitoring of 6-mercaptopurine in plasma.
concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%. Mammalian target of rapamycin inhibitors:
(sirolimus and everolimus)
myelotoxicity is dose dependent.
incidence 20% of sirolimus. (11%-19%) with Everolimus therapy. valganciclovir:
The higher bioavailability of this agent (70% vs 7% for oral ganciclovir) has also affected itsmyelotoxicity profile .
several factors may contribut to cytopenia
– higher doses of the drug (900 mg or more)
– low body mass index.
– concomitant MMF administration.
Dose reduction to 450 mg/day or transient drug
cessation may be sufficient for cytopenia reversal. Ganciclovir:
The bioavailability is poor when given orally therefore, it is always given intravenously.
causes leukopenia, with rates of 7.1% to 23.1%. Compared with valganciclovir, ganciclovir exerts modest myelosuppression. Considering the higher bioavailability of valgan ciclovir (10 times versus that with ganciclovir), the risk of neutropenia in the former agent exceeds 188%. A lesser incidence of leukopenia (7.1% vs 13.5%) and neutropenia (3.2% vs 8.2%) was observed in ganciclovir-treated patients compared with those on valganciclovir. Valacyclovir:
Compared with valganciclovir and ganciclovir,
myelotoxicity with valacyclovir is relatively mild. When compared with ganciclovir, dose modification is less frequently employed with valacyclovir. Trimethoprim-sulfamethoxazole:
Cause neutropenia and leukopenia and megaloblastic anemia. Trimethoprim per se can cause dose dependent inhibition of granulopoiesis.
Folinic acid can reverse this side effect.
Incidence is only 2% of recipients. Dapsone:
Dapsone is an alternate agent for Pneumocystis
jirovecii prevention.
It is associated with many hematological complications, including neutropenia. Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia:
1) medication-induced myelotoxicity.
2) Deficiency – B12, folic acid, zinc, and copper deficiencies,
3) Infection- Epstein-Barr virus-induced post transplant proliferative disorders invade bone marrow of recipients, causing cytopenia. Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses. Management:
1) full detailed history.
2) dose reduction or complete withdrawal with correction of WBC count may serve as the only available technique to find a diagnosis.
3) administration of “colony stimulating” factors if there is no accepted response to the previous maneuvers.
level 5
Manal Malik
2 years ago
Summary of Drug-Induced Myelosuppression in Kidney Transplant PatientsIntroduction
Myelosuppression can presenting by cytopenia in kidney transplant patient from 20% to 60% of KTRs patient. The risk of CMV will increase after cession of valganciclovir or risk of pneumocystis jirovecii after trimethoprim -sulfamethoxazole withdrawal. Pancytopenia affect all three cells lines. Consequences of Haematological Cytopenia
The function of neutrophils and lymphocytes are to prevent infection and especially opportunistic infections. neutropenic KTRs commonly experience more intraabdominal infection22.5%. Both MMF and tacrolimus therapy are associated with neutropenia. To reduce the severity of neutropenia is reduced or withhold MMF, so that will increase the risk of acute rejection if the reduction of MMF more than 50% of the dose. the risk it will be higher in highly immunological risk patients and those within 3 month after transplant. The rituximab is cause neutropenia when it uses as induction therapy which can be treated by reduce the dose or withdrawal the medication. Ant thymocyte globulin
ATG can cause neutropenia in addition their effect on t lymphocytes as treated by reducing the dose or withhold ATG. Alemtuzumab
Alemtuzumab is an anti-CD52 humanized monoclonal immunoglobulin GI antibody.it use for induction or rejection treatment. The incidence of leukopenia 33% to 42% in various reports so the management is a dose reduction of MMF so we need to monitoring allograft function especially in high risk patients. Interleukin receptor antagonists
Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab a monoclonal chimeric and daclizumab a humanized antibody against CD25 that can suppress iL-2 mediated T- cell activation and proliferation in KTRs.The anti-IL-2R agents would be an optimal option for leukopenia KTRs with low to moderate risk for leukopenia risk of rejection. Mycophenolic mofetil and enteric -coted mycophenolate sodium.
MMF can cause heamatotoxicity,11.8% to 40% of KTRs can develop leukopenia related to MMF therapy. The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA concomitant administration of valganciclovir, valacyclovir and fenofibrate may exaggerate MMF related leukopenia .
The treatment of MMF induced neutropenia is dose reduction or drug withdrawal there will be risk of graft loss Tacrolimus
Tacrolimus is the mainstay of clinical immune suppression regimens and 16.9%of haematological alteration in cardiothoracic transplant recipients were related to tacrolimus therapy including anaemia ,neutropenia and combined anaemia and neutropenia. Treatment of TAC induced neutropenia a dose reduction of MMF is suggested in patient with dual immunosuppression therapy or other alternative include everolimus abatacept, or eculizumab. Azathioprine
Azathioprine may cause leukopenia and neutropenia in almost half of KTRs. So a dose reduction or drug with drawl is the treatment option. And to diagnose the azathioprine-induced myelotoxicity is by TPMT activity. Drugs that interact with azathioprine is allopurinol so concomitant administration with allopurinol needs a dose reduction by 25% to 50%. Azathioprine levels should be monitored weekly with full blood count mentoring in the first month then twice per month for the second and third months and monthly. Mammalian target of rapamycin inhibitors:
The severity of mTOR is dose dependence especially if the trough level is more than 12 ng/dl.
Sirolimus and MMF therapy after alemtuzumab induction in steroid and CNI -free regimens may result in severe leukopenia. In most of the patients, m TOR-induced leukopenia, resolves spontaneously if persist MMF reduction with simultaneous reduction of mTOR to a lower therapeutic range is required. Or last drug cessation for resistant cases Valganciclovir
Account 10% to 25% of KTRs develop leukopenia related. Valganciclovir
Dose reduction or transient drug cessation may be sufficient for cytopenia reversal. Ganciclovir
Gan aciclovir is used for anti-CMV and prophylaxis in KTRs and can respond to dose reduction but some require ganciclovir cessation. Valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herps simplexes in KTRs.
The incidence of leukopenia ranges from 6% to 14% in randomized clinical trials.
Withdrawal of ganciclovir is more frequent than valacyclovir. Dapsone
Is an alternative agent for pneumocystis jirevoci prevention that is associated with many haematological complications inducing neutropenia.
Post transplant drug induced thrombocytopenia: Rituximab
Rituximab- induced thrombocytopenia has reported 48% of patients. Anti thymocytes globulin
Cross-section of antibodies towards non-lymphoid tissue may result in the development of thrombotic events and thrombocytopenia.
Treatment is reducing or holding MMF. Alemtuzumab
Autoimmune thrombocytopenia has been observed in multiple doses and CLL with an incidence range 1% to 2.5% Interleukin receptor antagonist
Anti LI-2R activity is confirmed to activated T-cells.
thrombocytopenia is rare about 5.8 % of KTRs who received basiliximab mycophenolate mofetil and enteric-coated mycophenolate sodium
MMF dose reduction is required to treat anaemia, thrombocytopenia and cytopenia.
Myelotoxicity of MMF is dose-dependent and usually related to the trough level of MPA. Mammalian target of rapamycin inhibitors
The severity of myelotoxicity is dose-dependent is about 20% of KTRs on sirolimus therapy.
Everolimus is associated with thrombocytopenia in 10% to 17 patients. Ganciclovir
Can induce thrombocytopaenia in about 23.1% of KTRs. Trimethoprim-Sulfamethoxazole
Several haematological complications have been observed with this agent including thrombocytopenia. Differential diagnosis of drug-induced leukopenia and thrombocytopenia:
1-Drug induced .
2- B12 deficiency, folic acid , zinc and copper deficiency.
3- Epstein -Barr virus-induced posttransplant proliferative disorder.
4-CMV infection.
5-parvo virus B19.
6-Human herps virus 6 .
7- influenza virus .
8-tick borne bacterial infection Hemophagocytic syndrome
Can associate with cytopenia.
Several viral infections CMV adenoviruses, Epstein -Bar virus, human herpes virus 8,human herpes 6,bravo virus 19 and BK virus. Therapy for drug-induced haematological cytopenia
Specific treatment of neutropenia:
In medical emergencies such as severe pneumonia and septic shock sever neutropenia ANC less 500/ul or 0.5/l .if the further decline in WBCs count ANC less 100 cells /mm3 persisting for more than 7 days extending the high risk of opportunistic infection.
If dose reduction or drug with dual of the suspected agent, some of the study suggest that colony-stimulating agent can cause rejection but some evidence has suggest that G-csf may decrease rejection episodes. Summary
The first step in management is the reduction or withdrawal of the suspected agent.
Two important points should be considered until the treatment of cytopenia :
1-an opportunistic infection.
2-early signs of acute rejection.
Immunosuppression medication-induced cytopenia and a few randomized controlled trials serve to focus on the most recent evidence-based information.
Thrombopoietin receptor agonists have been efficacious in thrombocytopenia management. Conclusion
KTRs usually present with cytopenia.
The risk of leukopenia and neutropenia is opportunistic infection and life–threaten infection.
A number of new agents have been introduced to manage serious cytopenia G-CSF, GM-CSF and thrombopoietin agents however there is a dearth of safety and efficacy
level 5
CARLOS TADEU LEONIDIO
2 years ago
Briefly summarise this article
Although essential, immunosuppressive drugs and some prophylactic drugs for opportunistic infections are associated with the hematologic complication of myelotoxicity. Drug-related cytopenias can occur with any strain and in any number of associations: pancytopenia (3 strains); bicytopenia (2 lineages in any association), cytopenia , calling attention to the fact that situations where there is neutropenia or leukopenia even greater impairment of immunity occur, exposing patients to more opportunistic infections.
Leukopenia and lymphopenia in post-transplant patients increase the patient’s predisposition to infections in frequency and severity, and the severity of the event is related to its duration of time and also the degree of cell decline.
– Rituximab: Anti-CD20 monoclonal antibody, used in induction schemes for transplants with ABO incompatibility, in the treatment of acute rejection and some attempts to treat chronic rejection. Cytopenia has been related to its use in up to 48% of patients in one trial and can arise up to 4 weeks after using its last dose and can be influenced by the use of Mycophenolate mofetil, ganciclovir and valganciclovir used for prophylaxis or other therapies.
– Antithymocyte globulin (ATG): in addition to T cells, others are vulnerable to antibody action. Its myelosuppressive action is dose dependent, so that the higher the dose, the greater its action on blood cells other than T cells. Therefore, protocols using higher doses have a higher risk of developing cytopenias, reaching an incidence of 50% in some studies.
– Alemtuzumab: it is a humanized monoclonal antibody anti-CD52 immunoglobulin, used as an anti-induction agent and in some anti-rejection protocols. Although myelotoxic effects are more severe (lower white blood cell counts) than ATG, their infections are usually non-fatal.
– Antagonists of the interleukin 2 receptor (IL-2R): represented by Basiliximab (monoclonal chimeric) responsible for suppressing the proliferation of T cells measured by IL-R2. This group was also formed by Daclizumab (a humanized murine antibody against CD25) that left the market.
– Inosine Monophosphate Inhibitors – Mycophenolic Mofetil and Enteric Coated Miphenolate Sodium (MMF): disrupt T/B lymphocyte differentiation by suppressing the de novo pathways of guanosine nucleotide synthesis, thereby inhibiting humoral and cell-mediated responses. Its myetoxicity is also dose dependent and is strongly influenced by drugs used for prophylaxis or other therapies, such as: ganciclovir, valganciclovir and fenofibrates.
– Tacrolimus : Mechanisms of tacrolimus-induced neutropenia include direct suppression of myeloid cells, with bone marrow hypoplasia, but are not commonly seen in renal recipient patients, being observed in the first 3 months of use.
– Azathioprine: it is an antimetabolite widely used in the first immunosuppression schemes, but it was replaced by MMF, which is more myelotoxic. Usually its myelotoxicity appears in the 1st month and happens in almost half of the patients.
– Rapamycin inhibitors (Sirolimus and Everolimus): dose-dependent myelotoxicity and combined therapies lead to difficulty in defining the degree of responsibility in this group, but normally it is something transitory, with spontaneous resolution. If it does not resolve, doses of other drugs that may cause myelotoxicity must be changed.
– Valganciclovir: leukopenia can develop in up to 3 months and is expected to resolve spontaneously.
– Ganciclovir: Less myelosuppressive than valganciclovir.
– Valaciclovir: has less myelotoxicity than the other representatives of the class, but suffers the effect of other drugs such as MMF.
– Trimethoprim-sulfamethoxazole: used for prophylaxis of Pneumocystis jirovecii. The use of folinic acid can reverse this adverse effect.
TREATMENT:
As there are no diagnostic tools for which drug is causing myelotoxicity, treatment includes decreasing or discontinuing suspected drugs, with the risk of compromise and increased risk of rejection. Furthermore, the use of “colony stimulating factors” is a strategy that can be used, as it stimulates neutrophils, monocytes, macrophages and dendritic cells
What is the level of evidence provided by this article?
Level 05 – narrative review
Hamdy Hegazy
2 years ago
Briefly summarize this article.
Many medications commonly used post-TX can lead to myelosuppression which can be clinically manifested as cytopenias, infections, anaemia, bleeding. This list includes the following: 1- ATG. 2- Rituximab: especially 4 weeks after Rituximab therapy however it can happen later. 3- Almetuzumab: more severe myelosuppression than ATG AND BASILIXIMAB. 4- MMF/MFS: dose dependent, related to level of mycophenolic acid level. 5- Tacrolimus: within first 3 months post-TX. Can be switched to everolimus, belatacept or eculizumab. 6- Azathioprine: usually in First month post-TX. TPMT activity is essential before prescribing AZA. Don’t combine AZA with allopurinol. 7- M-TOR inhibitors: sirolimus level >12ng/dl is associated withleucopenia and thrombocytopenia. 8- Anti-viral medications: ganciclovir, acyclovir, valganciclovir. What is the level of evidence provided by this article? Level 5
Ahmed Abd El Razek
2 years ago
Introduction
About 20% to 60% of renal transplant recipients experience at least single episode of cytopenia post transplantation derived by the effect of immunosuppressive agents which are crucial to maintain proper graft function and avoid subsequent rejection episodes.
The susceptibility to increased frequency and severity of infection is linked to the duration of neutropenia as well as the magnitude of neutropenic decline. Leukopenia aggravates the risk of infection via disrupting immunogenic integrity with further liability of ubiquitous and opportunistic infections. Common agents inducing neutropenia are tacrolimus and MMF.
Transplant physicians tend to reduce or hold MMF dose to reduce the severity of neutropenia. This may be followed by higher risk of acute allograft rejection when exceeding 50% reduction in MMF dosage.
Drug-induced Leukopenia and Neutropenia
Rituximab
It is a known potent anti-CD20 monoclonal antibody causing in B-cell depletion. It is commonly used in various serious situations such as; the induction plan in ABO-incompatible transplant, treatment of acute rejection, chronic antibody mediated rejection, and as a resolution therapy of post-transplant lymphoproliferative disorder.
Rituximab late-onset neutropenia can occur 4 weeks after the last dose of therapy after exclusion of other causes as ganciclovir, Valgancyclovir, or MMF. It is usually apparent after the sixth rituximab dose.
The incidence of leukopenia after rituximab therapy ranges from 19% to 24.6%. The main line of management necessitates dose reduction or even drug withdrawal which usually results in an ideal response and good hematological recovery.
Antithymocyte globulin
The incidence of leukopenia with ATG is variable owing to the differences in protocols and periods of administration. ATG cessation or dose reduction was adopted in leukopenia and also when combined with thrombocytopenia. ATG dosage should be reduced to 50% when platelet count decreases to 50 000 up to 75 000 per mm3 or WBC count ranges from 2000 to 3000 per mm. ATG therapy is contraindicated below these values. Other culprits as MMF ought to be held off as well to minimize the concurrent ATG-induced cytopenia.
Alemtuzumab
A known anti-CD52 monoclonal immunoglobulin, used as an induction agent or an anti rejection agent. The incidence of leukopenia ranges from 33.3% to 42% following alemtuzumab administration. The myelotoxic effects of alemtuzumab are more severe than ATG. B-cell dysregulation associated with its use led to several autoimmune disorders.
Interleukin receptor antagonists
The commonly anti CD25 antibody IL-2R antagonist used as induction agent is basiliximab with associated 10.6% incidence of leukopenia. Its use is a good option for cases of low to moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
The main mechanism of action is by inhibiting both cell-mediated and humoral immune responses with subsequent inhibition of nucleotide synthesis de novo pathways in for T and B lymphocytes, arresting their further differentiation. MMF hematotoxicity is estimated around 11.8% up to 40% in renal transplant recipients in the form of leukopenia.
The myelotoxic effect of MMF is usually dose dependent which can also be monitored by trough levels of MPA. Other medications coadministered as valganciclovir and fenofibrates may potentiate MMF related leukopenia.
Management involves shifting to a suitable mammalian target of rapamycin inhibitor either sirolimus or everolimus that may reverse cytopenia, CMV prophylactic dose of valganciclovir reduction to 50% seems reasonable in these situations.
Tacrolimus
It is associated with neutropenia in 28% of renal transplant recipients.
Mechanisms of myelosuppression are:
Direct suppression of myeloid cells along with bone marrow hypoplasia.
Alteration of cytokine production by T lymphocytes and monocytes.
Production of antimyeloid precursors and anti-mature neutrophil antibodies.
Prevention of MPA glucuronidation with subsequent potentiation of its blood levels.
Azathioprine
Leukopenia and neutropenia induced by this antimetabolite reaches almost half of renal transplant recipients. The magnitude of azathioprine-induced myelotoxicity is related to the activity of thiopurine S-methyl transferase (TPMT). Individuals having complete lack or low TPMT activity are prone to severe life-threatening myelotoxicity.
The risk of myelosuppression can be detected by monitoring of 6-thioguanine nucleotide in RBCs, monitoring of 6-mercaptopurine in plasma, or further genotyping and phenotyping of TPMT. Regular monitoring of full blood count is indicated in renal transplant recipients on azathioprine.
Concomitant administration with allopurinol mandates dose reduction of azathioprine by 25% to 50% to avoid hazardous myelosuppression due to severe drug interaction.
Mammalian target of rapamycin inhibitors
Most commonly used are sirolimus and everolimus. Severity of myelotoxicity is known to be dose dependent. High trough levels are linked to the development of leukopenia and thrombocytopenia.
Sirolimus and MMF combination can cause severe leukopenia. Everolimus as well can lead to leukopenia by about (11%-19%). MTORi-induced myelotoxicity mechanisms are; disrupted signal transduction by mTORi through the gp130 β chain in addition to platelet aggregation and degranulation.MTORi-induced leukopenia mostly resolves spontaneously.
Valganciclovir
Cytopenia can be related to the use of higher doses of the drug, low body mass index and concomitant MMF administration. Leukopenia can be resolved spontaneously even without treatment by dose reduction to 450 mg/day which is usually sufficient.
Ganciclovir
Ganciclovir-treated patients have less incidence of leukopenia about 7.1% and neutropenia estimated by 3.2%.
Valacyclovir
Myelotoxicity with Valacyclovir is relatively mild ranges from 6% to 14%. As other agents combination of MMF and Valacyclovir therapy may potentiate drug induced myelotoxicity. The pill burden of valacyclovir is high and neurological complications are more frequently associated.
Trimethoprim-sulfamethoxazole
It is widely used for Pneumocystis jirovecii prophylaxis. Neutropenia, leukopenia and megaloblastic anemia are the commonest types of cytopenias associated with its use. Incidence of leukopenia is only 2% of recipients especially when combined with other antimetabolites.
Posttransplant Drug-induced Thrombocytopenia
Rituximab
Antithymocyte globulin Cross-reaction of antibodies toward nonlymphoid tissue can lead to serious thrombotic events and thrombocytopenia explained by nonspecific affinity to platelet cells. The incidence was estimated about 10% to 26.5%. It is advisable to hold off or reduce MMF dose with concurrent ATG-induced cytopenia.
Alemtuzumab
Interleukin receptor antagonists the selection of an anti-IL-2R agent is a wise choice for those thrombocytopenic renal transplant recipients with low to moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium Myelotoxicity of MMF is dose dependent and usually related to the trough levels of MPA.
Mammalian target of rapamycin inhibitors
Ganciclovir
Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
B12, folic acid, zinc, and copper deficiencies.
Epstein-Barr virus-induced posttransplant proliferative disorders.
Cytomegalovirus, parvovirus B19, human herpes virus 6.
Management:
The first step is determining the patient’s full detailed history.
Dose reduction or complete withdrawal of the suspected offending agent with correction of WBC count may be a wise initial action.
Colony stimulating factors if there is no accepted response to the previous measures.
Level of evidence is 5.
saja Mohammed
2 years ago
Introduction
Hematological complications post kidney transplantation including pancytopenia one of the common and serious complications and might have a deleterious impact on patient and graft survival as usually such complications related to the side effects of immunosuppression including induction IS like ATG and alemtuzumab in addition to maintenance immunotherapy with MMF and myofortic which can lead to myelosuppression like pancytopenia , both MMF and tacrolimus can cause pancytopenia and the highest incidence occur in first 3 months after kidney transplantation due to intense immunosuppression including induction therapies like ATG , Alemtuzumab , rituximab ,and maintenance IS like MMF , myofortic , azathioprine , CNI LIKE tacrolimus , M tor inhibitors like sirolimus , sirolimus , others like antiviral use like valaciclovir and ganciclovir, cotrimoxazole prophylaxis for bacterial infection including PJP, also certain viral infection like CMV, EBV, and parvoviral infection, and PTLP disorders, we should identify the cause and severity of hematological complication and treated accordingly
Pancytopenia indicates suppression in WBC, RBC, and platelet count
While bi-cytopenia involves 2 or 3cell lines like anemia and thrombocytopenia (Parvoviral infection)
Leucopenia and alternative neutropenia can be mild-moderate and severe leucopenia and the garden according to the level
Thrombocytopenia also can be graded based on the severity
Leucopenia KTRs are susceptible to a higher risk of opportunistic infections. When ANC is <1000 cells/μL, and more intra-abdominal focus of infections
S sirolimus and everolimus can cause myelosuppression with leucopenia as early as in the first two months and its dose related, especially in induction with alemtuzumab and in combination with MMF in CNI free protocols its can be resolved spontaneously up to 89% and only few cases need dose reduction and to less extent drug withdraw . Antiviral medication can lead to different degree of myelosuppression based on the oral bioavailability of the drugs some agents are poor oral bioavailability compared to IV route like ganciclovir associated with higher degree of leucopenia compared to valacyclovir for cmv prophylaxis which have lower percentage of leucopenia
MMF and mycophenolic acid responsible for > 46% of cases of pancytopenia and its usually dose related and in majority of cases responding to dose reduction.
Posttransplant Drug-induced Thrombocytopenia again includes induction IS like Rituximab, ATG and alemtuzumab, alemtuzumab-induced thrombocytopenia
has been observed in 14% of KTRs. Bleeding requiring surgical intervention has been observed in 12 % of KTRs.while rituximab induced thrombocytopenia usually mild and not complicated by bleeding or transfusion
interleukin 2 inhibitors like basiliximab have lower rate of thrombocytopenia compared to other induction IS
Differential diagnosis of hematological myelosuppression post kidney transplantation should include other than drug induced myelosuppression includes B12 , Folate deficiency , HUS , infections including CMV , EBV , parvo 19 , adenovirus , BKV especially in tacrolimus ,MMF combination protocols , human papilloma virus , HSV and EBV triggering lymphoproliferative disorder ;like PTLD, accelerated hemophygotic syndrome in sever infections with sepsis Specific treatment of myelosuppression in addition to dos reduction or transient withdraw of offending medications there is other specific therapies like in sever neutropenia with ANC < 500 can give G,CSF which can improve the neutropenia and act as anti-inflammatory with less effect on lymphopenia while GM -CSF can activate neutrophile , monocytes and NKC unlike G CSF its can promote inflammation however its safety further prospective trails but both g,csf , GM -CSF have been indicated as therapeutic and prophylaxis therapy in sever febrile neutropenia in sold organ transplantation with good safety profile
What is the level of evidence provided by this article?
level 5 narrative review
Naglaa Abdalla
2 years ago
Myelosuppression after transplantation can occur because of the use of immunosuppression drugs that are essential for good graft survival and prevention of rejection.
20% t0 60% of KTR can have at least one episode of Myelosuppression causing pancytopenia.
This mainly in the 1st 3 month post-transplant.
Sometimes dose reduction or withdrawal should be done but this can lead to acute rejection.
Other supportive and prophylactic drugs can also cause Myelosuppression.
Cytopenia can be identified as follows:
1- pancytopenia involves all 3 cells lines, white blood cells (WBCs), red blood cells (RBCs), and platelets.
2- bicytopenia involves 2 of 3 cell lines.
3- Thrombocytopenia involves low platelet count
4- leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.
These levels are 3000 cells/mm3 (normal), 2000 to
3000 WBCs/mm3, 1000 to 2000 WBCs/mm3, and
<1000 WBC/mm3 .
The normal platelet count Platelet count is 150 000/mm3 to 450 000/mm3
The CTCAE graded thrombocytopenia into 4 levels. These levels are grade I or subnormal (75 000-150,000 cells/mm3), grade II or low (50000-75000 cells/mm3, grade III or moderate (25 000-50 000 cells/mm3), and grade IV or critical (<25 000/mm3) Consequences of Hematological Cytopenia:
Leukopenia can lead to opportunistic infections.
The frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenia. Drug-induced Leukopenia and Neutropenia: 1- Rituximab
Rituximab-induced cytopenia (grade 3/4) has
been reported in 48% of patients in 1 trial as follows 40% lymphopenia, 6% neutropenia, and 4%
leukopenia in patients with lymphoma 2- Antithymocte globulin
It affects T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.
The dose of ATG should be halved when:
a- Platelet count reaches 50 000 to 75 000 per mm3
b- or WBC count reaches 2000 to 3000 per mm3
The dose of ATG should be held when:
a- platelet count declines to less than 50 000 per mm3
b- or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L. 3- Alemtuzumab
The incidence of leucopenia ranges from 33.3% to 42% in various reports.
The myelotoxic effects of alemtuzumab are more severe than ATG. 4- Interleukin receptor antagonists
basiliximab and daclizumab. 5- Mycophenolic mofetil and enteric-coated mycophenolate sodium
11.8% to 40% of KTRs can develop leukopenia related to MMF. 6- Tacrolimus
It is much less common to cause Myelosuppression in renal transplant recipients but can cause up to 16.92% of
hematological abnormalities in cardiothoracic transplant
recipients. 7-Azathioprine
It may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg
body weight/day. 8- Mammalian target of rapamycin inhibitors
These are (mTORi), sirolimus and everolimus.
The Severity of Myelotoxicity is dose dependent.
9- Anti-viral drugs like valganciclovir, Ganciclovir, valacyclovir, 10- Trimethoprim-sulfamethoxazole
It is used for Pneumocystis jirovecii prophylaxis and can cause neutropenia, leukopenia and megaloblastic
anemia. 11- Dapsone
as alternative drug for Pneumocystis jirovecii prevention. Can induce many hematological complications, including neutropenia. Drug-induced Lymphopenia:
lymphopenia is different from leukopenia
due to neutropenia. Neutropenia is usually complicated
serious infections but lymphopenia is usually due induction therapy like ATG. Post-transplant Drug-induced Thrombocytopenia:
Rituximab, Antithymocyte globulin, Alemtuzumab, interleukin receptor antagonists, Mycophenolic mofetil and enteric-coated
mycophenolate sodium, Mammalian target of rapamycin inhibitors, Ganciclovir, Trimethoprim-sulfamethoxazole Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia:
1- deficiency of B12, folic acid, zinc, and copper
2- Epstein-Barr virus-induced post-transplant proliferative disorders
3- Infection with cytomegalovirus, parvovirus
B19, human herpesvirus 6, influenza viruses, and
ehrlichiosis (a tick-borne bacterial infection) .
Wadia Elhardallo
2 years ago
Briefly summarise this article
Myelosuppression presenting as cytopenia is not uncommon in kidney transplant recipients from 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy -mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Cytopenia can be identified as follows: pancytopenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets; bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count. While Absolute neutrophil count (ANC) is used to assess the magnitude of neutropenic severity as ANC = (WBCs/μL) * (percentage of polymorphonuclear cells + bands)/100 (When ANC is <1000 cells/μL, susceptibility to infection increases)
Drug-induced Leukopenia and NeutropeniaAs detailed here, a number of agents have be enimplicated in posttransplant leukopenia and neutropenia development .
Rituximab
Cytopenia can occur 4 weeks after start of rituximab therapy. The reported incidence of late-onset neutropenia in KTRs has approached 37.5% to 48%.Dose reduction or drug withdrawal is usually the ideal response for hematological recovery
Antithymocyte globulin The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3. Treatment with should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3.
CD3+ T-cell count should be monitored when less than 0.05 × 109/L (<50/μLnormal range, 128-131/μL), Total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available.
Alemtuzumab
With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42%.Compared with ATG, the myelotoxic effects of alemtuzumab are more severe,34,46 with the lowest WBC counts observed 130 days after the last given dose. Although infectious episodes are not usually life-threatening
Mycophenolic mofetil and enteric-coated mycophenolate sodium
Account for about 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy, can be mask by induction therapy myelotoxicity. The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA and so dose reduction is the response to manage cytopenia.However, this response would trigger the risk of acute rejection and subsequently graft loss.
Azathioprine
traditional antimetabolite that may induce leukopenia and neutropenia in almost half of KTRs,
particularly with doses greater than 1.99 mg/kg body weight/day. The important factor to determine azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity. Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine. Patients with complete lack or low TPMT activity are at risk of developing life-threatening myelotoxicity.
Drugs that interact with azathioprine include allopurinol, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; to avoid catastrophic myelosuppression.
Tacrolimus
Although much less common in renal transplant recipients, 16.92% of hematological alteration including anemia, neutropenia. Tacrolimus may also intensify MMF myelotoxicity, induce neutropenia in 28% of KTRs. In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels.Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant. There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus.
Mammalian target of rapamycin inhibitors mTORi
Development of cytopenia with mTORi agents can beusually observed within the first 4 to 8 weeks . Severity of myelotoxicity is dose dependent, A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia, although it can commonly occur even with lower drug levels. For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously.
What is the level of evidence provided by this article?
Level 5
Reem Younis
2 years ago
Briefly summarise this article
-Immunosuppressive drugs are associated with hematological complications. Myelosuppression presenting as cyto – penia is not uncommon in kidney transplant recipients (KTRs).
– From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.
-The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy –
mocyte globulin (ATG), tacrolimus,sirolimus, and trimethoprim-sulfamethoxazole.
-Cytopenia can be identified as follows: pancy – topenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets; bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count.
-Leukopenia is also termed alternatively with neutropenia, although these
terms are not synonymous.
-laboratories have used neutropenia to classify severity of granulocytopenia.
-Platelet count of 150 000/mm3 is considered the lower limit of normal level in many laboratories.
-Neutrophils and lymphocytes have fundamental roles in prevention of infection. –Leukopenic KTRs are vulnerable to the deve – lopment of opportunistic infections. When ANC is <1000 cells/μL, susceptibility to infection increases.
-Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
-Both tacrolimus and MMF therapy are commonly associated with neutropenia.
-After clinical assessments, culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir,
ganciclovir, alemtuzumab, and ATG.
-The first therapeutic step is reduction or complete withdrawal of the suspected agent. Until correction of cytopenia is accomplished, the treating clinician should remain alert to look for:
(1) an opportunistic infection .
(2) early signs of acute rejection as a result of reduction of immunosuppression.
-Based on findings from G-CSF or GM-CSF use in oncology, these agents
can be utilized in solid-organ transplant, but there is no consensus.
-The prophylactic administration of these agents is suggested in patients with
febrile neutropenia, those with diminished bone marrow reserves (eg, ANC <1.5 × 109/L) due to extensive radiotherapy, patients with AID, and patients older
than 65 years.
-Therapeutic indications include sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infections, adjunctive therapy along with antibiotic, prolonged pyrexia, severe neutropenia with ANC <500/μL,94 and prolonged
neutropenia of more than 7 days.
– If thrombocytopenia is due to idiosyncratic reaction (eg, due to trimethoprimsulfamethoxazole), then immediate withdrawal of the suspected agent is required; if bone marrow suppression is the underlying mechanism, dose
reduction or complete drug cessation is required for correction of platelet decline.
-Platelet transfusion may be required, such as in life-threatening bleeding risk, serious decline of platelet count (<20 000/mm3), or before an invasive procedure (eg, organ biopsy).
-The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm3 with commencement of invasive maneuvers (eg, allograft
biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
-Because of the high vascularity of renal tissue, a minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
-Thrombopoietin receptor agonists have been efficacious in thrombocytopenia management. These agents include romiplostim and eltrombopag, which
have been used with better results in “idiopathic thrombocytopenic purpura” therapy.
What is the level of evidence provided by this article?
Level 5
Nandita Sugumar
2 years ago
Summary : Drug induced myelosuppression in kidney transplant patients
This study is about the hematological complications that come following kidney transplant. These include
posttransplant anemia
leukopenia
neutropenia
thrombocytopenia
These complications can predispose the patient to infection especially opportunistic infections. This can be a problem because of the immunosuppression that the recipient will be on.
Immunosuppressive agents that are linked with post transplant leukopenia and neutropenia include
Rituximab – Cytopenia can occur 4 weeks after start of Rituximab therapy.
ATG – high doses can lead to neutropenia
Alemtuzumab – can lead to leukopenia. Dose reduction of MMF is needed
IL-2R – Leukopenia
MMF – can cause cytopenia. Dose reduction or complete withdrawal is essential
tacrolimus – anemia, neutropenia, combined anemia -neutropenia can occur. It also intensifies MMF myelotoxicity. Treatment includes withdrawal of tacrolimus, dose reduction of MMF. Instead of tacrolimus, alternative therapy such as everolimus, Belatacept and eculizumab can be used.
azathioprine – can induce leukopenia and neutropenia in a significant number of patients. Can be seen in the first month after transplant in most cases.
Management strategies include :
Reduce immunosuppression as appropriate. Risk of acute rejection is present and careful monitoring is essential.
trial of less myelotoxic agents
early recognition of hematological changes
immediate detection and treatment of infection and any further episodes
New treatment to manage cytopenia – G-CSF, GM-CSF and thrombopoietic agents
Level of evidence
Narrative review – Level of evidence 5.
Giulio Podda
2 years ago
Briefly summarise this article
A number of immunosuppressive drugs are associated with haematological complications. Between 20% to 60% of KTRs have experienced at least 1 episode of cytopenia after transplant. Cytopenia are observed during the first 3 months after transplant. Reduction or withdraw of immunosuppressant agents is expected in case of cytopenia. However, after reduction of myelosuppressive immunosuppressive agents there is an increased risk of acute rejection.
Cytopenia is identified as: pancytopenia when involves all 3 cells lines, that is, white blood; Bicytopenia when involves 2 of 3 cell lines; thrombocytopenia involves low platelet count; and leukopenia
DRUG-INDUCED LEUKOPENIA AND NEUTROPENIA
Rituximab:
It is a chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion. Rituximab is used as induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection, in the treatment of chronic antibody- mediated rejection and in resolution therapy of posttransplant lymphoproliferative disorder. Cytopenia occurs approximately in 48% of patients and usually 4 weeks after commencing the treatment
Antithymocyte globulin:
Thymoglobulin activity affects T cells, B cells, natural killer cells, monocytes, neutrophils,platelets, and RBCs. It may cause neutropenia in view of cross-reaction ofantibodies toward nonlymphoid tissue. The incidence of Leukopenia with ATG is variable, and the variability depends as a result of differences in protocols and variabilities in periods of administration. When platelet count are between 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3, ATG dose should be halved. when platelet count drops below 50 000 per mm3 or when WBC falls below 2000 per mm3 ATG treatment should be held.
Alemtuzumab:
It is an anti-CD52 humanized monoclonal immunoglobulin G1 antibody. Alemtuzumab is used as an induction agent or as antirejection medication. The incidence of leukopenia in KTRs ranges from 33.3% to 42% in various reports. Alemtuzumab has a more severe myelotoxic effects than ATG.
Interleukin receptor antagonist:
Humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in KTRs. leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab. Anti-IL-2R agents is an optimum therapeutic option for leukopenicKTRs with low or moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium:
They are inosine monophosphate dehydro -genase inhibitors that can inhibit both cell-mediated and humoral immune responses. 11.8% to 40% of KTRs can develop leukopenia related to MMF treatment. The diagnosis of MMF myelotoxicity may be masked by ATG-related and alemtuzumab-related cytopenia. In case of leukopenia, anemia, thrombocytopenia we should reduce the dose as it is dose dependent effect.
Tacrolimus:
Increase MMF myelotoxicity. Tacrolimus with MMF induce neutropenia in 28% of KTRs. Tacrolimus-induces neutropenia through a direct suppression of myeloid cells. Patients on dual immunosuppression therapy should have a reduced dose of MMF. In such patients. In this cases possible options are everolimus, belatacept, or eculizumab
Azathioprine: Around 50% of KTRs may develop leukopenia and neutropenia on AZA. If patient develop leucopenia or neutropenia we should reduce or withdraw Azathioprine. If patient is on allopurinol, MMF dose should be reduced of 25 to 50 % to avoid myelosuppression.
Mammalian target of rapamycin inhibitors:
Severity of myelotoxicity is dose dependent,with involvement of about 20% of KTRs on sirolimus. Leukopenia and thrombocytopenia are more commonly seen when A trough level is >12 ng/dL but it can be seen in lower levels. Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia
Valganciclovir:
Its myelotoxicity profile is affected by the higher bioavailability of this agent. Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia. Several factors may increase the risk of cytopenia such as higher doses of the drug (900 mg or more), low body mass index, and associated MMF administration, which can also aggravate valganciclovir myelotoxicity.
Ganciclovir:
It is used as anti-CMV therapy and prophylaxis in KTRs. Ganciclovir is given intravenously in view of its poor bioavailability. It causes leukopenia through its myelosupressive effects, with rates of 7.1% to 23.1%. Ganciclovir is less myelosuppressive than valganciclovir. Considering the higher bioavailability of valganciclovir the risk of neutropenia in the former agent exceeds 188%.
Valacyclovir:
It is used for CMV prophylaxis and treatment of herpes simplex in KTRs. Valacyclovir has mild myelotoxicity when compared with valganciclovir and ganciclovir.
Trimethoprim-sulfamethoxazole:
It is used for Pneumocystis jirovecii prophylaxis. Trimethoprim-sulfamethoxazole can cause neutropenia and leukopenia and megaloblastic anemia. Folinic acid can reverse this side effect. The use of trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis in KTRs may induce leukopenia in only 2% of recipients.However, drug induced myelosuppression is aggravated by the combination of Trimethoprim-sulfamethoxazole with azathioprine.
Dapsone:
It is used as an alternate agent for Pneumocystis jirovecii prevention. Side effects include neutropenia. Agranulocytosis may aggravate the neutropenic effects of dapsone.
Drug-induced Lymphopenia:
Commonly seen with ATG use.
Posttransplant Drug-induced Thrombocytopenia:
The most common medications associated with Posttransplant Drug-induced Thrombocytoprnis are: Rituximab, Alemtuzumab, MMF, mTORi, ATG, , IL-6 antagonists, Ganciclovir, trimethoprim-sulfamethoxazole.
What is the level of evidence provided by this article?
Level 5
MICHAEL Farag
2 years ago
A number Is medications which can be used post kidney transplant are associated with hematological complications; Myelosuppression presenting as cytopenia. The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG),8 tacrolimus,9 sirolimus, and
trimethoprim-sulfamethoxazole.
Rituximab
Cytopenia can occur 4 weeks after start of rituximab therapy. Late-onset neutropenia canbe defined as neutropenia that is observed 4 weeks after the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF). With regard to rituximab management, the threshold of suspicion of rituximab-induced toxicity should be lowered, particularly 6 weeks after the sixth rituximab dose. Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
Antithymocyte globulin
Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3. Treatment with ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L
Alemtuzumab Alemtuzumab is an anti-CD52. Compared with ATG, the myelotoxic effects of alemtuzumab are more severe.leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab.With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required.
interleukin receptor antagonists
the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA. Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMFrelated leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable
response to MMF-induced neutropenia and leukopenia.
Tacrolimus
Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant. There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus. A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include everolimus, belatacept, or eculizumab
Azathioprine
Most cases of azathioprine induced leukopenia present in the first month after transplant. In this situation, a dose reduction or transient drug withdrawal is usually sufficient.
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity. Moderately active TPMT may lead to higher risk of myelotoxicity.
Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity
leading to decline in purine metabolism to uric acid.
Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will ensue.
Of note, the need for azathioprine instead of MMF is frequently utilized in areas with low economic standards.
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first monththen twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
Severity of myelotoxicity is dose dependent,80 with involvement of about 20% of
KTRs on sirolimus. A trough level of >12 ng/dL has been shown to be highly associated with
development of leukopenia and thrombocytopenia,81 although it can commonly occur even with lower drug levels.
In most patients, mTORi-induced leukopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required. However, drug cessation may be the last resort for resistant cases
What is the level of evidence provided by this article?
Level V
Huda Al-Taee
2 years ago
Briefly summarise this article
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, several drugs are associated with haematological complications (myelosuppression).
Consequences of Hematological Cytopenia:
Leukopenic KTRs are vulnerable to the development of opportunistic infections.
Neutropenic KTRs commonly experience more intra-abdominal infections.
Given the absence of robust evidence-based strategies to manage drug-induced cytopenia after kidney transplant, transplant clinicians should carefully analyze patient drug history and clinical experience to find the offending medication.
Clinical situations may also result in cytopenia and should be kept in mind.
Drug-induced Leukopenia and Neutropenia
Rituximab:
Rituximab-induced cytopenia has been reported in 48% of patients in 1 trial, it can occur 4 weeks after the start of rituximab therapy. Late-onset neutropenia is usually observed after the sixth rituximab dose. Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently implicated in its evolution.
Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
Antithymocyte globulin:
Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia. leukopenia incidence with ATG is variable and is associated with the use of other IS medications like azathioprine or MMF.
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3.
Alemtuzumab:
The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose.
A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia.
interleukin receptor antagonists:
the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection as it is rarely associated with cytopenia because its effect is limited to activated T cells.
Mycophenolic mofetil and enteric-coated mycophenolate sodium:
11.8% to 40% of KTRs can develop leukopenia related to MMF therapy, oth ATG-related and alemtuzumab-related cytopenia may mask the diagnosis of MMF myelotoxicity, as they may require MMF dose reduction.
The myelotoxic impact of MMF isdose-dependentt and is usually related to the trough levels of MPA. Concomitant administration of valganciclovir, valacyclovir and fenofibrate may exaggerate MMF-related leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia.
Tacrolimus:
It is less common in renal transplant patients. Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs. A dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
Azathioprine:
may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day. most cases are present in the first month after transplant.
To ameliorate the risk of myelosuppression, 2 techniques have been proposed. The first is the monitoring of 6-thioguanine nucleotide in RBCs, which is an efficacious and more beneficial method than the monitoring of 6-mercaptopurine in plasma. Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
concomitant administration with allopurinol necessitates a dose reduction of azathioprine by 25% to 50%.
Mammalian target of rapamycin inhibitors:
sirolimus and everolimus have been involved in many myelotoxic side effects. Severity of myelotoxicity is dose-dependent. sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
The development of cytopenia with mTORi agents can be observed within the first 4 to 8 weeks.
In most patients, mTORi-induced leukopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required.
valganciclovir:
The resultant cytopenia may be potentiated by several factors, including:
higher doses of the drug (900 mg or more).
low body mass index.
concomitant MMF administration.
Although leukopenia can develop within 3 months, resolution of leukopenia can occur spontaneously with or without treatment.
Ganciclovir:
Compared with valganciclovir, ganciclovir exerts modest myelosuppression.
Although patients on ganciclovir therapy respond to dose reduction, some require ganciclovir cessation.
valacyclovir:
myelotoxicity with valacyclovir is relatively mild. However, combined MMF and valacyclovir therapy may aggravate drug-induced myelotoxicity.
Dose modification is less frequently employed with valacyclovir.
Dapsone:
the neutropenic effects of dapsone may be aggravated by development of agranulocytosis.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia:
B12, folic acid, zinc, and copper deficiencies.
Epstein-Barr virus-induced PTLD.
Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis.
Therapy for Drug-induced Hematological Cytopenia:
Colony-stimulating factors have been introduced to manage severe leukopenia in KTRs.
Granulocyte-monocyte colony-stimulating factor (GM-CSF) is a stimulating agent that can activate neutrophils, monocytes, macrophages, and dendritic cells.
Unlike G-CSF, GM-CSF involves a pro-inflammatory criterion. However, the safety of this agent has been documented in solid-organ transplant patients, with improved WBC count and fewer infectious episodes. The safety and efficacy of this agent, however, warrant more randomized clinical trials.
Drug-induced lymphopenia:
Increases the risk of infection.
commonly seen with ATG use.
Posttransplant Drug-induced Thrombocytopenia
Large number of medications had been implicated:
Rituximab, ATG, Alemtuzumab, IL-6 antagonists, MMF, mTORi, Ganciclovir, trimethoprim-sulfamethoxazole.
What is the level of evidence provided by this article
Level 5 (review article)
Zahid Nabi
2 years ago
In this article Abbas and colleagues looked into hematological complications seen in post kidney transplant patients.Most of these complications are secondary to myelosuppression incurred by immunosuppressive drugs.
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. Myelosuppression presenting as cyto- penia is not uncommon in kidney transplant recipients (KTRs)From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
Cytopenia can be identified as follows: pancy- topenia involves all 3 cells lines, that is, white blood cells (WBCs),
red blood cells (RBCs),
and platelets;
bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count;
and leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.
These levels are 3000 cells/mm3 (normal),
2000 to 3000 WBCs/mm3,
1000 to 2000 WBCs/mm3, and
<1000 WBC/mm3 (the latter 3 levels indicating abnormal with variable severities).
Absolute Neutrophic count is calculated as ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100. An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as mild, moderate, or severe.
Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L,
moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L, and
severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L
Thrombocytopenia is also graded into 4 levels
Grade 1.75000-150000
Grade 2. 50000-75000
Grade 3. 25000-50000
Grafe 4 also considered critical is platelets count less than 25000.
Leucopenia and Neutropenia predispose transplant patients to all kind of infectious complications primarily opportunistic and intra abdominal infections.
Drugs mostly leading to these hematology Al complications are
Rituximab.
Cytopenias have been reported in 48% of patients in 1 trial as follows: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma. Cytopenia can occur 4 weeks after start of rituximab therapy however late onset neutropenia occurring 38 to 175 days has been reported as well
ATG.
Leucopenia incidence with ATG is quite variable depending upon different protocols adopted. It is reported from 10 to 50%.
Dose of ATG should be halved if platelet counts drops down to 5000-75000 or WBC count is less than 2000.
Alemtuzumab.
Leucopenia incidence ranges from 33.3% to 42%
Interleukin Receptor antagonist
Leucopenia incidence reported is around 10.6% far less than ATG and Alemtuzumab
MMF
11.8 to 40 % can develop Leucopenia.
Tacrolimus
Tac induced neutropenia can be observed within first three months of transplant.
16.92% of hematological alterations have been attributed to TAC in cardiothoracic transplant though it is rare in Kidney transplant.
Azathioprine Azathioprine may induce leukopenia and neutropenia in almost half of KTRs Mostly , one month post transplant Dose reduction or transient withdrawal of the drug is sufficient Drug interaction with Allopurinol which increase the risk of myelosuppression .so, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will occur. mTOR inhibitors
Cytopenia can be observed within the first 4 to 8 weeks. Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia mTORi-related leukopenia can resolve spontaneously dose reduction of MMF and mTORi is required with drug cessation being the last resort.
Valganciclovir/Ganciclovir/Valaciclovir
more with valganciclovir
potentiated by several factors, including higher doses of the drug (900 mg or more) ,
low body mass index and concomitant MMF administration .
leukopenia can develop within 3 months & resolution can occur spontaneously with or without treatment
Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal especially that with This dose level , has been shown to be equally effective as 900 mg/day for CMV prophylaxis ; consequently, the lower dose has been recommended.
Trimethoprim- Sulfamethoxazole a commonly used drug for Pneumocystis jirovecii prophylaxis may induce leukopenia in only 2% of recipients. However, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression Dapsone It can be used as an alternative to Trimethoprim-sulfamethoxazole for pneumocystis prophylaxis in KT patients and can cause agranulocytosis As almost all of the drugs used in post kidney transplant patients can lead to myelosuppression expressing as Leucopenia Neutopenia Lymphopenia Thrombocytopenia The management is individualized, at times reducing the dose is enough, in other cases stopping the drug or even using Gcsf is required
abosaeed mohamed
2 years ago
Drug-Induced Myelosuppression in Kidney Transplant Patients
immunosuppressive drugs are crucial to allograft survival in transplant recipients. Many of them are associated with hematological complications. Around 20% to 60% of KTRs experienced at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.
The list of culprit agents includes :
1-mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium .
2-ganciclovir and valganciclovir
3-antithy mocyte globulin (ATG)
4- tacrolimus
5-sirolimus
6- trimethoprim-sulfamethoxazole.
Cytopenia can be identified as follows:
1- pancytopenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets
>> grade I or subnormal (75 000-150,000 cells//mm3)
>>grade II or low (50000-75000 cells/mm3
>>grade III or moderate (25 000-50 000 cells/mm3)
>>grade IV or critical (<25 000/mm3) (Figure 2). >less than 25000 cells/mm3)
4- leukopenia ( neutropenia) can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels :
>>3000 -4000 cells/mm3 (normal) , according to the laboratory limit
>>2000 to 3000 WBCs/mm3
>>1000 to 2000 WBCs/mm3
>>less than 1000 WBCs/mm3
– According to absolute neutrophilic count (ANC) :
>>ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
>>neutropenia if less than 1500
>>Mild neutropenia if 1500-1000
>>Moderated neutropenia if 999-500
>>Severe neutropenia ( agranulocytosis) if less than 500
– Leukopenic KTRs are vulnerable to the development of opportunistic infections if ANC is less than 1000
– Infection with Escherichia coli & intra abdominal infections is more prevalent in neutropenic KTRs.
Drugs causing leukopenia & neutropenia :
1- Rituximab :
– Monoclonal AB , against CD20 , leading to B cell depletion
– Uses :
>>induction for ABO incomapatability
>>treatment of acute rejection
>>in resolution therapy of post transplant lymphoproliferateive disorders
>>in attempted treatment of chronic AB mediated rejection
– Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia) defined as neutropenia that is observed 4 weeks after the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF).
– usually observed after the sixth rituximab dose
– Dose reduction or drug withdrawal is usually the ideal response for hematological recovery
2- Antithymocyte globulin :
– The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000
– should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000
– to avoid unnecessary higher doses , CD3+ T-cell count should be monitored when less than 0.05 × 109/L or < 50 μL (<50/μL;>normal range, 128-131/μL) , Total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available.
3- Alemtuzumab :
– Anti CD 52 humanized monoclonal immunoglobulin G1 antibody
– can be administrated as an induction agent or as antirejection medication
– more severe myelosuppression as compared with ATG
4- interleukin receptor antagonists :
– basiliximab (monoclonal chimeric)
– daclizumab, a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation , withdrawn from the market
– rare myelosuppression compared with ATG and alemtuzumab , so would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
5- Mycophenolic mofetil and enteric-coated mycophenolate sodium :
– myelosuppression is the most common cause requiring MMF dose reduction – dose dependent and is usually related to the trough levels of MPA & Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMF related leukopenia
– to manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia.
But , this response would trigger the risk of acute rejection, with subsequent high risk of graft loss in many retrospective reports.
6- Tacrolimus:
– the mainstay of clinical immunosuppression regimens.
– Direct inhibition of myeloid precursors may not be a convincing mechanism for tacrolimus-induced neutropenia and leukopenia
– may intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
– A dose reduction of MMF is suggested in patients on dual immunosuppression therapy In such patients, other alternatives include everolimus, belatacept, or eculizumab
7- Azathioprine :
– Azathioprine may induce leukopenia and neutropenia in almost half of KTRs
– Mostly , one month post transplant
– Dose reduction or transient withdraw the drug is sufficient
– Drug interaction with Allopurinol which increase the risk of myelosuppression .
– so, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will occur
8- Mammalian target of rapamycin inhibitors :
– Sirolimus & everolimus
– Usually with high doses , trough level > 12
– Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
– Observe , reduce the dose , decrease MMF dose & lastly hold the drug
9- valganciclovir , ganciclovir & valacyclocir :
– more with valganciclovir
– may be potentiated by several factors, including higher doses of the drug (900 mg or more) , low body mass index and concomitant MMF administration .
– leukopenia can develop within 3 months & resolution can occur spontaneously with or without treatment
– Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal especially that with This dose level , has been shown to be equally effective as 900 mg/day for CMV prophylaxis ; consequently, the lower dose has been recommended.
– Ganciclovir , given IV due to poor bioavailability & Compared with valganciclovir, it exerts modest myelosuppression
10- Trimethoprim-sulfamethoxazole :
– a commonly used drug for Pneumocystis jirovecii prophylaxis
– may induce leukopenia in only 2% of recipients. However, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression
11- Dapsone :
– is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
Drug-induced Lymphopenia
In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia. The latter is usually complicated by augmented risk of serious infection , lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG) .
>>Differential Diagnosis :
1- vit B12, folic acid, zinc, and copper deficiencies
2- Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia.
3- Cytomegalovirus
5- parvovirus B19, human herpes virus , influenza viruses,
6- ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
>>Hemophagocytic syndrome
can be associated with cytopenia. Several viral infections (CMV, adenovirus, Epstein-Barr virus, human herpesvirus , human herpesvirus , parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
>>Thrombocytic microangiopathy
with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection and viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
>>Specific treatment of neutropenia :
– medical emergencies : such as severe pneumonia and septic shock, measurement of ANC can be used to evaluate the severity of neutropenia, with severe neutropenia indicated by ANC < 500 or further decrease of WBCs (ANC >100 , persist for > 7 days) carry high risk for severe opportunistic infection 1- patient’s full detailed history searching for the possible cause 2- dose reduction or complete withdrawal of the suspected agent 3- administration of “colonystimulating” factors if there is no accepted response
– is a stimulating agent that can activate neutrophils, monocytes, macrophages, and dendritic cells
– Granulocyte colony-stimulating factor has 3 major effects: neutrophil proliferation, reduction of inflammatory cytokines (eg, tumor necrosis factor, interleukin 1 [IL-1], IL-12, and interferon), and production of anti-inflammatory soluble tumor necrosis factor receptors p55 and p75, in addition to IL-l receptor antagonist and prostaglandin E2.
– Several studies have reported improved WBCs counts, fewer infection episodes, and absence of related rejection episodes
– The prophylactic administration of these agents is suggested in patients with febrile neutropenia, those with diminished bone marrow reserves (eg, ANC <1.5 ) , medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC
– therapeutic indications include sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infections , and adjunctive therapy along with antibiotics in the aforementioned indications.
>>Indications of platelet transfusion :
– life-threatening bleeding risk
– Presence of active bleeding
– serious decline of platelet count (<20 000/mm3), or before an invasive procedure (eg, organ biopsy; Figure 9).107 The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy )
– Before ocular and neurosurgical invasive procedures, a minimum platelet count of ≥100 000/mm3 is usually advised.
– For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
– For renal biobsy , keep above 100 000/mm3 >>level 5
Theepa Nesam
2 years ago
Drug-Induced Myelosuppression in Kidney Transplant Patients
KT is considered a “cure” for ESKD, and IS medications is associated with different adverse effects, and myelosuppression is one of these serious and severe adverse effects.
Drugs such as MMF, enteric-coated mycophenolate sodium MPA, AZA, ganciclovir and valganciclovir, ATG, tacrolimus, sirolimus, and TMP
Myelosuppression May present as serious infection or appeared as asymptomatic cytopenia From the blood lab results.
Pancytopenia
Bicytopenia
Thrombocytopenia
CTCAE has graded thrombocytopenia into 4 grades:
Subnormal :75 000-150,000 cells/mm3
low :50000-75000 cells/mm3
Imoderate :25 000-50 000 cells/mm3
critical :<25 000/mm3
d. Leukopenia
CTCAE has graded leukopenia into:
normal-3000 cells/mm3
2000 to 3000 WBCs/mm3
I1000 to 2000 WBCs/mm3
<1000 WBC/mm3
ANC is used to assess the magnitude of neutropenic severity as follows:
ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia
Grades of Neutropenia:
· Mild neutropenia: ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L.
· Moderate neutropenia: ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L.
· Severe neutropenia (agranulocytosis): ANC level of <500/μL or <0.5 × 109/L
Drug-induced neutropenia and leukopenia
RTX:
· anti-CD20 monoclonal antibody.
· Resulting in B-cell depletion and thus affecting phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells.
· Uses in KT; induction agent in ABOi-Kx, acute rejection, cABMR and resolution therapy of posttransplant lymphoproliferative disorder.
· RTX-induced cytopenia has been reported in 48% of patients in one trial. Cytopenia can occur 4 weeks after start of RTX.
· Incidence of leukopenia after rituximab therapy ranges from 19% to 24.6%.
ATG:
· Cross-reaction of antibodies toward nonlymphoid tissue may result in the development of neutropenia.
· Higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
· Incidence of leukopenia up to 50% when ATG is combined with AZA
· ATG should be held if Plt < 50000/mm3 or WBC < 2000/mm3
· Medications that cause leukopenia should be monitored when used together with of ATG
· MMF
· AZA
· steroids
Alemtuzumab:
· anti-CD52 monoclonal immunoglobulin G1 antibody
· Incidence of leukopenia ranges from 33.3% to 42%
· The incidence is higher neutropenia is present together – 47%
· Myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose
· Dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required for the management
Interleukin 2 Receptor (IL-2R) antagonists:
· Incidence of leukopenia is 10.6% in KTRs receiving Basiliximab.
· Would be an option for leukopenia KTRs with low/moderate risk of rejection.
MMF and MPA
· 11.8% to 40% can develop leukopenia
· Both ATG-related and alemtuzumab- related cytopenia may mask the diagnosis of MMF myelotoxicity.
· Treatment is dose reduction or complete withdrawal.
Tacrolimus:
· Tacrolimus may intensify MMF myelotoxicity in 28% of KTRs
· can be treated with dose reduction of MMF with consideration of everolimus, Belatacept or eculizumab
AZA:
· May induce leukopenia and neutropenia in almost 50% of KTRs (doses greater than 1.99 mg/kg body weight/day)
· presents in the 1st after KTx and can be treated with dose reduction or withdrawal
· Concomitant administration with allopurinol requires dose reduction of azathioprine by 25% to 50%.
mTORi
· Cytopenia can be observed within the first 4 to 8 weeks.
· Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia
· mTORi-related leukopenia can resolve spontaneously
dose reduction of MMF and mTORi is required with drug cessation being the last resort
Valganciclovir:
· 10% to 28% of KTRs developes leukopenia
· Valganciclovir myelotoxicity and leukopenia can be potentiated and aggravated by concomitant use of MMF, higher doses of 900 mg or more and low body mass index.
· the risk of neutropenia exceeds 188% In comparison to ganciclovir
· G-CSF may be required with prolonged periods of prophylaxis
Ganciclovir:
· Anti-CMV therapy and prophylaxis
· causes leukopenia, with rates of 7.1% to 23.1%.
· Less myelosuppressive than valganciclovir
· Related leukopenia responds to dose reduction, and some may need drug withdrawal
Valacyclovir:
· CMV prophylaxis and treatment of herpes simplex
· Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild
· leukopenia ranges from 6% to 14% in KTRs
· The risk of neutropenia with 730% higher than with valacyclovir
· Combined MMF and valacyclovir therapy may aggravate drug- induced myelotoxicity
· MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
TMP SMX:
· Used for Pneumocystis jirovecii prophylaxis
· Associated with neutropenia, leukopenia, and megaloblastic anaemia
· Trimethoprim per se can cause dose- dependent inhibition of granulopoiesis in vitro
· Induce cytopenia in KTRs in only 2%
· Concurrent use of AZA can aggravate myelosuppression effect of TMP/SMX.
Dapsone:
· Alternate agent for Pneumocystis jirovecii prevention
· associated with many haematological complications, including neutropenia
· The neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Drug-induced lymphopenia
· Results from induction therapy with lymphocyte-depleting agent(rATG)
Drug-induced thrombocytopenia
· RTX-related thrombocytopenia rarely induces bleeding; platelet infusion is rarely indicated
· Alemtuzumab can cause auto-immune thrombocytopenia. Bleeding requiring surgical intervention has been observed in 12% of KTRs
· mTORi-related myelotoxicity is dose dependent
· Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anaemia, thrombocytopenia
· Thrombocytopenia occurs in 5.8% receiving Basiliximab which is preferred for thrombocytopenic KTRs with low to moderate risk of rejection
· Myelotoxicity of MMF is dose dependent and usually related to the trough levels of MPA
Differential diagnosis of drug-induced leukopenia and thrombocytopenia:
· Deficiency of B12, folic acid, zinc, and copper
· EBV-induced PTLD
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses
· Ehrlichiosis can lead to myelosuppression-induced cytopenia
Hemophagocytic Syndrome
· Associated with cytopenia
· CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpes virus 6, parvovirus B19, and BK polyomavirus
Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B19)
Therapy for drug-induced haematological cytopenia
Specific treatment of neutropenia:
ANC <100 cells/mm3 persisting more than 7 days constitutes an extremely high risk of opportunistic infection.
· Dose reduction or complete withdrawal of the suspected agent.
· Correction of WBC count with G-CSF or GM-CSF.
· Therapeutic indications for G-CSF/GM-CSF are sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infection and adjunctive therapy with antibiotics
· Prophylactic administration of G-CSF/GM-CSF is needed in: prolonged fever, severe neutropenia with ANC <500/μL, and prolonged neutropenia of more than 7 days.
Treatment of thrombocytopenia
· Immediate withdrawal of suspected agent in case of idiosyncratic effect. For bone marrow suppression, dose reduction or cessation may be required.
· Platelet transfusion is needed in the followings; life-threatening bleeding risk, serious decline of platelet(<20000/mm3) or before an invasive procedure.
· Thrombopoietin receptor agonists (romiplostim and eltrombopag) have been efficacious in thrombocytopenia management.
· Cut off values for platelet count before procedure.
The cut-off therapeutic level >50 000/mm3 with commencement of invasive manoeuvres (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy)
> 50000/mm3 is recommended for lumbar puncture
≥100 000/mm3 ; before ocular and neurosurgical invasive procedure. Also recommended for invasive renal procedure because of high vascularity of renal tissue
This is a review article with level of evidence grade 5
Hussam Juda
2 years ago
Introduction
· From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
· Most episodes of cytopenia are observed during the first 3 months.
· The responsible drugs includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole
· Cytopenia can be: pancytopenia, bicytopenia and leukopenia
· Many laboratories consider 4000 cells/mm3 is the lower limit of normal WBCs, and 150 000/mm3 is the lower limit of normal Platelet
· The reduction or stopping MMF as a trial to reduce neutropenia, increases risk of rejection mainly in first year of transplantation. Drug-induced Leukopenia and Neutropenia Rituximab
· is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion
· commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes, in attempted treatment of chronic antibody mediated rejection, and in resolution therapy of posttransplant lymphoproliferative disorder
· Late-onset neutropenia observed 4 weeks after the last dose of rituximab after exclusion of other causes (ganciclovir, valganciclovir, or MMF)
· Recovery occurs by dose reduction or rituximab withdrawal. Antithymocyte globulin
· Leukopenia incidence with ATG is variable,10%- 50%. The highest was when used with azathioprine.
· The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3
· ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3 Alemtuzumab
· is an anti-CD52 humanized mono – clonal immunoglobulin G1 antibody
· can be used in induction or as antirejection medication
· the leukopenic incidence in KTRs ranges from 33.3% to 42%
· the myelotoxic effects of alemtuzumab are more severe than with ATG
· MMF or valganciclovir or cotrimoxazole doses should be reduced Interleukin receptor antagonists: basiliximab, and daclizumab(withdrawn)
· leukopenia is 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab
· leukopenia is significantly higher in KTRs who received thymoglobulin compared with those who received basiliximab
· the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection Mycophenolic mofetil and enteric-coated mycophenolate sodium
· 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy.
· Both ATG-related and alemtuzumab related cytopenia may mask the diagnosis of MMF myelotoxicity, as they may require MMF dose reduction
· Concomitant use of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMF related leukopenia
· Leukopenia managed by: preemptive dose reduction of MMF after ATG and alemtuzumab induction, shifting to a suitable mammalian target of rapamycin inhibitor (sirolimus or everolimus may reverse cytopenia), and halving the CMV prophylactic dose of valganciclovir Tacrolimus
· 16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia
· Tacrolimus may intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs
· Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant
· A dose reduction of MMF is suggested in patients on dual immunosuppression therapy Azathioprine
· greatly replaced by the more potent MMF in immunosuppression after kidney transplant
· may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
· Most cases of azathioprine induced leukopenia present in the first month after transplant, when a dose reduction or transient drug withdrawal is usually sufficient
· thiopurine S-methyl transferase (TPMT) activity may be used to predict risk of myelotoxicity
· concomitant administration with allo – purinol necessitates dose reduction of azathioprine by 25% to 50%
· Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment Mammalian target of rapamycin inhibitors: sirolimus and everolimus
· Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia
· The development of cytopenia can be usually observed within the first 4 to 8 weeks.
· For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously Valganciclovir
· Leukopenia potentiated by: higher doses of valganciclovir, low body mass index, and concomitant MMF use
· Dose reduction to 450 mg/day (equally effective as 900 mg/day for CMV prophylaxis) or transient drug cessation may be sufficient for cytopenia reversal. Ganciclovir
· A lesser incidence of leukopenia and neutropenia was observed in ganciclovir-treated patients compared with those on valganciclovir therapy Valacyclovir
· Used for CMV prophylaxis and treatment of herpes simplex in KTRs
· Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials.
· The risk of neutropenia with valganciclovir therapy is currently 730% higher than with valacyclovir Trimethoprim-sulfamethoxazole
· It’s use for Pneumocystis jirovecii prophylaxis in KTRs may induce leukopenia in only 2% of recipients.
· But, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression Dapsone
· alternate agent for Pneumocystis jirovecii prevention
· the neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Drug-induced Lymphopenia
lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG) Posttransplant Drug-induced Thrombocytopenia
Rituximab, Antithymocyte globulin, Alemtuzumab, interleukin receptor antagonists, Mycophenolic mofetil and enteric-coated mycophenolate sodium, Mammalian target of rapamycin inhibitors, Ganciclovir, Trimethoprim-sulfamethoxazole.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
· medication-induced myelotoxicity
· B12, folic acid, zinc, and copper deficiencies
· Epstein-Barr virus-induced posttransplant proliferative disorders
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection) Hemophagocytic Syndrome
can be associated with cytopenia. Several viral infections (CMV, adenovirus Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) could be involved
Specific treatment of neutropenia
· severe neutropenia indicated by ANC <0.5 × 109/L should be measured in severe pneumonia and septic shock
· A further decline in WBC count (ANC <100 cells/mm3) persisting more than 7 days constitutes an extremely high risk of opportunistic infection
· After withdrawal of the suspected agent, colony stimulating factor can be given
· Granulocyte colony-stimulating factor has 3 major effects: neutrophil proliferation, reduction of inflammatory cytokines, and production of anti-inflammatory soluble tumor necrosis factor receptors p55 and p75, in addition to IL-l receptor antagonist and prostaglandin E2
· G-CSF may decrease rejection episodes
· Granulocyte-monocyte colony-stimulating factor (GM-CSF) safe in solid-organ transplant patients, with improved WBC count and fewer infectious episodes Thrombocytopenia in kidney transplant
The following steps in care are suggested
· if thrombocytopenia is due to idiosyncratic reaction, immediate withdrawal of the suspected agent is required
· if bone marrow suppression is the underlying mechanism, dose reduction or complete drug cessation is required for correction of platelet decline
· indications for platelets transfusion:
1. Thrombocytopenia with bleeding
2. Keep platelet >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
3. for ocular and neurosurgical invasive procedures, keep platelet count of ≥100 000/mm3
4. For lumbar puncture procedures, a platelet count of ≥50 000/ mm3
5. minimum level of 100 000/mm3 is usually recommended for kidney biopsy
What is the level of evidence provided by this article? 5
Eusha Ansary
2 years ago
This journal provides one of the most important grave clinical condition, myelosuppression usually due to adverse effect of immunosuppression.
The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy – mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Drugs may lead to leukopenia (decreasingly) rATG, azathioprine, Alemtuzumab, MMF, sulfa drugs, valganciclovir, rituximab, everolimus, basiliximab and valaciclovir. Some of these drugs can cause neutropenia, such as rituximab, alemtuzumab, valganciclovir, the combination of MMF with tacrolimus, sulfa drugs, and tacrolimus.
Drugs can cause thrombocytopenia, such as rATG, Ganciclovir, Sirolimus, Sulfa drugs, Everolimus, Alemtuzumab and Basiliximab.
Due to these drugs, as well as the dose, duration, and clinical and metabolic conditions of the individual can intensify myelosuppression. Sometimes dose reduction or hold of these culprit agents according to the response may become life saving strategy.
Level 5 study (Narrative review)
Rahul Yadav rahulyadavdr@gmail.com
2 years ago
Briefly summarize this article
Myelosuppression is not uncommon after Kidney Transplant and presents as cytopenia.
At least one episode of cytopenia is observed in 20 to 60% KTR and mostly within first 3 months.
List of drugs commonly implicated in myelosuppression are:
Types of Cytopenia and grading as per Common terminology criteria for adverse events(CTCAE):
1. Pancytopenia: All 3 lines (RBC,WBC and platelets) involved
2. Bicytopenia: Involves 2 out of 3 lines involved
3. Thrombocytopenia: Low Platelet count
Grade 1: 75k to 1.5L cells/mm3
Grade 2:50k to 75K cells/mm3
Grade 3:25k to 75K cells/mm3
Grade 4: Less than 25K cells/mm3
4. Leukopenia/Neutropenia:
Normal:>3000 or 4000/mm depending upon lower laboratory limit
Mild:2000-3000/mm3
Moderate:1000-2000/mm3
Severe: Less than 1000/mm3
ANC(Absolute Neutrophil count) is used to assess the magnitude of neutropenic activity:
Mild Netropenia:1000-1500/uL or 1 to 1.5×109/L
Moderate Neutropenia:500 to 999/uL or 0.5 to 0.99×109/L
Severe Neutropenia(agranulocytosis):Less than 500/uL or 0.5×109/L
Consequences of Cytopenia:
When ANC counts decrease below 1000 cells/mm3, susceptibility to opportunistic infection rises. Commonly experience intra-abdominal infections
Drug Induced Leukopenia/Neutropenia:
1. Rituximab:
MOA: Potent Chimeric anti-CD20 antibody, resulting in B cell depletion affecting phagocytosis by macrophages, complement mediated cytotoxicity and antibody dependent cell mediated toxicity by NK cells.
Use: Induction agent in ABOi Transplant, Treatment of acute rejection, attempted treatment of chronic antibody mediated rejection and in resolution therapy of post-transplant Lymphoproliferative disorder.
Incidence: 19 to 24.6%
Mycophenolate, Ganciclovir and valgancyclovir are frequently implicated along.
Suspicion should be lowered 6 weeks after 6th Rituximab dose.
Dose reduction/withdrawal is needed for recovery.
2. ATG:
MOA: Its activity affects wide ranges of cells (T cell, B cell, NK cells, Monocytes, neutrophils, platelets, and RBCs) due to nonspecific avidity to platelets and neutrophils and cross reaction toward non lymphoid tissue
Incidence-10 to 50% in various studies.
Treatment: Dose of ATG halved when platelet count reaches 50 to 75k or WBC count reaches 2000 to 3000.
Dosage Held if Platelets decline beyond 50k or WBC beyond 2000.
Monitoring of dosage: CD3+ T cells to be maintained less than 50/uL or 0.05×109/L or Total lymphocyte count less than 0.3×109/L.
Hold off MMF with concurrent ATG-induced cytopenia
3. Alemtuzumab:
MOA: Anti-CD52 humanized monoclonal Ig1 antibody which effects mononuclear cells (T and B Lymphocyte),Monocytes and NK cells. Can cause autoimmune disorders through B cell dysregulation
Use: Induction or antirejection
Incidence: 33 to 42% in various reports
Compared to ATG: Myelotoxic SE severe, lowest WBC count observed 130 days post last dosage
Treatment: Dose reduction, along with dose modification of MMF/Valgancyclovir/TMP-SMX.
4. Interleukin Receptor Antagonist:
MOA: Basiliximab, monoclonal chimeric antibody against CD 25, suppress IL 2 mediated T cell activation add proliferation in transplant patients.
Cytopenia are rare with IL 2 receptor antagonist compared to other induction agents like Alemtuzumab/ATG.
Knowing the fact, basiliximab is considered as an optimal therapeutic option for leukopenic Transplant patients With low/moderate risk of rejection.
5. Mycophenolic Mofetil and enteric coated mycophenolate sodium
MOA: It arrest differentiation of T/B lymphocyte and hence inhibit both cell mediated and humoral immune response.
Incidence: 11.8% to 40%
Myelotoxic effects of MMF is dose dependent and usually related to trough levels of MPA.
Dose reduction or complete withdrawal is required for MMF induced myelosuppression, although ATG/Alemtuzumab related cytopenia would require dose reduction of MMF and hence may mask myelotoxicity of MMF.
6. Tacrolimus:
MOA: Direct Suppression of myeloid cell, altered cytokine production by T lymphocytes and monocytes, production of anti-myeloid precursors and anti-mature neutrophilic antibodies
Usually observed within first 3 months after transplant
Combination of Tacrolimus with MMF expands area under curve for MMF within 3 months by 20 to 30% due to inhibition of MPA glucuronidation and non-interference with MMF enterohepatic circulation
7. Azathioprine:
Relationship with dosage: more than 1.99mg/kg have 50% incidence of neutropenia and leukopenia in KTR.
Usually present in first month.
TMPT (Thiopurine S-methyl Transferase) activity determines azathioprine induced myelosuppression. Complete lack/Low TMPT activity vulnerable to severe life-threatening myelosuppression while moderate activity predisposes to higher risk of myelotoxicity.
Dose reduction to 25 to 50% with concomitant Allopurinol administration.
Azathioprine levels should be monitored weekly, with CBC in first month, fortnightly during next 2 months and monthly or less according to dosage adjustment
8. mTOR inhibitors:
Prevalence: 20% in Sirolimus and 11 to 19% in Evorlimus.
Usually observed within 4 to 8 weeks.
Most cases resolve spontaneously or with MMF dose reduction
9. Valgancyclovr/Ganciclovir/Valacyclovir:
Myelotoxicity of Valgancyclovir>Ganciclovir>Valacyclovir.
Usually developed within 3 months.
For Valgancyclovir, Dose reduction to 450mg/day or transient drug cessation usually sufficient. Need for G-CSF may be required with prolonged period of prophylaxis.
10. TMP-SMX:
Used for Pneumocystis Jirovecii prophylaxis
.
May cause neutropenia/Leukopenia and megaloblastic anemia.
MOA: Dose dependent inhibition of Granulopoiesis, Folinic acid can reverse it
Incidence: 2%
11. Dapsone: also associated with neutropenia
Drug Induced Lymphopenia:
Usually, the result of ATG
Post-Transplant Drug induced Thrombocytopenia: Causative drugs
1. Rituximab: rarely induces bleeding and platelet transfusion rarely required.
2. ATG: Due to cross reacting antibodies with platelets with incidence ranging from 10 to 26% and can be exaggerated with mTORi combination
3. Alemtuzumab: Incidence 14% and surgical re-exploration is required in 12% of KTR due to bleeding.
4. IL2R antagonist: Rare
5. MMF and enteric coated Mycophenolate Mofetil: Dose dependent and related to trough level of MPA
6. Ganciclovir/TMP-SMX
D/D of Drug induced Leukopenia/Thrombocytopenia: apart from drugs
1. Nutritional Deficiencies: Vit B12/Folic acid/Zinc/Copper
3. Thrombotic microangiopathy with consequent thrombocytopenia: Renal Ischemic events, Antibody mediated rejection and Viral infections (CMV, HIV and parvovirus B19)
Hemophagocytic syndrome: CMV, Adeno, EBV, HHV6,HHV 8,Parvovirus B19 and BK polyoma virus.
Treatment:
Neutropenia/Cytopenia:
· Detail History
· Dose reduction of offending drugs/complete withdrawal.
· G-CSF: MOA: Neutrophil proliferation, reduction of inflammatory cytokines(like TNF,IL1,IL 12 and INF), production of anti-inflammatory soluble TNF receptors p55 and p75,IL1 receptor antagonist. Devoid of effects on lymphocytes
· GM-CSF: MOA: stimulates neutrophils, monocytes, macrophages and dendritic cells, involves a pro-inflammatory state and needs to be studies further before advocating its efficacy and safety.
· G-CSF/GM-CSF: Prophylactic Indications are febrile neutropenia, sever neutropenia (ANC<500uL) and ANC 1.5×109/L in patients with extensive radiotherapy, HIV, older than 65 due to reduced bone marrow reserve
· G-CSF/GM-CSF: Therapeutic indications: sepsis, hypotension, neutropenic fever more than 7 days, pneumonia, fungal infections
· Watchful for opportunistic infections and early signs if rejection till correction of cytopenia
Thrombocytopenia:
· Detail history
· Dose reduction/Complete drug withdrawal in case of BM suppression. If idiosyncratic reaction (like TMP-SMX),immediate withdrawal of drug
· Platelet transfusion: Low platelet count<20K or before invasive procedure
What is level of evidence produced by this article:
This is a narrative review and level of evidence is 5
Marius Badal
2 years ago
The article was a good one with detailed information about the immunosuppressive medications that can be used in transplants. For the success of kidney transplant, these medications have to be used but they all have some form of complications or adverse effects and if not detected timely can be detrimental to the patient and or the allograft. There are many classes of the immunosuppressive medications, and they are as follows:
1) Rituximab
2) MMF and enteric-coated mycophenolate sodium
3) Ani-thymocyte globulin
4) Azathioprine
5) Ganciclovir and valganciclovir
6) Tacrolimus
7) Sirolimus
8) Trimethoprim-sulfamethoxazole
Once these drugs are introduced either by inductions or as part of maintenance, they will cause myelosuppression and they can be as follows:
1) Pancytopenia
2) Bicytopenia
3) Thrombocytopenia
4) leukopenia
The CTCAE has classified the base of the different line on the degree of their levels obtain and complications. They are:
1) Thrombocytopenia has 4 grades:
a) Subnormal 75000-150000 cells/mm3
b) Low 50000-75000 cells/mm3
c) Moderate 25000-50000 cells/mm3
d) Critical/severe less than 25000 cells/mm3
2) Leukopenia has 4 grades
a) Level 1: 3000 cells/mm3
e) Level 2: 2000-3000 cells/mm3
f) Level 3: 1000-2000 cells/mm3
g) Level 4: less than 1000 cells/mm3
3) Grades of neutropenia
a) Mild neutropenia: 1000-1500 /μL or 1-1.5 x 109/L
b) Moderate neutropenia: 500- 999 /μL or 0.5 to 0.99 x 109/L
c) Severe neutropenia: less than 500 /μL or less than 0.5 x 109/L
The different drugs and their possible complication or adverse reactions:
1) Rituximab: it is an anti CD20 monoclonal antibody. It causes B- cell depletion and affects phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells. It is used it kidney transplants and induction in ABO incompatibility, and acute rejection. It causes renal transplant cytopenia and as such based-on studies about 48 % of transplant patients have had cytopenia.
2) ATG: It affects a wide range of blood cells like T and B cells natural killer cells, monocytes, neutrophils, platelets, and RBCs. The higher the dose the greater it is to develop neutropenia. ATG combined with AZA increases neutropenia by 50%. It causes low platelets and low WBC.
3) Alemtuzumab: this medication is specific, and it is an anti-CD52 monoclonal immunoglobulin G1 antibody. In a kidney transplant, there is an incidence of 33.3% to 42% of leukopenia. Myelotoxic effects are greater than ATG. When combined with other medications its dose needs to be reduced.
4) MMF and enteric-coated mycophenolate sodium: with this treatment, in kidney transplants about 11.8-40% develop leukopenia. MMF-related cytopenia can be treated with dose reduction.
5) Tacrolimus causes neutropenia and combination with MMF will worsen neutropenia by 28%.
6) Azathioprine: in kidney transplant, it will cause leukopenia and neutropenia at a dose greater than 1.99 mg/kg /day. Once combined with allopurinol, its dose must be reduced by about 25 to 50%.
7) mTORi agents. It causes cytopenia within the first 4-8 weeks. A combination of MMF, sirolimus will worsen leukopenia. Its leukopenia can be resolved spontaneously or by drug reduction.
8) Valganciclovir: It is and anti-CMV. In transplant, 10-28% develop leukopenia. Its adverse effect may potentiate MMF.
9) Ganciclovir: it is an anti-CMV and causes leukopenia by 7.1-23.1%. As it relates to leukopenia, it will respond to dose reduction.
10) Valacyclovir: also use in CMV treatment or prophylaxis. Its complication is less when it is related to the other medications. MMF and valacyclovir will aggravate myelotoxicity and may cause bone marrow toxicity.
11) Trimethoprim-sulfamethoxazole: it is used for Pneumocystic jirovecii prophylaxis. It causes neutropenia, leukopenia, and megaloblastic anemia. Induce cytopenia in transplant by 2%. A combination of AZA aggravates myelosuppression.
The drugs that cause lymphopenia are related to induction therapy with lymphocyte-depleting agents.
Drugs that induced thrombocytopenia: Rituximab, ATG, alemtuzumab, anti-IL2R, MMF, mTORi, ganciclovir, and TMP/SMX.
Differential diagnosis of leukopenia and thrombocytopenia:
1) CMV, parvovirus B 19, human herpesvirus and influenza virus
2) Deficiency of vitamin B12, folic acid, zinc, and copper.
3) Epstein-Barr virus-induced posttransplant proliferative disorders
4) Others.
Treatment of neutropenia:
1) Neutropenia with less than 100 cells/mm3 has a high risk of infection. It is there wise to reduce the dose of medications and or increase WBC count by using G-CSF or GM-CSF.
2) Treatment starts with G-CSF or GM-CSF when there is sepsis, hypotension, neutropenia, fever, etc.
3) Prophylaxis with G-CSF or GM-CSF should continue until WBC is in an acceptable range.
Thrombocytopenia treatment:
1) Immunosuppressive medications should be discontinued, or a dose reduction is required. Platelets transfusion is needed especially if it is below 20000/ mm3.
2) Other medications like thrombopoietin receptor agonists like romiplostim and eltrombopag.
The level of evidence is level 5
Muntasir Mohammed
2 years ago
Briefly summarise this article
· Introduction
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number of these drugs are associated with hematological complications. Myelosuppression presenting as cyto -penia is not uncommon in kidney transplant recipients (KTRs).1 From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
Most episodes of cytopenia are observed during the first 3 months. culprit agents include:
1. Mycophenolate mofetil (MMF) and enteric-coated mycophenolate Sodium.
2. Rituximab Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients
3. Ganciclovirand valganciclovir.
4. Antithy -mocyte globulin (ATG).
5. Tacrolimus.
6. Sirolimus.
7. Trimethoprim-sulfamethoxazole.
Cautious reduction or complete withdrawal of the offending agent may be urgently warranted; however, as described here, potential risks should be expected and managed accordingly. These risks include acute rejection in case of immunosuppression reduction or infection if prophylactic medications held.
Neutropenic KTRs commonly experience more intra-abdominal infections (22.5%) than those with normal neutrophil counts (7%-10%). Both tacrolimus and MMF therapy are commonly associated with neutropenia.
Consequences of Hematological Cytopenia
Neutrophils and lymphocytes have fundamental roles in prevention of infection. However, as detailed here, cytopenia can cause additional drawbacks. Leukopenic KTRs are vulnerable to the development of opportunistic infections, On the other side physicians should be cautious in the treatment of patients with high immunological
risk, when considering reducing their MMF especially those within 3 months after transplant, as some reports up to 50% increased risk of acute rejection with reduction or withdrawal of MMF.
Drug-induced Leukopenia and Neutropenia
As detailed here, a number of agents have been implicated in posttransplant leukopenia and neutropenia development.
Rituximab
Rituximab is a potent chimeric anti-CD20 monoclonal antibody.
Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial as follows: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma. It is usually late onset, that means after 4 weeks of dose, Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
Antithymocyte globulin
Thymoglobulin activity is not confined to T cells; rather, a wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs. Leukopenia incidence with ATG is variable, with studies showing 10%,38 %, 33.5% and 50%,as a result of differences in protocols and variabilities in periods of administration. The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3.36,39 Treatment with ATG should be held when platelet count declines to
less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L.
Alemtuzumab
Alemtuzumab is an anti-CD52 humanized mono – clonal immunoglobulin G1 antibody. With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports. With regard to management, dose modification of other drugs such as MMF or
valganciclovir or cotrimoxazole is required.
interleukin receptor antagonists
Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab, a monoclonal chimeric, and daclizumab, a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in KTRs. Because anti-IL-2R activity is confined to activated T cells, their leukopenic and thrombocytopenic drawbacks are currently rare compared with drawbacks with ATG and alemtuzumab (10%
to 15% vs 5% for basiliximab). Considering these observations, the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
These agents are inosine monophosphate dehydro -genase inhibitors that can inhibit both cell-mediated and humoral immune responses through suppression of guanosine nucleotide synthesis de novo pathways in T/B lymphocytes, arresting their differentiation. Regarding MMF hematotoxicity, 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy. To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia with monitoring for possible rejection that could occur as seen in retrospective studies. Several approaches could be added for the management of this type of leukopenia, including:
1. Preemptive dose reduction of MMF after ATG and alemtuzumab induction,
2. Shifting to a suitable mammalian target of rapamycin inhibitor (eg, sirolimus or everolimus may reverse cytopenia5,),
3. Halving the CMV prophylactic dose of valganciclovir.
Tacrolimus
Tacrolimus is the mainstay of clinical immuno -suppression regimens.63 Although much less common in renal transplant recipients, 16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia. A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include everolimus, belatacept, or eculizumab.
Azathioprine
Azathioprine is a traditional antimetabolite that was introduced in 1960 and has been greatly replaced by the more potent MMF in immunosuppression after kidney transplant. It may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day. An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity. Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine. Patients with complete lack or low TPMT activity are
vulnerable to developing severe, life-threatening myelotoxicity. To ameliorate the risk of myelosuppression, 2 techniques have been proposed:
· The first is monitoring of 6-thioguanine nucleotide in RBCs,
· Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
Significant drug interaction with allopurinol can occur, so 25-50% dose reduction is recommended.
Mammalian target of rapamycin inhibitors Severity of myelotoxicity is dose dependent, with involvement of about 20% of
KTRs on sirolimus. A trough level of >12 ng/dL is associated with development of leukopenia and thrombocytopenia. In most patients, mTORi-induced leukopenia
resolves spontaneously, dose reduction of MMF or sirolimus rarely needed.
valganciclovir
The higher bioavailability of this agent (70% vs 7%nfor oral ganciclovir) has also affected its myelotoxicity profile. Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia. The resultant
cytopenia may be potentiated by several factors:
1. Higher doses of the drug (900 mg or more)
2. Low body mass index.
3. Concomitant MMF administration.
Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal. This dose level, however, has been shown to be equally effective as 900 mg/day for CMV prophylaxis; consequently, the lower dose has been recommended.
Ganciclovir
Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs. The bioavailability of this drug is rather poor when given orally; therefore, it is always given intravenously. Through its myelosuppressive effects, ganciclovir causes leukopenia, with
rates of 7.1% to 23.1%.
valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole
Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis. Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia.
Folinic acid can reverse this side effect. Similarly, folate-depleted granulocyte precursors have been observed in another in vitro report.
Dapsone
Dapsone is an alternate agent for Pneumocystis jirovecii prevention that is associated with manyhematological complications, including neutropenia. Moreover, the neutropenic effects of dapsone may beaggravated by development of agranulocytosis.
Drug-induced Lymphopenia
In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia. The latter is usually complicated by augmented risk of serious infection; on the other hand, lymphopenia is usually the result of induction
therapy with lymphocyte-depleting medication (eg, rabbit ATG).
Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia, rituximab, ATG, basiliximab, alemtuzumab, sirolimus, TMP/SMX, ganciclovir, MMF and MPA.
Hemophagocytic Syndrome
Hemophagocytic syndrome can be associated with cytopenia. Several viral infections (CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
Therapy for Drug-induced Hematological Cytopenia
In addition to the protocols above, administration of “colony stimulating” factors if there is no accepted response to the previous maneuvers. Of note, activation of the innate immunity would lead to acute rejection as a side effect. Some evidence has suggested that G-CSF may decrease rejection episodes.
What is the level of evidence provided by this article?
Level 4, review article.
Abdul Rahim Khan
2 years ago
Briefly summarise this article
Renal transplant is the best treatment option in ESRD. Post transplant patient require immune suppressants. Anaemia,leukopenia, neutropenia, and thrombocytopenia are common haematological complications. This can lead to opportunistic infections. This can lead to stopping the immune suppressant which will increase the risk of graft rejection. Identifying culprit is not possible usually and the only option remains to stop immunosuppressants. Future strategies should focus on less toxic agents, early identification and prompt treatment of infections. This can improve graft outcome.
Drugs causing myelotoxicity
Rituximab
With cytopenia grade 3/4 is seen in 48% , lymphopenia in 40%, neutropenia in 6% and leukopenia in 4%.
Dose needs adjustment and some time we have to stop it.
ATG
It can affect wide range of cells and cross reactivity with lymphoid cell can lead to neutropenia.
Dose can reduced to 50% if –
Platelets count drops to 50000-75000/mm2
WBC-2000-3000/mm2
It should be stopped if-
Platelets <50000
WBC<2000
Almetuzumab
More toxic than ATG. Leucopenia is seen in around 33-42%.
Dose reduction can reach uppto 14 mg/kg.
Dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is needed.
IL2 receptor Antagonists
In less than 50 % recepeints leukopenia and thrombocytopenia can be seen. Optimum in low to moderate risk patients.
MMF
The toxicity depends upon dose and leukopenia seen in 11-40%. The option can be to reduce dose but cost can be rejection. In this situation the way forward can be to adjust other drugs which cause myelosuppression.
Tacrolimus
It can cause netropenia especially if used with MMF. This is least bone marrow toxic
Azathioprine
Azathioprine induced leukopenia presents in first month. Dose reduction or temporary withdrawl is required. Previous history of drug induced leukopenia will increase the risk by 70%. An important factor to determine azathioprine toxicity is thiopurine S-methyl transferase (TPMT) activity. Those with lack of low TPMT activity are at high risk.
mTOR inhibitors
Myelosuppression is dose dependent. If used with almetuzumab and MMF then it can be more severe
Dapsone
It is used against P.Jirvecii. It can cause neutropenia and effects can aggravated by development of agranulocytosis.
Valganciclovir, ganciclovir, valacyclovir
These can cause leukopenia and it can be worsened if used with MMF. Leukopenia can resolve spontaneously . CMV prophylaxis recommended.
Identification of different causes of myelosuppression is the best choice.
What is the level of evidence provided by this article?
Review article
Level V
Filipe prohaska Batista
2 years ago
It is a level 5 study (Narrative review)
The paper describes myelosuppression (leukocyte, lymphocyte, or platelet) induced by medications used in kidney transplantation, in addition to discussing the overlap caused by the concomitant use of two or more drugs.
Medications may present leukopenia (decreasingly) rATG, azathioprine, Alemtuzumab, MMF, sulfa drugs, valganciclovir, rituximab, everolimus, basiliximab and valaciclovir.
Some of these drugs can cause neutropenia, such as rituximab, alemtuzumab, valganciclovir, the combination of MMF with tacrolimus, sulfa drugs, and tacrolimus alone.
Other drugs can cause thrombocytopenia, such as rATG, Ganciclovir, Sirolimus, Sulfas, Everolimus, Alemtuzumab and Basiliximab.
The association of these drugs, as well as the dose, duration, and clinical and metabolic conditions of the individual can intensify these symptoms.
Differential diagnosis includes metabolic issues related to vitamin B12, folic acid, zinc, or copper. Epstein Baar, Cytomegalovirus, Parvovirus B19, Herpesvirus 6, Influenza, and Rickettsiae infections should be included.
Mu'taz Saleh
2 years ago
summary of the article Drug-Induced Myelosuppression in Kidney Transplant Patients
kidney transplantation is a solution for ESRD, and the used immunosuppressive medications is associated with different adverse effects, myelosuppression is one of these serious and severe adverse effects. Myelosuppression In KTRs(drug induced) Incriminating Agents:
MMF, enteric-coated mycophenolate sodium, AZA, ganciclovir and valganciclovir, anti-thymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole. Presentation of Myelosuppression:
May present clinically with serious infection or appeared as cytopenia in the lab results.
a. Pancytopenia involves the 3 cell lines(RBCs, WBCs and Platelets).
b. Bicytopenia involves 2 of 3 cell lines.
c. Thrombocytopenia involves low platelet count(<150). The CTCAE has graded thrombocytopenia into 4 grades:
I.subnormal (75 000-150,000 cells//mm3).
II.low (50000-75000 cells/mm3.
III moderate (25 000-50 000 cells/mm3).
IV. critical (<25 000/mm3).
d.leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.(the latter 3 levels indicating abnormal with variable severities).
I. 3000 cells/mm3 (normal).
II. 2000 to 3000 WBCs/mm3.
III.1000 to 2000 WBCs/mm3.
IV. <1000 WBC/mm3 Absolute neutrophil count (ANC) is used to assess the magnitude of neutropenic severity as follows:
ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia. Grades of Neutropenia:
· Mild neutropenia: ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L.
· Moderate neutropenia: ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L.
· Severe neutropenia (agranulocytosis): ANC level of <500/μL or <0.5 × 109/L Drug-induced neutropenia and leucopenia Rituximab:
· It is anti-CD20 monoclonal antibody.
· Resulting in B-cell depletion and thus affecting phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells.
· Uses in KT; induction agent in ABOi-Kx, acute rejection, cABMR and resolution therapy of posttransplant lymphoproliferative disorder.
· RTX-induced cytopenia has been reported in 48% of patients in one trial. Cytopenia can occur 4 weeks after start of RTX.
· Incidence of leukopenia after rituximab therapy ranges from 19% to 24.6%. ATG:
· cross-reaction of antibodies toward nonlymphoid tissue may result in the development of neutropenia.
· higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
· Incidence of leucopenia is high when ATG is combined with AZA( up to 50%).
· ATG should be held if Plt < 50000/mm3 or WBC < 2000/mm3.
· Medications that cause leucopenia should be monitored when there’s concurrent use of ATG( MMF, AZA and steroids). Alemtuzumab:
· It is anti-CD52 monoclonal immunoglobulin G1 antibody.
· The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
· The incidence is higher (47%) if neutropenia is also present.
· Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose.
· With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required. Interleukin 2 Receptor (IL-2R) antagonists:
· Incidence of leucopenia is 10.6% in KTRs receiving Basiliximab.
· Would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection. Mycophenolic mofetil and enteric-coated mycophenolate sodium
· 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy.
· Both ATG-related and alemtuzumab- related cytopenia may mask the diagnosis of MMF myelotoxicity.
· MMF-related cytopenia can be treated with dose reduction or complete withdrawal. Tacrolimus :
· Tacrolimus may intensify MMF myelotoxicity. Tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
· TAC-related cytopenia can be treated with dose reduction of MMF with consideration of alternatives(everolimus, Belatacept and eculizumab). Azathioprine:
· May induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
· AZA-related cytopenia presents in the 1st after Kx and can be treated with dose reduction or withdrawal.
· Concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%. mTORi agents
· Cytopenia with mTORi agents can be observed within the first 4 to 8 weeks.
· Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
· mTORi-related leucopenia can resolve spontaneously, if not; dose reduction of MMF and mTORi is required with drug cessation being the last resort. Valganciclovir:
· Anti-CMV therapy and prophylaxis in KTRs.
· 10% to 28% of KTRs are vulnerable for leukopenia development.
· Valganciclovir myelotoxicity and leucopenia can be potentiated and aggravated by concomitant use of MMF, higher doses of 900 mg or more and low body mass index.
· In comparison to ganciclovir, the risk of neutropenia exceeds 188%.
· G-CSF may be required with prolonged periods of prophylaxis.
· Ganciclovir:
· Anti-CMV therapy and prophylaxis in KTRs.
· It causes leukopenia, with rates of 7.1% to 23.1%.
· Less myelosuppressive than valganciclovir.
· Related leucopenia responds to dose reduction and some may need drug withdrawal. Valacyclovir:
· Used for CMV prophylaxis and treatment of herpes simplex in KTRs.
· Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
· Incidence of leukopenia ranges from 6% to 14% in RCT.
· The risk of neutropenia with valganciclovir therapy is currently 730% higher than with valacyclovir.
· Combined MMF and valacyclovir therapy may aggravate drug- induced myelotoxicity.
· MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
· Demerits; high pill burden and more neurological complications. Trimethoprim-sulfamethoxazole:
· Used for Pneumocystis jirovecii prophylaxis.
· Associated with neutropenia, leukopenia and megaloblastic anemia.
· Trimethoprim per se can cause dose- dependent inhibition of granulopoiesis in vitro. Folinic acid can reverse this side effect.
· Induce cytopenia in KTRs in only 2%.
· Concurrent use of AZA can aggravate myelosuppression effect of TMP/SMX. Dapsone:
· It is an alternate agent for Pneumocystis jirovecii prevention.
· It is associated with many hematological complications, including neutropenia.
· The neutropenic effects of dapsone may be aggravated by development of agranulocytosis. Drug-induced lymphopenia
· It results from induction therapy with lymphocyte-depleting agent(rATG). Drug-induced thrombocytopenia
Numbers of agents have been incriminated in the evolution of post-transplant thrombocytopenia, including: RTX, ATG, Alemtuzumab, anti-IL2R, MMF, mTORi, ganciclovir and TMP/SMX.
· Because rituximab-related thrombocytopenia rarely induces bleeding, platelet infusion is rarely indicated.
· Alemtuzumab can cause auto-immune thrombocytopenia. Bleeding requiring surgical intervention has been observed in 12% of KTRs.
· mTORi-related myelotoxicity is dose dependent.
· Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia, and
· Thrombocytopenia occurs in 5.8% of KTRs receiving Basiliximab which is preferred for thrombocytopenic KTRs with low to moderate risk of rejection.
· Myelotoxicity of MMF is dose dependent and usually related to the trough levels of MPA. Differential diagnosis of drug-induced leucopenia and thrombocytopenia:
· Deficiency of B12, folic acid, zinc and copper.
· Epstein-Barr virus-induced posttransplant proliferative disorders.
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses.
· Ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia. Hemophagocytic Syndrome
· can be associated with cytopenia.
· Incriminated viral infections: CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpes virus 6, parvovirus B19, and BK polyomavirus. Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B19). Therapy for drug-induced hematological cytopenia
There are a number of other specific interventions beside aforementioned policies. Specific treatment of neutropenia:
ANC <100 cells/mm3 persisting more than 7 days constitutes an extremely high risk of opportunistic infection.
· dose reduction or complete withdrawal of the suspected agent.
· correction of WBC count with G-CSF or GM-CSF.
· Therapeutic indications for G-CSF/GM-CSF are: sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infection and adjunctive therapy with antibiotics in the aforementioned situations.
· Prophylactic administration of G-CSF/GM-CSF is needed in the followings : prolonged pyrexia, severe neutropenia with ANC <500/μL, and prolonged neutropenia of more than 7 days. Treatment of thrombocytopenia
· Immediate withdrawal of suspected agent in case of idiosyncratic effect. For bone marrow suppression, dose reduction or cessation may be required.
· Platelet transfusion is needed in the followings; life-threatening bleeding risk, serious decline of platelet(<20000/mm3) or before an invasive procedure.
· Thrombopoietin receptor agonists (romiplostim and eltrombopag) have been efficacious in thrombocytopenia management.
· Cut off values for platelet count before procedure;
I. The cut-off therapeutic level >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
II. > 50000/mm3 is recommended for lumbar puncture.
III. ≥100 000/mm3 ; before ocular and neurosurgical invasive procedure. Also recommended for invasive renal procedure because of high vascularity of renal tissue. This is a review article with level of evidence grade V
amiri elaf
2 years ago
# Briefly summarise this article
*Immunosuppressive medication are important for better graft outcome, but it associated with many hematological complications that occur after kidney transplant include posttransplant anemia, leukopenia, neutropenia, and thrombocytopenia.
* Myelosuppression presenting as cytopenia occure in 20% to 60% of KTRs and most episodes of cytopenia are seen during the first 3 months.
*Cytopenia can be identified as follows:
Pancy topenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets;
bicytopenia involves 2 of 3 cell lines
leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels
3000 cells/mm3 (normal),
2000 to 3000 WBCs/mm3,
1000 to 2000 WBCs/mm3,
<1000 WBC/mm3 (the latter 3 levels indicating abnormal with variable severities).
# Absolute neutrophil count (ANC) = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
*Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to
1.5 × 109/L,
* Moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L,
*Severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L
# Platelet count of 150 000/mm3 is considered the lower limit of normal level in many laboratories.The CTCAE graded thrombocytopenia into 4 levels.
*Grade I or subnormal (75 000-150,000 cells//mm3)
*Grade II or low (50000-75000 cells/mm3
*Grade III or moderate (25 000-50 000 cells/mm3)
*Grade IV or critical (<25 000/mm3).
# Consequences of Hematological Cytopenia
*When ANC is <1000 cells/μL, susceptibility to infection increases, the predisposition to frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenic decline.
*Both tacrolimus and MMF therapy are commonly associated with neutropenia.
Withdrawal of prophylactic agents
# Drug-induced Leukopenia and Neutropenia
# Rituximab
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that lead to B-cell depletion.
It induced cytopenia (grade 3/4) in 48% of patients in 1 trial as follows: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma.
* Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia), it seen post sixth rituximab dose.
* Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently implicated in its evolution.
* Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
# Antithymocyte globulin
* Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia. Leukopenia incidence with ATG is variable as showed with different studies (highest incidence 50%, explained by the concurrent use of azathioprine.
*The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3, the treatment should be held when platelet less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L or total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available and other medications that may cause cytopenia should also be monitored
* This approach is successful in reducing the AR, infections, and cytopenia.
# Alemtuzumab
*The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports, the incidence is higher (47%) if neutropenia is also present.
* Compared with ATG, the myelotoxic effects of alemtuzumab are more seve. However, infectious episodes are usually not life-threatening.
* A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may much less than that required for ATG-induced leucopenia also reduction of valganciclovir or cotrimoxazole is required
#Interleukin receptor antagonists
*Two interleukin 2 receptor (IL-2R) antagonist induction (Basiliximab and Daclizumab)
*Because anti-IL-2R activity is confined to activated T cells, their leukopenic and thrombocytopenic are rare compared with ATG and alemtuzumab (10% to 15% vs 5% for basiliximab).
* It is optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
# Mycophenolic mofetil and enteric-coated mycophenolate sodium
*Due to MMF hematotoxicity, 11.8% to 40% of KTRs can develop leucopenia
*The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA
*Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMFrelated leukopenia.
*The management by reduce the dose or complete withdrawal has benefit in MMF-induced neutropenia and leukopenia, but it can result in AR.
*Shifting to a suitable mammalian target of rapamycin inhibitor (sirolimus or everolimus) may reverse cytopenia and halving the CMV prophylactic dose of valganciclovir, which could also be another
preventive measure.
# Tacrolimus
*hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy,
including anemia, neutropenia, and combined anemia/neutropenia
*May also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
*Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant.
*Dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
# Azathioprine
*May induce leukopenia and neutropenia in almost half of KTRs, and most cases of leukopenia present in the first month after transplant, so, dose reduction or transient drug withdrawal is usually sufficient.
*An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine
S-methyl transferase (TPMT) activity.
*Drugs that interact with azathioprine include Allopurinol, so concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%
*Azathioprine drug levels should be measure weekly, with full blood count in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment.
# Mammalian target of rapamycin inhibitors
*The most common (mTORi), sirolimus and everolimus, have been involved in many myelotoxic side effects.
*Leukopenia had been showen in a meta-analysis that involved conversion from (CNI) to mTORi and the severity of myelotoxicity is dose dependent and about 20% of KTRs on sirolimus.
*A trough level of >12 ng/dL is highly associated with development of leukopenia and thrombocytopenia although it can occur even with lower drug levels.
*Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free
regimens may result in severe leukopenia.
* mTORi cytopenia seen the first 4 to 8 weeks
*Patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously and drug cessation may be the last resort for resistant cases.
# valganciclovir
*Although 10% to 28% of KTRs are vulnerable for leukopenia development in 4.9% to 37.5% of patients may develop neutropenia.
*Cytopenia may be potentiated by several factors, including higher doses of the drug, low body mass index, concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
*Although leukopenia can develop within 3 months, resolution of leukopenia can occur spontaneously with or without treatment.
* Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal.
# Ganciclovir
* A lesser incidence of leukopenia (7.1% vs 13.5%) and neutropenia (3.2% vs 8.2%) was observed in
ganciclovir-treated patients compared with those on valganciclovir therapy
# Valacyclovir
* Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials. The risk of neutropenia
with valganciclovir therapy is currently 30% higher than with valacyclovir.
*Combined MMF and valacyclovir therapy may aggravate druginduced myelotoxicity
*When compared with ganciclovir, dose modification is less frequently employed with valacyclovir.
# Trimethoprim-sulfamethoxazole
*Several types of cytopenia are associated with it is use include neutropenia and leukopenia and Megaloblastic anemia.
* Trimethoprim per se can cause dosedependent inhibition of granulopoiesis in vitro.
*The use of trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis in KTRs may
induce leukopenia in only 2%
*In combined with azathioprine therapy can aggravate drug-induced myelosuppression.
# Dapsone
*The neutropenic effects of dapsone may be aggravated by development of agranulocytosis
# Drug-induced Lymphopenia
*In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia
due to neutropenia. The latter is usually complicated
by augmented risk of serious infection
# Posttransplant Drug-induced Thrombocytopenia
Rituximab
*Has been reported in 48% of patients in one trial, with rate of thrombocytopenia in 2% of lymphoma patients.
*Antithymocyte globulin
An incidence of thrombocytopenia ranging from 10% to 26.5%
*Alemtuzumab
Alemtuzumab-induced thrombocytopenia has been observed in 14% of KTR
*Interleukin receptor antagonists
.*Mycophenolic mofetil and enteric-coated
mycophenolate sodium
Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia, and pancytopenia.
*Mammalian target of rapamycin inhibitors
*Ganciclovir
Induce thrombocytopenia in 23.1% of KTRs.
*Trimethoprim-sulfamethoxazole
Several hematologic complications like thrombocytopenia.
# Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
B12, folic acid, zinc, and copper deficiencies, Epstein-Barr virus-induced posttransplant proliferative disorders, Cytomegalovirus, parvovirus B19, human herpesvirus , influenza viruses, and Ehrlichiosis and Hemophagocytic Syndrome
# What is the level of evidence provided by this article
Level 5
Khadija Alshehabi
2 years ago
Briefly summarise this article
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number
of these drugs can cause myelosuppression. 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.2 Most episodes of cytopenia are observed during the first 3 months.
Cytopenia can be identified as follows: pancytopenia, bicytopenia, thrombocytopenia and leukopenia in which can be graded into 4 levels. Leukopenia is also termed alternatively with neutropenia, although these terms are not synonymous. Leukopenic KTRs are vulnerable to the development of opportunistic infections.
Drug-induced Leukopenia and Neutropenia
Rituximab
· A potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion.
· Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes, in attempted treatment of chronic antibody-mediated rejection, and in resolution therapy of posttransplant lymphoproliferative disorder.
· Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial.
· Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia: usually observed after the sixth rituximab dose with incidence around 37.5% -48%.)
· Dose reduction or drug withdrawal maybe indicated.
Antithymocyte globulin
· Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
· The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm 3 or WBC count reaches 2000 to 3000 per mm3. Treatment with ATG should be held when platelet count declines to less than 50 000 per mm 3 or when WBC count is less than 2000 per mm3.
Alemtuzumab
· An anti-CD52 humanized monoclonal immunoglobulin G1 antibody
· The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports
· Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose
· However, infectious episodes are usually not life-threatening
Interleukin receptor antagonists
· Both Basiliximab and daclizumab can suppress IL-2 meditated T cell activation and proliferation.
· Basiliximab has lower incidence of Leukopenia around 10.6% in one study.
· The anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
· The hematological sequelae with myelosuppression are the most common cause requiring MMF dose reduction, with 46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
· The myelotoxic impact of MMF is dose dependent.
· To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response at the expense of increased risk of acute rejection.
Tacrolimus
· Mainstay of clinical immunosuppression regimens.
· Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
· Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant.
· A dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
Azathioprine
· Azathioprine may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
· Most cases of azathioprine induced leukopenia present in the first month after transplant. In this situation, a dose reduction or transient drug withdrawal is usually sufficient
· An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
· Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid. Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%.
· Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
· Sirolimus and everolimus are most common examples and are associated with myelosuppression.
· Severity of myelotoxicity is dose dependent, with involvement of about 20% of KTRs on sirolimus. A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia.
· Development of cytopenia with mTORi agents can be usually observed within the first 4 to 8 weeks.
· In most patients, mTORi-induced leukopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required.
Valganciclovir
· Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia.
· The resultant cytopenia may be potentiated by several factors, including higher doses of the drug (900 mg or more), low BMI and concomitant MMF administration.
· leukopenia can develop within 3 months, but resolution of leukopenia can occur spontaneously with or without treatment. Risk of infection is usually low.
· Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal.
Ganciclovir
· Ganciclovir is used for anti-CMV therapy and prophylaxis.
· Ganciclovir causes leukopenia, with rates of 7.1% to 23.1%.
Vlacyclovir
· Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs.
· Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild with incidence ranges from 6-14%.
Trimethoprim-sulfamethoxazole
· Commonly used drug for Pneumocystis jirovecii prophylaxis.
· It may induce leukopenia in only 2% of KTRs recipients.
· Folinic acid can reverse this side effect.
Dapsone
· An alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
· The neutropenic effects of dapsone may be aggravated by development of agranulocytosis.
Drug-induced Lymphopenia
· Usually complicated by augmented risk of serious infection
· lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG).
Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia:
1- Rituximab 48%
2- Antithymocyte globulin 10 – 26.5%
2- Alemtuzumab: 14%
3- Interleukin receptor antagonists 2.8 – 5.8%
4- Mycophenolic mofetil and enteric-coated mycophenolate sodium 46.5% (pancytopenia)
5- Mammalian target of rapamycin inhibitors 10 – 17%
6- Ganciclovir 23.1%
7- Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
· In addition to medication-induced myelotoxicity, a variety of etiologies can share in the development of these serious hematological events, including B12, folic acid, zinc, and copper deficiencies.
· Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia.
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Hemophagocytic syndrome
· Can be associated with cytopenia.
· Several viral infections (CMV, adenovirus Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
Specific treatment of neutropenia
· The first step is determining the patient’s full detailed history to unravel possible culprit.
· Measurement of ANC can be used to evaluate the severity of neutropenia, with severe neutropenia indicated by ANC <500/μL.
· The next therapeutic step for WBC count correction would be administration of “colony- stimulating” factors if there is no accepted response to the previous maneuvers.
· Colony-stimulating factors have been introduced to manage severe leukopenia in KTRs.
What is the level of evidence provided by this article?
Level of evidence V: Evidence from systematic reviews of descriptive and qualitative studies (meta-synthesis).
Tahani Ashmaig
2 years ago
Drug-Induced Myelosuppression in Kidney Transplant Patients
Introduction
Cytopenia is not uncommon in kidney transplant recipients (KTRs).
From 20% to 60% of KTRs experience at least
episode of cytopenia after transplant (which are observed mostly during the first 3 months). The list of culprit agents includes MMF and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, ATG, tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Consequences of Hematological Cytopenia
leukopenia augments the risk of infection by disrupting immunogenic integrity
and liability of ubiquitous and opportunistic infections
Drug-induced Leukopenia and Neutropenia
A number of agents have been implicated in posttransplant leukopenia and
neutropenia development:
1- Rituximab:
Cause B-cell depletion and thus affecting phagocytosis, complement-mediated cytotoxicity, and ADCC
Can cause Rituximab-induced cytopenia (grade 3/4)
Can cause late-onset neutropenia
2. Antithymocyte globulin
A wide range of blood cells are vulnerable to
the antibody effects of this agent, including T cells, B
antibodies toward nonlymphoid tissue may result in
the development of neutropenia.
3. Alemtuzumab: an anti-CD52
Compared with ATG, the myelotoxic effects
of alemtuzumab are more severe, with the lowest
WBC counts observed 130 days after the last given
dose. However, infectious episodes are usually not
life-threatening.
4. Interleukin receptor antagonists
Interleukin 2 receptor (IL-2R) antagonist ( basiliximab, and daclizumab) , Because anti-IL-2R activity is confined to activated T cells, their leukopenic and throm bocytopenic drawbacks are rare compared
with with ATG and alemtuzumab
These agents would be an optimum therapeutic option for leukopenic
KTRs with low/moderate risk of rejection.
5. MMF and enteric-coated mycophenolate sodium
MMF can cause hematotoxicity ( the diagnosis could be masked with ATG-related and alemtuzumabrelated cytopenia)
The myelotoxic impact of MMF is dose dependent
Concomitant administration of valganciclovir,
valacyclovir, and fenofibrate may exaggerate MMF related leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and
leukopenia.
Tacrolimus
anemia, neutropenia, and combined
anemia/neutropenia is less common.
It may intensify MMF myelotoxicity, and tacrolimus and MMF
combinations can induce neutropenia
Neutropenia can be observed
within the first 3 months after transplant.
No particular test for diagnosis, except for leukocytic
count normalization after the withdrawal of
tacrolimus. A dose reduction of MMF is suggested in
patients on dual immunosuppression therapy.
Azathioprine
May induce leukopenia and neutropenia in almost half of KTRs,
particularly with doses greater than 1.99 mg/kg
body weight/day.
leukopenia present in the first month after
transplant.
In this situation, a dose reduction or
transient drug withdrawal is usually sufficient.
Thiopurine S-methyl transferase (TPMT) activity determine the magnitude of its toxicity.
active TPMT may lead to higher risk of myelotoxicity
Allopurinol interact with azathioprine
Azathioprine levels should be monitored weekly,
with full blood count monitoring in the first month,
then twice per month during the second and third
months, and then monthly or less according to dose
adjustment.
Mammalian target of rapamycin inhibitors
rapamycin
inhibitors (mTORi), sirolimus and everolimus,
can cause dose sependent myelotoxicity
Sirolimus and MMF combination therapy after
alemtuzumab induction in steroid and CNI-free
regimens may result in severe leukopenia.
Everolimus can cause leukopenia
Cytopenia can be observed within the first 4 to 8 weeks.
valganciclovir
cytopenia may be potentiated by higher doses of the drug (900 mg or more)
low body mass index, and
concomitant MMF administration,
Although leukopenia can develop within 3
months, resolution of leukopenia can occur
spontaneously with or without treatment.
Risk of infection is usually low.
Ganciclovir
Causes leukopenia, with rates of 7.1% to 23.1%.
therapy respond to dose reduction, and some
require ganciclovir cessation.
valacyclovir
Compared with valganciclovir and ganciclovir,
myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole
Can cause neutropenia and leukopenia and megaloblastic
anemia.
combined azathioprine therapy with it can aggravate drug-induced
myelosuppression.
Dapsone
Can cause neutropenia which may be
aggravated by development of agranulocytosis
Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia
1. Rituximab
2. ATG
For treatment, medications that affect cytopenia
prevalence should be monitored (eg, holding off or
reducing MMF with concurrent ATG-induced
cytopenia) Thrombocytopenia can also be
exacerbated with ATG and mTORi combination.
3. Alemtuzumab
4. Interleukin receptor antagonists
5. MMF and enteric-coated mycophenolate sodium
6. Mammalian target of rapamycin inhibitors
7. Sirolimus
and everolimus,
Ganciclovir
Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia
and Thrombocytopenia
In addition to medication-induced myelotoxicity, a
variety of etiologies can share in the development of
these serious hematological events, including B12,
decline of platelet count (<20 000/mm3), or before
an invasive procedure.
The recommended cut-off therapeutic level for
platelet transfusion should be >50 000/mm3 with
commencement of invasive maneuvers
6. Further Developments
Thrombopoietin receptor agonists have been
efficacious in thrombocytopenia management.
▪︎Level of evidence: 5
Nahla Allam
2 years ago
Drug-Induced Myelosuppression in Kidney Transplant Patients
Briefly summarise this article
What is the level of evidence provided by this article?
Summary:
Introduction:
A kidney transplant is the best therapeutic option for suitable patients with end-stage kidney failure.
Hematological complications after kidney transplant include post-transplant anemia, leukopenia, neutropenia, and thrombocytopenia. Severely persistent leukopenia and neutropenia events predispose patients to infection, including opportunistic infections
Immunosuppressive drugs are crucial to allograft survival in transplant recipients:
Mycophenolate mofetil (MMF) .
Enteric-coated Mycophenolate sodium.
Ganciclovir.
Valganciclovir.
Anti Thy -myocyte Globulin (ATG).
Tacrolimus.
Sirolimus.
Trimethoprim-sulfamethoxazole.
Mycophenolic mofetil and enteric-coated mycophenolate sodium MMF:
These agents are inosine monophosphate dehydrogenase inhibitors that can inhibit cell-mediated and humoral immune responses by suppressing guanosine nucleotide synthesis de novo pathways in T/B lymphocytes, arresting their differentiation.
The hematological sequelae with myelosuppression are the most common cause requiring MMF dose reduction, with 46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
Azathioprine:
Azathioprine is a traditional antimetabolite that was introduced in 1960 and has been significantly replaced by the more potent MMF in immunosuppression after kidney transplant.
Thiopurine S-methyl transferase (TPMT) activity is a critical factor in determining the magnitude of azathioprine-induced myelotoxicity.
Drugs that interact with azathioprine include allopurinol, which inhibits and should be monitore for xanthine oxidase activity leading to a decline in purine metabolism to uric acid
. Azathioprine levels weekly,
Tacrolimus:
Tacrolimus is the mainstay of clinical immunosuppression regimens
Mechanisms of tacrolimus-induced neutropenia
include direct suppression of myeloid cells, with bone marrow hypoplasia observed in hepatic
Transplant recipients,64 altered cytokine production by T lymphocytes and monocytes, and output of antimyeloid precursors and anti-mature neutrophil antibodies.
Rituximab:
Rituximab is a potent chimeric anti-CD20 monoclonal antibody
is commonly used as a part of the induction agent in ABO-incompatible transplant
procedures, in the Treatment of acute rejection episodes, in attempted Treatment of chronic antibody-mediated rejection.
Antithymocyte globulin:
Thymoglobulin activity is not confined to T cells; rather, a wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.32,33 Moreover, cross-reaction of
antibodies toward nonlymphoid tissue may result in the development of neutropenia
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3, or WBC count comes 2000 to 3000 per mm3.36,39 Treatment with
ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3
Alemtuzumab
Alemtuzumab is an anti-CD52 humanized mono – clonal immunoglobulin G1 antibody.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe.
interleukin receptor antagonists:
basiliximab,
daclizumab,
the incidence of leukopenia was 10.6% for KTRs who received basiliximab
Mammalian target of rapamycin inhibitors
The most common mammalian target of rapamycin inhibitors (mTOR), sirolimus and everolimus
The development of cytopenia with mTOR agents can usually be observed within the first 4 to 8 weeks.
In most patients, mTOR-induced leucopenia resolves spontaneously.
valganciclovir
The higher bioavailability of this agent (70% vs. 7% for oral ganciclovir) has also affected its myelotoxicity profile
leukopenia can develop within three months. Three resolution of leukopenia can occur spontaneously with or without treatment.
Ganciclovir
Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs. .the bioavailability of the drug is poor when given orally; therefore, it is always given intravenously.
valacyclovir
Valacyclovir is a remarkable agent for CMV prevention and Treatment of herpes simplex in KTRs.
Moreover, MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
Trimethoprim-sulfamethoxazole
are associated with trimethoprim-sulfamethoxazole; these include neutropenia, leukopenia, and megaloblastic anemia.
Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis. Several types of cytopenia
Dapsone
Dapsone is an alternate agent for Pneumocystis jirovecii prevention associated with manyhematological complications, including neutropenia.
Drug-induced Lymphopenia:
Lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (e.g., rabbit ATG).
Posttransplant Drug-induced Thrombocytopenia:
Rituximab
Antithymocyte globulin
Alemtuzumab
interleukin receptor antagonists
Mycophenolic mofetil and enteric-coated mycophenolate sodium
Level 5
Mohamad Habli
2 years ago
Briefly summarise this article
Renal recipients are at high risk of post-transplant hematological complications such as leukopenia, thrombocytopenia and anemia. The pathophysiology of myelosuppression is multifactorial. However in this article, authors focus on drug induced myelosuppression due to various drugs used in kidney transplant recipients. It is reported that 20-60% of transplant recipients experience cytopenia postoperatively.
Cytopenias can be divided based on affected clones into pancytopenia, bicytopenia, thrombocytopenia, leukopenia or anemia. The severity of cytopenias is graded into mild, moderate, and severe.
It is well established that cytopenias expose immunocompromised renal recipients to higher risk of infections and malignancies while reduction of immunosuppression increases the risk of acute rejection.
Immunosuppression drugs attributed to myelosuppression are as follow:
1- Rituximab: incidence of 37.5% to 48%, with higher incidence among ABO incompatible transplant. Onset of cytopenia is usually 4 weeks after administered dose. Associated with thrombocytopenia in 48% of patients. Dose adjustment or discontinuation is required for recovery.
2- ATG is associated with more frequent leukopenia with an incidence of 10-50% (more severe leukopenia with MMF), thrombocytopenia 10% – 26.5% (more severe with higher doses and use of mToi)
It is recommened to hold rATG if platelet count drops to less than 50000 or wbc < 2000
3- Alemtuzumab: incidence 33.3% -42%, 47%, thrombocytopenia in 14%, more toxic than ATG on the bone marrow, long lasting toxic effect – 130 days post-last dose
4- Basiliximab: lower immunosuppressive effect compared to ATG and alemtuzumab , with lower incidence of myelosuppression. Leukopenia occurs in 10.6%, thrombocytopenia 5%
5- MMF and EC- MPS: cytopenia incidence 11.8% to 40%, higher risk when combined with rATG or alemtuzumab induction, toxic effect is dose dependent, concomitant use of valganciclovir, valacyclovir and fenofibrate increase the myelotoxic effect.
6- CNI – Tacrolimus: incidence of neutropenia is 28% when combined with MMF. Overall, low incidence of leukopenia when prescribed alone. Leukopenia is usually observed in the first 3 months following transplantation.
7- Azathioprine: high incidence 50%, up to 70% in patient with past medical history of leukopenia. Higher risk with higher doses >1.99mg/kg/day. Early onset after transplantation (first month), monitoring of azathioprine levels, 6-Thioguanine nucleotide levels in RBCs is adviced to prevent myelosuppression. Development of leukopenia necessitates reduction of the dose. Concomitant allopurinol should be avoided.
8- mTORi – Sirolimus and Everolimus: incidence with sirolimus is 20% while incidence with everolimus is 11-19% , toxicity is dose dependent (sirolimus trough level >12 ng/dl), usally resolve spontaneously, thrombocytopenia is observed with Tthrombotic microangiopathy
9- Antiviral prophylaxis: Valgancyclovir: incidence of leukopenia is 10-28%, more severe with higher doses, observed within 3 months of drug use. Gancyclovir: incidence of leucopenia is 7.1% – 23.1%, thrombocytopenia in 23%, 23% respond to dose reduction. Valacyclovir: incidence of leukopenia in 6-14%, more severe with concomitant use of MMF.
10- Antibiotic prophylaxis: Trimethoprim-sulfamethoxazole: low myelotoxic risk, risk of neutropenia, megaloblastic anemia and leukopenia – 2%.
What is the level of evidence provided by this article?
Level of evidence 5
Huda Mazloum
2 years ago
KTRs experience 1 episode of cytopenia after transplant in 20 – 60 %
Most are observed during the first 3 months after RTx
Cytopenia involves all 3 cells lines white blood cells , red blood cells , and platelets.
bicytopenia involves 2 of 3 cell lines thrombocytop
** Many laboratories indicate 4000 cells mm3 as the lower limit of normal
Mild neutropenia is ANC level of 1000 to 1500/μL
moderate neutropenia is ANC level of 500 to 999/μL
severe neutropenia (agranulocytosis) is ANC level of <500/μL
** Thrombocytopenia into 4 levels
Level I : subnormal (75 000-150,000 cells/mm3)
grade II or low (50000-75000 cells/mm3, grade III or moderate (25 000-50 000 cells/mm3)
grade IV or critical (<25 000/mm3)
When ANC is <1000 cells/μL there is a risk for opportunistic infections.
Drug-induced Leukopenia and Neutropenia :
** Rituximab
Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia)
Leukopenia in 19 – 24.6 % and neutropenia in 37 – 48 %
rituximab-related thrombocytopenia rarely induces bleeding
** Antithymocyte globulin
The leukopenia incidence 10- 50
Thrombocytopenia in 14.3%
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3
Or WBC count reaches 2000 to 3000 per mm3.
incidence of thrombocytopenia 10% to 26.5% hasbeen in KTRs
Alemtuzumab :
The leukopenia incidence 33.3 – 42 %
The neutopenia incidence 2.5 – 47 %
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe
with the lowest WBC counts observed 130 days after the last given dose
infectious episodes are usually not life-threatening
thrombocytopenia observed in 14% of KTRs
Bleeding requiring surgical intervention observed in 12% of KTRs.
The leukopenia incidence 10 – 15 %
leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab.
anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Basiliximab induces thrombocytopenia in
5 % so an anti-IL-2R agent would be an optimum therapeutic option for thrombocytopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
Incidence of leukopenia 11.8 – 40 %
46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
The myelotoxic impact of MMF is dose dependent
Concomitant administration of valganciclovir,valacyclovir,may exaggerate MMF-related leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal and this would
trigger the risk of acute rejection, with subsequent graft loss
approaches for the management of this type of leukopenia, including
** preemptive dose reduction of MMF after ATG and alemtuzumab induction
** shifting to mammalian target of rapamycin inhibitor
** halving the CMV prophylactic dose of valganciclovir,
cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal
Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia
Tacrolimus
including anemia, neutropenia, and combined anemia/neutropenia
Tacrolimus may also intensify MMF myelotoxicity, as combinations have been shown to induce neutropenia in 28% of KTRs.
Mechanisms
▪︎direct suppression of myeloid cells,
▪︎bone marrow hypoplasia in hepatic transplant recipients
▪︎altered cytokine production by T lymphocytes and monocytes
▪︎production of antimyeloid precursors and anti-mature neutrophil antibodies. Tacrolimus has been shown to prevent MPA glucuronidation that results in intensification of blood levels.
In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels.
Azathioprine
Azathioprine may induce leukopenia and neutropenia in almost half of KTRs,
particularly with doses greater than 1.99 mg/kg body weight/day.
Most cases present in the first month after transplant.
Moderately
To ameliorate the risk of myelosuppression, 2 techniques have been proposed. The first is monitoring of 6-thioguanine nucleotide in RBCs,
concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%
Mammalian target of rapamycin inhibitors
sirolimus and everolimus
Severity of myelotoxicity is dose dependent,
20% of KTRs on sirolimus
development of leukopenia and thrombocytopenia
with lower drug levels.
Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia
Sirolimus and MMF combination may result in severe leukopenia.
Everolimus complicated by leukopenia (11%-19%)
cytopenia with mTORi observed within the first 4 to 8 weeks.
For patients with sirolimus-induced cytopenia 89% resolve spontaneously.
Both everolimus84-86 and sirolimus have a potential capability to induce thrombocytic microangiopathy
valganciclovir
10% to 28% of KTRs are vulnerable for leukopenia development and 4.9% to 37.5% of patients may develop neutropenia.
For several factors including
* higher doses of the drug
* low body mass index, which
* concomitant MMF administration
leukopenia can develop within 3 months resolution of leukopenia can occur spontaneously with or without treatment. Risk of infection is low.
Ganciclovir
it is always given intravenously.
causes leukopenia 7.1% to 23% and neutropenia (3.2% )
it can induce thrombocytopenia in 23.1% of KTRs.42
valacyclovir
Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Incidence of leukopenia 6% to 14%
combined MMF and valacyclovir therapy may aggravate drug-induced myelotoxicity.
When compared with ganciclovir, dose modification
Trimethoprim-sulfamethoxazole
Can cause neutropenia and leukopenia and megaloblastic anemia.
can cause dose leukopenia in only 2% of recipients.
combined azathioprine therapy with trimethoprim-sulfamethoxazole can aggravate drug-induced myelosuppression.
Dapsone
It is an alternate agent for Pneumocystis jirovecii prevention with many hematological complications, including neutropenia and agranulocytosis
Drug-induced Lymphopenia
is usually the result of induction therapy with lymphocyte-depleting medication as ATG
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
Epstein-Barr virus
Cytomegalovirus
parvovirus B19,
human herpesvirus 6,
influenza viruses
ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Specific treatment of neutropenia
evaluate the severity of neutropenia
determining the patient’s full detailed history to unravel possible culprit
A dose reduction or complete withdrawal of the suspected agent
administration of “colony-stimulating” factors if there is no accepted response
Level : V
Amit Sharma
2 years ago
Briefly summarise this article
Post-transplant hematological complications include leukopenia, neutropenia, thrombocytopenia and anemia. The article focusses on myelosuppression due to various drugs used in kidney transplant recipients. The incidence of cytopenias in kidney transplant recipients range from 20-60%.
Cytopenias can be pancytopenia, bicytopenia, thrombocytopenia or leukopenia. The degree of cytopenias can be further graded as mild, moderate, and severe depending on their counts.
Cytopenias are associated with increased risk of infections and reduction of immunosuppressives as a treatment strategy in such scenarios increase risk of acute rejection.
Various drugs responsible and their effects include:
1) Rituximab:
-Usually late onset cytopenia (more than 4 weeks after last dose) occur with incidence of 37.5% to 48%.
-The relative risk increases to 8.8 with use in ABO incompatible transplant.
-Causes grade3/4 thrombocytopenia in 48% patients.
– Dose reduction/ withdrawal is required for recovery
2) Antithymocyte globulin (ATG):
– Leukopenia Incidence 10-50%
– Thrombocytopenia incidence 10% to 26.5%
– More leukopenia with concomitant MMF use and steroid withdrawal regimens
– More thrombocytopenia with higher doses and associated mTOR inhibitor use.
– Dose should be withheld if platelet counts are less than 50000 and leukocyte count is less than 2000
– MMF dose reduction may improve cytopenias
3) Alemtuzumab:
– Leukopenia seen in 33.3% to 42%, 47% if neutropenia present
– Incidence of leukopenia is 10.6%, thrombocytopenia seen in 5%
– Useful in low or moderate risk patients with leukopenia and/or thrombocytopenia
5) Mycophenolate mofetil (MMF) and enteric coated mycophenolate sodium:
– Dose-dependent effect, with cytopenia incidence 11.8% to 40%
– Increased incidence if concomitant use of valganciclovir, valacyclovir and fenofibrate
– Management involves reduction in MMF dose (but keep close watch for acute rejection), reduction in valganciclovir dose, shift to sirolimus or everolimus, decreasing dose pre-emptively in patients given ATG, and stopping MMF and valganciclovir as a last resort.
6) Tacrolimus:
– Low incidence of leukopenia in kidney transplants, 28% neutropenia in concomitant tacrolimus and MMF use
– More in cardiac transplants
– Seen within first 3 months
– Management involves reducing MMF dose or replacing tacrolimus with everolimus, belatacept or eculizumab.
7) Azathioprine:
– Incidence is 50%, 70% if past history of leukopenia. More in patients receiving >1.99mg/kg/day dose.
– Seen within first month
– Depends on TPMT activity (low or absent TPMT activity leads to severe myelosuppression)
– Monitoring azathioprine levels, 6-Thioguanine nucleotide levels in RBCs, genotyping and phenotyping of TPMT are some methods to prevent myelosuppression
– Decrease dose by 25-50% in concomitant allopurinol use
– Treatment includes dose reduction or transient withdrawal.
8) Mammalian target of rapamycin inhibitors (mTORi) – Sirolimus, Everolimus:
– Inhibit signal transduction through bgp130beta chain
– Dose dependent effect (sirolimus trough level >12 ng/dl)
– 20% incidence with sirolimus, 11-19% incidence with everolimus
– Thrombotic microangiopathy leads to thrombocytopenia
– Mostly resolve spontaneously
– May require reducing dose of mOTRi with MMF dose reduction
9) Valgancyclovir:
– 10-28% leukopenia, 4.9%-37.5% neutropenia.
– More with higher doses, low BMI and concomitant MMF use
– Usually within 3 months
– Management involves dose reduction or transient drug withdrawal.
10) Gancyclovir:
– Leukopenia incidence 7.1% to 23.1%
– Thrombocytopenia incidence 23%
– Less than that with valganciclovir
– 23% respond to dose reduction, 2.4% require drug cessation
11) Valacyclovir:
– Leukopenia in 6-14%
– More with concomitant MMF use (MMF increases intracellular concentration of valacyclovir leading to bone marrow toxicity)
12) Trimethoprim-sulfamethoxazole
– Trimethoprime inhibits granulopoiesis
– Causes neutropenia, megaloblastic anemia and leukopenia (2%)
– More in patients on concomitant azathioprine
13) Dapsone:
– Causes neutropenia and agranulocytosis
Other causes of post-transplant leukopenia and thrombocytopenia include deficiency of vitamin B12, folic acid, Copper or zinc; infections like EBV associated PTLD, CMV, HHV, parvovirus B19, influenza virus or Ehrlichiosis; hemophagocytic syndrome due to infections like CMV, Adenovirus, EBV, HHV-8, HHV-6, BK Virus, and Parvovirus B19; or renal ischemic events and acute antibody mediated rejection.
Treatment involves dose reduction, use of colony stimulating factors (GCSF and GMCSF), drug withdrawal and platelet transfusion in case of bleeding with thrombocytopenia
What is the level of evidence provided by this article?
This is Level 5: A narrative review
Last edited 2 years ago by Amit Sharma
Huda Saadeddin
2 years ago
Immunosuppressive drugs are crucial to allograft survival in transplant recipients and also they often present with hematological cytopenia.From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months .
The risk of infection, including opportunistic, is life-threatening in the presence of leukopenia and neutropenia. Moreover, risk of bleeding can be also triggered once thrombocytopenia ensues. Drug withdrawal or dose reduction may be the only technique to recognize the suspected medication or medications.
The higher risk of acute rejection after reduction of myelosuppressive immunosuppressive agents requires careful consideration.
Drug-induced Leukopenia and Neutropenia
Rituximab Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen.
Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes, in attempted treatment of chronic antibodymediated rejection,and in resolution therapy of posttransplant lymphoproliferative disorder
Rituximab induced 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma. 24 Cytopenia can occur 4 weeks after start of rituximab therapy
Late-onset neutropenia can be defined as neutropenia that is observed 4 weeks after the last dose of rituximab usually observed after the sixth rituximab dose.
Antithymocyte globulin
Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm 3 or WBC count reaches 2000 to 3000 per mm3 . 36,39 Treatment with ATG should be held when platelet count declines to less than 50 000 per mm 3 or when WBC count is less than 2000 per mm3.
Other medications that may cause cytopenia should also be monitored, including MMF (hold off MMF with concurrent ATG-induced cytopenia37 ) and steroids (loss of stimulatory effects on bone marrow in early steroid withdrawal regimens after ATG induction can be complicated with a higher incidence of leukopenia41 ).
Alemtuzumab is an anti-CD52 humanized monoclonal immunoglobulin G1 antibody
the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe.
interleukin receptor antagonists
basiliximab and daclizumab leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
The hematological sequelae with myelosuppression are the most common cause requiring MMF dose reduction, with 46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
The myelotoxic impact of MMF is dose dependent.
Concomitant administration of valganciclovir,3 valacyclovir, and fenofibrate 59 may exaggerate MMFrelated leukopenia.
Tacrolimus is the mainstay of clinical immunosuppression regimens.Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.14
Mechanisms of tacrolimus-induced neutropenia include direct suppression of myeloid cells, with bone marrow hypoplasia observed in hepatic transplant recipients,Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant. 9 There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus. 9 A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. 68,69 In such patients, other alternatives include everolimus, belatacept, or eculizumab.
Azathioprine
Azathioprine may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid.
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month,then twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
valganciclovir
Although 10% to 28% of KTRs are vulnerable for leukopenia development, 3,38,41,42 4.9% to 37.5% of patients may develop neutropenia. 3,38-40 The resultant cytopenia may be potentiated by several factors, including higher doses of the drug (900 mg or more) having a significant impact on leukopenia and neutropenia development, 43 low body mass index, which is a significant potentiating factor for leukopenia, 40 and concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
Ganciclovir
Ganciclovir is used for anti-CMV therapy and prophylaxis . ganciclovir causes leukopenia, with rates of 7.1% to 23.1%.
valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis.Folinic acid can reverse this side effect
However, combined azathioprine therapy with trimethoprimsulfamethoxazole can aggravate drug-induced myelosuppression.
Dapsone Dapsone is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.69 Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis .
the same drugs mentioned above also induced lymphocytopenia and thrombocytopenia.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia In addition to medication-induced myelotoxicity, a variety of etiologies can share in the development of these serious hematological events, including B12, folic acid, zinc, and copper deficiencies, as shown in a nontransplant cohort.92
Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia. 11 Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
What is the level of evidence provided by this article?
Level V
Sahar elkharraz
2 years ago
Drug-Induced Myelosuppression in Kidney transplant patients
This article focus on complications of immunosuppressive therapy in haematological system and predisposed patients to opportunity infection which are life threatening conditions leading to increase incidence of mortality post transplant. Also this article focus who to optimise immunosuppressive therapy to reduce chance of cytopenia and infection.
Cytopenia defined as reduction of WBC and RBC and platelets level with leukopenia and neutropenia and lymphopenia.
Grade of leukopenia to WBC 3 grades I ( 3000 mm2); grade 2 (3000-2000); grade 3 (1000 & less).
Platelets grades to 4 // grade 1(150,000-75000), grade 2(75000-50000); grade 3(50000-25000); grade 4(less than 25000).
Tacrolimus and MMF associated with neutropenia and risk intra abdominal infection and E coli infection.
In this situation reduce dose to half or withdrawal drug but may lead to risk of rejection.
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion.
Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures.
Incidence of cytopenia in induction therapy with rituximab is 73.5% to 48%, days and usually in sixth dose post kidney transplant. It’s treated usually with reduce dose or withdrawal drug.
ATG
It’s inhibit activity of T cells. inhibition of B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.
ATG lead to leukopenia (neutropenia ), and thrombocytopenia and should be reduce ATG to half if WBC between 3000-2000, platelets between 75000-50000, and stop ATG if platelets less than 50000 and WBC less than 2000. CD3 T cell should be monitoring.
Alemtuzumab:
It’s an anti-CD52 humanized mono clonal immunoglobulin G1 antibody.
Alemtuzumab can be administrated as an induction agent to prevent kidney transplant rejection.
leukopenic incidence is ranges from 33.3% to 42%. It’s mainly cause neutropenia.
the myelotoxic effects of alemtuzumab are more severe.
A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia. it’s with reduce dose should be a strict monitoring of allograft function.
With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required.
interleukin 2 receptor (IL-2R) antagonist:
There’s induction agents are basiliximab and daclizumab a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in kidney transplant.
It’s side effects are leukopenic and thrombocytopenia.
Incidence of leukopenia is 10% with basiliximab.
mycophenolate moftile
It’s common cause of leukopenia and anemia and pancytopenia leading to reduce dose to half.
It’s common haematological complications and myelotoxicity.
If pan cytopenia evident should be shift to rapamycin inhibitors like sirolimus and everolimus. And reduce CMV prophylactic dose to half.
Tacrolimus:
It’s may induce neutropenia with combination of MMF to 28%.
It’s suppress myeloid cell and can be shifted by other drug in severe leukopenia and neutropenia by everolimus / beltacept / eculizumab.
Azathioprine:
It’s traditional prodrug used for kidney transplant
It’s may lead to pancytopenia.
Azathioprine in combination with allopurinol lead to inhibition of xanthine oxidase and decline purine metabolism of uric acid. So increase level of azathioprine lead to myelotoxicity and should be reduce dose to half.
Rapamycine inhibitors (mTOR), everolimus and sirolimus with use of MMF lead to leukopenia.
Valgancyclovir: high dose more than 900 mg associated with leukopenia. The recommended dose is 400mg daily.
Rituximab can induce thrombocytopenia but rarely lead to bleeding.
Alemtuzmab induce thrombocytopenia in 14% of kidney transplant and cause bleeding need to surgical intervention.
What is the level of evidence provided by this article?
Level V
Mahmoud Wadi
2 years ago
III. Drug-Induced Myelosuppression in Kidney Transplant Patients
Briefly summarise this article
1- Renal transplant is considered the best therapeutic option for suitable patients with end-stage kidney failure and Hematological complications that occur after kidney transplant include posttransplant anemia, leukopenia, neutropenia, and thrombocytopenia.
2- Myelosuppression is known to occur in kidney transplant recipients because of widely used immunosuppressant chemotherapeutic agents. 3- Cytopenia can be identified as follows:-
3-1 pancytopenia involves all 3 cells (WBCs, RBCs and Platelet).
3-2 Bicytopenia involves 2 of 3 cell .
3-3 Thrombocytopenia involves low platelet count.
3-4 Leukopenia can be graded according to the Common Terminology
Criteria for Adverse Events (CTCAE) into 4 levels:-
A- These levels are 3000 cells/mm3 (normal),
B-2000 to 3000 WBCs/mm3,(mild).
C-1000 to 2000 WBCs/mm3(modreate),
D-and <1000 WBC/mm3 (severe).
4- Absolute neutrophil count (ANC).
4-1An ANC of<1500 (neutropenia)
4-2 ANC level of 1000 to 1500/μL (mild)
4-3 ANC level of 500 to 999/μL (moderate)
4-4 ANC level <500/μL (sever), and severe
neutropenia (agranulocytosis).
5- Platelet count of 150 000/mm 3 is considered the
lower limit of normal level in many laboratories and are 4 grade:-
5-1 Grade I or subnormal (75 000-150,000 cells//mm 3).
5-2 Grade II or low (50000-75000 cells/mm 3).
5-3 Grade III or moderate (25 000-50 000 cells/mm 3).
5-4 Grade IV or critical (<25 000/mm3).
6- Consequences of Hematological Cytopenia
Neutrophils and lymphocytes have fundamental roles in prevention of infection.
6-1 When ANC is <1000 cells/μL, susceptibility to infection increases.
6-2 Neutropenic KTRs commonly experience more intra-abdominal infections and tacrolimus and MMF therapy are commonly associate with neutropenia.
6-3 Withdrawal of prophylactic agents for CMV or Pneumocystis jirovecii causes their spread.
6-4 To summarize, leukopenia augments the risk of infection by disrupting immunogenic integrity and liability of ubiquitous an opportunistic infections.
6-5 Cautious in the treatment of patients with high immunological
risk, especially those within 3 months after transplant.
*Drug-induced Leukopenia and Neutropenia Rituximab 1- Rituximab an anti CD20 antigen, monoclonal antibody.
2- Rituximab is commonly used
3- Induction agent in ABO-incompatible transplant procedure.
4- Treatment of acute rejection .
5- Treatment of chronic antibody mediated rejection.
6- Resolution therapy of post transplant lymphoproliferative disorder.
7- Cytopenia can occur 4 weeks after start of rituximab therapy
(late-onset neutropenia).
8- Late-onset neutropenia can be defined as neutropenia that is observed 4 weeks after
the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF).
9- Late-onset neutropenia is usually observed after the sixth rituximab dose.
10- Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently
implicated in its evolution.
11- The threshold of suspicion of rituximab induced toxicity should be lowered, particularly 6 weeks after the sixth rituximab dose.
12- Dose reduction or drug withdrawal is usually the ideal response for
hematological recovery.
Administration
1- Rituximab use by intravenous infusion and should not be administered as IV bolus or push.
2- Patients should be given acetaminophen and antihistamine before each infusion.
3- Rituximab should be diluted in an infusion bag of either 0.9% sodium chloride, 5% dextrose.
4- Patients should be observed for 15 minutes after administration. Antithymocyte globulin:
.1- ATG a polyclonal immungloulin prepared by immunizing horses or rabbits with human thymocytes and harvesting the IgG.
2- Has awidespread activity against blood cell T and B cell.
3- high risk of leukopenia 50%
4- treatment dose should be halved when PLT.between 5000-75000 per mm3
5- IF PLT.less than 50000 and WBCs less than 2000per mm3need stoped ATG
6- During ATG monitoring of other cytopenic medication .
Alemtuzumab
1- Is an anti-CD52 humanized monoclonal immunoglobulin G1 antibody.
2- Compared with ATG, the myelotoxic effects of alemtuzumab are more severe, with the lowest WBC counts observed 130 days after the last given dose.
3- With regard to management, dose modification of other drugs such as MMF or
valganciclovir or cotrimoxazole is required.
interleukin receptor antagonists
1- Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab, a monoclonal chimeric, and daclizumab, a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in KTRs.
2- Rarely with leukopenia or thmobocytopenia <50% of KTX pateint.
3-The anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
1- Hematotoxicity, can develop leukopenia related to MMF therapy. 11.8% to 40%. 2- Both ATG-related and alemtuzumab- related cytopenia may mask the diagnosis of MMF myelotoxicity, as they may require MMF dose reduction.
3- The most common cause requiring MMF dose
reduction, with 46.5% of MMF-reducing events dueto leukopenia, anemia thrombocytopenia, andpancytopenia.
4- The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA and Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMF- related leukopenia.
5-Dose reduction of MMF has been mostly attempted in the first year posttransplant, a time of highest risk of allograft rejection.
Tacrolimus 1-Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
2-Tacrolimus-induced direct myeloid inhibition has not been observed in vitro.
3- Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant.
4- A dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
Azathioprine
1- Azathioprine may induce leukopenia and neutropenia in almost half of KTRs.
2- Most cases of azathioprine- induced leukopenia present in the first month after transplant.
3- Drugs that interact with azathioprine include
allopurinol, with allo- purinol necessitates dose reduction of azathioprine by 25% to 50%.
4- Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dos adjustment.
Mammalian target of rapamycin inhibitors
1- (mTORi), sirolimus and everolimus, have
been involved in many myelotoxic side effects.
2- Severity of myelotoxicity is dose dependent,80 with involvement of about 20% of KTRs on sirolimus.
3- A trough level of >12 ng/dL has been shown to be highly development of leukopenia and thrombocytopenia,
although it can commonly occur even with lower drug
levels.
4- Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
5-mTORi agents can be usually observed within the first 4 to 8 weeks.
For patients with sirolimus-induced cytopenia, 7% need
dose reduction, 4% need drug withdrawal, and 89%
resolve spontaneously.
Valganciclovir
1- Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia.
2- Cytopenia potentiate several factors, including higher doses of the drug (900 mg or more). low BMI.
Ganciclovir
1-Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs.
2- The bioavailability of this drug is rather poor when given orally; therefore, it is always given intravenously.
3-Through its myelosuppressive effects, ganciclovir causes leukopenia, with rates of 7.1% to 23.1%.
4-Compared with valganciclovir, ganciclovir exerts modest myelosuppression
5-Although patients (23%) on ganciclovir therapy respond to dose reduction, some (2.4%) require ganciclovir cessation.
valacyclovir
1- Is agent for CMV prophylaxis and treatment of herpes simplex in KTRs.
2- Compared with valganciclovir and ganciclovir,myelotoxicity with valacyclovir is mild.
3-Incidence of leukopenia ranges from 6% to 14%
. Trimethoprim-sulfamethoxazole
1- Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis.
2-Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia.
3-However, combined azathioprine therapy with trimethoprim- sulfamethoxazole can aggravate drug-induced myelosuppression.
Dapsone
1- Is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
2- May be aggravated by development of agranulocytosis.
Posttransplant Drug-induced Thrombocytopenia
1- Rituximab 48%
2- Antithymocyte globulin 10-20%
2- Alemtuzumab-induced thrombocytopenia has been observed in 14% of KTRs.
3- interleukin receptor antagonists 14,6%
4- Mycophenolic mofetil and enteric-coated mycophenolate sodium48%
5- Mammalian target of rapamycin inhibitors 20%
6- Trimethoprim-sulfamethoxazole18.18%
7- Ganciclovir 23%
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
1- Defciency vit. B12, folic acid, zinc, and copper
1- Epstein-Barr virus.
2- Cytomegalovirus.
3- Parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
5- Hemophagocytic Syndrome can be associated with cytopenia. Several viral infections (CMV, adenovirus,Epstein-Barr virus, human herpesvirus 8, human
herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
6- Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations:
-renal ischemic events,
-antibody-mediated rejection,
-And viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
Specific treatment of neutropenia
1- Consequently, the first step is determining the patient’s full detailed history to
unravel possible culprit.
2- Measurement of ANC can be used to evaluate the severity of neutropenia, with
severe neutropenia indicated by ANC <500/μL.
3- The next therapeutic step for WBC count correction would be administration of “colony- stimulating” factors if there is no accepted responseto the previous maneuvers.
4- Neutropenia ;G-CSF OR GM-CSF used in onocology ,this agents can be utilazed in solid organ transplant,but no consensus.
5- The prophylactic adminstration of these agent is suggested in pateints with febrail neutropenia and with diminshed bone marrow reserves with extended radiotherapy and AIDS human and older age more than 65 years .
What is the level of evidence provided by this article?
LeveL V
References
1-Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literatur
2-In ,Meyler’s Side Effects of Drugs (Sixteenth Edition) 2016
3-Delate T, Hansen ML, Gutierrez AC, Le KN. Indications for Rituximab Use in an Integrated Health Care Delivery System. J Manag Care Spec Pharm. 2020 Jul;26(7):832-838.
4- Pierpont TM, Limper CB, Richards KL. Past, Present, and Future of Rituximab-The World’s First Oncology Monoclonal Antibody Therapy. Front Oncol. 2018;8:163
5- Anja De Rycke, Daan Dierickx and Dirk R. Kuypers
CJASN March 2011, 6 (3) 690-694; DOI: https://doi.org/10.2215/CJN.07320810
Wael Jebur
2 years ago
Myelosuppression is commonely encountered in the context of maintenance anti -rejection threrapy. Its always a challenging condition as modifying the doses of medicines is often linked to triggering the immunological rejection in one hand and might pave the way for opportunistic infections consequent to that change of medications.
Medications that can precipitate leukopenia , anemia , thrombocytopenia and pancytopenia are Mycophenolate mofetil and enteric coated Mycophenolate sodium, CNI, ATG, Alemtuzumab, Gancyclovir, valgancyclovir and trimethoprim-sulfamethoxasol TMS.
Myelosuppression is either broad with resultant pancytopenia or selective , affecting one of the cellular line .Incidence of Myelosuppression is variable between 20-60 % of Kidney transplant recipients KTR.
neutropenia is another descriptive entity , that is not interchangeable with leukopenia.
Its used to address the level of deficiency of neutrophil count as follows:
1000-1500 mild
500-1000 moderate
Below 500 severe.
The risk of infection is manifold when neutropenia is overwhelming .
particularly gram negative bacteria , like E.coli and more intra-abdomenal infection.
There is no consensus on the management of myelosuppression secondary to anti-rejection therapy. But,in general, precocious down adjustment of the dose of immune-suppressants is the rule of thumb in managing this condition, which portend gradual reduction of the dose or cessation of the medicine alltogether.
This modification of therapy might harbor an escalated risk of acute rejection.
Similarly reducing the dose of prophylactic antibiotic TMS or antiviral valgancyclovir might potentially escalate the risk of pneumocystis jiruvici pneumonia PJP and CMV infection.
other causes of Myelosuppression are common post transplantation and have to be precluded, like viral infection Parvo virus.
Combination of certain induction and maintenance medications might be potentiating the myelosuppressant outcome. such as induction with ATG or Alemtezumab and maintaining with MMF and Tacrolimus.
Special considerations:
MMF:up to 40 % of KTR might develop hematoxicity . It is causing dose dependent myelosuppresion. therefore , reducing the dose might be reversing the suppression.
On some occasions it might be masked by Alemtuzumab or ATG induced myelosuppression.
prescribing Gancyclovir , Valgancyclovir ot TMS might augment the hematoxicity of MMF..
And adjustment of MMF dose after ATG and Alemtuzumab induction, and similarly the antiviral ganvalcyclovir to 450 mg per day might lessen the risk of hematoxicity.
Tacrolimus:
Incidence is less with up to 10 % risk, augmented by combining with MMF and induction with ATG. and Alemtuzumab.Reduction or withdrawal of the dose can improve the myelosuppression.
III. Drug-Induced Myelosuppression in Kidney Transplant Patients Briefly summarise this article Definitions
Pancytopenia: all 3 cells lines involved (WBCs, RBCs, & platelets).
Bicytopenia involves 2 of 3 cell lines.
Leucopenia graded according to the CTCAE into 4 levels:
3000 cells/mm3 (normal)
2000 to 3000 WBCs/mm3(mild)
1000 to 2000 WBCs/mm3(moderate)
<1000 WBC/mm3 (severe).
Absolute neutrophil count (ANC):
ANC<1500/μL is termed neutropenia.
Mild neutropenia is ANC level of 1000 to 1500/μL
Moderate neutropenia is ANC level of
500 to 999/μL
Severe neutropenia (agranulocytosis)is ANC level of <500/μL
Thrombocytopenia is graded into:
Grade I or subnormal (75 000-150,000 cells/mm3)
Grade II or low (50000-75000 cells/mm3 Grade III or moderate (25 000-50 000 cells/mm3)
Grade IV or critical (<25 000/mm3).
Consequences of Hematological Cytopenia
When ANC is <1000 cells/μL, susceptibility to opportunistic infection increases.
Both tacrolimus & MMF are common causes of neutropenia.
Withdrawal of prophylactic agents for CMV or PJP leads to their spread.
Reduction or withdrawal of tacrolimus or MMF will result in rise of WBC counts, but will increase risk of rejection(Zafrani et al, Vanhove).
Caution should be entertained in the treatment of patients with high immunological risk, especially in the 1st 3 months after transplant.
Drug-induced Leukopenia & Neutropenia Rituximab:(anti-CD20 monoclonal antibody).
Uses:
– Induction in ABO-I transplant.
– Treatment of acute rejection.
– Attempted treatment of CAMR.
– Resolution therapy of PTLD.
It results in B-cell depletion & thus affects phagocytosis by macrophages, complement -mediated cytotoxicity, & antibody dependent cell-mediated toxicity by natural killer cells.
Late-onset neutropenia (after the 6th rituximab dose) in KTRs occurs in 37.5% to 48%.
Dose reduction or drug withdrawal is the ideal method for hematological recovery. Antithymocyte globulin (ATG)
Its activity is not confined to T cells.
T cells, B cells, NK cells, monocytes, neutrophils, platelets, & RBCs are all affected.
Leukopenia incidence is variable in different studies; the highest incidence (50%), reported by Gaber et al, may be explained by the concurrent use of azathioprine.
ATG dose halved if platelet count is 50 000 -75 000 /mm3 or WBC count 2000 to 3000 / mm3.
Hold dose if platelet count is < 50 000 / mm3 or when WBC count is <2000 /mm3.
MMF might need to be held with concurrent ATG-induced cytopenia.
Alemtuzumab (an anti-CD52 humanized monoclonal Ig G1 antibody).
CD52 is expressed on mononuclear cells (T & B lymphocytes), monocytes, & NK cells.
Used as an induction agent or as anti-rejection.
Leucopenia occurs in 33.3%-42%.
More severe myelotoxicity compared with ATG ; however, infectious events are usually not life threatening.
Dose modification of MMF or valganciclovir or cotrimoxazole is required. Interleukin receptor antagonists
(basiliximab & daclizumab)
Leucopenia & thrombocytopenia are rare compared with ATG & alemtuzumab (b/c anti-IL-2R activity is confined to activated T cells).
Anti-IL-2R agents are optimum therapeutic option for leukopenic KTRs with low/ moderate risk of rejection. MMF & enteric-coated MPA
Are inosine monophosphate dehydro –
genase inhibitors; inhibit both cell-mediated & humoral immune responses.
Leucopenia occurs in 11.8% to 40% of KTRs.
ATG-related & alemtuzumab related cytopenia may mask the diagnosis of MMF
myelotoxicity, as they may require MMF dose reduction.
Myelosuppression is the most common cause requiring MMF dose reduction.
Concomitant use of valganciclovir, valacyclovir, & fenofibrate may aggravate MMFrelated leukopenia. Treatment approaches for MMF-induced neutropenia:
– Dose reduction or complete withdrawal; however, this would trigger the risk of acute rejection, with subsequent high risk of graft loss (many retrospective reports).
– Preemptive dose reduction of MMF after ATG & alemtuzumab induction
– Shifting to a suitable mTOR inhibitor (eg, sirolimus or everolimus may reverse cytopenia)
– Halving the CMV prophylactic dose of valganciclovir. Valganciclovir 450 mg daily is as effective as 900 mg daily for CMV prophylaxis.
– Cessation of both MMF & valganciclovir may be needed in resistant cases. Tacrolimus
May intensify MMF myelotoxicity. Combination MMF with induce neutropenia in 28% of KTRs.
In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels.
Neutropenia can be observed within the 1st 3 months after transplant.
No particular test for diagnosis, apart from count normalization after the withdrawal of
tacrolimus. A dose reduction of MMF is suggested in patients on dual IS therapy.
Azathioprine
Is largely replaced by the more potent MMF
May induce leukopenia & neutropenia in almost half of KTRs, particularly with higher doses.
Most cases present in the 1st month after transplant. A dose reduction or transient drug withdrawal is usually sufficient.
Patients with low or lack of thiopurine S-methyl transferase (TPMT) activity are likely to develop severe, life-threatening myelo-toxicity.
Methods to ameliorate the risk of myelo-suppression:
– Monitoring of 6-thioguanine nucleotide in RBC (more beneficial than monitoring of 6-mercaptopurine in plasma)
– Genotyping & phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
Concomitant use with allopurinol necessitates dose reduction of azathioprine (allopurinol inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid).
Mammalian target of rapamycin inhibitors
(sirolimus and everolimus)
Severity of myelotoxicity is dose dependent. A trough level of >12 ng/dL is highly associated with development of leukopenia & thrombocytopenia.
Sirolimus & MMF combination therapy after
alemtuzumab induction in steroid & CNI-free regimens may result in severe leukopenia.
Everolimus can be also be complicated by leukopenia (11%-19%).
In mTORi-induced leucopenia usually resolves spontaneously. If it persists, then a reduction of the MMF dose with reduction of mTORi to a lower therapeutic range is required.
Drug cessation may be the last resort for resistant cases.
Valganciclovir
Leucopenia in 4.9% to 37.5% of patients. The cytopenia may be potentiated by:
– Higher doses of the drug (900 mg or more).
– Low BMI
– Concomitant MMF use.
Dose reduction to 450 mg/day or transient cessation may be enough for reversal of cytopenias.
Ganciclovir
Used for anti-CMV therapy & prophylaxis.
Given IV.
Modest myelosuppression Compared with valganciclovir. Valacyclovir
Used for CMV prophylaxis & treatment of herpes simplex.
Mild myelotoxicity compared with valganciclovir & ganciclovir.
Combination with MMF may aggravate the myelotoxicity. Trimethoprim-sulfamethoxazole
Commonly used for PJP prophylaxis.
Can cause neutropenia, leukopenia & megaloblastic anemia.
Combination with azathioprine therapy can aggravate drug-induced myelosuppression. Dapsone
Used for PJP prevention.
Causes manyhematological complications, e.g. neutropenia. Drug-induced Lymphopenia
Result of induction therapy with ATG. Posttransplant Drug-induced Thrombocytopenia Implicated medications include:
Rituximab
ATG
Alemtuzumab
IL2 receptor antagonists
MMF & enteric-coated MPA
MTOR inhibitors
Ganciclovir
Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia & Thrombocytopenia:
EBV-induced PTLD
CMV
ParvovirusB19
HHV 6
Influenza viruses
Ehrlichiosis (a tick-borne bacterial infection) Hemophagocytic Syndrome
Is associated with cytopenia.
Incriminated infections include:
CMV, EBV, HHV 8, parvovirus B19, & BKV.
Therapy for Drug-induced Hematological Cytopenia.
1st step: detailed history to reveal the cause. Dose reduction or hold the suspected agent.
Next step is use of “colonystimulating” factors (GM-CSF, G-CSF). ================== What is the level of evidence provided by this article? Level V
Abdulrahman Ishag
2 years ago
Cytopenia can be identified as follows:
1-Pancy-topenia;
involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets.
2-Bicytopenia ;
involves 2 of 3 cell lines
3-Thrombocytopenia ;involves low platelet count
Platelet count of 150 000/mm 3 is considered the lower limit of normal level in many laboratories.
The CTCAE has graded thrombocytopenia into 4 levels;
A- grade I or subnormal (75 000-150,000 cells//mm 3)
B- grade II orlow (50000-75000 cells/mm 3
C- grade III or moderate (25 000-50 000 cells/mm 3)
D- grade IV or critical(<25 000/mm3) .
3- Leukopenia;
Absolute neutrophil count (ANC); is used to assess the magnitude of neutropenic severity as follows :
ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as ;
1-Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to 1.5 × 10 9/L .
2-moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 10 9 /L .
3- severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L .
Consequences of Hematological Cytopenia;
The predisposition to frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenic decline.
Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
Neutropenic KTRs commonly experience more intra-abdominal infections (22.5%) than those with normal neutrophil counts (7%-10%).
Withdrawal of prophylactic agents for CMV or Pneumocystis jirovecii opens the door to their spread.
leukopenia augments the risk of infection by disrupting immunogenic integrity and liability of ubiquitous and opportunistic infections.
In an attempt to reduce the severity of neutropenia, transplant physicians often reduce or withhold MMF.Despite the expected rise in WBC counts, risk of rejection increases, which is usually evident in the first year post transplant.
Drug-induced Leukopenia and Neutropenia;
A number of agents have been implicated in posttransplant leukopenia and neutropenia development; Through clinical assessments, culprit medications in
cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia;
1- medication-induced myelotoxicity.
2-B12, folic acid, zinc, and copper deficiencies.
3-Epstein-Barr virus-induced post transplant proliferative disorders invade bone marrow of recipients, causing cytopenia .
4-Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and
ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Hemophagocytic Syndrome;
Hemophagocytic syndrome can be associated with cytopenia.
Several viral infections (CMV, adenovirus, pstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations:
1-renal ischemic events,
2-antibody-mediated rejection
3-viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
Drugs induced cytopenia ;
1-Rituximab;
Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia).
Late-onset neutropenia can be defined as neutropenia that is observed 4 weeks after the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF).
2-Antithymocyte globulin;
The dose of ATG should be halved when;
1- platelet count reaches 50 000 to 75 000 per mm3
2-WBC count reaches 2000 to 3000 per mm .
Treatment with ATG should be held when;
1- platelet count declines to less than 50 000 per mm .
2- 2- WBC count is less than 2000 per mm 3 . CD3 + T-cell count should be monitored when less than 0.05 × 10 9 /L (<50/μL; normal range, 128-131/μL) to avoid unnecessary higher doses.
This approach is successful in reducing the incidence of acute rejection episodes, infections, and cytopenia.
Total lymphocyte count should be maintained as less than 0.3 × 10 9 /L, which is a suitable alternative if CD3 monitoring is not available.
3-Alemtuzumab;
With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose. However, infectious episodes are usually not life-threatening.
A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia.
Subsequently, a strict monitoring of allograft function at that time is mandated, particularly in high-risk KTRs.
4-Interleukin receptor antagonists;
Considering all these observations, the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
5-Mycophenolic mofetil and enteric-coated mycophenolate sodium;
The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA.
Concomitant administration of valganciclovir,valacyclovir, and fenofibrate59 may exaggerate MMF- related leukopenia.
Several approaches could be added for the management of this type of leukopenia, including;
1-preemptive dose reduction of MMF after ATG and alemtuzumab induction
2-shifting to a suitable mammalian target of rapamycin inhibit
3-halving the CMV prophylactic dose of valganciclovir, which could also be another preventive measure.
4-For resistant cases, cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal .
6-Tacrolimus;
Mechanisms of tacrolimus-induced neutropenia include;
1-direct suppression of myeloid cells, with bone marrow hypoplasia ,However, tacrolimus-induced direct myeloid inhibition has not been observed in vitro.
Direct inhibition of myeloid precursors may not be a convincing mechanism for tacrolimus-induced neutropenia and leukopenia.
2-altered cytokine production by T lymphocytes and monocytes,
3-production of antimyeloid precursors and anti-mature neutrophil antibodies.
4-Tacrolimus has been shown to prevent MPA glucuronidation that results in intensification of blood levels.
In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels.
A combination of tacrolimus and MMF expands the area under the curve for MMF within 3 months by pproximately 20% to 30%.
A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include everolimus, belatacept, or eculizumab.
7-Azathioprine;
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine.
Patients with complete lack or low TPMT activity are vulnerable to developing severe, life-threatening myelotoxicity.
To ameliorate the risk of myelosuppression, techniques have been proposed.;
1-The first is monitoring of 6-thioguanine nucleotide in RBCs, which is an efficacious and more beneficial method than monitoring of 6-mercaptopurine in plasma.
2-Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
3-Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid.
Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50% .
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment.
8-Mammalian target of rapamycin inhibitors;
Severity of myelotoxicity is dose dependent,with involvement of about 20% of
KTRs on sirolimus.
A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia ,although it can commonly occur even with lower drug levels.
Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
The development of cytopenia with mTORi agents can be usually observed within the first 4 to 8 weeks.
For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously.
In most patients, mTORi-induced leucopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required.
However, drug cessation may be the last resort for resistant cases.
9-Valganciclovir;
The higher bioavailability of this agent (70% vs 7% for oral ganciclovir) has also affected its myelotoxicity profile
The resultant cytopenia may be potentiated by several factors, including ;
1-higher doses of the drug (900 mg or more)having a significant impact on leukopenia and neutropenia development.
2-low body mass index, which is a significant potentiating factor for leucopenia.
3-concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
Although leukopenia can develop within 3 months, resolution of leukopenia can occur spontaneously with or without treatment.
Risk of infection is usually low.
The need for G-CSF administration may be required with prolonged
periods of prophylaxis.
Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal.
10-Ganciclovir;
The bioavailability of this drug is rather poor when given orally; therefore, it is
always given intravenously.
Compared with valganciclovir, ganciclovir exerts modest myelosuppression.
Although patients (23%) on ganciclovir therapy respond to dose reduction, some (2.4%) require ganciclovir cessation.
11- Valacyclovir;
Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild. However, combined MMF and valacyclovir therapy may aggravate drug-
induced myelotoxicity. Moreover, MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
When compared with ganciclovir, dose modification is less frequently employed with valacyclovir.
12-Trimethoprim-sulfamethoxazole;
Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include; neutropenia and leukopenia and megaloblastic
anemia.
Trimethoprim per se can cause dose- dependent inhibition of granulopoiesis in vitro.
combined azathioprine therapy with trimethoprim- sulfamethoxazole can aggravate drug-induced myelosuppression
Folinic acid can reverse this side effect.
13-Dapsone;
Many hematological complications, including neutropenia.
Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Therapy for Drug-induced Hematological Cytopenia;
In addition to the aforementioned protocols, there are a number of other specific interventions, as detailed below.
1-Specific treatment of neutropenia;
therapeutic step for WBC count correction would be administration of “colony-
stimulating” factors if there is no accepted response to the previous maneuvers.
The prophylactic administration of these agents is suggested in patients with;
1-febrile neutropenia .
2-those with diminished bone marrow reserves (eg, ANC <1.5 × 10 9/L) d
3-extensive radiotherapy
4-patients with AIDS/human immunodeficiency virus infection, and
5-patients older than 65 years.
Therapeutic indications include ;
1-sepsis, hypotension, neutropenic pyrexia of >7 days,
2-pneumonia or fungal infections, and adjunctive therapy along with antibiotics in the aforementioned indications.
3-Some conditions constitute medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC <500/μL, 94 and prolonged
neutropenia of more than 7 days.
2-Thrombocytopenia in kidney transplant;
can be attributed to either bone marrow suppression or to an idiosyncratic drug reaction.
The following steps in care are suggested:
1-if thrombocytopenia is due to idiosyncratic reaction ( due to trimethoprimulfamethoxazole), then immediate withdrawal of the suspected agent is required.
2-if bone marrow suppression is the underlying mechanism, dose reduction or complete drug cessation is required for correction of platelet decline.
3-Occasionally, platelet transfusion may be required, such as;
A- in life-threatening bleeding risk, serious decline of platelet count (<20 000/mm 3 ).
B- before an invasive procedure .
The recommended cut-off therapeutic level for platelet transfusion should be;
1->50 000/mm3 withcommencement of invasive maneuvers (eg, allograft
biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
2-Before ocular and neurosurgical invasive procedures, a minimum platelet count of ≥100 000/mm3is usually advised.
3-For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
4- Because of the high vascularity of renal tissue, a minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
What is the level of evidence provided by this article?
Level v
I like Dr Ben Lomatayo’s response, hence, would like to draw your attention to his reply yesterday to my question in this thread.
At least one episode of either neutropenia or cytopenia occurs in 20-60% of KTR during their transplant.1,2 Cytopenia is more common in the initial period due to induction therapy and intense maintenance immunosuppression.2 The episodes can last for 1-4 weeks.1
The offending drugs include mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS), ganciclovir/valganciclovir, anti thymocyte globulin (ATG), tacrolimus, sirolimus, and cotrimoxazole.1,2 Unfortunately, there is no evidence-based approach to identifying the culprit agent and modifying the medications.2 In case of persistent neutropenia, autoimmune etiology should be considered.3 Finally, neutropenia may occur because of a viral (CMV) or bacterial infection.1
In Liverpool, I have seen CNI-induced neutropenia only once over the last 35 years and the most plausible explanation for this association is due to its pharmacokinetic interaction with MMF: Tacrolimus increases the availability of the active form of MMF. Induction therapy may also contribute to neutropenia, especially ATG. In our experience, IL2R blocker (such as simulect) has never been found to be causing leucopenia either due to their own effect or as an additive to other medication.
Approach to this patient with leucopenia:
My approach would, therefore, be first to ensure that the patient is not septic or have a fever, in which case they would need to be admitted for treatment with broad-spectrum antibiotics in a side room. I would advise the patient to seek medical help immediately if they develop a fever and advise them to avoid crowded places and people with ongoing infections.
In addition to MMF, other causes that would need to be considered are as follows.
1. Investigating potential causes:
CMV/EBV infection can cause leucopenia so I would send off CMV and EBV PCR to exclude this as well as look at the donor status of these viruses. Additionally, the patient is immunosuppressed and is susceptible to a wide range of other viral infections that can also cause leucopenia (Adenovirus, enterovirus, influenza, etc.
2. Hematological malignancies although rare would be something that I would bear at the back of my mind.
When I note leucopenia, my first step would be to reduce or stop the MMF and add prednisolone 10 mg per day just to cover for the period when the recovery from leucopenia recovers and that patient would be in a phase of higher risk of acute rejection. If leucopenia is associated with altered LFTs, then the first drug that I would stop is co-trimoxazole and replace it with dapsone 100 mg per day. The caveat is that a longer interruption (>6 days) of MMF has been linked to an increased risk of acute rejection during the recovery phase when a patient is discharged to home. Some clinicians hold off co-trimoxazole and valganciclovir as well. G-CSF has been considered a second-line of therapy after adjustment of the other medications, however, it is required only rarely.1
I do not know any transplant unit personally where MPA levels (or even more reliable IPMDH levels) are measured for routine clinical application. The reason is that there is a tremendous degree of overlap between the ‘therapeutic range’ and ‘toxic level range’.
References:
1. Bagnasco SM, Gottipati S, Kraus E, Alachkar N, Montgomery RA, Racusen LC, Arend LJ. Sarcoidosis in native and transplanted kidneys: incidence, pathologic findings, and clinical course. PLOS One. 2014; 9: e110778.
2. Knoll GA, Macdonald I, Khan A, Van Walraven C. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol. 2003; 14: 2381-2386.
3. Shigemitsu H, Patel HV, Schreiber MP. Extrapulmonary Sarcoidosis. In: Judson M. (eds) Pulmonary Sarcoidosis. Respiratory Medicine. 2014; 17. Humana Press, New York, NY
4. Leonardo Riella. Neutropenia in transplant recipients. Renal Fellow Network. Dec 2010. https://www.renalfellow.org/2010/12/22/neutropenia-in-transplant-recipients/
5. Khalil M.A.U, Khan T.F.T, Tan J. Drug-Induced Hematological Cytopenia in Kidney Transplantation and the Challenges It Poses for Kidney Transplant Physicians. Journal of transplantation. August 2018. Volume 2018. 22 pages.
6. Olivier A, Rebecca S, Anne S, et al. Autoimmune Neutropenia After Kidney Transplantation. A Disregarded Entity of Posttransplant Neutropenia. Transplantation: April 15th, 2014;97(7):725-729.
Dear Prof
I fully agree with you. We also need to look for other etiologies of the cytopenia. Drugs are the most common cause, but due to the immunosuppression these patients have a high risk of getting opportunistic infections like CMV. The other important thing highlighted is autoimmune etiologies. It is always important to look for connective tissue disease in these patients. One of the things that we in Sub Saharan Africa have to always think of is tuberculosis as it can also cause bone marrow suppression and the diagnosis of TB can be very challenging in the background of immunosuppression
Yes, the issue of TB is quiet common in this part of the world and it requires high index of suspicion. In terms of diagnostic urine LAM may be helpful although it was not originally design for transplant population. I think it should be of evaluation of persistent unexplained pan or bi-cytopenia in transplant setting specially in Africa or endemic areas.
I appreciate your great remarks.
This summarizes and highlights the most important ideas
Thank you Prof, That is very informative and clear approach to any case leucopenia
very informative, thank you
thanks for sharing your experience with drug-induced cytopenia
thanks, prof
tactful and informative summary and highlight the main points in this interesting topic
Dear Professor ,
Thank you so much for the informative and reasonable approach .
At my center we recently started to check the MMF level once at least (done outside in a Tx center in Spain) especially for those with persistent leucopenia or recurrent infections or weight loss -those are mostly suspected from side effects of MMF .
Reducing the dose of the MMF is done for sure along with trial to keep the FK level on the higher therapeutic level as most of those recipients are recently transplanted .
we believe that the MMF side effects of leucopenia are mostly evident in the early post transplant period , Steroids free regimen is occasionally done but its not an option for those with reduced MMF dose
Valcyte leucopenia nearly occurs in all patients ( bicytopenia too ) so close follow up is highly recommended .
Renal transplant recipients need immunosuppression medications post –op to maintain graft survival.But they are associated with number of side effects –one of which is myelosuppression. About 20-60% of Kidney transplant recipients had an episode of cytopenia Approximately 20-60% of KTRs experience one episode of cytopenia after transplant. Most episodes of cytopenia are observed within the first 3 months post-transplant. Drugs which cause cytopenias (neutropenia and leucopenia) include: 1-Rituximab: is a monoclonal antibody that binds CD20 antigen resulting in B cell depletion.According to one study,cytopenias occur in about 48% with Rituximab.
2-Antithymocyte globulin- Cytopenias more common with ATG if high doses given and also if administered with antimetabolite that is why antimetabolite withheld when ATG administered.Dose need to be modified and reduced according to WBC and platelet count.
3-Alemtuzumab– more severe cytopenias compared to ATG and this study stated 33.4% to 42% incidence of leucopenia.
4-Interleukin receptor antagonists (basiliximab and dacliuzumab)-cytopenia rare.
5-Mycophenolic mofetil and enteric-coated mycophenolate sodium-11.8%-40% incidence of leucopenia mentioned in the literature.
For all of the above mentioned drugs-drugs need to be reduced or stopped if cytopenias occur.
6-Tacrolimus- neutropenia noticed in the first 3 months after transplant.
7-Azathioprine- usually observed in the first month after transplant with doses >1.99 mg/kg body Mammalian target of rapamycin inhibitors (sirolimus and everolimus)
8- Mammalian target of rapamycin inhibitors (sirolimus and everolimus)-dose dependent myelosuppression-Combination therapy with MMF cause severe leucopenia.In some cases , it resolves spontaneously ,however, few cases require dose reduction or cessation.
9-Valganciclovir-Several factors like co-administeratin with MMF,high doses of drug and low BMI can increase the chances of cytopenias .
10-Ganciclovir- incidence reported is 7.1% to 23.1%. Cytoenias less than valganciclovir.
11-Trimethoprim-sulfamethoxazole-dose-dependent inhibition of granulopoiesis. Folinic acid can reverse this side effect.
12-Dapsone-also causes of agranulocytosis.
Posttransplant Drug-induced Thrombocytopenia-Similar drugs which cause leucopenia –also causes thrombocytopenia like Rituximab,ATG,Alemtuzumab ,Basiliximab ,etc.
Differential Diagnosis of Leukopenia and Thrombocytopenia-Other causes which are responsible for causing this includes:B12, folic acid, zinc, and copper deficiencies, Infections with EBV, CMV, parvovirus B19, HHV 6, condition which causes Thrombocytic microangiopathy like renal ischemic events, ABMR, and viral infection .
Therapy for Drug-induced Hematological Cytopenia: dose reduction or cessation of the offending agent
–Specific treatment: G-CSF or GM-CSF-reserved for specific cases like febrile neutropenia and those with diminished bone marrow reserves: extensive radiotherapy, patients with AIDS/human, and patients older than 65 years.Thrombopoietin receptor agonists for thrombocytopenia.
What is the level of evidence provided by this article?
This is a narrative review, level V.
Kidney transplant recipients often have hematological cytopenia due to immunosuppressant.
Common culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG.
The approach in managing myelosuppression include judicious reduction or withdrawal of suspected agents. The treating clinician should remain alert to look for opportunistic infection and early signs of acute rejection as a result of reduction of immunosuppression. The prophylactic administration of G-CSF or GM-CSF is suggested in patients with febrile neutropenia,103 those with diminished bone marrow reserves (eg, ANC <1.5 × 109/L) , patients with AIDS/human immunodeficiency virus infection, and patients older than 65 years, sepsis, neutropenic pyrexia of more than 7 days.
Some conditions constitute medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC <500/μL,94 and prolonged neutropenia of more than 7 days.
Thrombocytopenia in kidney transplant can be attributed to either bone marrow suppression or to an idiosyncratic drug reaction. if thrombocytopenia is due to idiosyncratic reaction (eg, due to trimethoprim sulfamethoxazole), then immediate withdrawal of the suspected agent is required. Occasionally, platelet transfusion may be required, such as in life-threatening bleeding risk, serious decline of platelet count (<20 000/mm3), or before an invasive procedure. The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
Before ocular and neurosurgical invasive procedures, a minimum platelet count of ≥100 000/mm3 is usually advised.
For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
Platelets count with minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
optimization of the myelopoietic function and normalization of the hematological profile, resulting in better allograft and patient survival.
Hematological complications are common after kidney transplantion affecting 20-60 % of patients in the form of uni , bi or pancytopenia as anemia , leukopenia or thrombocytopenia that increase the risk of opportunistic infection as CMV and Pneumocystis jeroviki endangering the recipient life , mean while the only effective treatment strategy is to reduce the dose of IS drugs which increase the risk of graft rejection.
Leukopenia can be classified according to severity into Mild : WBC count >2000-3000 cell /mm3, Moderate 1000-2000 cell /mm3 and Severe < 1.000 cell .Severity and duration of leukopenia increase the risk of opportunistic infection specially after withdrawal of Prophylactic against CMV and Pneumocystis jeroviki.
Drugs causing leukopenia
1- Rituximab: used for desensitization, induction in ABO incompatibile kidney transplantion and treatment of ABMR , is associated with leukopenia in 36 % of cases and this leukopenia could start as late as 4 weeks from last rituximab dose
2-ATG
wide range and non specific effects on different blood cell lineages that causes cytopenia in up to 50% of cases
Management of ATG induced cytopenia
1- half the ATG dose when platelets drop 50000-75000 or WBCs to 2000-3000
2- Hold ATG when platelets< 50000 or WBCs <2000
3- Alemtizumab: anti CD52 agent that’s expressed on surface of mononuclearsl cells including neutrophils . Causes leukopenia in 30% of cases.
4- Basiliximan : least common drug in inducing leukopenia compared with other agents used for induction.
5- Drugs used for maintenance therapy as
MMF, tacrolimus and azathioprine: all can cause myelosuppressive. Their dose should be Prophylactically decrease with induction with ATG or basiliximab
Non-IS drugs also may cause leukopenia including valganciclovir, ganciclovir and trimethoprim -Sulha.
Management of drug induced leukopenia
1- Prophylactically, deceased the dose of MMF and tacrolimus during induction with ATG and alemtuzumab.
2- close monitoring of CBC.
3- Adjust the dose or hold it according to severity of leukopenia.
Conclusion
In kidney transplantation, both immunosuppressive and non-immune suppressive drug could lead to cytopenia via different mechanisms, that requires close monitoring of the patient, adjust or stop the offending drug when needed which in turn increase the risk of graft rejection thus, we need to balance the risk and benefits of those drugs.
Myelosupression presenting as cytopenia is common in kidney transplantation, 20 to 60 % of kidney recipients develop at least 1 episode of cytopenia after transplant.
Most episodes occurs during the first 3 months
Immunosuppressive drugs are important for allograft survival, but they carry the risk of harmatological complications as myelosuppression.
Cautions should be taken in reduction or complete withdrawal of the causative agent as there is increased risk of acute rejection and increased risk of opportunistic infections.
Cytopenia can be pancytopenia involves all 3 cells lines ( WBC,RBC and platelets) or bicytopenia involves 2 of 3 lines
Rituximab
Late onset neutropenia is a neutropenia that is occurred 4 weeks after the last dose of rituximab after exclusion of other causes
It’s incidence is about 37% to 48%.
Leucopenia after rituximab occurs in about 19 % to 24%.
Dose reduction or drug withdrawal is usually the ideal response for harmatological recovery.
Antithymocyte globulin
Leukopenia incidence with ATG is variable as a result of differences in protocols and variabilities in periods of administration 10%,38%,50%.
Thrombocytopenia in 14%.
The dose of ATG should be halved when platelet count reaches 50000 to 75000 per mm or WBC count reaches 2000 to 3000 per mm. ATG should be held when platelet count less than 50000 per mm or WBC count below 2000 per mm.
Alemtuzumab
Leukopenia incidence is 33% to 42%
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe, with the lowest WBC count observed 130 days after last given dose.
IL-2R antagonists
Their leucopenic and thrombocytopenia effects are rare compared with ATG and alemtuzumab
So they would be an optimum therapeutic option for Leukopenic KTRs with low/moderate risk of rejection.
MMF
Incidence of Leukopenia is 11.8% to 40%.
The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MMF.
Treated by dose reduction or complete withdrawal
Prevention can be done by preemptive dose reduction of MMF after ATG and alemtuzumab induction, shifting to mTOR inhibitors and halving the CMV prophylactic dose of valganciclovir.
Tacrolimus
Combined Tac and MMF cause neutropenia in 28% of KTRs.
Observed within 3 months after transplantation
Reduction dose of MMF
Azathioprine
Azathioprine induces Leukopenia and neutropenia in 50% of KTRs, which occur mainly in the first month after transplantation
Azathioprine levels should be monitored weekly, with full blood count monitoring.
mTORi
Everolimus therapy can be complicated by Leukopenia in 11 to 19%.
Observed within the first 4 to 8 weeks
Most cases resolve spontaneously, if no dose reduction
If resistant, drug cessation
Valganciclovir
10 to 28 % of KTRs are vulnerable for Leukopenia development
5 to 37% of patients develop neutropenia
This occurs with higher doses of drug 900 mg or more.
It occurs within 3 months
Resolve spontaneously or by dose reduction or cessation of drug
Ganciclovir
Cause Leukopenia in 7.1 to 23.1% , it exerts modest myelosupression compared with Valganciclovir
Trimethoprim- sulfamethoxazole
Can cause neutropenia , Leukopenia or megaloblastic anemia
Induce Leukopenia in only 2% of recipient.
Dapsone
Cause neutropenia
Drug induced lymphopenia
Is usually due to induction therapy with ATG
Drug induced thrombocytopenia
Rituximab causes thrombocytopenia in 48% of cases
ATG , incidence of thrombocytopenia 10 to 26 %
Alemtuzumab causes thrombocytopenia in 14% of KTRs
IL- 2R antagonists cause rare thrombocytopenia compared with ATG
MMF, MTORi
Ganciclovir
Trimethoprim- sulfamethoxazole
DD of drug induced neutropenia and thrombo
cytopenia
B12 , folic acid , zinc and copper deficiency
EBV
CMV
Parovirus B19
Hemophagocytic syndrome
Specific management of neutropenia
Severe neutropenia , ANC < 500 / ul
Drug reduction or complete withdrawal of the suspected agent WBC count correction with administration of colony-stimulating factors.
Thrombocytopenia
Dose reduction or complete withdrawal of causative agent
Platelet transfusion if number below 20000 per mm3
pancytopenia involves all 3 cells lines: WBCs, RBCs and platelets. bicytopenia involves 2 of 3 cell lines.
Rituximab
Rituximab is associated with Late-onset neutropenia which occur 4 weeks after start of rituximab therapy, usually observed after the sixth rituximab dose. The incidence ranges from 19% to 24.6% .Dose reduction or drug withdrawal is usually the ideal response for hematological recovery. Rituximab-induced thrombocytopenia rarely induces bleeding and so platelet infusion is rarely indicated.
Anti-thymocyte globulin
Leukopenia incidence is variable as a result of differences in protocols and administration periods. administration. Monitoring is through CD3+ T-cell count or total lymphocyte count. The dose of ATG should be halved when any of the following occur:
-platelet count reaches 50 000 to 75 000 per mm3
-WBC count reaches 2000 to 3000 per mm3.
Treatment with ATG should be held when any of the following occur
-platelet count declines to less than 50 000 per mm3
-WBC count is less than 2000 per mm3.
Antithymocyte globulin may induce thrombocytopenia from 10% to 26.5% and lymphopenia can also result .
Alemtuzumab
the myelotoxic effects are more severe when compared with ATG but the infectious episodes are usually not life-threatening. Alemtuzumab Autoimmune thrombocytopenia has been observed in 14% of KTRs with bleeding requiring surgical intervention in 12% of KTRs.
interleukin receptor antagonists basiliximab and daclizumab
the incidence of leukopenia was lesser than ATG ,so they can be an option for leukopenic recipients with low/moderate risk of rejection. interleukin receptor antagonists thrombocytopenic drawbacks are currently rare .
Mycophenolic mofetil and enteric-coated mycophenolate sodium
Both ATG-related and alemtuzumab related cytopenia may mask the diagnosis of MMF myelotoxicity. The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA so, dose reduction or complete withdrawal can reverse this. other alternatives are reduction of other cytotoxic medication or shifting in to mTOTi. MMF dose reduction is required for leukopenia, anemia, thrombocytopenia, andpancytopenia.
Tacrolimus
May cause anemia, neutropenia, and combined anemia/neutropenia and intensify MMF myelotoxicity. Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant.
Azathioprine
may induce leukopenia and neutropenia with doses greater than 1.99 mg/kg body weight/day and present mostly in the first month after transplant. a past history of drug-induced leukopenic events would increase the risk of leukopenia by 70%. Patients with complete lack or low thiopurine S-methyl transferase activity are vulnerable to developing severe, life-threatening myelotoxicity. Monitoring can be through RBC 6-thioguanine nucleotide in RBCs. Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity. Azathioprine levels should be monitored weekly in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
Severity of myelotoxicity is dose dependent and can be usually observed within the first 4 to 8 weeks. In most patients, leukopenia resolves spontaneouslybut, if persists, then a reduction of the MMF dose with simultaneous reduction of mTORi or total withdrawal can be tried. Thrombocytopenia has been reported with mTORi and it is dose dependent.
valganciclovir
cytopenia may be potentiated by several factors, including doses 900 mg or more , low body mass index and concomitant MMF . Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal.
Ganciclovir
exerts modest myelosuppression and a lesser incidence of leukopenia and which respond to dose reduction but some require ganciclovir cessation. Ganciclovir can induce thrombocytopenia in 23.1% of KTRs.
Valacyclovir
myelotoxicity is relatively mild but increase with other cytopenic drugs
Trimethoprim-sulfamethoxazole
associated with neutropenia and leukopenia , megaloblastic anemia and dosedependent inhibition of granulopoiesis ,the latter can be reversed with use of Folinic acid . Trimethoprim-sulfamethoxazole thrombocytopenia is observed.
Dapsone
is associated with neutropenia and agranulocytosis
Differential diagnosis of drug-induced leukopenia and thrombocytopenia
1- Metabolic:B12, folic acid, zinc, and copper deficiencies,
2- Infections: Epstein-Barr virus-,Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis
3- Hemophagocytic Syndrome can be associated with cytopenia and several viral infections (CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
4- Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
Therapy for Drug-induced Hematological Cytopenia
the first step is determining the patient’s full detailed history to unravel possible culprit. if no cause was identyified, then a dose reduction or complete withdrawal of the suspected agent with correction of WBC count through administration of “colonystimulating” factors if there is no accepted response to the previous maneuvers.
level of evidence is 5
Drug-Induced Myelosuppression in Kidney Transplant Patients
It is common for kidney transplant recipients to experience myelosuppression that manifests as cytopenia (KTRs). After transplant, at least 1 episode of cytopenia affects 20% to 60% of KTRs. The majority of cytopenia episodes are seen in the first three months.
Mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole are included on the list of responsible substances.
It may be urgently necessary to carefully reduce or completely remove the problematic substance; but, as was mentioned below, possible dangers should be anticipated and managed appropriately.
Consideration must be given to the increased risk of acute rejection following the discontinuation of myelosuppressive immunosuppressive drugs. After stopping valganciclovir, there is a higher risk of infection, including opportunistic infections like cytomegalovirus (CMV), or after stopping trimethoprim-sulfamethoxazole, there is a higher risk of Pneumocystis jirovecii.
Drug-induced Leukopenia and Neutropenia:
Rituximab:
In one study, 48% of patients experienced rituximab-induced cytopenia (grade 3/4), with patients with lymphoma experiencing 40% lymphopenia, 6% neutropenia, and 4% leukopenia. Four weeks following the initiation of rituximab therapy, cytopenia may develop (late-onset neutropenia).
After the sixth rituximab, late-onset neutropenia is typically noted.
Antithymocyte globulin:
Neutropenia may be brought on by larger ATG doses as well as a general aversion to neutrophils and platelets.
When the WBC count or platelet count reaches 2000 to 3000 per mm3 or 50 000 to 75 000 per mm3, the dose of ATG should be cut in half.
36,39 When the platelet count drops to fewer than 50,000 per mm3 or the WBC count drops to less than 2,000 per mm3, ATG treatment should be stopped. When it falls below 0.05 109/L, the CD3+ T-cell count needs to be watched.
Alemtuzumab:
According to several data, the leukopenic incidence in KTRs treated with alemtuzumab ranged from 33.3% to 42%. When neutropenia is also present, the incidence is higher (47%) Alemtuzumab has more severe myelotoxic side effects than ATG,with the lowest WBC numbers seen 130 days after the last dosage. Infectious episodes, though, often do not pose a danger to life. MMF may be dosed down to 14 mg/kg in response to alemtuzumab-induced leukopenia, which is a substantially lower dose than that needed for ATG-induced leukopenia.
Mycophenolic mofetil and enteric-coated mycophenolate sodium :
ATG-related and alemtuzumab-related cytopenia may conceal the diagnosis of MMF myelotoxicity because they may require MMF dose reduction.Single-nucleotide polymorphism has its role in the development of MMF-related cytopenia.The hematological sequelae with myelosuppression are the most frequent cause requiring MMF dose reduction, accounting for 46.5% of MMF-reducing events.
The concurrent administration of valganciclovir,valacyclovir, and fenofibrate may exacerbate the leukopenia caused by MMF. The myelotoxic effect of MMF is dosage dependant and typically related to the trough levels of MPA.
An appropriate approach to MMF-induced neutropenia and leukopenia appears to be a dose reduction or complete withdrawal in order to manage cytopenia.
Tacrolimus :
The direct suppression of myeloid cells, which results in bone marrow hypoplasia in hepatic transplant recipients,altered cytokine production by T lymphocytes and monocytes, and production of antimyeloid precursors and anti-mature neutrophil antibodies are some of the mechanisms by which tacrolimus-induced neutropenia is brought on. It has been demonstrated that tacrolimus blocks MPA glucuronidation, which increases blood levels. Tacrolimus does not obstruct MMF enterohepatic circulation, in contrast to cyclosporine, resulting in elevated MPA levels. Within three months, tacrolimus and MMF together increase the area under the curve for MMF by 20% to 30%.
Within the first three months following transplant, tacrolimus-induced neutropenia can be seen.
Azathioprine :
Nearly half of KTRs may experience leukopenia and neutropenia after taking azathioprine, especially at doses higher than 1.99 mg/kg body weight/day. The first month following transplantation is when azathioprine-induced leukopenia most frequently manifests. A dose reduction or brief drug discontinuation usually suffices in this circumstance. Notably, the risk of leukopenia would rise by 70% if there was a history of drug-induced leukopenic episodes.
Mammalian target of rapamycin inhibitors:
Myelotoxicity severity is dosage dependent,with sirolimus involving 20% or less of KTRs. Although leukopenia and thrombocytopenia can frequently arise at lower drug levels, a trough level of >12 ng/dL has been demonstrated to be strongly related with their development.
valganciclovir:
Its myelotoxicity profile has been impacted by (for oral ganciclovir).
Disrupted signal transduction by mTORi through the gp130 chain and platelet activation are among the hypothesized mechanisms for mTORi-induced myelotoxicity.
Although 4.9% to 37.5% of patients may develop neutropenia, 10% to 28% of KTRs are susceptible to leukopenia development.
The development of leukopenia and neutropenia may be significantly impacted by greater doses of the drug (900 mg or more), a low body mass index, which is a substantial potentiator of leukopenia, and concurrent MMF use, which can also exacerbate valganciclovir myelotoxicity.
Ganciclovir:
Because this medication’s oral bioavailability is so low, it is usually administered intravenously. Ganciclovir causes leukopenia through the myelosuppressive effects it has, with rates ranging from 7.1% to 23.1%. 42 The myelosuppressive effects of ganciclovir are less than valganciclovir’s.
valacyclovir:
Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole:
A typical medication used for Pneumocystis jirovecii prevention is trimethoprim-sulfamethoxazole. Use of trimethoprim-sulfamethoxazole is linked to a number of cytopenias, including neutropenia, leukopenia, and megaloblastic anemia.
Dapsone:
Dapsone, a different medication for Pneumocystis jirovecii prophylaxis, has a number of hematological side effects, including neutropenia. Additionally, the emergence of agranulocytosis has the potential to exacerbate the neutropenic effects of dapsone.
Level of evidence 5.
introduction;
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number of these drugs are associated with hematological complications. Myelosuppression presenting as cytopenia is not uncommon in kidney transplant recipients.
From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
Most episodes of cytopenia are observed during the first 3 months.
The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Consequences of Hematological Cytopenia:
Leukopenia KTRs are vulnerable to the development of opportunistic infections.
Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
Neutropenic KTRs commonly experience more intra-abdominal infections, than those with normal neutrophil counts.
Both tacrolimus and MMF therapy are commonly associated with neutropenia.
In an attempt to reduce the severity of neutropenia, transplant physicians often reduce or withhold MMF. Despite the expected rise in WBC, its associated with increase risk of acute rejection.
Drug-induced Leukopenia and Neutropenia:
number of agents have been implicated in posttransplant leukopenia and neutropenia development.
Rituximab:
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen.
Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial as follows
: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma.
Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia). Late-onset neutropenia can, after 4weeks.
Late onset neutropenia is usually observed after the sixth rituximab dose. Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently implicated in its evolution.
The reported incidence of leukopenia after rituximab therapy ranges from 19% to 24.6% with an average relative risk of leukopenia of 8percdnt.
ATG:
leukopenia in 45.2% and as combined leukopenia and thrombocytopenia in 14.3% of studied KTRs38 (Figure 5).
dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm. Treatment with ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L.
Alemtuzumab :
is an anti-CD52 humanized mono – clonal immunoglobulin G1.
With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
The incidence is higher (47%) if neutropenia is also present.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe, with the lowest WBC counts observed 130 days after the last given dose.
However, infectious episodes are usually not life-threatening.
dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia.
With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required.
interleukin receptor antagonists :
basiliximab, a monoclonal chimeric, Because anti-IL-2R activity is confined to activated T cells, their leukopenia and thrombocytopenic drawbacks are currently rare compared with drawbacks with ATG and alemtuzumab (10% to 15% vs 5% for basiliximab).
Moreover, leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab.
Brennan and colleagues reported leukopenia in 33.3% of their patients who received ATG induction. In comparison, the incidence of leukopenia was 10.6% for KTRs who received basiliximab.38 Another study reported a significantly higher incidence of leukopenia in KTRs who received thymoglobulin compared with those who received basiliximab (22.8% vs 11.8%; P < . 05).
Considering all these observations, the anti-IL-2R agents would be an optimum therapeutic option for leukopenia KTRs with low/moderate risk of rejection.
Mycophenolic mofetil :
MMF hematotoxicity, 11.8% to 40% of KTRs can develop leukopenia .
Concomitant administration of valacyclovir, and fenofibrate may exaggerate MMF related leukopenia. To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia.
Several approaches could be added for the management of this type of leukopenia, including preemptive dose reduction of MMF after ATG and alemtuzumab induction, shifting to a suitable mammalian target of rapamycin inhibitor ,and halving the CMV prophylactic dose of valganciclovir, which could also be another preventive measure.
For resistant cases, cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal.
Tacrolimus:
Tacrolimus the mainstay of clinical immunosuppression regimens.
16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia.
Tacrolimus may also intensify MMF myelotoxicity.
There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus.
A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include Everolimus, Belatacept, or eculizumab.
Azathioprine
induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
Most cases of azathioprine induced leukopenia present in the first month after transplant.
In this situation, a dose reduction or transient drug withdrawal is usually sufficient.
Of note, a past history of drug-induced leukopenia events would increase the risk of leukopenia by 70%.
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine.
Patients with complete lack or low TPMT activity are vulnerable to developing severe, life-threatening myelotoxicity.
To ameliorate the risk of myelosuppression, 2 techniques have been proposed. The first is monitoring of 6-thioguanine nucleotide in RBCs, which is an efficacious and more beneficial method than monitoring of 6-mercaptopurine in plasma.
Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
Drugs that interact with azathioprine include allopurinol, Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will ensue.
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month
then twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
Severity of myelotoxicity is dose dependent, with involvement of about 20% of KTRs on sirolimus.
A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia, although it can commonly occur even with lower drug levels.
Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
Everolimus therapy, on the other hand, can be also complicated by leukopenia (11%-19%).
The development of cytopenia with mTor agents can be usually observed within the first 4 to 8 weeks. For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously.
valganciclovir
Although 10% to 28% of KTRs are vulnerable for leukopenia development,4.9% to 37.5% of patients may develop neutropenia.
The resultant cytopenia may be potentiated by several factors,
including higher doses of the drug (900 mg or more) having a significant impact on leukopenia and neutropenia development,
Low body mass index.
concomitant MMF administration.
Low dose is effective and less cytotoxic than high dose.
Ganciclovir:
Less myelotoxic ,but need IV administration. Through its myelosuppressive effects, ganciclovir causes leukopenia, with rates of 7.1% to 23.1% .
valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials.
Trimethoprim-sulfamethoxazole:
Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia.
Trimethoprim per se can cause dose dependent inhibition of granulopoiesis in vitro. Folinic acid can reverse this side effect. induce leukopenia in only 2% of recipients. However, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression.
Dapsone :
is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis.
Drug-induced Lymphopenia
In leukopenia KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia..
Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia.
Rituximab:
Rituximab-induced thrombocytopenia (grade 3/4)
has been reported in 48% of patients in one trial, with rate of thrombocytopenia in 2% of lymphoma patients.
Because rituximab-related thrombocytopenia rarely induces bleeding, platelet infusion is rarely
Antithymocyte globulin:
Cross-reaction of antibodies toward nonlymphoid tissue may result in the development of thrombotic events and thrombocytopenia.
Both higher doses of ATG and its nonspecific affinity to platelet cells may induce thrombocytopenia.
An incidence of thrombocytopenia ranging from 10% to 26.5% .
Alemtuzumab
incidence ranging from 1% to 2.5%.90,91 Alemtuzumab-induced thrombocytopenia has been observed in 14% of KTRs.
Bleeding requiring surgical intervention has been observed in 12% of KTRs.
interleukin receptor antagonists:
Because anti-IL-2R activity is confined to activated T cells, their thrombocytopenic drawbacks are currently rare compared with that shown with ATG and alemtuzumab (5% for basiliximab).
Mycophenolic mofetil and enteric-coated mycophenolate sodium
The hematological sequelae of myelosuppression are the most common reason for reducing MMF dose. Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia.
Mammalian target of rapamycin inhibitors :
The most common members of mTor :
Thrombocytopenia 20% of KTRs on sirolimus therapy. A trough level of >12 ng/dL is associated with thrombocytopenia.
Everolimus therapy is associated with thrombocytopenia in 10% to 17% patients
A suggested mechanism of mTor-induced myelotoxicity is the potential predisposition to thrombocytopenic micro – angiopathy with subsequent development of thrombocytopenia.
Ganciclovir
Through its myelosuppressive effect, it can induce thrombocytopenia in 23.1% of KTRs.
Trimethoprim-sulfamethoxazole :
Several hematologic complications have been observed with this agent, including thrombocytopenia.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia:
IB12, folic acid, zinc, and copper deficiencies.
Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia.
Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis , can lead to myelosuppression-induced cytopenia.
Hemophagocytic Syndrome :
Hemophagocytic syndrome can be associated with cytopenia.
Several viral infections (CMV, adenovir Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
thrombocytopenic microangiopathy with consequent thrombocytopenia can develop in the following situations:
renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B1.
Therapy for Drug-induced Hematological Cytopenia:
In addition to the aforementioned protocols.
Specific treatment of neutropenia
the patient’s full detailed history to unravel possible culprit(s).
a dose reduction or complete withdrawal of the suspected agent with correction of WBC count may serve as the only available technique to find a diagnosis.
administration of “colony stimulating” factors if there is no accepted response to the previous maneuvers.
Summary :
Through clinical assessments, culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG.
step is reduction or complete withdrawal of the suspected agent.
Until correction of cytopenia is accomplished, the treating clinician should remain alert to look for
(1) an opportunistic infection and (2) early signs of acute rejection as a result of reduction of immunosuppression.
Based on findings from G-CSF or GM-CSF use in oncology, these agents can be utilized in solid-organ transplant, but there is no consensus.
The prophylactic administration :
patients with febrile neutropenia.
those with diminished bone marrow reserves (eg, ANC <1.5 × 109/L) due to extensive radiotherapy, patients with AIDS/human immunodeficiency virus infection, and patients older than 65 years. On the other hand, therapeutic indications include sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infections, and adjunctive therapy along with antibiotics in the aforementioned indications.
medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC.
if bone marrow suppression is the underlying mechanism, dose reduction or complete drug cessation is required for correction of platelet decline.
Occasionally, platelet transfusion :
such as in life-threatening bleeding risk.
serious decline of platelet count (<20 000/mm3), or before an invasive procedure (eg, organ biopsy; Figure 9).107 The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy.
Before ocular and neurosurgical invasive procedures a minimum platelet count of ≥100 000/mm usually advised.
For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
Because of the high vascularity of renal tissue, a minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
The treating clinician should be aware that anemia associated with bleeding may lead to a major bleeding event, and platelet transfusion at that time may be required even if the platelet count is >100 000/μL.
Level of evidence 5.
Introduction
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number of these drugs are associated with hematological complications. Myelosuppression presenting as cyto penia is not uncommon in kidney transplant recipients (KTRs). From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole. Cautious reduction or complete withdrawal of the offending agent may be urgently warranted; however, as described here, potential risks should be expected and managed accordingly.
Cytopenia can be identified as follows: pancy topenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets; bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count; and leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.12 These levels are 3000 cells/mm3 (normal), 2000 to 3000 WBCs/mm3, 1000 to 2000 WBCs/mm3, and <1000 WBC/mm3 (the latter 3 levels indicating abnormal with variable severities). Leukopenia is also termed alternatively with neutropenia, although these terms are not synonymous.
Absolute neutrophil count (ANC) is used to
assess the magnitude of neutropenic severity as follows13: ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100. An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as mild, moderate, or severe. Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L, moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L, and severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L
Platelet count of 150 000/mm3 is considered the
lower limit of normal level in many laboratories. The CTCAE has also graded throm bocytopenia into 4 levels. These levels are grade I or subnormal (75 000-150,000 cells//mm3), grade II or low (50000-75000 cells/mm3, grade III or moderate (25 000-50 000 cells/mm3), and grade IV or critical (<25 000/mm3)
Drug-induced Leukopenia and Neutropenia
Rituximab Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion and thus affecting phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells. Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes,in attempted treatment of chronic antibodymediated rejection, and in resolution therapy of posttransplant lymphoproliferative disorder.
Antithymocyte globulin Thymoglobulin activity is not confined to T cells; rather, a wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.Moreover, cross-reaction of antibodies toward nonlymphoid tissue may result in the development of neutropenia. Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia
Alemtuzumab Alemtuzumab is an anti-CD52 humanized mono clonal immunoglobulin G1 antibody. The former is a glycoprotein expressed on mononuclear cells (eg, T and B lymphocytes), monocytes, and natural killer cells. Alemtuzumab can be administrated as an induction agent42,43 or as antirejection medication.
interleukin receptor antagonists Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab, a monoclonal chimeric, and daclizumab, a humanized murine antibody against CD25 that can suppress IL-2mediated T-cell activation and proliferation in KTRs. The latter agent has been withdrawn from the market.
Mycophenolic mofetil and enteric-coated mycophenolate sodium These agents are inosine monophosphate dehydro genase inhibitors that can inhibit both cell-mediated and humoral immune responses through sup pression of guanosine nucleotide synthesis de novo pathways in T/B lymphocytes, arresting their differentiation.
Tacrolimus Tacrolimus is the mainstay of clinical immuno suppression regimens.63 Although much less common in renal transplant recipients, 16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia.11 Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs
Azathioprine Azathioprine is a traditional antimetabolite that was introduced in 1960 and has been greatly replaced by the more potent MMF in immunosuppression after kidney transplant. Azathioprine may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day. Most cases of azathioprineinduced leukopenia present in the first month after transplant. In this situation, a dose reduction or transient drug withdrawal is usually sufficient. Of note, a past history of drug-induced leukopenic events would increase the risk of leukopenia by 70%.
Mammalian target of rapamycin inhibitors The most common mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, have been involved in many myelotoxic side effects.77,78 Leukopenia has been reported in a meta-analysis of 8 trials that involved conversion from calcineurin inhibitor (CNI) to mTORi.79 Severity of myelotoxicity is dose dependent,80 with involvement of about 20% of KTRs on sirolimus. A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia,81 although it can commonly occur even with lower drug levels.
valganciclovir The higher bioavailability of this agent (70% vs 7% for oral ganciclovir) has also affected its myelotoxicity profile42, 43 . Although 10% to 28% of KTRs are vulnerable for
leukopenia development, 4.9% to 37.5% of patients may develop neutropenia.The resultant cytopenia may be potentiated by several factors, including higher doses of the drug (900 mg or more) having a significant impact on leukopenia and neu tropenia development, low body mass index, which is a significant potentiating factor for leukopenia, and concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
Ganciclovir Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs. The bioavailability of this drug is rather poor when given orally; therefore, it is always given intravenously. Through its myelosup pressive effects, ganciclovir causes leukopenia, with rates of 7.1% to 23.1%
valacyclovir Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild. Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials
Trimethoprim-sulfamethoxazole Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis. Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia. Trimethoprim per se can cause dosedependent inhibition of granulopoiesis in vitro. Folinic acid can reverse this side effect. Similarly, folate-depleted granulocyte precursors have been observed in another in vitro report.
Dapsone Dapsone is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.69 Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Drug-induced Lymphopenia
In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia. The latter is usually complicated by augmented risk of serious infection; on the other and, lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG).
Posttransplant Drug-induced Thrombocytopenia A number of medications have been implicated in the evolution of posttransplant thrombocytopenia
Rituximab Rituximab-induced thrombocytopenia (grade 3/4) has been reported in 48% of patients in one trial, with rate of thrombocytopenia in 2% of lymphoma patients. Because rituximab-related thrombocytopenia rarely induces bleeding, platelet infusion is rarely indicated.
Antithymocyte globulin Cross-reaction of antibodies toward nonlymphoid tissue may result in the development of thrombotic events and thrombocytopenia. Both higher doses of ATG and its nonspecific affinity to platelet cells may induce thrombocytopenia.An incidence of thrombocytopenia ranging from 10% to 26.5% has been reported in KTRs. Brennan and associates reported cessation or reduction in doses of ATG due to thrombocytopenia in 11.9% of KTRs.
Alemtuzumab Autoimmune thrombocytopenia has been observed in multiple sclerosis and chronic lymphocytic leukemia with an incidence ranging from 1% to 2.5%.
interleukin receptor antagonists Because anti-IL-2R activity is confined to activated T cells, their thrombocytopenic drawbacks are currently rare compared with that shown with ATG and alemtuzumab (5% for basiliximab).
Mycophenolic mofetil and enteric-coated mycophenolate sodium The hematological sequelae of myelosuppression are the most common reason for reducing MMF dose.
Summary
Through clinical assessments, culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG. The first therapeutic step is reduction or complete withdrawal of the suspected agent. Until correction of cytopenia is accomplished, the treating clinician should remain alert to look for an opportunistic infection and early signs of acute rejection as a result of reduction of immunosuppression. Based on findings from G-CSF or GM-CSF use in oncology, these agents can be utilized in solid-organ transplant, but there is no consensus
Level 5
The article discusses myelosuppression induced by medications used for kidney transplantation, together with discussing the overlap caused by the use of combination of two or more drugs.
Medications may present with leukopenia ; in decreasing order r ATG, azathioprine, alemtuzumab, MMF, sulfa drugs, valganciclovir, rituximab ,everolimus, basiliximab and valaciclovir.
Some drugs can cause neutropenia, eg rituximab, alemtuzumab, valganciclovir, combination of MMF & tacrolimus, sulfa drugs, and tacrolimus alone.
Some drugs can cause thrombocytopenia, such as Ganciclovir, Sirolimus, Sulfas, everolimus, alemtuzumab and basiliximab.
Association of these drugs, in addition to the dose, duration, and clinical and metabolic conditions can increase these symptoms.
Differential diagnosis metabolic causes associated with vitamin B12, folic acid, zinc, or copper. Epstein Bar, Cytomegalovirus, Parvovirus B19, Herpesvirus 6, Influenza, and Rickettsia infections are also considered..
Level 5 study
Myelo-suppression induced by drugs in patients having kidney transplantation:
Best choice for patients with end-stage kidney failure is renal transplant. An important factor in allograft survival in transplant recipients is immunosuppressive medicines. Some common immunosuppressive drugs in kidney transplant causes complications such as myelosuppression presenting as cytopenia. 20% to 60% of KTRs experience cytopenia at least once post-transplant which is associated with hematological complications. During the first 3 months, they observe most episodes of cytopenia.
The list of medications can lead to enteric-coated mycophenolate sodium, cytopenia includes mycophenolate mofetil (MMF), ATG, ganciclovir and valganciclovir, Tacrolimus can strengthen the enhancement of the effect of Sirolimus, MMF, and trimethoprim-sulfamethoxazole. Making a balance between complete withdrawal of the offending agent and risk of rejection or reduction is crucial, in the direct post-transplantation period, in particular. Additionally, there is the risk of infections such as opportunistic infections like cytomegalovirus (CMV) infection, post valganciclovir cessation or the risk of Pneumocystis jirovecii, withdrawal of post trimethoprim-sulfamethoxazole.
Cytopenia induced by Rituximab (grade 3/4) been reported in 48% of patients in one trial such as: 6% neutropenia, 40% lymphopenia, and 4% leukopenia. In patients with lymphoma, 4 weeks after start of rituximab therapy, Cytopenia might happen (late-onset neutropenia).
We use absolute neutrophil count (ANC) for assessing the severity of neutropenia. We can grade an ANC less than1500/μL as mild, moderate, or severe and term it neutropenia. ANC level of 1000 to 1500/μL is Mild neutropenia, ANC level of 500 to 999/μL is moderate neutropenia, and ANC level of less than 500/μL is severe neutropenia (agranulocytosis). The development of opportunistic infections make vulnerability for leukopenic KTRs. The sensitivity to infection increases when ANC is less than 1000 cells/μL. Magnitude of neutropenic decline and the duration of neutropenia has a correlation with severity and predisposition to frequency of infection. In neutropenic KTRs, Infection with Escherichia coli is also more prevalent.
· Specific treatment of neutropenia:
Measurement of ANC can be used for evaluation of the severity of neutropenia, with ANC less than 500/μL in medical emergencies, such as septic shock and severe pneumonia. Determining the patient’s history in full detail for recognizing culprit drugs with reduction of dose or complete withdrawal of the suspected agent, is the first step. Administration of “colony stimulating” factors if there is no response accepted to the prior action is the next step for WBC count correction.
Three significant effects of the granulocyte colony-stimulating factor are: reduction of inflammatory cytokines, neutrophil proliferation, and production of anti-inflammatory soluble tumor necrosis factor and IL-l receptor antagonist and prostaglandin E2. There are minimal effects for Granulocyte colony-stimulating factor on lymphocytes since they are lacking specific receptors of G-CSF.
The level of evidence is 5 as this is a review article.
Drug-Induced Myelosuppression in Kidney Transplant Patients
Renal transplantation is considered the best option for patients with end-stage kidney failure. Immunosuppressive drugs are important to allograft survival in transplant recipients. There are number of immunosuppressive medications are associated with hematological complications such as myelosuppression presenting as cytopenia which is so common in kidney transplant recipients from 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.
The list of medications can cause cytopenia includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, ATG, Tacrolimus can cause potentiation of the effect of MMF, Sirolimus, and trimethoprim-sulfamethoxazole. It is important to make a balance between reduction or complete withdrawal of the offending agent and risk of rejection especially in the direct post transplant period. There is also risk of infection including opportunistic infections like cytomegalovirus (CMV) infection after cessation of valganciclovir or risk of Pneumocystis jirovecii after trimethoprim-sulfamethoxazole withdrawal.
Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial as follows:40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma.24 Cytopenia can occur 4 weeks after start of rituximab therapy
(late-onset neutropenia).
Absolute neutrophil count (ANC) is used to assess the severity of neutropenia, An ANC of <1500/μL can be termed neutropenia and graded as mild, moderate, or severe. Mild neutropenia is ANC level of 1000 to 1500/μL , moderate neutropenia is ANC level of 500 to 999/μL, and severe neutropenia (agranulocytosis) is ANC level of <500/μL . Leukopenic KTRs are vulnerable to the development of opportunistic infections. When ANC is <1000 cells/μL, susceptibility to infection increases. The predisposition to frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenic decline. Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
Specific treatment of neutropenia
In medical emergencies, such as severe pneumonia and septic shock, measurement of ANC can be used to evaluate the severity of neutropenia, ANC <500/μL. The first step is determining the patient’s full detailed history to recognize culprit medications with dose reduction or complete withdrawal of the suspected agent. The next therapeutic step for WBC count correction would be administration of “colony stimulating” factors if there is no accepted response to the previous action.
Granulocyte colony-stimulating factor has 3 major effects: neutrophil proliferation, reduction of inflammatory cytokines, and production of anti-inflammatory soluble tumor necrosis factor and IL-l receptor antagonist and prostaglandin E2. Granulocyte colony-stimulating factor has minimal effects on lymphocytes as they are devoid of specific G-CSF receptors.
Immunosuppression drugs are a crucial for allograft survival. However, these medications are associated with many complications from which hematological complicationsm cytopenia. This increases risk of infection, including opportunistic infection which is life-threatening in the presence of leukopenia and neutropenia. In addition, thrombocytopenia can lead to bleeding. Drug withdrawal or dose reduction may be the only way to recognize the offending medication or medications.
Severe neutropenia (agranulocytosis) is associated with grave outcoe, particularly in patients with febrile neutropenia. Many drugs have been introduced to manage serious cytopenia such as CSF, GM-CSF, and thrombopoietic agents. However, there is dearth of safety and efficacy profiles for these noval agents.
Level 5
Introduction
Immunosuppressive medications are mandatory for the graft survival but it can lead to myelo-suppression particularly during the first 3 months post-transplant. About 20-60% of KTR have at least I episode of myelo-suppression.
Myelo-suppression is categorized into:
· Leukopenia is either mild (≺3000), moderate (≺2000), severe (≺1000).
· Neutropenia is either mild (≺1500), moderate (≺1000), severe (≺500).
· Thrombocytopenia is divided into low (≺75000), moderate (≺50000), critical (≺25000).
Drugs that cause myelotoxicity:
1. ATG: its use is associated with leukopenia, neutropenia and thrombocytopenia. It is dose related, and increase with the use of other myelosuppressive drugs especially azathioprine.
2. Alemtuzumab: leucopenia occur in 33-42% of KTR. It causes more myelotoxicity than ATG.
– Valganciclovir cause leucopenia in 10-28% of KTR. Risk factors are high doses, combination with MMF and low BMI. leukopenia usually resolve spontaneously, but prophylaxis with G-CSF may be needed if the effect is prolonged.
– Ganciclovir is less toxic and Valacyclovir is the least myelotoxic.
9. Trimethoprim-sulfamethoxazole: leukopenia occur in only 2% of cases especially when combined with azathioprine
10. DD of Drug-induced Leukopenia and Thrombocytopenia:
– deficits in B12, folic acid, zinc, and copper
Infections: EBV, CMV, parvovirus B19, human herpes virus 6, and influenza viruses.
Management:
There is no evidence-based approach to identifying the culprit agent and modifying the medications in case of persistent neutropenia is required. However, infections should be excluded
Therapy for Drug-induced Hematological Cytopenia:
– Drug withdrawal or dose reduction may be the only way to recognize the culprit medication.
Specific treatment:
– Neutropenia: G-CSF or GM-CSF agents can be utilized in solid-organ transplants with no consensus. Used in patients with febrile neutropenia and those with diminished bone marrow reserves, patients with AIDS and those >65 years
-Thrombocytopenia: thrombopoietin receptor agonists.
What is the level of evidence provided by this article?
Narrative review, level of V evidence
Drug-Induced Myelosuppression in Kidney Transplant Patients
Introduction:
Anumber of immunosuppression drug are associated with hematological complications.
20% to 60% of KTRs may develop cytopenia posttransplant.
The cytopenia are commonly seen during the first 3 months.
Causes may includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy – mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
The higher risk of acute rejection and increased risk of infection, should be considered if cytopenia induced drug has to be reduced or withdrawn.
Cytopenia could be as : pancy topenia involves all 3 cells lines,
bicytopenia involves 2 of 3 cell lines; thrombocytopenia and leukopenia.
Definitions:
Leukopenia
– <3000 cells/mm3 (normal),
– 2000 to 3000 WBCs/mm3,
– 1000 to 2000 WBCs/mm3,
– <1000 WBC/mm3
(the latter 3 levels indicating abnormal with variable severities).
severity of granulocytopenia.
Absolute neutrophil count (ANC) is used to assess the magnitude of neutropenic severity as follows:
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as mild, moderate, or severe.
– Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to1.5 × 109/L,
– moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L,
– severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L.
thrombocytopenia:
Above 150,000 is normal.
– grade I or subnormal (75 000-150,000 cells//mm3),
– grade II or low (50000-75000 cells/mm3,
– grade III or moderate (25 000-50 000 cells/mm3),
– grade IV or critical (<25 000/mm3) .
Leukopenic patient are vulnerable to opportunistic infections.
On the other hand there is high risk of acute allograft rejection with more than 50% reduction in medication dose.
Drug-induced Leukopenia and Neutropenia:
Rituximab:
Rituximab-induced cytopenia has
been reported in 48% of patients .40% lymphopenia, 6% neutropenia, and 4% leukopenia . Cytopenia can occur 4 weeks after start of rituximab therapy.
Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
Antithymocyte globulin:
wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.
Leukopenia incidence with ATG is variable, with studies showing 10%, 38%, 33.5%, and 50%.
The dose of ATG should be halved when platelet
count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm.
Treatment should be stopped when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3.
CD3+ T-cell count should be monitored when less than 0.05 × 109/L (<50/µL; normal range, 128-131/µL) to avoid unnecessary higher doses. This approach is successful in reducing the incidence of acute rejection episodes, infections, and cytopenia.
Total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available.
Alemtuzumab:
Alemtuzumab is an anti-CD52 humanized mono –
clonal immunoglobulin G1 antibody.
With alemtuzumab, the leukopenic incidence in
KTRs ranges from 33.3% to 42% in various reports.34,46
The incidence is higher (47%) if neutropenia is also
present. Compared with ATG, the myelotoxic effects of alemtuzumab are more severe.
interleukin receptor antagonists:
the leukopenic and thrombocytopenic drawbacks are currently rare compared with drawbacks with ATG and alemtuzumab.
The anti-IL-2R agent is the optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium:
These agents are inosine monophosphate dehydro -genase inhibitors.
With regard to MMF hematotoxicity, 11.8% to 40%
These drug users develop leukopenia .
46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia. The myelotoxic effect of MMF is dose dependent.
Treatment :
– preemptive dose reduction of MMF after ATG and alemtuzumab induction,
– shifting to a suitable mammalian target of rapamycin inhibitor (eg, sirolimus or everolimus may reverse cytopenia)
– halving the CMV prophylactic dose of valganciclovir,
Efficacy of valganciclovir 450 mg daily has been proven to be equal to a dose of 900 mg daily for CMV prophylaxis. For resistant cases, cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal.
Tacrolimus:
Present as anemia, neutropenia, and combined anemia/neutropenia.
tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs. contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels. A combination of tacrolimus and MMF expands the area under the curve for MMF within 3 months by approximately 20% to 30%.
Azathioprine:
Azathioprine is antimetabolite.
Azathioprine may induce leukopenia and neutropenia in almost half of KTRs.
As a treatment a dose reduction or transient drug withdrawal is usually sufficient.
To ameliorate the risk of myelosuppression techniques have been proposed.
The first is
monitoring of 6-thioguanine nucleotide in RBCs,
which is an efficacious and more beneficial method
than monitoring of 6-mercaptopurine in plasma.
concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%.
Mammalian target of rapamycin inhibitors:
(sirolimus and everolimus)
myelotoxicity is dose dependent.
incidence 20% of sirolimus. (11%-19%) with Everolimus therapy.
valganciclovir:
The higher bioavailability of this agent (70% vs 7% for oral ganciclovir) has also affected itsmyelotoxicity profile .
several factors may contribut to cytopenia
– higher doses of the drug (900 mg or more)
– low body mass index.
– concomitant MMF administration.
Dose reduction to 450 mg/day or transient drug
cessation may be sufficient for cytopenia reversal.
Ganciclovir:
The bioavailability is poor when given orally therefore, it is always given intravenously.
causes leukopenia, with rates of 7.1% to 23.1%. Compared with valganciclovir, ganciclovir exerts modest myelosuppression. Considering the higher bioavailability of valgan ciclovir (10 times versus that with ganciclovir), the risk of neutropenia in the former agent exceeds 188%. A lesser incidence of leukopenia (7.1% vs 13.5%) and neutropenia (3.2% vs 8.2%) was observed in ganciclovir-treated patients compared with those on valganciclovir.
Valacyclovir:
Compared with valganciclovir and ganciclovir,
myelotoxicity with valacyclovir is relatively mild. When compared with ganciclovir, dose modification is less frequently employed with valacyclovir.
Trimethoprim-sulfamethoxazole:
Cause neutropenia and leukopenia and megaloblastic anemia. Trimethoprim per se can cause dose dependent inhibition of granulopoiesis.
Folinic acid can reverse this side effect.
Incidence is only 2% of recipients.
Dapsone:
Dapsone is an alternate agent for Pneumocystis
jirovecii prevention.
It is associated with many hematological complications, including neutropenia.
Differential Diagnosis of Drug-induced Leukopenia
and Thrombocytopenia:
1) medication-induced myelotoxicity.
2) Deficiency – B12, folic acid, zinc, and copper deficiencies,
3) Infection- Epstein-Barr virus-induced post transplant proliferative disorders invade bone marrow of recipients, causing cytopenia. Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses.
Management:
1) full detailed history.
2) dose reduction or complete withdrawal with correction of WBC count may serve as the only available technique to find a diagnosis.
3) administration of “colony stimulating” factors if there is no accepted response to the previous maneuvers.
level 5
Summary of Drug-Induced Myelosuppression in Kidney Transplant PatientsIntroduction
Myelosuppression can presenting by cytopenia in kidney transplant patient from 20% to 60% of KTRs patient. The risk of CMV will increase after cession of valganciclovir or risk of pneumocystis jirovecii after trimethoprim -sulfamethoxazole withdrawal. Pancytopenia affect all three cells lines.
Consequences of Haematological Cytopenia
The function of neutrophils and lymphocytes are to prevent infection and especially opportunistic infections. neutropenic KTRs commonly experience more intraabdominal infection22.5%. Both MMF and tacrolimus therapy are associated with neutropenia. To reduce the severity of neutropenia is reduced or withhold MMF, so that will increase the risk of acute rejection if the reduction of MMF more than 50% of the dose. the risk it will be higher in highly immunological risk patients and those within 3 month after transplant. The rituximab is cause neutropenia when it uses as induction therapy which can be treated by reduce the dose or withdrawal the medication.
Ant thymocyte globulin
ATG can cause neutropenia in addition their effect on t lymphocytes as treated by reducing the dose or withhold ATG.
Alemtuzumab
Alemtuzumab is an anti-CD52 humanized monoclonal immunoglobulin GI antibody.it use for induction or rejection treatment. The incidence of leukopenia 33% to 42% in various reports so the management is a dose reduction of MMF so we need to monitoring allograft function especially in high risk patients.
Interleukin receptor antagonists
Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab a monoclonal chimeric and daclizumab a humanized antibody against CD25 that can suppress iL-2 mediated T- cell activation and proliferation in KTRs.The anti-IL-2R agents would be an optimal option for leukopenia KTRs with low to moderate risk for leukopenia risk of rejection.
Mycophenolic mofetil and enteric -coted mycophenolate sodium.
MMF can cause heamatotoxicity,11.8% to 40% of KTRs can develop leukopenia related to MMF therapy. The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA concomitant administration of valganciclovir, valacyclovir and fenofibrate may exaggerate MMF related leukopenia .
The treatment of MMF induced neutropenia is dose reduction or drug withdrawal there will be risk of graft loss
Tacrolimus
Tacrolimus is the mainstay of clinical immune suppression regimens and 16.9%of haematological alteration in cardiothoracic transplant recipients were related to tacrolimus therapy including anaemia ,neutropenia and combined anaemia and neutropenia. Treatment of TAC induced neutropenia a dose reduction of MMF is suggested in patient with dual immunosuppression therapy or other alternative include everolimus abatacept, or eculizumab.
Azathioprine
Azathioprine may cause leukopenia and neutropenia in almost half of KTRs. So a dose reduction or drug with drawl is the treatment option. And to diagnose the azathioprine-induced myelotoxicity is by TPMT activity. Drugs that interact with azathioprine is allopurinol so concomitant administration with allopurinol needs a dose reduction by 25% to 50%. Azathioprine levels should be monitored weekly with full blood count mentoring in the first month then twice per month for the second and third months and monthly.
Mammalian target of rapamycin inhibitors:
The severity of mTOR is dose dependence especially if the trough level is more than 12 ng/dl.
Sirolimus and MMF therapy after alemtuzumab induction in steroid and CNI -free regimens may result in severe leukopenia. In most of the patients, m TOR-induced leukopenia, resolves spontaneously if persist MMF reduction with simultaneous reduction of mTOR to a lower therapeutic range is required. Or last drug cessation for resistant cases
Valganciclovir
Account 10% to 25% of KTRs develop leukopenia related.
Valganciclovir
Dose reduction or transient drug cessation may be sufficient for cytopenia reversal.
Ganciclovir
Gan aciclovir is used for anti-CMV and prophylaxis in KTRs and can respond to dose reduction but some require ganciclovir cessation.
Valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herps simplexes in KTRs.
The incidence of leukopenia ranges from 6% to 14% in randomized clinical trials.
Withdrawal of ganciclovir is more frequent than valacyclovir.
Dapsone
Is an alternative agent for pneumocystis jirevoci prevention that is associated with many haematological complications inducing neutropenia.
Post transplant drug induced thrombocytopenia:
Rituximab
Rituximab- induced thrombocytopenia has reported 48% of patients.
Anti thymocytes globulin
Cross-section of antibodies towards non-lymphoid tissue may result in the development of thrombotic events and thrombocytopenia.
Treatment is reducing or holding MMF.
Alemtuzumab
Autoimmune thrombocytopenia has been observed in multiple doses and CLL with an incidence range 1% to 2.5%
Interleukin receptor antagonist
Anti LI-2R activity is confirmed to activated T-cells.
thrombocytopenia is rare about 5.8 % of KTRs who received basiliximab
mycophenolate mofetil and enteric-coated mycophenolate sodium
MMF dose reduction is required to treat anaemia, thrombocytopenia and cytopenia.
Myelotoxicity of MMF is dose-dependent and usually related to the trough level of MPA.
Mammalian target of rapamycin inhibitors
The severity of myelotoxicity is dose-dependent is about 20% of KTRs on sirolimus therapy.
Everolimus is associated with thrombocytopenia in 10% to 17 patients.
Ganciclovir
Can induce thrombocytopaenia in about 23.1% of KTRs.
Trimethoprim-Sulfamethoxazole
Several haematological complications have been observed with this agent including thrombocytopenia.
Differential diagnosis of drug-induced leukopenia and thrombocytopenia:
1-Drug induced .
2- B12 deficiency, folic acid , zinc and copper deficiency.
3- Epstein -Barr virus-induced posttransplant proliferative disorder.
4-CMV infection.
5-parvo virus B19.
6-Human herps virus 6 .
7- influenza virus .
8-tick borne bacterial infection
Hemophagocytic syndrome
Can associate with cytopenia.
Several viral infections CMV adenoviruses, Epstein -Bar virus, human herpes virus 8,human herpes 6,bravo virus 19 and BK virus.
Therapy for drug-induced haematological cytopenia
Specific treatment of neutropenia:
In medical emergencies such as severe pneumonia and septic shock sever neutropenia ANC less 500/ul or 0.5/l .if the further decline in WBCs count ANC less 100 cells /mm3 persisting for more than 7 days extending the high risk of opportunistic infection.
If dose reduction or drug with dual of the suspected agent, some of the study suggest that colony-stimulating agent can cause rejection but some evidence has suggest that G-csf may decrease rejection episodes.
Summary
The first step in management is the reduction or withdrawal of the suspected agent.
Two important points should be considered until the treatment of cytopenia :
1-an opportunistic infection.
2-early signs of acute rejection.
Immunosuppression medication-induced cytopenia and a few randomized controlled trials serve to focus on the most recent evidence-based information.
Thrombopoietin receptor agonists have been efficacious in thrombocytopenia management.
Conclusion
KTRs usually present with cytopenia.
The risk of leukopenia and neutropenia is opportunistic infection and life–threaten infection.
A number of new agents have been introduced to manage serious cytopenia G-CSF, GM-CSF and thrombopoietin agents however there is a dearth of safety and efficacy
level 5
Although essential, immunosuppressive drugs and some prophylactic drugs for opportunistic infections are associated with the hematologic complication of myelotoxicity. Drug-related cytopenias can occur with any strain and in any number of associations: pancytopenia (3 strains); bicytopenia (2 lineages in any association), cytopenia , calling attention to the fact that situations where there is neutropenia or leukopenia even greater impairment of immunity occur, exposing patients to more opportunistic infections.
Leukopenia and lymphopenia in post-transplant patients increase the patient’s predisposition to infections in frequency and severity, and the severity of the event is related to its duration of time and also the degree of cell decline.
– Rituximab: Anti-CD20 monoclonal antibody, used in induction schemes for transplants with ABO incompatibility, in the treatment of acute rejection and some attempts to treat chronic rejection. Cytopenia has been related to its use in up to 48% of patients in one trial and can arise up to 4 weeks after using its last dose and can be influenced by the use of Mycophenolate mofetil, ganciclovir and valganciclovir used for prophylaxis or other therapies.
– Antithymocyte globulin (ATG): in addition to T cells, others are vulnerable to antibody action. Its myelosuppressive action is dose dependent, so that the higher the dose, the greater its action on blood cells other than T cells. Therefore, protocols using higher doses have a higher risk of developing cytopenias, reaching an incidence of 50% in some studies.
– Alemtuzumab: it is a humanized monoclonal antibody anti-CD52 immunoglobulin, used as an anti-induction agent and in some anti-rejection protocols. Although myelotoxic effects are more severe (lower white blood cell counts) than ATG, their infections are usually non-fatal.
– Antagonists of the interleukin 2 receptor (IL-2R): represented by Basiliximab (monoclonal chimeric) responsible for suppressing the proliferation of T cells measured by IL-R2. This group was also formed by Daclizumab (a humanized murine antibody against CD25) that left the market.
– Inosine Monophosphate Inhibitors – Mycophenolic Mofetil and Enteric Coated Miphenolate Sodium (MMF): disrupt T/B lymphocyte differentiation by suppressing the de novo pathways of guanosine nucleotide synthesis, thereby inhibiting humoral and cell-mediated responses. Its myetoxicity is also dose dependent and is strongly influenced by drugs used for prophylaxis or other therapies, such as: ganciclovir, valganciclovir and fenofibrates.
– Tacrolimus : Mechanisms of tacrolimus-induced neutropenia include direct suppression of myeloid cells, with bone marrow hypoplasia, but are not commonly seen in renal recipient patients, being observed in the first 3 months of use.
– Azathioprine: it is an antimetabolite widely used in the first immunosuppression schemes, but it was replaced by MMF, which is more myelotoxic. Usually its myelotoxicity appears in the 1st month and happens in almost half of the patients.
– Rapamycin inhibitors (Sirolimus and Everolimus): dose-dependent myelotoxicity and combined therapies lead to difficulty in defining the degree of responsibility in this group, but normally it is something transitory, with spontaneous resolution. If it does not resolve, doses of other drugs that may cause myelotoxicity must be changed.
– Valganciclovir: leukopenia can develop in up to 3 months and is expected to resolve spontaneously.
– Ganciclovir: Less myelosuppressive than valganciclovir.
– Valaciclovir: has less myelotoxicity than the other representatives of the class, but suffers the effect of other drugs such as MMF.
– Trimethoprim-sulfamethoxazole: used for prophylaxis of Pneumocystis jirovecii. The use of folinic acid can reverse this adverse effect.
TREATMENT:
As there are no diagnostic tools for which drug is causing myelotoxicity, treatment includes decreasing or discontinuing suspected drugs, with the risk of compromise and increased risk of rejection. Furthermore, the use of “colony stimulating factors” is a strategy that can be used, as it stimulates neutrophils, monocytes, macrophages and dendritic cells
Level 05 – narrative review
Many medications commonly used post-TX can lead to myelosuppression which can be clinically manifested as cytopenias, infections, anaemia, bleeding. This list includes the following:
1- ATG.
2- Rituximab: especially 4 weeks after Rituximab therapy however it can happen later.
3- Almetuzumab: more severe myelosuppression than ATG AND BASILIXIMAB.
4- MMF/MFS: dose dependent, related to level of mycophenolic acid level.
5- Tacrolimus: within first 3 months post-TX. Can be switched to everolimus, belatacept or eculizumab.
6- Azathioprine: usually in First month post-TX. TPMT activity is essential before prescribing AZA. Don’t combine AZA with allopurinol.
7- M-TOR inhibitors: sirolimus level >12ng/dl is associated withleucopenia and thrombocytopenia.
8- Anti-viral medications: ganciclovir, acyclovir, valganciclovir.
What is the level of evidence provided by this article? Level 5
Introduction
About 20% to 60% of renal transplant recipients experience at least single episode of cytopenia post transplantation derived by the effect of immunosuppressive agents which are crucial to maintain proper graft function and avoid subsequent rejection episodes.
The susceptibility to increased frequency and severity of infection is linked to the duration of neutropenia as well as the magnitude of neutropenic decline. Leukopenia aggravates the risk of infection via disrupting immunogenic integrity with further liability of ubiquitous and opportunistic infections. Common agents inducing neutropenia are tacrolimus and MMF.
Transplant physicians tend to reduce or hold MMF dose to reduce the severity of neutropenia. This may be followed by higher risk of acute allograft rejection when exceeding 50% reduction in MMF dosage.
Drug-induced Leukopenia and Neutropenia
Rituximab
It is a known potent anti-CD20 monoclonal antibody causing in B-cell depletion. It is commonly used in various serious situations such as; the induction plan in ABO-incompatible transplant, treatment of acute rejection, chronic antibody mediated rejection, and as a resolution therapy of post-transplant lymphoproliferative disorder.
Rituximab late-onset neutropenia can occur 4 weeks after the last dose of therapy after exclusion of other causes as ganciclovir, Valgancyclovir, or MMF. It is usually apparent after the sixth rituximab dose.
The incidence of leukopenia after rituximab therapy ranges from 19% to 24.6%. The main line of management necessitates dose reduction or even drug withdrawal which usually results in an ideal response and good hematological recovery.
Antithymocyte globulin
The incidence of leukopenia with ATG is variable owing to the differences in protocols and periods of administration. ATG cessation or dose reduction was adopted in leukopenia and also when combined with thrombocytopenia. ATG dosage should be reduced to 50% when platelet count decreases to 50 000 up to 75 000 per mm3 or WBC count ranges from 2000 to 3000 per mm. ATG therapy is contraindicated below these values. Other culprits as MMF ought to be held off as well to minimize the concurrent ATG-induced cytopenia.
Alemtuzumab
A known anti-CD52 monoclonal immunoglobulin, used as an induction agent or an anti rejection agent. The incidence of leukopenia ranges from 33.3% to 42% following alemtuzumab administration. The myelotoxic effects of alemtuzumab are more severe than ATG. B-cell dysregulation associated with its use led to several autoimmune disorders.
Interleukin receptor antagonists
The commonly anti CD25 antibody IL-2R antagonist used as induction agent is basiliximab with associated 10.6% incidence of leukopenia. Its use is a good option for cases of low to moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
The main mechanism of action is by inhibiting both cell-mediated and humoral immune responses with subsequent inhibition of nucleotide synthesis de novo pathways in for T and B lymphocytes, arresting their further differentiation. MMF hematotoxicity is estimated around 11.8% up to 40% in renal transplant recipients in the form of leukopenia.
The myelotoxic effect of MMF is usually dose dependent which can also be monitored by trough levels of MPA. Other medications coadministered as valganciclovir and fenofibrates may potentiate MMF related leukopenia.
Management involves shifting to a suitable mammalian target of rapamycin inhibitor either sirolimus or everolimus that may reverse cytopenia, CMV prophylactic dose of valganciclovir reduction to 50% seems reasonable in these situations.
Tacrolimus
It is associated with neutropenia in 28% of renal transplant recipients.
Mechanisms of myelosuppression are:
Direct suppression of myeloid cells along with bone marrow hypoplasia.
Alteration of cytokine production by T lymphocytes and monocytes.
Production of antimyeloid precursors and anti-mature neutrophil antibodies.
Prevention of MPA glucuronidation with subsequent potentiation of its blood levels.
Azathioprine
Leukopenia and neutropenia induced by this antimetabolite reaches almost half of renal transplant recipients. The magnitude of azathioprine-induced myelotoxicity is related to the activity of thiopurine S-methyl transferase (TPMT). Individuals having complete lack or low TPMT activity are prone to severe life-threatening myelotoxicity.
The risk of myelosuppression can be detected by monitoring of 6-thioguanine nucleotide in RBCs, monitoring of 6-mercaptopurine in plasma, or further genotyping and phenotyping of TPMT. Regular monitoring of full blood count is indicated in renal transplant recipients on azathioprine.
Concomitant administration with allopurinol mandates dose reduction of azathioprine by 25% to 50% to avoid hazardous myelosuppression due to severe drug interaction.
Mammalian target of rapamycin inhibitors
Most commonly used are sirolimus and everolimus. Severity of myelotoxicity is known to be dose dependent. High trough levels are linked to the development of leukopenia and thrombocytopenia.
Sirolimus and MMF combination can cause severe leukopenia. Everolimus as well can lead to leukopenia by about (11%-19%). MTORi-induced myelotoxicity mechanisms are; disrupted signal transduction by mTORi through the gp130 β chain in addition to platelet aggregation and degranulation.MTORi-induced leukopenia mostly resolves spontaneously.
Valganciclovir
Cytopenia can be related to the use of higher doses of the drug, low body mass index and concomitant MMF administration. Leukopenia can be resolved spontaneously even without treatment by dose reduction to 450 mg/day which is usually sufficient.
Ganciclovir
Ganciclovir-treated patients have less incidence of leukopenia about 7.1% and neutropenia estimated by 3.2%.
Valacyclovir
Myelotoxicity with Valacyclovir is relatively mild ranges from 6% to 14%. As other agents combination of MMF and Valacyclovir therapy may potentiate drug induced myelotoxicity. The pill burden of valacyclovir is high and neurological complications are more frequently associated.
Trimethoprim-sulfamethoxazole
It is widely used for Pneumocystis jirovecii prophylaxis. Neutropenia, leukopenia and megaloblastic anemia are the commonest types of cytopenias associated with its use. Incidence of leukopenia is only 2% of recipients especially when combined with other antimetabolites.
Posttransplant Drug-induced Thrombocytopenia
Rituximab
Antithymocyte globulin Cross-reaction of antibodies toward nonlymphoid tissue can lead to serious thrombotic events and thrombocytopenia explained by nonspecific affinity to platelet cells. The incidence was estimated about 10% to 26.5%. It is advisable to hold off or reduce MMF dose with concurrent ATG-induced cytopenia.
Alemtuzumab
Interleukin receptor antagonists the selection of an anti-IL-2R agent is a wise choice for those thrombocytopenic renal transplant recipients with low to moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium Myelotoxicity of MMF is dose dependent and usually related to the trough levels of MPA.
Mammalian target of rapamycin inhibitors
Ganciclovir
Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
B12, folic acid, zinc, and copper deficiencies.
Epstein-Barr virus-induced posttransplant proliferative disorders.
Cytomegalovirus, parvovirus B19, human herpes virus 6.
Management:
The first step is determining the patient’s full detailed history.
Dose reduction or complete withdrawal of the suspected offending agent with correction of WBC count may be a wise initial action.
Colony stimulating factors if there is no accepted response to the previous measures.
Level of evidence is 5.
Introduction
Hematological complications post kidney transplantation including pancytopenia one of the common and serious complications and might have a deleterious impact on patient and graft survival as usually such complications related to the side effects of immunosuppression including induction IS like ATG and alemtuzumab in addition to maintenance immunotherapy with MMF and myofortic which can lead to myelosuppression like pancytopenia , both MMF and tacrolimus can cause pancytopenia and the highest incidence occur in first 3 months after kidney transplantation due to intense immunosuppression including induction therapies like ATG , Alemtuzumab , rituximab ,and maintenance IS like MMF , myofortic , azathioprine , CNI LIKE tacrolimus , M tor inhibitors like sirolimus , sirolimus , others like antiviral use like valaciclovir and ganciclovir, cotrimoxazole prophylaxis for bacterial infection including PJP, also certain viral infection like CMV, EBV, and parvoviral infection, and PTLP disorders, we should identify the cause and severity of hematological complication and treated accordingly
Pancytopenia indicates suppression in WBC, RBC, and platelet count
While bi-cytopenia involves 2 or 3cell lines like anemia and thrombocytopenia (Parvoviral infection)
Leucopenia and alternative neutropenia can be mild-moderate and severe leucopenia and the garden according to the level
Thrombocytopenia also can be graded based on the severity
Leucopenia KTRs are susceptible to a higher risk of opportunistic infections. When ANC is <1000 cells/μL, and more intra-abdominal focus of infections
S sirolimus and everolimus can cause myelosuppression with leucopenia as early as in the first two months and its dose related, especially in induction with alemtuzumab and in combination with MMF in CNI free protocols its can be resolved spontaneously up to 89% and only few cases need dose reduction and to less extent drug withdraw .
Antiviral medication can lead to different degree of myelosuppression based on the oral bioavailability of the drugs some agents are poor oral bioavailability compared to IV route like ganciclovir associated with higher degree of leucopenia compared to valacyclovir for cmv prophylaxis which have lower percentage of leucopenia
MMF and mycophenolic acid responsible for > 46% of cases of pancytopenia and its usually dose related and in majority of cases responding to dose reduction.
Posttransplant Drug-induced Thrombocytopenia again includes
induction IS like Rituximab, ATG and alemtuzumab, alemtuzumab-induced thrombocytopenia
has been observed in 14% of KTRs. Bleeding requiring surgical intervention has been observed in 12 % of KTRs.while rituximab induced thrombocytopenia usually mild and not complicated by bleeding or transfusion
interleukin 2 inhibitors like basiliximab have lower rate of thrombocytopenia compared to other induction IS
Differential diagnosis of hematological myelosuppression post kidney transplantation should include other than drug induced myelosuppression includes B12 , Folate deficiency , HUS , infections including CMV , EBV , parvo 19 , adenovirus , BKV especially in tacrolimus ,MMF combination protocols , human papilloma virus , HSV and EBV triggering lymphoproliferative disorder ;like PTLD, accelerated hemophygotic syndrome in sever infections with sepsis
Specific treatment of myelosuppression in addition to dos reduction or transient withdraw of offending medications there is other specific therapies like in sever neutropenia with ANC < 500 can give G,CSF which can improve the neutropenia and act as anti-inflammatory with less effect on lymphopenia while GM -CSF can activate neutrophile , monocytes and NKC unlike G CSF its can promote inflammation however its safety further prospective trails but both g,csf , GM -CSF have been indicated as therapeutic and prophylaxis therapy in sever febrile neutropenia in sold organ transplantation with good safety profile
Myelosuppression after transplantation can occur because of the use of immunosuppression drugs that are essential for good graft survival and prevention of rejection.
20% t0 60% of KTR can have at least one episode of Myelosuppression causing pancytopenia.
This mainly in the 1st 3 month post-transplant.
Sometimes dose reduction or withdrawal should be done but this can lead to acute rejection.
Other supportive and prophylactic drugs can also cause Myelosuppression.
Cytopenia can be identified as follows:
1- pancytopenia involves all 3 cells lines, white blood cells (WBCs), red blood cells (RBCs), and platelets.
2- bicytopenia involves 2 of 3 cell lines.
3- Thrombocytopenia involves low platelet count
4- leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.
These levels are 3000 cells/mm3 (normal), 2000 to
3000 WBCs/mm3, 1000 to 2000 WBCs/mm3, and
<1000 WBC/mm3 .
The normal platelet count Platelet count is 150 000/mm3 to 450 000/mm3
The CTCAE graded thrombocytopenia into 4 levels. These levels are grade I or subnormal (75 000-150,000 cells/mm3), grade II or low (50000-75000 cells/mm3, grade III or moderate (25 000-50 000 cells/mm3), and grade IV or critical (<25 000/mm3)
Consequences of Hematological Cytopenia:
Leukopenia can lead to opportunistic infections.
The frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenia.
Drug-induced Leukopenia and Neutropenia:
1- Rituximab
Rituximab-induced cytopenia (grade 3/4) has
been reported in 48% of patients in 1 trial as follows 40% lymphopenia, 6% neutropenia, and 4%
leukopenia in patients with lymphoma
2- Antithymocte globulin
It affects T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.
The dose of ATG should be halved when:
a- Platelet count reaches 50 000 to 75 000 per mm3
b- or WBC count reaches 2000 to 3000 per mm3
The dose of ATG should be held when:
a- platelet count declines to less than 50 000 per mm3
b- or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L.
3- Alemtuzumab
The incidence of leucopenia ranges from 33.3% to 42% in various reports.
The myelotoxic effects of alemtuzumab are more severe than ATG.
4- Interleukin receptor antagonists
basiliximab and daclizumab.
5- Mycophenolic mofetil and enteric-coated
mycophenolate sodium
11.8% to 40% of KTRs can develop leukopenia related to MMF.
6- Tacrolimus
It is much less common to cause Myelosuppression in renal transplant recipients but can cause up to 16.92% of
hematological abnormalities in cardiothoracic transplant
recipients.
7-Azathioprine
It may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg
body weight/day.
8- Mammalian target of rapamycin inhibitors
These are (mTORi), sirolimus and everolimus.
The Severity of Myelotoxicity is dose dependent.
9- Anti-viral drugs like valganciclovir, Ganciclovir, valacyclovir,
10- Trimethoprim-sulfamethoxazole
It is used for Pneumocystis jirovecii prophylaxis and can cause neutropenia, leukopenia and megaloblastic
anemia.
11- Dapsone
as alternative drug for Pneumocystis
jirovecii prevention. Can induce many hematological complications, including neutropenia.
Drug-induced Lymphopenia:
lymphopenia is different from leukopenia
due to neutropenia. Neutropenia is usually complicated
serious infections but lymphopenia is usually due induction therapy like ATG.
Post-transplant Drug-induced Thrombocytopenia:
Rituximab, Antithymocyte globulin, Alemtuzumab, interleukin receptor antagonists, Mycophenolic mofetil and enteric-coated
mycophenolate sodium, Mammalian target of rapamycin inhibitors, Ganciclovir, Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia
and Thrombocytopenia:
1- deficiency of B12, folic acid, zinc, and copper
2- Epstein-Barr virus-induced post-transplant proliferative disorders
3- Infection with cytomegalovirus, parvovirus
B19, human herpesvirus 6, influenza viruses, and
ehrlichiosis (a tick-borne bacterial infection) .
Myelosuppression presenting as cytopenia is not uncommon in kidney transplant recipients from 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy -mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Cytopenia can be identified as follows: pancytopenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets; bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count. While Absolute neutrophil count (ANC) is used to assess the magnitude of neutropenic severity as ANC = (WBCs/μL) * (percentage of polymorphonuclear cells + bands)/100 (When ANC is <1000 cells/μL, susceptibility to infection increases)
Drug-induced Leukopenia and Neutropenia As detailed here, a number of agents have be enimplicated in posttransplant leukopenia and neutropenia development .
Rituximab
Cytopenia can occur 4 weeks after start of rituximab therapy. The reported incidence of late-onset neutropenia in KTRs has approached 37.5% to 48%. Dose reduction or drug withdrawal is usually the ideal response for hematological recovery
Antithymocyte globulin
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3. Treatment with should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3.
CD3+ T-cell count should be monitored when less than 0.05 × 109/L (<50/μL normal range, 128-131/μL), Total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available.
Alemtuzumab
With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42%. Compared with ATG, the myelotoxic effects of alemtuzumab are more severe,34,46 with the lowest WBC counts observed 130 days after the last given dose. Although infectious episodes are not usually life-threatening
Mycophenolic mofetil and enteric-coated mycophenolate sodium
Account for about 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy, can be mask by induction therapy myelotoxicity. The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA and so dose reduction is the response to manage cytopenia. However, this response would trigger the risk of acute rejection and subsequently graft loss.
Azathioprine
traditional antimetabolite that may induce leukopenia and neutropenia in almost half of KTRs,
particularly with doses greater than 1.99 mg/kg body weight/day. The important factor to determine azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity. Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine. Patients with complete lack or low TPMT activity are at risk of developing life-threatening myelotoxicity.
Drugs that interact with azathioprine include allopurinol, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; to avoid catastrophic myelosuppression.
Tacrolimus
Although much less common in renal transplant recipients, 16.92% of hematological alteration including anemia, neutropenia. Tacrolimus may also intensify MMF myelotoxicity, induce neutropenia in 28% of KTRs. In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels. Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant. There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus.
Mammalian target of rapamycin inhibitors mTORi
Development of cytopenia with mTORi agents can beusually observed within the first 4 to 8 weeks . Severity of myelotoxicity is dose dependent, A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia, although it can commonly occur even with lower drug levels. For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously.
Level 5
Briefly summarise this article
-Immunosuppressive drugs are associated with hematological complications. Myelosuppression presenting as cyto – penia is not uncommon in kidney transplant recipients (KTRs).
– From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.
-The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy –
mocyte globulin (ATG), tacrolimus,sirolimus, and trimethoprim-sulfamethoxazole.
-Cytopenia can be identified as follows: pancy – topenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets; bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count.
-Leukopenia is also termed alternatively with neutropenia, although these
terms are not synonymous.
-laboratories have used neutropenia to classify severity of granulocytopenia.
-Platelet count of 150 000/mm3 is considered the lower limit of normal level in many laboratories.
-Neutrophils and lymphocytes have fundamental roles in prevention of infection. –Leukopenic KTRs are vulnerable to the deve – lopment of opportunistic infections. When ANC is <1000 cells/μL, susceptibility to infection increases.
-Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
-Both tacrolimus and MMF therapy are commonly associated with neutropenia.
-After clinical assessments, culprit medications in cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir,
ganciclovir, alemtuzumab, and ATG.
-The first therapeutic step is reduction or complete withdrawal of the suspected agent. Until correction of cytopenia is accomplished, the treating clinician should remain alert to look for:
(1) an opportunistic infection .
(2) early signs of acute rejection as a result of reduction of immunosuppression.
-Based on findings from G-CSF or GM-CSF use in oncology, these agents
can be utilized in solid-organ transplant, but there is no consensus.
-The prophylactic administration of these agents is suggested in patients with
febrile neutropenia, those with diminished bone marrow reserves (eg, ANC <1.5 × 109/L) due to extensive radiotherapy, patients with AID, and patients older
than 65 years.
-Therapeutic indications include sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infections, adjunctive therapy along with antibiotic, prolonged pyrexia, severe neutropenia with ANC <500/μL,94 and prolonged
neutropenia of more than 7 days.
– If thrombocytopenia is due to idiosyncratic reaction (eg, due to trimethoprimsulfamethoxazole), then immediate withdrawal of the suspected agent is required; if bone marrow suppression is the underlying mechanism, dose
reduction or complete drug cessation is required for correction of platelet decline.
-Platelet transfusion may be required, such as in life-threatening bleeding risk, serious decline of platelet count (<20 000/mm3), or before an invasive procedure (eg, organ biopsy).
-The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm3 with commencement of invasive maneuvers (eg, allograft
biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
-Because of the high vascularity of renal tissue, a minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
-Thrombopoietin receptor agonists have been efficacious in thrombocytopenia management. These agents include romiplostim and eltrombopag, which
have been used with better results in “idiopathic thrombocytopenic purpura” therapy.
What is the level of evidence provided by this article?
Level 5
Summary : Drug induced myelosuppression in kidney transplant patients
This study is about the hematological complications that come following kidney transplant. These include
These complications can predispose the patient to infection especially opportunistic infections. This can be a problem because of the immunosuppression that the recipient will be on.
Immunosuppressive agents that are linked with post transplant leukopenia and neutropenia include
Management strategies include :
Level of evidence
Narrative review – Level of evidence 5.
A number of immunosuppressive drugs are associated with haematological complications. Between 20% to 60% of KTRs have experienced at least 1 episode of cytopenia after transplant. Cytopenia are observed during the first 3 months after transplant. Reduction or withdraw of immunosuppressant agents is expected in case of cytopenia. However, after reduction of myelosuppressive immunosuppressive agents there is an increased risk of acute rejection.
Cytopenia is identified as: pancytopenia when involves all 3 cells lines, that is, white blood; Bicytopenia when involves 2 of 3 cell lines; thrombocytopenia involves low platelet count; and leukopenia
DRUG-INDUCED LEUKOPENIA AND NEUTROPENIA
Rituximab:
It is a chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion. Rituximab is used as induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection, in the treatment of chronic antibody- mediated rejection and in resolution therapy of posttransplant lymphoproliferative disorder. Cytopenia occurs approximately in 48% of patients and usually 4 weeks after commencing the treatment
Antithymocyte globulin:
Thymoglobulin activity affects T cells, B cells, natural killer cells, monocytes, neutrophils,platelets, and RBCs. It may cause neutropenia in view of cross-reaction ofantibodies toward nonlymphoid tissue. The incidence of Leukopenia with ATG is variable, and the variability depends as a result of differences in protocols and variabilities in periods of administration. When platelet count are between 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3, ATG dose should be halved. when platelet count drops below 50 000 per mm3 or when WBC falls below 2000 per mm3 ATG treatment should be held.
Alemtuzumab:
It is an anti-CD52 humanized monoclonal immunoglobulin G1 antibody. Alemtuzumab is used as an induction agent or as antirejection medication. The incidence of leukopenia in KTRs ranges from 33.3% to 42% in various reports. Alemtuzumab has a more severe myelotoxic effects than ATG.
Interleukin receptor antagonist:
Humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in KTRs. leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab. Anti-IL-2R agents is an optimum therapeutic option for leukopenicKTRs with low or moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium:
They are inosine monophosphate dehydro -genase inhibitors that can inhibit both cell-mediated and humoral immune responses. 11.8% to 40% of KTRs can develop leukopenia related to MMF treatment. The diagnosis of MMF myelotoxicity may be masked by ATG-related and alemtuzumab-related cytopenia. In case of leukopenia, anemia, thrombocytopenia we should reduce the dose as it is dose dependent effect.
Tacrolimus:
Increase MMF myelotoxicity. Tacrolimus with MMF induce neutropenia in 28% of KTRs. Tacrolimus-induces neutropenia through a direct suppression of myeloid cells. Patients on dual immunosuppression therapy should have a reduced dose of MMF. In such patients. In this cases possible options are everolimus, belatacept, or eculizumab
Azathioprine:
Around 50% of KTRs may develop leukopenia and neutropenia on AZA. If patient develop leucopenia or neutropenia we should reduce or withdraw Azathioprine. If patient is on allopurinol, MMF dose should be reduced of 25 to 50 % to avoid myelosuppression.
Mammalian target of rapamycin inhibitors:
Severity of myelotoxicity is dose dependent,with involvement of about 20% of KTRs on sirolimus. Leukopenia and thrombocytopenia are more commonly seen when A trough level is >12 ng/dL but it can be seen in lower levels. Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia
Valganciclovir:
Its myelotoxicity profile is affected by the higher bioavailability of this agent. Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia. Several factors may increase the risk of cytopenia such as higher doses of the drug (900 mg or more), low body mass index, and associated MMF administration, which can also aggravate valganciclovir myelotoxicity.
Ganciclovir:
It is used as anti-CMV therapy and prophylaxis in KTRs. Ganciclovir is given intravenously in view of its poor bioavailability. It causes leukopenia through its myelosupressive effects, with rates of 7.1% to 23.1%. Ganciclovir is less myelosuppressive than valganciclovir. Considering the higher bioavailability of valganciclovir the risk of neutropenia in the former agent exceeds 188%.
Valacyclovir:
It is used for CMV prophylaxis and treatment of herpes simplex in KTRs. Valacyclovir has mild myelotoxicity when compared with valganciclovir and ganciclovir.
Trimethoprim-sulfamethoxazole:
It is used for Pneumocystis jirovecii prophylaxis. Trimethoprim-sulfamethoxazole can cause neutropenia and leukopenia and megaloblastic anemia. Folinic acid can reverse this side effect. The use of trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis in KTRs may induce leukopenia in only 2% of recipients.However, drug induced myelosuppression is aggravated by the combination of Trimethoprim-sulfamethoxazole with azathioprine.
Dapsone:
It is used as an alternate agent for Pneumocystis jirovecii prevention. Side effects include neutropenia. Agranulocytosis may aggravate the neutropenic effects of dapsone.
Drug-induced Lymphopenia:
Commonly seen with ATG use.
Posttransplant Drug-induced Thrombocytopenia:
The most common medications associated with Posttransplant Drug-induced Thrombocytoprnis are: Rituximab, Alemtuzumab, MMF, mTORi, ATG, , IL-6 antagonists, Ganciclovir, trimethoprim-sulfamethoxazole.
Level 5
A number Is medications which can be used post kidney transplant are associated with hematological complications; Myelosuppression presenting as cytopenia. The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG),8 tacrolimus,9 sirolimus, and
trimethoprim-sulfamethoxazole.
Rituximab
Cytopenia can occur 4 weeks after start of rituximab therapy. Late-onset neutropenia canbe defined as neutropenia that is observed 4 weeks after the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF). With regard to rituximab management, the threshold of suspicion of rituximab-induced toxicity should be lowered, particularly 6 weeks after the sixth rituximab dose. Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
Antithymocyte globulin
Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia. The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3. Treatment with ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L
Alemtuzumab
Alemtuzumab is an anti-CD52. Compared with ATG, the myelotoxic effects of alemtuzumab are more severe. leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab. With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required.
interleukin receptor antagonists
the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA. Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMFrelated leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable
response to MMF-induced neutropenia and leukopenia.
Tacrolimus
Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant. There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus. A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include everolimus, belatacept, or eculizumab
Azathioprine
Most cases of azathioprine induced leukopenia present in the first month after transplant. In this situation, a dose reduction or transient drug withdrawal is usually sufficient.
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity. Moderately active TPMT may lead to higher risk of myelotoxicity.
Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity
leading to decline in purine metabolism to uric acid.
Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will ensue.
Of note, the need for azathioprine instead of MMF is frequently utilized in areas with low economic standards.
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first monththen twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
Severity of myelotoxicity is dose dependent,80 with involvement of about 20% of
KTRs on sirolimus. A trough level of >12 ng/dL has been shown to be highly associated with
development of leukopenia and thrombocytopenia,81 although it can commonly occur even with lower drug levels.
In most patients, mTORi-induced leukopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required. However, drug cessation may be the last resort for resistant cases
Level V
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, several drugs are associated with haematological complications (myelosuppression).
Consequences of Hematological Cytopenia:
Leukopenic KTRs are vulnerable to the development of opportunistic infections.
Neutropenic KTRs commonly experience more intra-abdominal infections.
Given the absence of robust evidence-based strategies to manage drug-induced cytopenia after kidney transplant, transplant clinicians should carefully analyze patient drug history and clinical experience to find the offending medication.
Clinical situations may also result in cytopenia and should be kept in mind.
Drug-induced Leukopenia and Neutropenia
Rituximab:
Rituximab-induced cytopenia has been reported in 48% of patients in 1 trial, it can occur 4 weeks after the start of rituximab therapy. Late-onset neutropenia is usually observed after the sixth rituximab dose. Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently implicated in its evolution.
Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
Antithymocyte globulin:
Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia. leukopenia incidence with ATG is variable and is associated with the use of other IS medications like azathioprine or MMF.
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3.
Alemtuzumab:
The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose.
A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia.
interleukin receptor antagonists:
the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection as it is rarely associated with cytopenia because its effect is limited to activated T cells.
Mycophenolic mofetil and enteric-coated mycophenolate sodium:
11.8% to 40% of KTRs can develop leukopenia related to MMF therapy, oth ATG-related and alemtuzumab-related cytopenia may mask the diagnosis of MMF myelotoxicity, as they may require MMF dose reduction.
The myelotoxic impact of MMF isdose-dependentt and is usually related to the trough levels of MPA. Concomitant administration of valganciclovir, valacyclovir and fenofibrate may exaggerate MMF-related leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia.
Tacrolimus:
It is less common in renal transplant patients. Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs. A dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
Azathioprine:
may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day. most cases are present in the first month after transplant.
To ameliorate the risk of myelosuppression, 2 techniques have been proposed. The first is the monitoring of 6-thioguanine nucleotide in RBCs, which is an efficacious and more beneficial method than the monitoring of 6-mercaptopurine in plasma. Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
concomitant administration with allopurinol necessitates a dose reduction of azathioprine by 25% to 50%.
Mammalian target of rapamycin inhibitors:
sirolimus and everolimus have been involved in many myelotoxic side effects. Severity of myelotoxicity is dose-dependent. sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
The development of cytopenia with mTORi agents can be observed within the first 4 to 8 weeks.
In most patients, mTORi-induced leukopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required.
valganciclovir:
The resultant cytopenia may be potentiated by several factors, including:
Although leukopenia can develop within 3 months, resolution of leukopenia can occur spontaneously with or without treatment.
Ganciclovir:
Compared with valganciclovir, ganciclovir exerts modest myelosuppression.
Although patients on ganciclovir therapy respond to dose reduction, some require ganciclovir cessation.
valacyclovir:
myelotoxicity with valacyclovir is relatively mild. However, combined MMF and valacyclovir therapy may aggravate drug-induced myelotoxicity.
Dose modification is less frequently employed with valacyclovir.
Dapsone:
the neutropenic effects of dapsone may be aggravated by development of agranulocytosis.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia:
B12, folic acid, zinc, and copper deficiencies.
Epstein-Barr virus-induced PTLD.
Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis.
Therapy for Drug-induced Hematological Cytopenia:
Colony-stimulating factors have been introduced to manage severe leukopenia in KTRs.
Granulocyte-monocyte colony-stimulating factor (GM-CSF) is a stimulating agent that can activate neutrophils, monocytes, macrophages, and dendritic cells.
Unlike G-CSF, GM-CSF involves a pro-inflammatory criterion. However, the safety of this agent has been documented in solid-organ transplant patients, with improved WBC count and fewer infectious episodes. The safety and efficacy of this agent, however, warrant more randomized clinical trials.
Drug-induced lymphopenia:
Increases the risk of infection.
commonly seen with ATG use.
Posttransplant Drug-induced Thrombocytopenia
Large number of medications had been implicated:
Rituximab, ATG, Alemtuzumab, IL-6 antagonists, MMF, mTORi, Ganciclovir, trimethoprim-sulfamethoxazole.
What is the level of evidence provided by this article
Level 5 (review article)
In this article Abbas and colleagues looked into hematological complications seen in post kidney transplant patients.Most of these complications are secondary to myelosuppression incurred by immunosuppressive drugs.
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. Myelosuppression presenting as cyto- penia is not uncommon in kidney transplant recipients (KTRs)From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
Cytopenia can be identified as follows: pancy- topenia involves all 3 cells lines, that is, white blood cells (WBCs),
red blood cells (RBCs),
and platelets;
bicytopenia involves 2 of 3 cell lines; thrombocytopenia involves low platelet count;
and leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.
These levels are 3000 cells/mm3 (normal),
2000 to 3000 WBCs/mm3,
1000 to 2000 WBCs/mm3, and
<1000 WBC/mm3 (the latter 3 levels indicating abnormal with variable severities).
Absolute Neutrophic count is calculated as ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100. An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as mild, moderate, or severe.
Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L,
moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L, and
severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L
Thrombocytopenia is also graded into 4 levels
Grade 1.75000-150000
Grade 2. 50000-75000
Grade 3. 25000-50000
Grafe 4 also considered critical is platelets count less than 25000.
Leucopenia and Neutropenia predispose transplant patients to all kind of infectious complications primarily opportunistic and intra abdominal infections.
Drugs mostly leading to these hematology Al complications are
Rituximab.
Cytopenias have been reported in 48% of patients in 1 trial as follows: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma. Cytopenia can occur 4 weeks after start of rituximab therapy however late onset neutropenia occurring 38 to 175 days has been reported as well
ATG.
Leucopenia incidence with ATG is quite variable depending upon different protocols adopted. It is reported from 10 to 50%.
Dose of ATG should be halved if platelet counts drops down to 5000-75000 or WBC count is less than 2000.
Alemtuzumab.
Leucopenia incidence ranges from 33.3% to 42%
Interleukin Receptor antagonist
Leucopenia incidence reported is around 10.6% far less than ATG and Alemtuzumab
MMF
11.8 to 40 % can develop Leucopenia.
Tacrolimus
Tac induced neutropenia can be observed within first three months of transplant.
16.92% of hematological alterations have been attributed to TAC in cardiothoracic transplant though it is rare in Kidney transplant.
Azathioprine
Azathioprine may induce leukopenia and neutropenia in almost half of KTRs
Mostly , one month post transplant
Dose reduction or transient withdrawal of the drug is sufficient
Drug interaction with Allopurinol which increase the risk of myelosuppression .so, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will occur.
mTOR inhibitors
Cytopenia can be observed within the first 4 to 8 weeks.
Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia
mTORi-related leukopenia can resolve spontaneously
dose reduction of MMF and mTORi is required with drug cessation being the last resort.
Valganciclovir/Ganciclovir/Valaciclovir
more with valganciclovir
potentiated by several factors, including higher doses of the drug (900 mg or more) ,
low body mass index and concomitant MMF administration .
leukopenia can develop within 3 months & resolution can occur spontaneously with or without treatment
Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal especially that with This dose level , has been shown to be equally effective as 900 mg/day for CMV prophylaxis ; consequently, the lower dose has been recommended.
Trimethoprim- Sulfamethoxazole
a commonly used drug for Pneumocystis jirovecii prophylaxis may induce leukopenia in only 2% of recipients. However, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression
Dapsone
It can be used as an alternative to Trimethoprim-sulfamethoxazole for pneumocystis prophylaxis in KT patients and can cause agranulocytosis
As almost all of the drugs used in post kidney transplant patients can lead to myelosuppression expressing as
Leucopenia
Neutopenia
Lymphopenia
Thrombocytopenia
The management is individualized, at times reducing the dose is enough, in other cases stopping the drug or even using Gcsf is required
Drug-Induced Myelosuppression in Kidney Transplant Patients
immunosuppressive drugs are crucial to allograft survival in transplant recipients. Many of them are associated with hematological complications. Around 20% to 60% of KTRs experienced at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months.
The list of culprit agents includes :
1-mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium .
2-ganciclovir and valganciclovir
3-antithy mocyte globulin (ATG)
4- tacrolimus
5-sirolimus
6- trimethoprim-sulfamethoxazole.
Cytopenia can be identified as follows:
1- pancytopenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets
2- bicytopenia involves 2 of 3 cell lines
3- thrombocytopenia involves low platelet count , 4 levels:
>> grade I or subnormal (75 000-150,000 cells//mm3)
>>grade II or low (50000-75000 cells/mm3
>>grade III or moderate (25 000-50 000 cells/mm3)
>>grade IV or critical (<25 000/mm3) (Figure 2). >less than 25000 cells/mm3)
4- leukopenia ( neutropenia) can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels :
>>3000 -4000 cells/mm3 (normal) , according to the laboratory limit
>>2000 to 3000 WBCs/mm3
>>1000 to 2000 WBCs/mm3
>>less than 1000 WBCs/mm3
– According to absolute neutrophilic count (ANC) :
>>ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
>>neutropenia if less than 1500
>>Mild neutropenia if 1500-1000
>>Moderated neutropenia if 999-500
>>Severe neutropenia ( agranulocytosis) if less than 500
– Leukopenic KTRs are vulnerable to the development of opportunistic infections if ANC is less than 1000
– Infection with Escherichia coli & intra abdominal infections is more prevalent in neutropenic KTRs.
Drugs causing leukopenia & neutropenia :
1- Rituximab :
– Monoclonal AB , against CD20 , leading to B cell depletion
– Uses :
>>induction for ABO incomapatability
>>treatment of acute rejection
>>in resolution therapy of post transplant lymphoproliferateive disorders
>>in attempted treatment of chronic AB mediated rejection
– Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia) defined as neutropenia that is observed 4 weeks after the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF).
– usually observed after the sixth rituximab dose
– Dose reduction or drug withdrawal is usually the ideal response for hematological recovery
2- Antithymocyte globulin :
– The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000
– should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000
– to avoid unnecessary higher doses , CD3+ T-cell count should be monitored when less than 0.05 × 109/L or < 50 μL (<50/μL;>normal range, 128-131/μL) , Total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available.
3- Alemtuzumab :
– Anti CD 52 humanized monoclonal immunoglobulin G1 antibody
– can be administrated as an induction agent or as antirejection medication
– more severe myelosuppression as compared with ATG
4- interleukin receptor antagonists :
– basiliximab (monoclonal chimeric)
– daclizumab, a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation , withdrawn from the market
– rare myelosuppression compared with ATG and alemtuzumab , so would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
5- Mycophenolic mofetil and enteric-coated mycophenolate sodium :
– myelosuppression is the most common cause requiring MMF dose reduction
– dose dependent and is usually related to the trough levels of MPA & Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMF related leukopenia
– to manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia.
But , this response would trigger the risk of acute rejection, with subsequent high risk of graft loss in many retrospective reports.
6- Tacrolimus:
– the mainstay of clinical immunosuppression regimens.
– Direct inhibition of myeloid precursors may not be a convincing mechanism for tacrolimus-induced neutropenia and leukopenia
– may intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
– A dose reduction of MMF is suggested in patients on dual immunosuppression therapy In such patients, other alternatives include everolimus, belatacept, or eculizumab
7- Azathioprine :
– Azathioprine may induce leukopenia and neutropenia in almost half of KTRs
– Mostly , one month post transplant
– Dose reduction or transient withdraw the drug is sufficient
– Drug interaction with Allopurinol which increase the risk of myelosuppression .
– so, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%; otherwise, catastrophic myelosuppression will occur
8- Mammalian target of rapamycin inhibitors :
– Sirolimus & everolimus
– Usually with high doses , trough level > 12
– Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
– Observe , reduce the dose , decrease MMF dose & lastly hold the drug
9- valganciclovir , ganciclovir & valacyclocir :
– more with valganciclovir
– may be potentiated by several factors, including higher doses of the drug (900 mg or more) , low body mass index and concomitant MMF administration .
– leukopenia can develop within 3 months & resolution can occur spontaneously with or without treatment
– Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal especially that with This dose level , has been shown to be equally effective as 900 mg/day for CMV prophylaxis ; consequently, the lower dose has been recommended.
– Ganciclovir , given IV due to poor bioavailability & Compared with valganciclovir, it exerts modest myelosuppression
10- Trimethoprim-sulfamethoxazole :
– a commonly used drug for Pneumocystis jirovecii prophylaxis
– may induce leukopenia in only 2% of recipients. However, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression
11- Dapsone :
– is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
Drug-induced Lymphopenia
In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia. The latter is usually complicated by augmented risk of serious infection , lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG) .
>>Differential Diagnosis :
1- vit B12, folic acid, zinc, and copper deficiencies
2- Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia.
3- Cytomegalovirus
5- parvovirus B19, human herpes virus , influenza viruses,
6- ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
>>Hemophagocytic syndrome
can be associated with cytopenia. Several viral infections (CMV, adenovirus, Epstein-Barr virus, human herpesvirus , human herpesvirus , parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
>>Thrombocytic microangiopathy
with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection and viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
>>Specific treatment of neutropenia :
– medical emergencies : such as severe pneumonia and septic shock, measurement of ANC can be used to evaluate the severity of neutropenia, with severe neutropenia indicated by ANC < 500 or further decrease of WBCs (ANC >100 , persist for > 7 days) carry high risk for severe opportunistic infection
1- patient’s full detailed history searching for the possible cause
2- dose reduction or complete withdrawal of the suspected agent
3- administration of “colonystimulating” factors if there is no accepted response
>>Granulocyte-monocyte colony-stimulating factor (GM-CSF)
– is a stimulating agent that can activate neutrophils, monocytes, macrophages, and dendritic cells
– Granulocyte colony-stimulating factor has 3 major effects: neutrophil proliferation, reduction of inflammatory cytokines (eg, tumor necrosis factor, interleukin 1 [IL-1], IL-12, and interferon), and production of anti-inflammatory soluble tumor necrosis factor receptors p55 and p75, in addition to IL-l receptor antagonist and prostaglandin E2.
– Several studies have reported improved WBCs counts, fewer infection episodes, and absence of related rejection episodes
– The prophylactic administration of these agents is suggested in patients with febrile neutropenia, those with diminished bone marrow reserves (eg, ANC <1.5 ) , medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC
– therapeutic indications include sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infections , and adjunctive therapy along with antibiotics in the aforementioned indications.
>>Indications of platelet transfusion :
– life-threatening bleeding risk
– Presence of active bleeding
– serious decline of platelet count (<20 000/mm3), or before an invasive procedure (eg, organ biopsy; Figure 9).107 The recommended cut-off therapeutic level for platelet transfusion should be >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy )
– Before ocular and neurosurgical invasive procedures, a minimum platelet count of ≥100 000/mm3 is usually advised.
– For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
– For renal biobsy , keep above 100 000/mm3
>>level 5
Drug-Induced Myelosuppression in Kidney Transplant Patients
KT is considered a “cure” for ESKD, and IS medications is associated with different adverse effects, and myelosuppression is one of these serious and severe adverse effects.
Drugs such as MMF, enteric-coated mycophenolate sodium MPA, AZA, ganciclovir and valganciclovir, ATG, tacrolimus, sirolimus, and TMP
Myelosuppression May present as serious infection or appeared as asymptomatic cytopenia From the blood lab results.
CTCAE has graded thrombocytopenia into 4 grades:
d. Leukopenia
CTCAE has graded leukopenia into:
ANC is used to assess the magnitude of neutropenic severity as follows:
ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia
Grades of Neutropenia:
· Mild neutropenia: ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L.
· Moderate neutropenia: ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L.
· Severe neutropenia (agranulocytosis): ANC level of <500/μL or <0.5 × 109/L
Drug-induced neutropenia and leukopenia
RTX:
· anti-CD20 monoclonal antibody.
· Resulting in B-cell depletion and thus affecting phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells.
· Uses in KT; induction agent in ABOi-Kx, acute rejection, cABMR and resolution therapy of posttransplant lymphoproliferative disorder.
· RTX-induced cytopenia has been reported in 48% of patients in one trial. Cytopenia can occur 4 weeks after start of RTX.
· Incidence of leukopenia after rituximab therapy ranges from 19% to 24.6%.
ATG:
· Cross-reaction of antibodies toward nonlymphoid tissue may result in the development of neutropenia.
· Higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
· Incidence of leukopenia up to 50% when ATG is combined with AZA
· ATG should be held if Plt < 50000/mm3 or WBC < 2000/mm3
· Medications that cause leukopenia should be monitored when used together with of ATG
· MMF
· AZA
· steroids
Alemtuzumab:
· anti-CD52 monoclonal immunoglobulin G1 antibody
· Incidence of leukopenia ranges from 33.3% to 42%
· The incidence is higher neutropenia is present together – 47%
· Myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose
· Dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required for the management
Interleukin 2 Receptor (IL-2R) antagonists:
· Incidence of leukopenia is 10.6% in KTRs receiving Basiliximab.
· Would be an option for leukopenia KTRs with low/moderate risk of rejection.
MMF and MPA
· 11.8% to 40% can develop leukopenia
· Both ATG-related and alemtuzumab- related cytopenia may mask the diagnosis of MMF myelotoxicity.
· Treatment is dose reduction or complete withdrawal.
Tacrolimus:
· Tacrolimus may intensify MMF myelotoxicity in 28% of KTRs
· can be treated with dose reduction of MMF with consideration of everolimus, Belatacept or eculizumab
AZA:
· May induce leukopenia and neutropenia in almost 50% of KTRs (doses greater than 1.99 mg/kg body weight/day)
· presents in the 1st after KTx and can be treated with dose reduction or withdrawal
· Concomitant administration with allopurinol requires dose reduction of azathioprine by 25% to 50%.
mTORi
· Cytopenia can be observed within the first 4 to 8 weeks.
· Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia
· mTORi-related leukopenia can resolve spontaneously
dose reduction of MMF and mTORi is required with drug cessation being the last resort
Valganciclovir:
· 10% to 28% of KTRs developes leukopenia
· Valganciclovir myelotoxicity and leukopenia can be potentiated and aggravated by concomitant use of MMF, higher doses of 900 mg or more and low body mass index.
· the risk of neutropenia exceeds 188% In comparison to ganciclovir
· G-CSF may be required with prolonged periods of prophylaxis
Ganciclovir:
· Anti-CMV therapy and prophylaxis
· causes leukopenia, with rates of 7.1% to 23.1%.
· Less myelosuppressive than valganciclovir
· Related leukopenia responds to dose reduction, and some may need drug withdrawal
Valacyclovir:
· CMV prophylaxis and treatment of herpes simplex
· Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild
· leukopenia ranges from 6% to 14% in KTRs
· The risk of neutropenia with 730% higher than with valacyclovir
· Combined MMF and valacyclovir therapy may aggravate drug- induced myelotoxicity
· MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
TMP SMX:
· Used for Pneumocystis jirovecii prophylaxis
· Associated with neutropenia, leukopenia, and megaloblastic anaemia
· Trimethoprim per se can cause dose- dependent inhibition of granulopoiesis in vitro
· Induce cytopenia in KTRs in only 2%
· Concurrent use of AZA can aggravate myelosuppression effect of TMP/SMX.
Dapsone:
· Alternate agent for Pneumocystis jirovecii prevention
· associated with many haematological complications, including neutropenia
· The neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Drug-induced lymphopenia
· Results from induction therapy with lymphocyte-depleting agent(rATG)
Drug-induced thrombocytopenia
· RTX-related thrombocytopenia rarely induces bleeding; platelet infusion is rarely indicated
· Alemtuzumab can cause auto-immune thrombocytopenia. Bleeding requiring surgical intervention has been observed in 12% of KTRs
· mTORi-related myelotoxicity is dose dependent
· Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anaemia, thrombocytopenia
· Thrombocytopenia occurs in 5.8% receiving Basiliximab which is preferred for thrombocytopenic KTRs with low to moderate risk of rejection
· Myelotoxicity of MMF is dose dependent and usually related to the trough levels of MPA
Differential diagnosis of drug-induced leukopenia and thrombocytopenia:
· Deficiency of B12, folic acid, zinc, and copper
· EBV-induced PTLD
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses
· Ehrlichiosis can lead to myelosuppression-induced cytopenia
Hemophagocytic Syndrome
· Associated with cytopenia
· CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpes virus 6, parvovirus B19, and BK polyomavirus
Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B19)
Therapy for drug-induced haematological cytopenia
Specific treatment of neutropenia:
ANC <100 cells/mm3 persisting more than 7 days constitutes an extremely high risk of opportunistic infection.
· Dose reduction or complete withdrawal of the suspected agent.
· Correction of WBC count with G-CSF or GM-CSF.
· Therapeutic indications for G-CSF/GM-CSF are sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infection and adjunctive therapy with antibiotics
· Prophylactic administration of G-CSF/GM-CSF is needed in: prolonged fever, severe neutropenia with ANC <500/μL, and prolonged neutropenia of more than 7 days.
Treatment of thrombocytopenia
· Immediate withdrawal of suspected agent in case of idiosyncratic effect. For bone marrow suppression, dose reduction or cessation may be required.
· Platelet transfusion is needed in the followings; life-threatening bleeding risk, serious decline of platelet(<20000/mm3) or before an invasive procedure.
· Thrombopoietin receptor agonists (romiplostim and eltrombopag) have been efficacious in thrombocytopenia management.
· Cut off values for platelet count before procedure.
This is a review article with level of evidence grade 5
Introduction
· From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
· Most episodes of cytopenia are observed during the first 3 months.
· The responsible drugs includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole
· Cytopenia can be: pancytopenia, bicytopenia and leukopenia
· Many laboratories consider 4000 cells/mm3 is the lower limit of normal WBCs, and 150 000/mm3 is the lower limit of normal Platelet
· The reduction or stopping MMF as a trial to reduce neutropenia, increases risk of rejection mainly in first year of transplantation.
Drug-induced Leukopenia and Neutropenia
Rituximab
· is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion
· commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes, in attempted treatment of chronic antibody mediated rejection, and in resolution therapy of posttransplant lymphoproliferative disorder
· Late-onset neutropenia observed 4 weeks after the last dose of rituximab after exclusion of other causes (ganciclovir, valganciclovir, or MMF)
· Recovery occurs by dose reduction or rituximab withdrawal.
Antithymocyte globulin
· Leukopenia incidence with ATG is variable,10%- 50%. The highest was when used with azathioprine.
· The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3
· ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3
Alemtuzumab
· is an anti-CD52 humanized mono – clonal immunoglobulin G1 antibody
· can be used in induction or as antirejection medication
· the leukopenic incidence in KTRs ranges from 33.3% to 42%
· the myelotoxic effects of alemtuzumab are more severe than with ATG
· MMF or valganciclovir or cotrimoxazole doses should be reduced
Interleukin receptor antagonists: basiliximab, and daclizumab(withdrawn)
· leukopenia is 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab
· leukopenia is significantly higher in KTRs who received thymoglobulin compared with those who received basiliximab
· the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection
Mycophenolic mofetil and enteric-coated mycophenolate sodium
· 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy.
· Both ATG-related and alemtuzumab related cytopenia may mask the diagnosis of MMF myelotoxicity, as they may require MMF dose reduction
· Concomitant use of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMF related leukopenia
· Leukopenia managed by: preemptive dose reduction of MMF after ATG and alemtuzumab induction, shifting to a suitable mammalian target of rapamycin inhibitor (sirolimus or everolimus may reverse cytopenia), and halving the CMV prophylactic dose of valganciclovir
Tacrolimus
· 16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia
· Tacrolimus may intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs
· Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant
· A dose reduction of MMF is suggested in patients on dual immunosuppression therapy
Azathioprine
· greatly replaced by the more potent MMF in immunosuppression after kidney transplant
· may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
· Most cases of azathioprine induced leukopenia present in the first month after transplant, when a dose reduction or transient drug withdrawal is usually sufficient
· thiopurine S-methyl transferase (TPMT) activity may be used to predict risk of myelotoxicity
· concomitant administration with allo – purinol necessitates dose reduction of azathioprine by 25% to 50%
· Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment
Mammalian target of rapamycin inhibitors: sirolimus and everolimus
· Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia
· The development of cytopenia can be usually observed within the first 4 to 8 weeks.
· For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously
Valganciclovir
· Leukopenia potentiated by: higher doses of valganciclovir, low body mass index, and concomitant MMF use
· Dose reduction to 450 mg/day (equally effective as 900 mg/day for CMV prophylaxis) or transient drug cessation may be sufficient for cytopenia reversal.
Ganciclovir
· A lesser incidence of leukopenia and neutropenia was observed in ganciclovir-treated patients compared with those on valganciclovir therapy
Valacyclovir
· Used for CMV prophylaxis and treatment of herpes simplex in KTRs
· Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials.
· The risk of neutropenia with valganciclovir therapy is currently 730% higher than with valacyclovir
Trimethoprim-sulfamethoxazole
· It’s use for Pneumocystis jirovecii prophylaxis in KTRs may induce leukopenia in only 2% of recipients.
· But, combined azathioprine therapy with trimethoprim sulfamethoxazole can aggravate drug-induced myelosuppression
Dapsone
· alternate agent for Pneumocystis jirovecii prevention
· the neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Drug-induced Lymphopenia
lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG)
Posttransplant Drug-induced Thrombocytopenia
Rituximab, Antithymocyte globulin, Alemtuzumab, interleukin receptor antagonists, Mycophenolic mofetil and enteric-coated mycophenolate sodium, Mammalian target of rapamycin inhibitors, Ganciclovir, Trimethoprim-sulfamethoxazole.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
· medication-induced myelotoxicity
· B12, folic acid, zinc, and copper deficiencies
· Epstein-Barr virus-induced posttransplant proliferative disorders
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection)
Hemophagocytic Syndrome
can be associated with cytopenia. Several viral infections (CMV, adenovirus Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) could be involved
Specific treatment of neutropenia
· severe neutropenia indicated by ANC <0.5 × 109/L should be measured in severe pneumonia and septic shock
· A further decline in WBC count (ANC <100 cells/mm3) persisting more than 7 days constitutes an extremely high risk of opportunistic infection
· After withdrawal of the suspected agent, colony stimulating factor can be given
· Granulocyte colony-stimulating factor has 3 major effects: neutrophil proliferation, reduction of inflammatory cytokines, and production of anti-inflammatory soluble tumor necrosis factor receptors p55 and p75, in addition to IL-l receptor antagonist and prostaglandin E2
· G-CSF may decrease rejection episodes
· Granulocyte-monocyte colony-stimulating factor (GM-CSF) safe in solid-organ transplant patients, with improved WBC count and fewer infectious episodes
Thrombocytopenia in kidney transplant
The following steps in care are suggested
· if thrombocytopenia is due to idiosyncratic reaction, immediate withdrawal of the suspected agent is required
· if bone marrow suppression is the underlying mechanism, dose reduction or complete drug cessation is required for correction of platelet decline
· indications for platelets transfusion:
1. Thrombocytopenia with bleeding
2. Keep platelet >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
3. for ocular and neurosurgical invasive procedures, keep platelet count of ≥100 000/mm3
4. For lumbar puncture procedures, a platelet count of ≥50 000/ mm3
5. minimum level of 100 000/mm3 is usually recommended for kidney biopsy
This journal provides one of the most important grave clinical condition, myelosuppression usually due to adverse effect of immunosuppression.
The list of culprit agents includes mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, antithy – mocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Drugs may lead to leukopenia (decreasingly) rATG, azathioprine, Alemtuzumab, MMF, sulfa drugs, valganciclovir, rituximab, everolimus, basiliximab and valaciclovir.
Some of these drugs can cause neutropenia, such as rituximab, alemtuzumab, valganciclovir, the combination of MMF with tacrolimus, sulfa drugs, and tacrolimus.
Drugs can cause thrombocytopenia, such as rATG, Ganciclovir, Sirolimus, Sulfa drugs, Everolimus, Alemtuzumab and Basiliximab.
Due to these drugs, as well as the dose, duration, and clinical and metabolic conditions of the individual can intensify myelosuppression. Sometimes dose reduction or hold of these culprit agents according to the response may become life saving strategy.
Level 5 study (Narrative review)
Briefly summarize this article
Myelosuppression is not uncommon after Kidney Transplant and presents as cytopenia.
At least one episode of cytopenia is observed in 20 to 60% KTR and mostly within first 3 months.
List of drugs commonly implicated in myelosuppression are:
1. Mycophenolate Mofetil (MMF)/Entero-coated mycophenolate sodium
2. Ganciclovir/Valgancyclovir
3. Antithymocyte Globulin(ATG)
4. Tacrolimus
5. Sirolimus
6. Trimethoprim-Sulfamethoxazole (TMP-SMX)
Types of Cytopenia and grading as per Common terminology criteria for adverse events(CTCAE):
1. Pancytopenia: All 3 lines (RBC,WBC and platelets) involved
2. Bicytopenia: Involves 2 out of 3 lines involved
3. Thrombocytopenia: Low Platelet count
Grade 1: 75k to 1.5L cells/mm3
Grade 2:50k to 75K cells/mm3
Grade 3:25k to 75K cells/mm3
Grade 4: Less than 25K cells/mm3
4. Leukopenia/Neutropenia:
Normal:>3000 or 4000/mm depending upon lower laboratory limit
Mild:2000-3000/mm3
Moderate:1000-2000/mm3
Severe: Less than 1000/mm3
ANC(Absolute Neutrophil count) is used to assess the magnitude of neutropenic activity:
Mild Netropenia:1000-1500/uL or 1 to 1.5×109/L
Moderate Neutropenia:500 to 999/uL or 0.5 to 0.99×109/L
Severe Neutropenia(agranulocytosis):Less than 500/uL or 0.5×109/L
Consequences of Cytopenia:
When ANC counts decrease below 1000 cells/mm3, susceptibility to opportunistic infection rises. Commonly experience intra-abdominal infections
Drug Induced Leukopenia/Neutropenia:
1. Rituximab:
MOA: Potent Chimeric anti-CD20 antibody, resulting in B cell depletion affecting phagocytosis by macrophages, complement mediated cytotoxicity and antibody dependent cell mediated toxicity by NK cells.
Use: Induction agent in ABOi Transplant, Treatment of acute rejection, attempted treatment of chronic antibody mediated rejection and in resolution therapy of post-transplant Lymphoproliferative disorder.
Incidence: 19 to 24.6%
Mycophenolate, Ganciclovir and valgancyclovir are frequently implicated along.
Suspicion should be lowered 6 weeks after 6th Rituximab dose.
Dose reduction/withdrawal is needed for recovery.
2. ATG:
MOA: Its activity affects wide ranges of cells (T cell, B cell, NK cells, Monocytes, neutrophils, platelets, and RBCs) due to nonspecific avidity to platelets and neutrophils and cross reaction toward non lymphoid tissue
Incidence-10 to 50% in various studies.
Treatment: Dose of ATG halved when platelet count reaches 50 to 75k or WBC count reaches 2000 to 3000.
Dosage Held if Platelets decline beyond 50k or WBC beyond 2000.
Monitoring of dosage: CD3+ T cells to be maintained less than 50/uL or 0.05×109/L or Total lymphocyte count less than 0.3×109/L.
Hold off MMF with concurrent ATG-induced cytopenia
3. Alemtuzumab:
MOA: Anti-CD52 humanized monoclonal Ig1 antibody which effects mononuclear cells (T and B Lymphocyte),Monocytes and NK cells. Can cause autoimmune disorders through B cell dysregulation
Use: Induction or antirejection
Incidence: 33 to 42% in various reports
Compared to ATG: Myelotoxic SE severe, lowest WBC count observed 130 days post last dosage
Treatment: Dose reduction, along with dose modification of MMF/Valgancyclovir/TMP-SMX.
4. Interleukin Receptor Antagonist:
MOA: Basiliximab, monoclonal chimeric antibody against CD 25, suppress IL 2 mediated T cell activation add proliferation in transplant patients.
Cytopenia are rare with IL 2 receptor antagonist compared to other induction agents like Alemtuzumab/ATG.
Knowing the fact, basiliximab is considered as an optimal therapeutic option for leukopenic Transplant patients With low/moderate risk of rejection.
5. Mycophenolic Mofetil and enteric coated mycophenolate sodium
MOA: It arrest differentiation of T/B lymphocyte and hence inhibit both cell mediated and humoral immune response.
Incidence: 11.8% to 40%
Myelotoxic effects of MMF is dose dependent and usually related to trough levels of MPA.
Dose reduction or complete withdrawal is required for MMF induced myelosuppression, although ATG/Alemtuzumab related cytopenia would require dose reduction of MMF and hence may mask myelotoxicity of MMF.
6. Tacrolimus:
MOA: Direct Suppression of myeloid cell, altered cytokine production by T lymphocytes and monocytes, production of anti-myeloid precursors and anti-mature neutrophilic antibodies
Usually observed within first 3 months after transplant
Combination of Tacrolimus with MMF expands area under curve for MMF within 3 months by 20 to 30% due to inhibition of MPA glucuronidation and non-interference with MMF enterohepatic circulation
7. Azathioprine:
Relationship with dosage: more than 1.99mg/kg have 50% incidence of neutropenia and leukopenia in KTR.
Usually present in first month.
TMPT (Thiopurine S-methyl Transferase) activity determines azathioprine induced myelosuppression. Complete lack/Low TMPT activity vulnerable to severe life-threatening myelosuppression while moderate activity predisposes to higher risk of myelotoxicity.
Dose reduction to 25 to 50% with concomitant Allopurinol administration.
Azathioprine levels should be monitored weekly, with CBC in first month, fortnightly during next 2 months and monthly or less according to dosage adjustment
8. mTOR inhibitors:
Prevalence: 20% in Sirolimus and 11 to 19% in Evorlimus.
Usually observed within 4 to 8 weeks.
Most cases resolve spontaneously or with MMF dose reduction
9. Valgancyclovr/Ganciclovir/Valacyclovir:
Myelotoxicity of Valgancyclovir>Ganciclovir>Valacyclovir.
Usually developed within 3 months.
For Valgancyclovir, Dose reduction to 450mg/day or transient drug cessation usually sufficient. Need for G-CSF may be required with prolonged period of prophylaxis.
10. TMP-SMX:
Used for Pneumocystis Jirovecii prophylaxis
.
May cause neutropenia/Leukopenia and megaloblastic anemia.
MOA: Dose dependent inhibition of Granulopoiesis, Folinic acid can reverse it
Incidence: 2%
11. Dapsone: also associated with neutropenia
Drug Induced Lymphopenia:
Usually, the result of ATG
Post-Transplant Drug induced Thrombocytopenia: Causative drugs
1. Rituximab: rarely induces bleeding and platelet transfusion rarely required.
2. ATG: Due to cross reacting antibodies with platelets with incidence ranging from 10 to 26% and can be exaggerated with mTORi combination
3. Alemtuzumab: Incidence 14% and surgical re-exploration is required in 12% of KTR due to bleeding.
4. IL2R antagonist: Rare
5. MMF and enteric coated Mycophenolate Mofetil: Dose dependent and related to trough level of MPA
6. Ganciclovir/TMP-SMX
D/D of Drug induced Leukopenia/Thrombocytopenia: apart from drugs
1. Nutritional Deficiencies: Vit B12/Folic acid/Zinc/Copper
2. Infections: EBV, CMV, Parvovirus B19, HHV 6, Influenza virus, ehrlichiosis.
3. Thrombotic microangiopathy with consequent thrombocytopenia: Renal Ischemic events, Antibody mediated rejection and Viral infections (CMV, HIV and parvovirus B19)
Hemophagocytic syndrome: CMV, Adeno, EBV, HHV6,HHV 8,Parvovirus B19 and BK polyoma virus.
Treatment:
Neutropenia/Cytopenia:
· Detail History
· Dose reduction of offending drugs/complete withdrawal.
· G-CSF: MOA: Neutrophil proliferation, reduction of inflammatory cytokines(like TNF,IL1,IL 12 and INF), production of anti-inflammatory soluble TNF receptors p55 and p75,IL1 receptor antagonist. Devoid of effects on lymphocytes
· GM-CSF: MOA: stimulates neutrophils, monocytes, macrophages and dendritic cells, involves a pro-inflammatory state and needs to be studies further before advocating its efficacy and safety.
· G-CSF/GM-CSF: Prophylactic Indications are febrile neutropenia, sever neutropenia (ANC<500uL) and ANC 1.5×109/L in patients with extensive radiotherapy, HIV, older than 65 due to reduced bone marrow reserve
· G-CSF/GM-CSF: Therapeutic indications: sepsis, hypotension, neutropenic fever more than 7 days, pneumonia, fungal infections
· Watchful for opportunistic infections and early signs if rejection till correction of cytopenia
Thrombocytopenia:
· Detail history
· Dose reduction/Complete drug withdrawal in case of BM suppression. If idiosyncratic reaction (like TMP-SMX),immediate withdrawal of drug
· Platelet transfusion: Low platelet count<20K or before invasive procedure
What is level of evidence produced by this article:
This is a narrative review and level of evidence is 5
The article was a good one with detailed information about the immunosuppressive medications that can be used in transplants. For the success of kidney transplant, these medications have to be used but they all have some form of complications or adverse effects and if not detected timely can be detrimental to the patient and or the allograft. There are many classes of the immunosuppressive medications, and they are as follows:
1) Rituximab
2) MMF and enteric-coated mycophenolate sodium
3) Ani-thymocyte globulin
4) Azathioprine
5) Ganciclovir and valganciclovir
6) Tacrolimus
7) Sirolimus
8) Trimethoprim-sulfamethoxazole
Once these drugs are introduced either by inductions or as part of maintenance, they will cause myelosuppression and they can be as follows:
1) Pancytopenia
2) Bicytopenia
3) Thrombocytopenia
4) leukopenia
The CTCAE has classified the base of the different line on the degree of their levels obtain and complications. They are:
1) Thrombocytopenia has 4 grades:
a) Subnormal 75000-150000 cells/mm3
b) Low 50000-75000 cells/mm3
c) Moderate 25000-50000 cells/mm3
d) Critical/severe less than 25000 cells/mm3
2) Leukopenia has 4 grades
a) Level 1: 3000 cells/mm3
e) Level 2: 2000-3000 cells/mm3
f) Level 3: 1000-2000 cells/mm3
g) Level 4: less than 1000 cells/mm3
3) Grades of neutropenia
a) Mild neutropenia: 1000-1500 /μL or 1-1.5 x 109/L
b) Moderate neutropenia: 500- 999 /μL or 0.5 to 0.99 x 109/L
c) Severe neutropenia: less than 500 /μL or less than 0.5 x 109/L
The different drugs and their possible complication or adverse reactions:
1) Rituximab: it is an anti CD20 monoclonal antibody. It causes B- cell depletion and affects phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells. It is used it kidney transplants and induction in ABO incompatibility, and acute rejection. It causes renal transplant cytopenia and as such based-on studies about 48 % of transplant patients have had cytopenia.
2) ATG: It affects a wide range of blood cells like T and B cells natural killer cells, monocytes, neutrophils, platelets, and RBCs. The higher the dose the greater it is to develop neutropenia. ATG combined with AZA increases neutropenia by 50%. It causes low platelets and low WBC.
3) Alemtuzumab: this medication is specific, and it is an anti-CD52 monoclonal immunoglobulin G1 antibody. In a kidney transplant, there is an incidence of 33.3% to 42% of leukopenia. Myelotoxic effects are greater than ATG. When combined with other medications its dose needs to be reduced.
4) MMF and enteric-coated mycophenolate sodium: with this treatment, in kidney transplants about 11.8-40% develop leukopenia. MMF-related cytopenia can be treated with dose reduction.
5) Tacrolimus causes neutropenia and combination with MMF will worsen neutropenia by 28%.
6) Azathioprine: in kidney transplant, it will cause leukopenia and neutropenia at a dose greater than 1.99 mg/kg /day. Once combined with allopurinol, its dose must be reduced by about 25 to 50%.
7) mTORi agents. It causes cytopenia within the first 4-8 weeks. A combination of MMF, sirolimus will worsen leukopenia. Its leukopenia can be resolved spontaneously or by drug reduction.
8) Valganciclovir: It is and anti-CMV. In transplant, 10-28% develop leukopenia. Its adverse effect may potentiate MMF.
9) Ganciclovir: it is an anti-CMV and causes leukopenia by 7.1-23.1%. As it relates to leukopenia, it will respond to dose reduction.
10) Valacyclovir: also use in CMV treatment or prophylaxis. Its complication is less when it is related to the other medications. MMF and valacyclovir will aggravate myelotoxicity and may cause bone marrow toxicity.
11) Trimethoprim-sulfamethoxazole: it is used for Pneumocystic jirovecii prophylaxis. It causes neutropenia, leukopenia, and megaloblastic anemia. Induce cytopenia in transplant by 2%. A combination of AZA aggravates myelosuppression.
The drugs that cause lymphopenia are related to induction therapy with lymphocyte-depleting agents.
Drugs that induced thrombocytopenia: Rituximab, ATG, alemtuzumab, anti-IL2R, MMF, mTORi, ganciclovir, and TMP/SMX.
Differential diagnosis of leukopenia and thrombocytopenia:
1) CMV, parvovirus B 19, human herpesvirus and influenza virus
2) Deficiency of vitamin B12, folic acid, zinc, and copper.
3) Epstein-Barr virus-induced posttransplant proliferative disorders
4) Others.
Treatment of neutropenia:
1) Neutropenia with less than 100 cells/mm3 has a high risk of infection. It is there wise to reduce the dose of medications and or increase WBC count by using G-CSF or GM-CSF.
2) Treatment starts with G-CSF or GM-CSF when there is sepsis, hypotension, neutropenia, fever, etc.
3) Prophylaxis with G-CSF or GM-CSF should continue until WBC is in an acceptable range.
Thrombocytopenia treatment:
1) Immunosuppressive medications should be discontinued, or a dose reduction is required. Platelets transfusion is needed especially if it is below 20000/ mm3.
2) Other medications like thrombopoietin receptor agonists like romiplostim and eltrombopag.
The level of evidence is level 5
· Introduction
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number of these drugs are associated with hematological complications. Myelosuppression presenting as cyto -penia is not uncommon in kidney transplant recipients (KTRs).1 From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.
Most episodes of cytopenia are observed during the first 3 months. culprit agents include:
1. Mycophenolate mofetil (MMF) and enteric-coated mycophenolate Sodium.
2. Rituximab Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients
3. Ganciclovirand valganciclovir.
4. Antithy -mocyte globulin (ATG).
5. Tacrolimus.
6. Sirolimus.
7. Trimethoprim-sulfamethoxazole.
Cautious reduction or complete withdrawal of the offending agent may be urgently warranted; however, as described here, potential risks should be expected and managed accordingly. These risks include acute rejection in case of immunosuppression reduction or infection if prophylactic medications held.
Neutropenic KTRs commonly experience more intra-abdominal infections (22.5%) than those with normal neutrophil counts (7%-10%). Both tacrolimus and MMF therapy are commonly associated with neutropenia.
Consequences of Hematological Cytopenia
Neutrophils and lymphocytes have fundamental roles in prevention of infection. However, as detailed here, cytopenia can cause additional drawbacks. Leukopenic KTRs are vulnerable to the development of opportunistic infections, On the other side physicians should be cautious in the treatment of patients with high immunological
risk, when considering reducing their MMF especially those within 3 months after transplant, as some reports up to 50% increased risk of acute rejection with reduction or withdrawal of MMF.
Drug-induced Leukopenia and Neutropenia
As detailed here, a number of agents have been implicated in posttransplant leukopenia and neutropenia development.
Rituximab
Rituximab is a potent chimeric anti-CD20 monoclonal antibody.
Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial as follows: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma. It is usually late onset, that means after 4 weeks of dose, Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
Antithymocyte globulin
Thymoglobulin activity is not confined to T cells; rather, a wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs. Leukopenia incidence with ATG is variable, with studies showing 10%,38 %, 33.5% and 50%,as a result of differences in protocols and variabilities in periods of administration. The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3.36,39 Treatment with ATG should be held when platelet count declines to
less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L.
Alemtuzumab
Alemtuzumab is an anti-CD52 humanized mono – clonal immunoglobulin G1 antibody. With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports. With regard to management, dose modification of other drugs such as MMF or
valganciclovir or cotrimoxazole is required.
interleukin receptor antagonists
Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab, a monoclonal chimeric, and daclizumab, a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in KTRs. Because anti-IL-2R activity is confined to activated T cells, their leukopenic and thrombocytopenic drawbacks are currently rare compared with drawbacks with ATG and alemtuzumab (10%
to 15% vs 5% for basiliximab). Considering these observations, the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated
mycophenolate sodium
These agents are inosine monophosphate dehydro -genase inhibitors that can inhibit both cell-mediated and humoral immune responses through suppression of guanosine nucleotide synthesis de novo pathways in T/B lymphocytes, arresting their differentiation. Regarding MMF hematotoxicity, 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy. To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and leukopenia with monitoring for possible rejection that could occur as seen in retrospective studies. Several approaches could be added for the management of this type of leukopenia, including:
1. Preemptive dose reduction of MMF after ATG and alemtuzumab induction,
2. Shifting to a suitable mammalian target of rapamycin inhibitor (eg, sirolimus or everolimus may reverse cytopenia5,),
3. Halving the CMV prophylactic dose of valganciclovir.
Tacrolimus
Tacrolimus is the mainstay of clinical immuno -suppression regimens.63 Although much less common in renal transplant recipients, 16.92% of hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy, including anemia, neutropenia, and combined anemia/neutropenia. A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include everolimus, belatacept, or eculizumab.
Azathioprine
Azathioprine is a traditional antimetabolite that was introduced in 1960 and has been greatly replaced by the more potent MMF in immunosuppression after kidney transplant. It may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day. An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity. Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine. Patients with complete lack or low TPMT activity are
vulnerable to developing severe, life-threatening myelotoxicity. To ameliorate the risk of myelosuppression, 2 techniques have been proposed:
· The first is monitoring of 6-thioguanine nucleotide in RBCs,
· Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
Significant drug interaction with allopurinol can occur, so 25-50% dose reduction is recommended.
Mammalian target of rapamycin inhibitors
Severity of myelotoxicity is dose dependent, with involvement of about 20% of
KTRs on sirolimus. A trough level of >12 ng/dL is associated with development of leukopenia and thrombocytopenia. In most patients, mTORi-induced leukopenia
resolves spontaneously, dose reduction of MMF or sirolimus rarely needed.
valganciclovir
The higher bioavailability of this agent (70% vs 7%nfor oral ganciclovir) has also affected its myelotoxicity profile. Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia. The resultant
cytopenia may be potentiated by several factors:
1. Higher doses of the drug (900 mg or more)
2. Low body mass index.
3. Concomitant MMF administration.
Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal. This dose level, however, has been shown to be equally effective as 900 mg/day for CMV prophylaxis; consequently, the lower dose has been recommended.
Ganciclovir
Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs. The bioavailability of this drug is rather poor when given orally; therefore, it is always given intravenously. Through its myelosuppressive effects, ganciclovir causes leukopenia, with
rates of 7.1% to 23.1%.
valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole
Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis. Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia.
Folinic acid can reverse this side effect. Similarly, folate-depleted granulocyte precursors have been observed in another in vitro report.
Dapsone
Dapsone is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia. Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis.
Drug-induced Lymphopenia
In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia due to neutropenia. The latter is usually complicated by augmented risk of serious infection; on the other hand, lymphopenia is usually the result of induction
therapy with lymphocyte-depleting medication (eg, rabbit ATG).
Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia, rituximab, ATG, basiliximab, alemtuzumab, sirolimus, TMP/SMX, ganciclovir, MMF and MPA.
Hemophagocytic Syndrome
Hemophagocytic syndrome can be associated with cytopenia. Several viral infections (CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
Therapy for Drug-induced Hematological Cytopenia
In addition to the protocols above, administration of “colony stimulating” factors if there is no accepted response to the previous maneuvers. Of note, activation of the innate immunity would lead to acute rejection as a side effect. Some evidence has suggested that G-CSF may decrease rejection episodes.
Level 4, review article.
Briefly summarise this article
Renal transplant is the best treatment option in ESRD. Post transplant patient require immune suppressants. Anaemia,leukopenia, neutropenia, and thrombocytopenia are common haematological complications. This can lead to opportunistic infections. This can lead to stopping the immune suppressant which will increase the risk of graft rejection. Identifying culprit is not possible usually and the only option remains to stop immunosuppressants. Future strategies should focus on less toxic agents, early identification and prompt treatment of infections. This can improve graft outcome.
Drugs causing myelotoxicity
Rituximab
With cytopenia grade 3/4 is seen in 48% , lymphopenia in 40%, neutropenia in 6% and leukopenia in 4%.
Dose needs adjustment and some time we have to stop it.
ATG
It can affect wide range of cells and cross reactivity with lymphoid cell can lead to neutropenia.
Dose can reduced to 50% if –
Platelets count drops to 50000-75000/mm2
WBC-2000-3000/mm2
It should be stopped if-
Platelets <50000
WBC<2000
Almetuzumab
More toxic than ATG. Leucopenia is seen in around 33-42%.
Dose reduction can reach uppto 14 mg/kg.
Dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is needed.
IL2 receptor Antagonists
In less than 50 % recepeints leukopenia and thrombocytopenia can be seen. Optimum in low to moderate risk patients.
MMF
The toxicity depends upon dose and leukopenia seen in 11-40%. The option can be to reduce dose but cost can be rejection. In this situation the way forward can be to adjust other drugs which cause myelosuppression.
Tacrolimus
It can cause netropenia especially if used with MMF. This is least bone marrow toxic
Azathioprine
Azathioprine induced leukopenia presents in first month. Dose reduction or temporary withdrawl is required. Previous history of drug induced leukopenia will increase the risk by 70%. An important factor to determine azathioprine toxicity is thiopurine S-methyl transferase (TPMT) activity. Those with lack of low TPMT activity are at high risk.
mTOR inhibitors
Myelosuppression is dose dependent. If used with almetuzumab and MMF then it can be more severe
Dapsone
It is used against P.Jirvecii. It can cause neutropenia and effects can aggravated by development of agranulocytosis.
Valganciclovir, ganciclovir, valacyclovir
These can cause leukopenia and it can be worsened if used with MMF. Leukopenia can resolve spontaneously . CMV prophylaxis recommended.
Identification of different causes of myelosuppression is the best choice.
What is the level of evidence provided by this article?
Review article
Level V
It is a level 5 study (Narrative review)
The paper describes myelosuppression (leukocyte, lymphocyte, or platelet) induced by medications used in kidney transplantation, in addition to discussing the overlap caused by the concomitant use of two or more drugs.
Medications may present leukopenia (decreasingly) rATG, azathioprine, Alemtuzumab, MMF, sulfa drugs, valganciclovir, rituximab, everolimus, basiliximab and valaciclovir.
Some of these drugs can cause neutropenia, such as rituximab, alemtuzumab, valganciclovir, the combination of MMF with tacrolimus, sulfa drugs, and tacrolimus alone.
Other drugs can cause thrombocytopenia, such as rATG, Ganciclovir, Sirolimus, Sulfas, Everolimus, Alemtuzumab and Basiliximab.
The association of these drugs, as well as the dose, duration, and clinical and metabolic conditions of the individual can intensify these symptoms.
Differential diagnosis includes metabolic issues related to vitamin B12, folic acid, zinc, or copper. Epstein Baar, Cytomegalovirus, Parvovirus B19, Herpesvirus 6, Influenza, and Rickettsiae infections should be included.
summary of the article
Drug-Induced Myelosuppression in Kidney Transplant Patients
kidney transplantation is a solution for ESRD, and the used immunosuppressive medications is associated with different adverse effects, myelosuppression is one of these serious and severe adverse effects.
Myelosuppression In KTRs(drug induced)
Incriminating Agents:
MMF, enteric-coated mycophenolate sodium, AZA, ganciclovir and valganciclovir, anti-thymocyte globulin (ATG), tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Presentation of Myelosuppression:
May present clinically with serious infection or appeared as cytopenia in the lab results.
a. Pancytopenia involves the 3 cell lines(RBCs, WBCs and Platelets).
b. Bicytopenia involves 2 of 3 cell lines.
c. Thrombocytopenia involves low platelet count(<150). The CTCAE has graded thrombocytopenia into 4 grades:
I.subnormal (75 000-150,000 cells//mm3).
II.low (50000-75000 cells/mm3.
III moderate (25 000-50 000 cells/mm3).
IV. critical (<25 000/mm3).
d.leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels.(the latter 3 levels indicating abnormal with variable severities).
I. 3000 cells/mm3 (normal).
II. 2000 to 3000 WBCs/mm3.
III.1000 to 2000 WBCs/mm3.
IV. <1000 WBC/mm3
Absolute neutrophil count (ANC) is used to assess the magnitude of neutropenic severity as follows:
ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia.
Grades of Neutropenia:
· Mild neutropenia: ANC level of 1000 to 1500/μL or 1 to 1.5 × 109/L.
· Moderate neutropenia: ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L.
· Severe neutropenia (agranulocytosis): ANC level of <500/μL or <0.5 × 109/L
Drug-induced neutropenia and leucopenia
Rituximab:
· It is anti-CD20 monoclonal antibody.
· Resulting in B-cell depletion and thus affecting phagocytosis by macrophages, complement-mediated cytotoxicity, and antibody-dependent cell-mediated toxicity by natural killer cells.
· Uses in KT; induction agent in ABOi-Kx, acute rejection, cABMR and resolution therapy of posttransplant lymphoproliferative disorder.
· RTX-induced cytopenia has been reported in 48% of patients in one trial. Cytopenia can occur 4 weeks after start of RTX.
· Incidence of leukopenia after rituximab therapy ranges from 19% to 24.6%.
ATG:
· cross-reaction of antibodies toward nonlymphoid tissue may result in the development of neutropenia.
· higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
· Incidence of leucopenia is high when ATG is combined with AZA( up to 50%).
· ATG should be held if Plt < 50000/mm3 or WBC < 2000/mm3.
· Medications that cause leucopenia should be monitored when there’s concurrent use of ATG( MMF, AZA and steroids).
Alemtuzumab:
· It is anti-CD52 monoclonal immunoglobulin G1 antibody.
· The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
· The incidence is higher (47%) if neutropenia is also present.
· Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose.
· With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required.
Interleukin 2 Receptor (IL-2R) antagonists:
· Incidence of leucopenia is 10.6% in KTRs receiving Basiliximab.
· Would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
· 11.8% to 40% of KTRs can develop leukopenia related to MMF therapy.
· Both ATG-related and alemtuzumab- related cytopenia may mask the diagnosis of MMF myelotoxicity.
· MMF-related cytopenia can be treated with dose reduction or complete withdrawal.
Tacrolimus :
· Tacrolimus may intensify MMF myelotoxicity. Tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
· TAC-related cytopenia can be treated with dose reduction of MMF with consideration of alternatives(everolimus, Belatacept and eculizumab).
Azathioprine:
· May induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
· AZA-related cytopenia presents in the 1st after Kx and can be treated with dose reduction or withdrawal.
· Concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%.
mTORi agents
· Cytopenia with mTORi agents can be observed within the first 4 to 8 weeks.
· Combination of sirolimus and MMF after Alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
· mTORi-related leucopenia can resolve spontaneously, if not; dose reduction of MMF and mTORi is required with drug cessation being the last resort.
Valganciclovir:
· Anti-CMV therapy and prophylaxis in KTRs.
· 10% to 28% of KTRs are vulnerable for leukopenia development.
· Valganciclovir myelotoxicity and leucopenia can be potentiated and aggravated by concomitant use of MMF, higher doses of 900 mg or more and low body mass index.
· In comparison to ganciclovir, the risk of neutropenia exceeds 188%.
· G-CSF may be required with prolonged periods of prophylaxis.
·
Ganciclovir:
· Anti-CMV therapy and prophylaxis in KTRs.
· It causes leukopenia, with rates of 7.1% to 23.1%.
· Less myelosuppressive than valganciclovir.
· Related leucopenia responds to dose reduction and some may need drug withdrawal.
Valacyclovir:
· Used for CMV prophylaxis and treatment of herpes simplex in KTRs.
· Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
· Incidence of leukopenia ranges from 6% to 14% in RCT.
· The risk of neutropenia with valganciclovir therapy is currently 730% higher than with valacyclovir.
· Combined MMF and valacyclovir therapy may aggravate drug- induced myelotoxicity.
· MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
· Demerits; high pill burden and more neurological complications.
Trimethoprim-sulfamethoxazole:
· Used for Pneumocystis jirovecii prophylaxis.
· Associated with neutropenia, leukopenia and megaloblastic anemia.
· Trimethoprim per se can cause dose- dependent inhibition of granulopoiesis in vitro. Folinic acid can reverse this side effect.
· Induce cytopenia in KTRs in only 2%.
· Concurrent use of AZA can aggravate myelosuppression effect of TMP/SMX.
Dapsone:
· It is an alternate agent for Pneumocystis jirovecii prevention.
· It is associated with many hematological complications, including neutropenia.
· The neutropenic effects of dapsone may be aggravated by development of agranulocytosis.
Drug-induced lymphopenia
· It results from induction therapy with lymphocyte-depleting agent(rATG).
Drug-induced thrombocytopenia
Numbers of agents have been incriminated in the evolution of post-transplant thrombocytopenia, including: RTX, ATG, Alemtuzumab, anti-IL2R, MMF, mTORi, ganciclovir and TMP/SMX.
· Because rituximab-related thrombocytopenia rarely induces bleeding, platelet infusion is rarely indicated.
· Alemtuzumab can cause auto-immune thrombocytopenia. Bleeding requiring surgical intervention has been observed in 12% of KTRs.
· mTORi-related myelotoxicity is dose dependent.
· Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia, and
· Thrombocytopenia occurs in 5.8% of KTRs receiving Basiliximab which is preferred for thrombocytopenic KTRs with low to moderate risk of rejection.
· Myelotoxicity of MMF is dose dependent and usually related to the trough levels of MPA.
Differential diagnosis of drug-induced leucopenia and thrombocytopenia:
· Deficiency of B12, folic acid, zinc and copper.
· Epstein-Barr virus-induced posttransplant proliferative disorders.
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses.
· Ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Hemophagocytic Syndrome
· can be associated with cytopenia.
· Incriminated viral infections: CMV, adenovirus, Epstein-Barr virus, human herpesvirus 8, human herpes virus 6, parvovirus B19, and BK polyomavirus.
Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations: renal ischemic events, antibody-mediated rejection, and viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
Therapy for drug-induced hematological cytopenia
There are a number of other specific interventions beside aforementioned policies.
Specific treatment of neutropenia:
ANC <100 cells/mm3 persisting more than 7 days constitutes an extremely high risk of opportunistic infection.
· dose reduction or complete withdrawal of the suspected agent.
· correction of WBC count with G-CSF or GM-CSF.
· Therapeutic indications for G-CSF/GM-CSF are: sepsis, hypotension, neutropenic pyrexia of >7 days, pneumonia or fungal infection and adjunctive therapy with antibiotics in the aforementioned situations.
· Prophylactic administration of G-CSF/GM-CSF is needed in the followings : prolonged pyrexia, severe neutropenia with ANC <500/μL, and prolonged neutropenia of more than 7 days.
Treatment of thrombocytopenia
· Immediate withdrawal of suspected agent in case of idiosyncratic effect. For bone marrow suppression, dose reduction or cessation may be required.
· Platelet transfusion is needed in the followings; life-threatening bleeding risk, serious decline of platelet(<20000/mm3) or before an invasive procedure.
· Thrombopoietin receptor agonists (romiplostim and eltrombopag) have been efficacious in thrombocytopenia management.
· Cut off values for platelet count before procedure;
I. The cut-off therapeutic level >50 000/mm3 with commencement of invasive maneuvers (eg, allograft biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
II. > 50000/mm3 is recommended for lumbar puncture.
III. ≥100 000/mm3 ; before ocular and neurosurgical invasive procedure. Also recommended for invasive renal procedure because of high vascularity of renal tissue.
This is a review article with level of evidence grade V
# Briefly summarise this article
*Immunosuppressive medication are important for better graft outcome, but it associated with many hematological complications that occur after kidney transplant include posttransplant anemia, leukopenia, neutropenia, and thrombocytopenia.
* Myelosuppression presenting as cytopenia occure in 20% to 60% of KTRs and most episodes of cytopenia are seen during the first 3 months.
*Cytopenia can be identified as follows:
Pancy topenia involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets;
bicytopenia involves 2 of 3 cell lines
leukopenia can be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) into 4 levels
3000 cells/mm3 (normal),
2000 to 3000 WBCs/mm3,
1000 to 2000 WBCs/mm3,
<1000 WBC/mm3 (the latter 3 levels indicating abnormal with variable severities).
# Absolute neutrophil count (ANC) = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
*Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to
1.5 × 109/L,
* Moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 109/L,
*Severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L
# Platelet count of 150 000/mm3 is considered the lower limit of normal level in many laboratories.The CTCAE graded thrombocytopenia into 4 levels.
*Grade I or subnormal (75 000-150,000 cells//mm3)
*Grade II or low (50000-75000 cells/mm3
*Grade III or moderate (25 000-50 000 cells/mm3)
*Grade IV or critical (<25 000/mm3).
# Consequences of Hematological Cytopenia
*When ANC is <1000 cells/μL, susceptibility to infection increases, the predisposition to frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenic decline.
*Both tacrolimus and MMF therapy are commonly associated with neutropenia.
Withdrawal of prophylactic agents
# Drug-induced Leukopenia and Neutropenia
# Rituximab
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that lead to B-cell depletion.
It induced cytopenia (grade 3/4) in 48% of patients in 1 trial as follows: 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma.
* Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia), it seen post sixth rituximab dose.
* Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently implicated in its evolution.
* Dose reduction or drug withdrawal is usually the ideal response for hematological recovery.
# Antithymocyte globulin
* Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia. Leukopenia incidence with ATG is variable as showed with different studies (highest incidence 50%, explained by the concurrent use of azathioprine.
*The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3 or WBC count reaches 2000 to 3000 per mm3, the treatment should be held when platelet less than 50 000 per mm3 or when WBC count is less than 2000 per mm3. CD3+ T-cell count should be monitored when less than 0.05 × 109/L or total lymphocyte count should be maintained as less than 0.3 × 109/L, which is a suitable alternative if CD3 monitoring is not available and other medications that may cause cytopenia should also be monitored
* This approach is successful in reducing the AR, infections, and cytopenia.
# Alemtuzumab
*The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports, the incidence is higher (47%) if neutropenia is also present.
* Compared with ATG, the myelotoxic effects of alemtuzumab are more seve. However, infectious episodes are usually not life-threatening.
* A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may much less than that required for ATG-induced leucopenia also reduction of valganciclovir or cotrimoxazole is required
#Interleukin receptor antagonists
*Two interleukin 2 receptor (IL-2R) antagonist induction (Basiliximab and Daclizumab)
*Because anti-IL-2R activity is confined to activated T cells, their leukopenic and thrombocytopenic are rare compared with ATG and alemtuzumab (10% to 15% vs 5% for basiliximab).
* It is optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
# Mycophenolic mofetil and enteric-coated mycophenolate sodium
*Due to MMF hematotoxicity, 11.8% to 40% of KTRs can develop leucopenia
*The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA
*Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMFrelated leukopenia.
*The management by reduce the dose or complete withdrawal has benefit in MMF-induced neutropenia and leukopenia, but it can result in AR.
*Shifting to a suitable mammalian target of rapamycin inhibitor (sirolimus or everolimus) may reverse cytopenia and halving the CMV prophylactic dose of valganciclovir, which could also be another
preventive measure.
# Tacrolimus
*hematological alterations in cardiothoracic transplant recipients were related to tacrolimus therapy,
including anemia, neutropenia, and combined anemia/neutropenia
*May also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
*Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant.
*Dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
# Azathioprine
*May induce leukopenia and neutropenia in almost half of KTRs, and most cases of leukopenia present in the first month after transplant, so, dose reduction or transient drug withdrawal is usually sufficient.
*An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine
S-methyl transferase (TPMT) activity.
*Drugs that interact with azathioprine include Allopurinol, so concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%
*Azathioprine drug levels should be measure weekly, with full blood count in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment.
# Mammalian target of rapamycin inhibitors
*The most common (mTORi), sirolimus and everolimus, have been involved in many myelotoxic side effects.
*Leukopenia had been showen in a meta-analysis that involved conversion from (CNI) to mTORi and the severity of myelotoxicity is dose dependent and about 20% of KTRs on sirolimus.
*A trough level of >12 ng/dL is highly associated with development of leukopenia and thrombocytopenia although it can occur even with lower drug levels.
*Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free
regimens may result in severe leukopenia.
* mTORi cytopenia seen the first 4 to 8 weeks
*Patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously and drug cessation may be the last resort for resistant cases.
# valganciclovir
*Although 10% to 28% of KTRs are vulnerable for leukopenia development in 4.9% to 37.5% of patients may develop neutropenia.
*Cytopenia may be potentiated by several factors, including higher doses of the drug, low body mass index, concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
*Although leukopenia can develop within 3 months, resolution of leukopenia can occur spontaneously with or without treatment.
* Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal.
# Ganciclovir
* A lesser incidence of leukopenia (7.1% vs 13.5%) and neutropenia (3.2% vs 8.2%) was observed in
ganciclovir-treated patients compared with those on valganciclovir therapy
# Valacyclovir
* Incidence of leukopenia ranges from 6% to 14% in randomized clinical trials. The risk of neutropenia
with valganciclovir therapy is currently 30% higher than with valacyclovir.
*Combined MMF and valacyclovir therapy may aggravate druginduced myelotoxicity
*When compared with ganciclovir, dose modification is less frequently employed with valacyclovir.
# Trimethoprim-sulfamethoxazole
*Several types of cytopenia are associated with it is use include neutropenia and leukopenia and Megaloblastic anemia.
* Trimethoprim per se can cause dosedependent inhibition of granulopoiesis in vitro.
*The use of trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis in KTRs may
induce leukopenia in only 2%
*In combined with azathioprine therapy can aggravate drug-induced myelosuppression.
# Dapsone
*The neutropenic effects of dapsone may be aggravated by development of agranulocytosis
# Drug-induced Lymphopenia
*In leukopenic KTRs, it is essential to recognize lymphopenia, which is different from leukopenia
due to neutropenia. The latter is usually complicated
by augmented risk of serious infection
# Posttransplant Drug-induced Thrombocytopenia
Rituximab
*Has been reported in 48% of patients in one trial, with rate of thrombocytopenia in 2% of lymphoma patients.
*Antithymocyte globulin
An incidence of thrombocytopenia ranging from 10% to 26.5%
*Alemtuzumab
Alemtuzumab-induced thrombocytopenia has been observed in 14% of KTR
*Interleukin receptor antagonists
.*Mycophenolic mofetil and enteric-coated
mycophenolate sodium
Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia, and pancytopenia.
*Mammalian target of rapamycin inhibitors
*Ganciclovir
Induce thrombocytopenia in 23.1% of KTRs.
*Trimethoprim-sulfamethoxazole
Several hematologic complications like thrombocytopenia.
# Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
B12, folic acid, zinc, and copper deficiencies, Epstein-Barr virus-induced posttransplant proliferative disorders, Cytomegalovirus, parvovirus B19, human herpesvirus , influenza viruses, and Ehrlichiosis and Hemophagocytic Syndrome
# What is the level of evidence provided by this article
Level 5
Briefly summarise this article
Immunosuppressive drugs are crucial to allograft survival in transplant recipients. However, a number
of these drugs can cause myelosuppression. 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant.2 Most episodes of cytopenia are observed during the first 3 months.
Cytopenia can be identified as follows: pancytopenia, bicytopenia, thrombocytopenia and leukopenia in which can be graded into 4 levels. Leukopenia is also termed alternatively with neutropenia, although these terms are not synonymous. Leukopenic KTRs are vulnerable to the development of opportunistic infections.
Drug-induced Leukopenia and Neutropenia
Rituximab
· A potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion.
· Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes, in attempted treatment of chronic antibody-mediated rejection, and in resolution therapy of posttransplant lymphoproliferative disorder.
· Rituximab-induced cytopenia (grade 3/4) has been reported in 48% of patients in 1 trial.
· Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia: usually observed after the sixth rituximab dose with incidence around 37.5% -48%.)
· Dose reduction or drug withdrawal maybe indicated.
Antithymocyte globulin
· Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
· The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm 3 or WBC count reaches 2000 to 3000 per mm3. Treatment with ATG should be held when platelet count declines to less than 50 000 per mm 3 or when WBC count is less than 2000 per mm3.
Alemtuzumab
· An anti-CD52 humanized monoclonal immunoglobulin G1 antibody
· The leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports
· Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose
· However, infectious episodes are usually not life-threatening
Interleukin receptor antagonists
· Both Basiliximab and daclizumab can suppress IL-2 meditated T cell activation and proliferation.
· Basiliximab has lower incidence of Leukopenia around 10.6% in one study.
· The anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
· The hematological sequelae with myelosuppression are the most common cause requiring MMF dose reduction, with 46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
· The myelotoxic impact of MMF is dose dependent.
· To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response at the expense of increased risk of acute rejection.
Tacrolimus
· Mainstay of clinical immunosuppression regimens.
· Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
· Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant.
· A dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
Azathioprine
· Azathioprine may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
· Most cases of azathioprine induced leukopenia present in the first month after transplant. In this situation, a dose reduction or transient drug withdrawal is usually sufficient
· An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
· Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid. Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%.
· Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
· Sirolimus and everolimus are most common examples and are associated with myelosuppression.
· Severity of myelotoxicity is dose dependent, with involvement of about 20% of KTRs on sirolimus. A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia.
· Development of cytopenia with mTORi agents can be usually observed within the first 4 to 8 weeks.
· In most patients, mTORi-induced leukopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required.
Valganciclovir
· Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia.
· The resultant cytopenia may be potentiated by several factors, including higher doses of the drug (900 mg or more), low BMI and concomitant MMF administration.
· leukopenia can develop within 3 months, but resolution of leukopenia can occur spontaneously with or without treatment. Risk of infection is usually low.
· Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal.
Ganciclovir
· Ganciclovir is used for anti-CMV therapy and prophylaxis.
· Ganciclovir causes leukopenia, with rates of 7.1% to 23.1%.
Vlacyclovir
· Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs.
· Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild with incidence ranges from 6-14%.
Trimethoprim-sulfamethoxazole
· Commonly used drug for Pneumocystis jirovecii prophylaxis.
· It may induce leukopenia in only 2% of KTRs recipients.
· Folinic acid can reverse this side effect.
Dapsone
· An alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
· The neutropenic effects of dapsone may be aggravated by development of agranulocytosis.
Drug-induced Lymphopenia
· Usually complicated by augmented risk of serious infection
· lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (eg, rabbit ATG).
Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia:
1- Rituximab 48%
2- Antithymocyte globulin 10 – 26.5%
2- Alemtuzumab: 14%
3- Interleukin receptor antagonists 2.8 – 5.8%
4- Mycophenolic mofetil and enteric-coated mycophenolate sodium 46.5% (pancytopenia)
5- Mammalian target of rapamycin inhibitors 10 – 17%
6- Ganciclovir 23.1%
7- Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
· In addition to medication-induced myelotoxicity, a variety of etiologies can share in the development of these serious hematological events, including B12, folic acid, zinc, and copper deficiencies.
· Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia.
· Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Hemophagocytic syndrome
· Can be associated with cytopenia.
· Several viral infections (CMV, adenovirus Epstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
Specific treatment of neutropenia
· The first step is determining the patient’s full detailed history to unravel possible culprit.
· Measurement of ANC can be used to evaluate the severity of neutropenia, with severe neutropenia indicated by ANC <500/μL.
· The next therapeutic step for WBC count correction would be administration of “colony- stimulating” factors if there is no accepted response to the previous maneuvers.
· Colony-stimulating factors have been introduced to manage severe leukopenia in KTRs.
What is the level of evidence provided by this article?
Level of evidence V: Evidence from systematic reviews of descriptive and qualitative studies (meta-synthesis).
Drug-Induced Myelosuppression in Kidney Transplant Patients
Introduction
Cytopenia is not uncommon in kidney transplant recipients (KTRs).
From 20% to 60% of KTRs experience at least
episode of cytopenia after transplant (which are observed mostly during the first 3 months). The list of culprit agents includes MMF and enteric-coated mycophenolate sodium, ganciclovir and valganciclovir, ATG, tacrolimus, sirolimus, and trimethoprim-sulfamethoxazole.
Consequences of Hematological Cytopenia
leukopenia augments the risk of infection by disrupting immunogenic integrity
and liability of ubiquitous and opportunistic infections
Drug-induced Leukopenia and Neutropenia
A number of agents have been implicated in posttransplant leukopenia and
neutropenia development:
1- Rituximab:
Cause B-cell depletion and thus affecting phagocytosis, complement-mediated cytotoxicity, and ADCC
Can cause Rituximab-induced cytopenia (grade 3/4)
Can cause late-onset neutropenia
2. Antithymocyte globulin
A wide range of blood cells are vulnerable to
the antibody effects of this agent, including T cells, B
cells, natural killer cells, monocytes, neutrophils,
platelets, and RBCs. Also, cross-reaction of
antibodies toward nonlymphoid tissue may result in
the development of neutropenia.
3. Alemtuzumab: an anti-CD52
Compared with ATG, the myelotoxic effects
of alemtuzumab are more severe, with the lowest
WBC counts observed 130 days after the last given
dose. However, infectious episodes are usually not
life-threatening.
4. Interleukin receptor antagonists
Interleukin 2 receptor (IL-2R) antagonist ( basiliximab, and daclizumab) , Because anti-IL-2R activity is confined to activated T cells, their leukopenic and throm bocytopenic drawbacks are rare compared
with with ATG and alemtuzumab
These agents would be an optimum therapeutic option for leukopenic
KTRs with low/moderate risk of rejection.
5. MMF and enteric-coated mycophenolate sodium
MMF can cause hematotoxicity ( the diagnosis could be masked with ATG-related and alemtuzumabrelated cytopenia)
The myelotoxic impact of MMF is dose dependent
Concomitant administration of valganciclovir,
valacyclovir, and fenofibrate may exaggerate MMF related leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal seems to be a reasonable response to MMF-induced neutropenia and
leukopenia.
Tacrolimus
anemia, neutropenia, and combined
anemia/neutropenia is less common.
It may intensify MMF myelotoxicity, and tacrolimus and MMF
combinations can induce neutropenia
Neutropenia can be observed
within the first 3 months after transplant.
No particular test for diagnosis, except for leukocytic
count normalization after the withdrawal of
tacrolimus. A dose reduction of MMF is suggested in
patients on dual immunosuppression therapy.
Azathioprine
May induce leukopenia and neutropenia in almost half of KTRs,
particularly with doses greater than 1.99 mg/kg
body weight/day.
leukopenia present in the first month after
transplant.
In this situation, a dose reduction or
transient drug withdrawal is usually sufficient.
Thiopurine S-methyl transferase (TPMT) activity determine the magnitude of its toxicity.
active TPMT may lead to higher risk of myelotoxicity
Allopurinol interact with azathioprine
Azathioprine levels should be monitored weekly,
with full blood count monitoring in the first month,
then twice per month during the second and third
months, and then monthly or less according to dose
adjustment.
Mammalian target of rapamycin inhibitors
rapamycin
inhibitors (mTORi), sirolimus and everolimus,
can cause dose sependent myelotoxicity
Sirolimus and MMF combination therapy after
alemtuzumab induction in steroid and CNI-free
regimens may result in severe leukopenia.
Everolimus can cause leukopenia
Cytopenia can be observed within the first 4 to 8 weeks.
valganciclovir
cytopenia may be potentiated by higher doses of the drug (900 mg or more)
low body mass index, and
concomitant MMF administration,
Although leukopenia can develop within 3
months, resolution of leukopenia can occur
spontaneously with or without treatment.
Risk of infection is usually low.
Ganciclovir
Causes leukopenia, with rates of 7.1% to 23.1%.
therapy respond to dose reduction, and some
require ganciclovir cessation.
valacyclovir
Compared with valganciclovir and ganciclovir,
myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole
Can cause neutropenia and leukopenia and megaloblastic
anemia.
combined azathioprine therapy with it can aggravate drug-induced
myelosuppression.
Dapsone
Can cause neutropenia which may be
aggravated by development of agranulocytosis
Posttransplant Drug-induced Thrombocytopenia
A number of medications have been implicated in the evolution of posttransplant thrombocytopenia
1. Rituximab
2. ATG
For treatment, medications that affect cytopenia
prevalence should be monitored (eg, holding off or
reducing MMF with concurrent ATG-induced
cytopenia) Thrombocytopenia can also be
exacerbated with ATG and mTORi combination.
3. Alemtuzumab
4. Interleukin receptor antagonists
5. MMF and enteric-coated mycophenolate sodium
6. Mammalian target of rapamycin inhibitors
7. Sirolimus
and everolimus,
Ganciclovir
Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia
and Thrombocytopenia
In addition to medication-induced myelotoxicity, a
variety of etiologies can share in the development of
these serious hematological events, including B12,
folic acid, zinc, and copper deficiencies
1. Epstein-Barr virus-induced posttransplant proli –
ferative disorders
2. CMV, parvovirus
B19, human herpesvirus 6, influenza viruses, and
ehrlichiosis
3. Hemophagocytic Syndrome
Caused by (CMV, adenovirus,
EBV, HHV 8 & 6, parvovirus B19, and BKV)
4. TMA
Therapy for Drug-induced Hematological Cytopenia
1. reduction or complete withdrawal
of the suspected agent.
2. clinician should remain
alert to look for (1) an opportunistic infection and (2)
early signs of acute rejection as a result of reduction
of immunosuppression.
3. G-CSF or GM-CSF can be utilized in
4. If thrombocytopenia is due to idiosyncratic reaction, immediate withdrawal of
the suspected agent is required; if BM suppression is the underlying mechanism, dose reduction or complete drug cessation is required
5. Patelet transfusion: life-threatening bleeding risk, serious
decline of platelet count (<20 000/mm3), or before
an invasive procedure.
The recommended cut-off therapeutic level for
platelet transfusion should be >50 000/mm3 with
commencement of invasive maneuvers
6. Further Developments
Thrombopoietin receptor agonists have been
efficacious in thrombocytopenia management.
▪︎Level of evidence: 5
Drug-Induced Myelosuppression in Kidney Transplant Patients
Summary:
Introduction:
A kidney transplant is the best therapeutic option for suitable patients with end-stage kidney failure.
Hematological complications after kidney transplant include post-transplant anemia, leukopenia, neutropenia, and thrombocytopenia. Severely persistent leukopenia and neutropenia events predispose patients to infection, including opportunistic infections
Immunosuppressive drugs are crucial to allograft survival in transplant recipients:
Mycophenolate mofetil (MMF) .
Enteric-coated Mycophenolate sodium.
Ganciclovir.
Valganciclovir.
Anti Thy -myocyte Globulin (ATG).
Tacrolimus.
Sirolimus.
Trimethoprim-sulfamethoxazole.
Mycophenolic mofetil and enteric-coated mycophenolate sodium MMF:
These agents are inosine monophosphate dehydrogenase inhibitors that can inhibit cell-mediated and humoral immune responses by suppressing guanosine nucleotide synthesis de novo pathways in T/B lymphocytes, arresting their differentiation.
The hematological sequelae with myelosuppression are the most common cause requiring MMF dose reduction, with 46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
Azathioprine:
Azathioprine is a traditional antimetabolite that was introduced in 1960 and has been significantly replaced by the more potent MMF in immunosuppression after kidney transplant.
Thiopurine S-methyl transferase (TPMT) activity is a critical factor in determining the magnitude of azathioprine-induced myelotoxicity.
Drugs that interact with azathioprine include allopurinol, which inhibits and should be monitore for xanthine oxidase activity leading to a decline in purine metabolism to uric acid
. Azathioprine levels weekly,
Tacrolimus:
Tacrolimus is the mainstay of clinical immunosuppression regimens
Mechanisms of tacrolimus-induced neutropenia
include direct suppression of myeloid cells, with bone marrow hypoplasia observed in hepatic
Transplant recipients,64 altered cytokine production by T lymphocytes and monocytes, and output of antimyeloid precursors and anti-mature neutrophil antibodies.
Rituximab:
Rituximab is a potent chimeric anti-CD20 monoclonal antibody
is commonly used as a part of the induction agent in ABO-incompatible transplant
procedures, in the Treatment of acute rejection episodes, in attempted Treatment of chronic antibody-mediated rejection.
Antithymocyte globulin:
Thymoglobulin activity is not confined to T cells; rather, a wide range of blood cells are vulnerable to the antibody effects of this agent, including T cells, B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.32,33 Moreover, cross-reaction of
antibodies toward nonlymphoid tissue may result in the development of neutropenia
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3, or WBC count comes 2000 to 3000 per mm3.36,39 Treatment with
ATG should be held when platelet count declines to less than 50 000 per mm3 or when WBC count is less than 2000 per mm3
Alemtuzumab
Alemtuzumab is an anti-CD52 humanized mono – clonal immunoglobulin G1 antibody.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe.
interleukin receptor antagonists:
basiliximab,
daclizumab,
the incidence of leukopenia was 10.6% for KTRs who received basiliximab
Mammalian target of rapamycin inhibitors
The most common mammalian target of rapamycin inhibitors (mTOR), sirolimus and everolimus
The development of cytopenia with mTOR agents can usually be observed within the first 4 to 8 weeks.
In most patients, mTOR-induced leucopenia resolves spontaneously.
valganciclovir
The higher bioavailability of this agent (70% vs. 7% for oral ganciclovir) has also affected its myelotoxicity profile
leukopenia can develop within three months. Three resolution of leukopenia can occur spontaneously with or without treatment.
Ganciclovir
Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs. .the bioavailability of the drug is poor when given orally; therefore, it is always given intravenously.
valacyclovir
Valacyclovir is a remarkable agent for CMV prevention and Treatment of herpes simplex in KTRs.
Moreover, MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
Trimethoprim-sulfamethoxazole
are associated with trimethoprim-sulfamethoxazole; these include neutropenia, leukopenia, and megaloblastic anemia.
Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis. Several types of cytopenia
Dapsone
Dapsone is an alternate agent for Pneumocystis jirovecii prevention associated with many hematological complications, including neutropenia.
Drug-induced Lymphopenia:
Lymphopenia is usually the result of induction therapy with lymphocyte-depleting medication (e.g., rabbit ATG).
Posttransplant Drug-induced Thrombocytopenia:
Rituximab
Antithymocyte globulin
Alemtuzumab
interleukin receptor antagonists
Mycophenolic mofetil and enteric-coated mycophenolate sodium
Level 5
Briefly summarise this article
Renal recipients are at high risk of post-transplant hematological complications such as leukopenia, thrombocytopenia and anemia. The pathophysiology of myelosuppression is multifactorial. However in this article, authors focus on drug induced myelosuppression due to various drugs used in kidney transplant recipients. It is reported that 20-60% of transplant recipients experience cytopenia postoperatively.
Cytopenias can be divided based on affected clones into pancytopenia, bicytopenia, thrombocytopenia, leukopenia or anemia. The severity of cytopenias is graded into mild, moderate, and severe.
It is well established that cytopenias expose immunocompromised renal recipients to higher risk of infections and malignancies while reduction of immunosuppression increases the risk of acute rejection.
Immunosuppression drugs attributed to myelosuppression are as follow:
1- Rituximab: incidence of 37.5% to 48%, with higher incidence among ABO incompatible transplant. Onset of cytopenia is usually 4 weeks after administered dose. Associated with thrombocytopenia in 48% of patients. Dose adjustment or discontinuation is required for recovery.
2- ATG is associated with more frequent leukopenia with an incidence of 10-50% (more severe leukopenia with MMF), thrombocytopenia 10% – 26.5% (more severe with higher doses and use of mToi)
It is recommened to hold rATG if platelet count drops to less than 50000 or wbc < 2000
3- Alemtuzumab: incidence 33.3% -42%, 47%, thrombocytopenia in 14%, more toxic than ATG on the bone marrow, long lasting toxic effect – 130 days post-last dose
4- Basiliximab: lower immunosuppressive effect compared to ATG and alemtuzumab , with lower incidence of myelosuppression. Leukopenia occurs in 10.6%, thrombocytopenia 5%
5- MMF and EC- MPS: cytopenia incidence 11.8% to 40%, higher risk when combined with rATG or alemtuzumab induction, toxic effect is dose dependent, concomitant use of valganciclovir, valacyclovir and fenofibrate increase the myelotoxic effect.
6- CNI – Tacrolimus: incidence of neutropenia is 28% when combined with MMF. Overall, low incidence of leukopenia when prescribed alone. Leukopenia is usually observed in the first 3 months following transplantation.
7- Azathioprine: high incidence 50%, up to 70% in patient with past medical history of leukopenia. Higher risk with higher doses >1.99mg/kg/day. Early onset after transplantation (first month), monitoring of azathioprine levels, 6-Thioguanine nucleotide levels in RBCs is adviced to prevent myelosuppression. Development of leukopenia necessitates reduction of the dose. Concomitant allopurinol should be avoided.
8- mTORi – Sirolimus and Everolimus: incidence with sirolimus is 20% while incidence with everolimus is 11-19% , toxicity is dose dependent (sirolimus trough level >12 ng/dl), usally resolve spontaneously, thrombocytopenia is observed with Tthrombotic microangiopathy
9- Antiviral prophylaxis: Valgancyclovir: incidence of leukopenia is 10-28%, more severe with higher doses, observed within 3 months of drug use. Gancyclovir: incidence of leucopenia is 7.1% – 23.1%, thrombocytopenia in 23%, 23% respond to dose reduction. Valacyclovir: incidence of leukopenia in 6-14%, more severe with concomitant use of MMF.
10- Antibiotic prophylaxis: Trimethoprim-sulfamethoxazole: low myelotoxic risk, risk of neutropenia, megaloblastic anemia and leukopenia – 2%.
What is the level of evidence provided by this article?
Level of evidence 5
KTRs experience 1 episode of cytopenia after transplant in 20 – 60 %
Most are observed during the first 3 months after RTx
Cytopenia involves all 3 cells lines white blood cells , red blood cells , and platelets.
bicytopenia involves 2 of 3 cell lines thrombocytop
** Many laboratories indicate 4000 cells mm3 as the lower limit of normal
Mild neutropenia is ANC level of 1000 to 1500/μL
moderate neutropenia is ANC level of 500 to 999/μL
severe neutropenia (agranulocytosis) is ANC level of <500/μL
** Thrombocytopenia into 4 levels
Level I : subnormal (75 000-150,000 cells/mm3)
grade II or low (50000-75000 cells/mm3, grade III or moderate (25 000-50 000 cells/mm3)
grade IV or critical (<25 000/mm3)
When ANC is <1000 cells/μL there is a risk for opportunistic infections.
Drug-induced Leukopenia and Neutropenia :
** Rituximab
Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia)
Leukopenia in 19 – 24.6 % and neutropenia in 37 – 48 %
rituximab-related thrombocytopenia rarely induces bleeding
** Antithymocyte globulin
The leukopenia incidence 10- 50
Thrombocytopenia in 14.3%
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm3
Or WBC count reaches 2000 to 3000 per mm3.
incidence of thrombocytopenia 10% to 26.5% hasbeen in KTRs
Alemtuzumab :
The leukopenia incidence 33.3 – 42 %
The neutopenia incidence 2.5 – 47 %
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe
with the lowest WBC counts observed 130 days after the last given dose
infectious episodes are usually not life-threatening
thrombocytopenia observed in 14% of KTRs
Bleeding requiring surgical intervention observed in 12% of KTRs.
interleukin receptor antagonists
basiliximab,and daclizumab
The leukopenia incidence 10 – 15 %
leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab.
anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Basiliximab induces thrombocytopenia in
5 % so an anti-IL-2R agent would be an optimum therapeutic option for thrombocytopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
Incidence of leukopenia 11.8 – 40 %
46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
The myelotoxic impact of MMF is dose dependent
Concomitant administration of valganciclovir,valacyclovir,may exaggerate MMF-related leukopenia.
To manage cytopenia, a dose reduction or complete withdrawal and this would
trigger the risk of acute rejection, with subsequent graft loss
approaches for the management of this type of leukopenia, including
** preemptive dose reduction of MMF after ATG and alemtuzumab induction
** shifting to mammalian target of rapamycin inhibitor
** halving the CMV prophylactic dose of valganciclovir,
cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal
Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia
Tacrolimus
including anemia, neutropenia, and combined anemia/neutropenia
Tacrolimus may also intensify MMF myelotoxicity, as combinations have been shown to induce neutropenia in 28% of KTRs.
Mechanisms
▪︎direct suppression of myeloid cells,
▪︎bone marrow hypoplasia in hepatic transplant recipients
▪︎altered cytokine production by T lymphocytes and monocytes
▪︎production of antimyeloid precursors and anti-mature neutrophil antibodies. Tacrolimus has been shown to prevent MPA glucuronidation that results in intensification of blood levels.
In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels.
Azathioprine
Azathioprine may induce leukopenia and neutropenia in almost half of KTRs,
particularly with doses greater than 1.99 mg/kg body weight/day.
Most cases present in the first month after transplant.
Moderately
To ameliorate the risk of myelosuppression, 2 techniques have been proposed. The first is monitoring of 6-thioguanine nucleotide in RBCs,
concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50%
Mammalian target of rapamycin inhibitors
sirolimus and everolimus
Severity of myelotoxicity is dose dependent,
20% of KTRs on sirolimus
development of leukopenia and thrombocytopenia
with lower drug levels.
Up to 46.5% of patients require a reduction in MMF dose for leukopenia, anemia, thrombocytopenia
Sirolimus and MMF combination may result in severe leukopenia.
Everolimus complicated by leukopenia (11%-19%)
cytopenia with mTORi observed within the first 4 to 8 weeks.
For patients with sirolimus-induced cytopenia 89% resolve spontaneously.
Both everolimus84-86 and sirolimus have a potential capability to induce thrombocytic microangiopathy
valganciclovir
10% to 28% of KTRs are vulnerable for leukopenia development and 4.9% to 37.5% of patients may develop neutropenia.
For several factors including
* higher doses of the drug
* low body mass index, which
* concomitant MMF administration
leukopenia can develop within 3 months resolution of leukopenia can occur spontaneously with or without treatment. Risk of infection is low.
Ganciclovir
it is always given intravenously.
causes leukopenia 7.1% to 23% and neutropenia (3.2% )
it can induce thrombocytopenia in 23.1% of KTRs.42
valacyclovir
Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Incidence of leukopenia 6% to 14%
combined MMF and valacyclovir therapy may aggravate drug-induced myelotoxicity.
When compared with ganciclovir, dose modification
Trimethoprim-sulfamethoxazole
Can cause neutropenia and leukopenia and megaloblastic anemia.
can cause dose leukopenia in only 2% of recipients.
combined azathioprine therapy with trimethoprim-sulfamethoxazole can aggravate drug-induced myelosuppression.
Dapsone
It is an alternate agent for Pneumocystis jirovecii prevention with many hematological complications, including neutropenia and agranulocytosis
Drug-induced Lymphopenia
is usually the result of induction therapy with lymphocyte-depleting medication as ATG
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia
Epstein-Barr virus
Cytomegalovirus
parvovirus B19,
human herpesvirus 6,
influenza viruses
ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Specific treatment of neutropenia
evaluate the severity of neutropenia
determining the patient’s full detailed history to unravel possible culprit
A dose reduction or complete withdrawal of the suspected agent
administration of “colony-stimulating” factors if there is no accepted response
Level : V
Post-transplant hematological complications include leukopenia, neutropenia, thrombocytopenia and anemia. The article focusses on myelosuppression due to various drugs used in kidney transplant recipients. The incidence of cytopenias in kidney transplant recipients range from 20-60%.
Cytopenias can be pancytopenia, bicytopenia, thrombocytopenia or leukopenia. The degree of cytopenias can be further graded as mild, moderate, and severe depending on their counts.
Cytopenias are associated with increased risk of infections and reduction of immunosuppressives as a treatment strategy in such scenarios increase risk of acute rejection.
Various drugs responsible and their effects include:
1) Rituximab:
-Usually late onset cytopenia (more than 4 weeks after last dose) occur with incidence of 37.5% to 48%.
-The relative risk increases to 8.8 with use in ABO incompatible transplant.
-Causes grade3/4 thrombocytopenia in 48% patients.
– Dose reduction/ withdrawal is required for recovery
2) Antithymocyte globulin (ATG):
– Leukopenia Incidence 10-50%
– Thrombocytopenia incidence 10% to 26.5%
– More leukopenia with concomitant MMF use and steroid withdrawal regimens
– More thrombocytopenia with higher doses and associated mTOR inhibitor use.
– Dose should be withheld if platelet counts are less than 50000 and leukocyte count is less than 2000
– MMF dose reduction may improve cytopenias
3) Alemtuzumab:
– Leukopenia seen in 33.3% to 42%, 47% if neutropenia present
– Thrombocytopenia seen in 14%
– More myelotoxic than ATG
– 3.6 times more myelotoxic than Basiliximab
– Maximum effect at 130 days post-last dose
4) Interleukin-2 receptor antagonists (Basiliximab, Daclizumab):
– Decreased effect than ATG and alemtuzumab
– Incidence of leukopenia is 10.6%, thrombocytopenia seen in 5%
– Useful in low or moderate risk patients with leukopenia and/or thrombocytopenia
5) Mycophenolate mofetil (MMF) and enteric coated mycophenolate sodium:
– Dose-dependent effect, with cytopenia incidence 11.8% to 40%
– Increased incidence if concomitant use of valganciclovir, valacyclovir and fenofibrate
– Management involves reduction in MMF dose (but keep close watch for acute rejection), reduction in valganciclovir dose, shift to sirolimus or everolimus, decreasing dose pre-emptively in patients given ATG, and stopping MMF and valganciclovir as a last resort.
6) Tacrolimus:
– Low incidence of leukopenia in kidney transplants, 28% neutropenia in concomitant tacrolimus and MMF use
– More in cardiac transplants
– Seen within first 3 months
– Management involves reducing MMF dose or replacing tacrolimus with everolimus, belatacept or eculizumab.
7) Azathioprine:
– Incidence is 50%, 70% if past history of leukopenia. More in patients receiving >1.99mg/kg/day dose.
– Seen within first month
– Depends on TPMT activity (low or absent TPMT activity leads to severe myelosuppression)
– Monitoring azathioprine levels, 6-Thioguanine nucleotide levels in RBCs, genotyping and phenotyping of TPMT are some methods to prevent myelosuppression
– Decrease dose by 25-50% in concomitant allopurinol use
– Treatment includes dose reduction or transient withdrawal.
8) Mammalian target of rapamycin inhibitors (mTORi) – Sirolimus, Everolimus:
– Inhibit signal transduction through bgp130beta chain
– Dose dependent effect (sirolimus trough level >12 ng/dl)
– 20% incidence with sirolimus, 11-19% incidence with everolimus
– Thrombotic microangiopathy leads to thrombocytopenia
– Mostly resolve spontaneously
– May require reducing dose of mOTRi with MMF dose reduction
9) Valgancyclovir:
– 10-28% leukopenia, 4.9%-37.5% neutropenia.
– More with higher doses, low BMI and concomitant MMF use
– Usually within 3 months
– Management involves dose reduction or transient drug withdrawal.
10) Gancyclovir:
– Leukopenia incidence 7.1% to 23.1%
– Thrombocytopenia incidence 23%
– Less than that with valganciclovir
– 23% respond to dose reduction, 2.4% require drug cessation
11) Valacyclovir:
– Leukopenia in 6-14%
– More with concomitant MMF use (MMF increases intracellular concentration of valacyclovir leading to bone marrow toxicity)
12) Trimethoprim-sulfamethoxazole
– Trimethoprime inhibits granulopoiesis
– Causes neutropenia, megaloblastic anemia and leukopenia (2%)
– More in patients on concomitant azathioprine
13) Dapsone:
– Causes neutropenia and agranulocytosis
Other causes of post-transplant leukopenia and thrombocytopenia include deficiency of vitamin B12, folic acid, Copper or zinc; infections like EBV associated PTLD, CMV, HHV, parvovirus B19, influenza virus or Ehrlichiosis; hemophagocytic syndrome due to infections like CMV, Adenovirus, EBV, HHV-8, HHV-6, BK Virus, and Parvovirus B19; or renal ischemic events and acute antibody mediated rejection.
Treatment involves dose reduction, use of colony stimulating factors (GCSF and GMCSF), drug withdrawal and platelet transfusion in case of bleeding with thrombocytopenia
This is Level 5: A narrative review
Immunosuppressive drugs are crucial to allograft survival in transplant recipients and also they often present with hematological cytopenia.From 20% to 60% of KTRs experience at least 1 episode of cytopenia after transplant. Most episodes of cytopenia are observed during the first 3 months .
The risk of infection, including opportunistic, is life-threatening in the presence of leukopenia and neutropenia. Moreover, risk of bleeding can be also triggered once thrombocytopenia ensues. Drug withdrawal or dose reduction may be the only technique to recognize the suspected medication or medications.
The higher risk of acute rejection after reduction of myelosuppressive immunosuppressive agents requires careful consideration.
Drug-induced Leukopenia and Neutropenia
Rituximab Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen.
Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures, in the treatment of acute rejection episodes, in attempted treatment of chronic antibodymediated rejection,and in resolution therapy of posttransplant lymphoproliferative disorder
Rituximab induced 40% lymphopenia, 6% neutropenia, and 4% leukopenia in patients with lymphoma. 24 Cytopenia can occur 4 weeks after start of rituximab therapy
Late-onset neutropenia can be defined as neutropenia that is observed 4 weeks after the last dose of rituximab usually observed after the sixth rituximab dose.
Antithymocyte globulin
Both higher doses of ATG and the nonspecific avidity to neutrophils and platelets may induce neutropenia.
The dose of ATG should be halved when platelet count reaches 50 000 to 75 000 per mm 3 or WBC count reaches 2000 to 3000 per mm3 . 36,39 Treatment with ATG should be held when platelet count declines to less than 50 000 per mm 3 or when WBC count is less than 2000 per mm3.
Other medications that may cause cytopenia should also be monitored, including MMF (hold off MMF with concurrent ATG-induced cytopenia37 ) and steroids (loss of stimulatory effects on bone marrow in early steroid withdrawal regimens after ATG induction can be complicated with a higher incidence of leukopenia41 ).
Alemtuzumab is an anti-CD52 humanized monoclonal immunoglobulin G1 antibody
the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe.
interleukin receptor antagonists
basiliximab and daclizumab leukopenia has been reported to be 3.6 times higher in KTRs with alemtuzumab induction compared with basiliximab.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
The hematological sequelae with myelosuppression are the most common cause requiring MMF dose reduction, with 46.5% of MMF-reducing events due to leukopenia, anemia, thrombocytopenia, and pancytopenia.
The myelotoxic impact of MMF is dose dependent.
Concomitant administration of valganciclovir,3 valacyclovir, and fenofibrate 59 may exaggerate MMFrelated leukopenia.
Tacrolimus is the mainstay of clinical immunosuppression regimens.Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.14
Mechanisms of tacrolimus-induced neutropenia include direct suppression of myeloid cells, with bone marrow hypoplasia observed in hepatic transplant recipients,Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant. 9 There is no particular test for diagnosis, except for leukocytic count normalization after the withdrawal of tacrolimus. 9 A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. 68,69 In such patients, other alternatives include everolimus, belatacept, or eculizumab.
Azathioprine
Azathioprine may induce leukopenia and neutropenia in almost half of KTRs, particularly with doses greater than 1.99 mg/kg body weight/day.
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid.
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month,then twice per month during the second and third months, and then monthly or less according to dose adjustment.
Mammalian target of rapamycin inhibitors
valganciclovir
Although 10% to 28% of KTRs are vulnerable for leukopenia development, 3,38,41,42 4.9% to 37.5% of patients may develop neutropenia. 3,38-40 The resultant cytopenia may be potentiated by several factors, including higher doses of the drug (900 mg or more) having a significant impact on leukopenia and neutropenia development, 43 low body mass index, which is a significant potentiating factor for leukopenia, 40 and concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
Ganciclovir
Ganciclovir is used for anti-CMV therapy and prophylaxis . ganciclovir causes leukopenia, with rates of 7.1% to 23.1%.
valacyclovir
Valacyclovir is a remarkable agent for CMV prophylaxis and treatment of herpes simplex in KTRs. Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild.
Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis.Folinic acid can reverse this side effect
However, combined azathioprine therapy with trimethoprimsulfamethoxazole can aggravate drug-induced myelosuppression.
Dapsone Dapsone is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.69 Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis .
the same drugs mentioned above also induced lymphocytopenia and thrombocytopenia.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia In addition to medication-induced myelotoxicity, a variety of etiologies can share in the development of these serious hematological events, including B12, folic acid, zinc, and copper deficiencies, as shown in a nontransplant cohort.92
Epstein-Barr virus-induced posttransplant proliferative disorders invade bone marrow of recipients, causing cytopenia. 11 Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Level V
Drug-Induced Myelosuppression in Kidney transplant patients
This article focus on complications of immunosuppressive therapy in haematological system and predisposed patients to opportunity infection which are life threatening conditions leading to increase incidence of mortality post transplant. Also this article focus who to optimise immunosuppressive therapy to reduce chance of cytopenia and infection.
Cytopenia defined as reduction of WBC and RBC and platelets level with leukopenia and neutropenia and lymphopenia.
Grade of leukopenia to WBC 3 grades I ( 3000 mm2); grade 2 (3000-2000); grade 3 (1000 & less).
Platelets grades to 4 // grade 1(150,000-75000), grade 2(75000-50000); grade 3(50000-25000); grade 4(less than 25000).
Tacrolimus and MMF associated with neutropenia and risk intra abdominal infection and E coli infection.
In this situation reduce dose to half or withdrawal drug but may lead to risk of rejection.
Rituximab is a potent chimeric anti-CD20 monoclonal antibody that binds CD20 antigen, resulting in B-cell depletion.
Rituximab is commonly used as a part of the induction agent in ABO-incompatible transplant procedures.
Incidence of cytopenia in induction therapy with rituximab is 73.5% to 48%, days and usually in sixth dose post kidney transplant. It’s treated usually with reduce dose or withdrawal drug.
ATG
It’s inhibit activity of T cells. inhibition of B cells, natural killer cells, monocytes, neutrophils, platelets, and RBCs.
ATG lead to leukopenia (neutropenia ), and thrombocytopenia and should be reduce ATG to half if WBC between 3000-2000, platelets between 75000-50000, and stop ATG if platelets less than 50000 and WBC less than 2000. CD3 T cell should be monitoring.
Alemtuzumab:
It’s an anti-CD52 humanized mono clonal immunoglobulin G1 antibody.
Alemtuzumab can be administrated as an induction agent to prevent kidney transplant rejection.
leukopenic incidence is ranges from 33.3% to 42%. It’s mainly cause neutropenia.
the myelotoxic effects of alemtuzumab are more severe.
A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia. it’s with reduce dose should be a strict monitoring of allograft function.
With regard to management, dose modification of other drugs such as MMF or valganciclovir or cotrimoxazole is required.
interleukin 2 receptor (IL-2R) antagonist:
There’s induction agents are basiliximab and daclizumab a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in kidney transplant.
It’s side effects are leukopenic and thrombocytopenia.
Incidence of leukopenia is 10% with basiliximab.
mycophenolate moftile
It’s common cause of leukopenia and anemia and pancytopenia leading to reduce dose to half.
It’s common haematological complications and myelotoxicity.
If pan cytopenia evident should be shift to rapamycin inhibitors like sirolimus and everolimus. And reduce CMV prophylactic dose to half.
Tacrolimus:
It’s may induce neutropenia with combination of MMF to 28%.
It’s suppress myeloid cell and can be shifted by other drug in severe leukopenia and neutropenia by everolimus / beltacept / eculizumab.
Azathioprine:
It’s traditional prodrug used for kidney transplant
It’s may lead to pancytopenia.
Azathioprine in combination with allopurinol lead to inhibition of xanthine oxidase and decline purine metabolism of uric acid. So increase level of azathioprine lead to myelotoxicity and should be reduce dose to half.
Rapamycine inhibitors (mTOR), everolimus and sirolimus with use of MMF lead to leukopenia.
Valgancyclovir: high dose more than 900 mg associated with leukopenia. The recommended dose is 400mg daily.
Rituximab can induce thrombocytopenia but rarely lead to bleeding.
Alemtuzmab induce thrombocytopenia in 14% of kidney transplant and cause bleeding need to surgical intervention.
Level V
III. Drug-Induced Myelosuppression in Kidney Transplant Patients
1- Renal transplant is considered the best therapeutic option for suitable patients with end-stage kidney failure and Hematological complications that occur after kidney transplant include posttransplant anemia, leukopenia, neutropenia, and thrombocytopenia.
2- Myelosuppression is known to occur in kidney transplant recipients because of widely used immunosuppressant chemotherapeutic agents.
3- Cytopenia can be identified as follows:-
3-1 pancytopenia involves all 3 cells (WBCs, RBCs and Platelet).
3-2 Bicytopenia involves 2 of 3 cell .
3-3 Thrombocytopenia involves low platelet count.
3-4 Leukopenia can be graded according to the Common Terminology
Criteria for Adverse Events (CTCAE) into 4 levels:-
A- These levels are 3000 cells/mm3 (normal),
B-2000 to 3000 WBCs/mm3,(mild).
C-1000 to 2000 WBCs/mm3(modreate),
D-and <1000 WBC/mm3 (severe).
4- Absolute neutrophil count (ANC).
4-1An ANC of<1500 (neutropenia)
4-2 ANC level of 1000 to 1500/μL (mild)
4-3 ANC level of 500 to 999/μL (moderate)
4-4 ANC level <500/μL (sever), and severe
neutropenia (agranulocytosis).
5- Platelet count of 150 000/mm 3 is considered the
lower limit of normal level in many laboratories and are 4 grade:-
5-1 Grade I or subnormal (75 000-150,000 cells//mm 3).
5-2 Grade II or low (50000-75000 cells/mm 3).
5-3 Grade III or moderate (25 000-50 000 cells/mm 3).
5-4 Grade IV or critical (<25 000/mm3).
6- Consequences of Hematological Cytopenia
Neutrophils and lymphocytes have fundamental roles in prevention of infection.
6-1 When ANC is <1000 cells/μL, susceptibility to infection increases.
6-2 Neutropenic KTRs commonly experience more intra-abdominal infections and tacrolimus and MMF therapy are commonly associate with neutropenia.
6-3 Withdrawal of prophylactic agents for CMV or Pneumocystis jirovecii causes their spread.
6-4 To summarize, leukopenia augments the risk of infection by disrupting immunogenic integrity and liability of ubiquitous an opportunistic infections.
6-5 Cautious in the treatment of patients with high immunological
risk, especially those within 3 months after transplant.
*Drug-induced Leukopenia and Neutropenia
Rituximab
1- Rituximab an anti CD20 antigen, monoclonal antibody.
2- Rituximab is commonly used
3- Induction agent in ABO-incompatible transplant procedure.
4- Treatment of acute rejection .
5- Treatment of chronic antibody mediated rejection.
6- Resolution therapy of post transplant lymphoproliferative disorder.
7- Cytopenia can occur 4 weeks after start of rituximab therapy
(late-onset neutropenia).
8- Late-onset neutropenia can be defined as neutropenia that is observed 4 weeks after
the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF).
9- Late-onset neutropenia is usually observed after the sixth rituximab dose.
10- Mycophenolate mofetil, ganciclovir, and valganciclovir are frequently
implicated in its evolution.
11- The threshold of suspicion of rituximab induced toxicity should be lowered, particularly 6 weeks after the sixth rituximab dose.
12- Dose reduction or drug withdrawal is usually the ideal response for
hematological recovery.
Administration
1- Rituximab use by intravenous infusion and should not be administered as IV bolus or push.
2- Patients should be given acetaminophen and antihistamine before each infusion.
3- Rituximab should be diluted in an infusion bag of either 0.9% sodium chloride, 5% dextrose.
4- Patients should be observed for 15 minutes after administration.
Antithymocyte globulin:
.1- ATG a polyclonal immungloulin prepared by immunizing horses or rabbits with human thymocytes and harvesting the IgG.
2- Has awidespread activity against blood cell T and B cell.
3- high risk of leukopenia 50%
4- treatment dose should be halved when PLT.between 5000-75000 per mm3
5- IF PLT.less than 50000 and WBCs less than 2000per mm3need stoped ATG
6- During ATG monitoring of other cytopenic medication .
Alemtuzumab
1- Is an anti-CD52 humanized monoclonal immunoglobulin G1 antibody.
2- Compared with ATG, the myelotoxic effects of alemtuzumab are more severe, with the lowest WBC counts observed 130 days after the last given dose.
3- With regard to management, dose modification of other drugs such as MMF or
valganciclovir or cotrimoxazole is required.
interleukin receptor antagonists
1- Two interleukin 2 receptor (IL-2R) antagonist induction agents are basiliximab, a monoclonal chimeric, and daclizumab, a humanized murine antibody against CD25 that can suppress IL-2- mediated T-cell activation and proliferation in KTRs.
2- Rarely with leukopenia or thmobocytopenia <50% of KTX pateint.
3-The anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
Mycophenolic mofetil and enteric-coated mycophenolate sodium
1- Hematotoxicity, can develop leukopenia related to MMF therapy. 11.8% to 40%.
2- Both ATG-related and alemtuzumab- related cytopenia may mask the diagnosis of MMF myelotoxicity, as they may require MMF dose reduction.
3- The most common cause requiring MMF dose
reduction, with 46.5% of MMF-reducing events dueto leukopenia, anemia thrombocytopenia, andpancytopenia.
4- The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA and Concomitant administration of valganciclovir, valacyclovir, and fenofibrate may exaggerate MMF- related leukopenia.
5-Dose reduction of MMF has been mostly attempted in the first year posttransplant, a time of highest risk of allograft rejection.
Tacrolimus
1-Tacrolimus may also intensify MMF myelotoxicity, and tacrolimus and MMF combinations have been shown to induce neutropenia in 28% of KTRs.
2-Tacrolimus-induced direct myeloid inhibition has not been observed in vitro.
3- Tacrolimus-induced neutropenia can be observed within the first 3 months after transplant.
4- A dose reduction of MMF is suggested in patients on dual immunosuppression therapy.
Azathioprine
1- Azathioprine may induce leukopenia and neutropenia in almost half of KTRs.
2- Most cases of azathioprine- induced leukopenia present in the first month after transplant.
3- Drugs that interact with azathioprine include
allopurinol, with allo- purinol necessitates dose reduction of azathioprine by 25% to 50%.
4- Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dos adjustment.
Mammalian target of rapamycin inhibitors
1- (mTORi), sirolimus and everolimus, have
been involved in many myelotoxic side effects.
2- Severity of myelotoxicity is dose dependent,80 with involvement of about 20% of KTRs on sirolimus.
3- A trough level of >12 ng/dL has been shown to be highly development of leukopenia and thrombocytopenia,
although it can commonly occur even with lower drug
levels.
4- Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
5-mTORi agents can be usually observed within the first 4 to 8 weeks.
For patients with sirolimus-induced cytopenia, 7% need
dose reduction, 4% need drug withdrawal, and 89%
resolve spontaneously.
Valganciclovir
1- Although 10% to 28% of KTRs are vulnerable for leukopenia development, 4.9% to 37.5% of patients may develop neutropenia.
2- Cytopenia potentiate several factors, including higher doses of the drug (900 mg or more). low BMI.
Ganciclovir
1-Ganciclovir is used for anti-CMV therapy and prophylaxis in KTRs.
2- The bioavailability of this drug is rather poor when given orally; therefore, it is always given intravenously.
3-Through its myelosuppressive effects, ganciclovir causes leukopenia, with rates of 7.1% to 23.1%.
4-Compared with valganciclovir, ganciclovir exerts modest myelosuppression
5-Although patients (23%) on ganciclovir therapy respond to dose reduction, some (2.4%) require ganciclovir cessation.
valacyclovir
1- Is agent for CMV prophylaxis and treatment of herpes simplex in KTRs.
2- Compared with valganciclovir and ganciclovir,myelotoxicity with valacyclovir is mild.
3-Incidence of leukopenia ranges from 6% to 14%
.
Trimethoprim-sulfamethoxazole
1- Trimethoprim-sulfamethoxazole is a commonly used drug for Pneumocystis jirovecii prophylaxis.
2-Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include neutropenia and leukopenia and megaloblastic anemia.
3-However, combined azathioprine therapy with trimethoprim- sulfamethoxazole can aggravate drug-induced myelosuppression.
Dapsone
1- Is an alternate agent for Pneumocystis jirovecii prevention that is associated with many hematological complications, including neutropenia.
2- May be aggravated by development of agranulocytosis.
Posttransplant Drug-induced Thrombocytopenia
1- Rituximab 48%
2- Antithymocyte globulin 10-20%
2- Alemtuzumab-induced thrombocytopenia has been observed in 14% of KTRs.
3- interleukin receptor antagonists 14,6%
4- Mycophenolic mofetil and enteric-coated mycophenolate sodium48%
5- Mammalian target of rapamycin inhibitors 20%
6- Trimethoprim-sulfamethoxazole 18.18%
7- Ganciclovir 23%
Differential Diagnosis of Drug-induced Leukopenia
and Thrombocytopenia
1- Defciency vit. B12, folic acid, zinc, and copper
1- Epstein-Barr virus.
2- Cytomegalovirus.
3- Parvovirus B19, human herpesvirus 6, influenza viruses, and ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
5- Hemophagocytic Syndrome can be associated with cytopenia. Several viral infections (CMV, adenovirus,Epstein-Barr virus, human herpesvirus 8, human
herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
6- Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations:
-renal ischemic events,
-antibody-mediated rejection,
-And viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
Specific treatment of neutropenia
1- Consequently, the first step is determining the patient’s full detailed history to
unravel possible culprit.
2- Measurement of ANC can be used to evaluate the severity of neutropenia, with
severe neutropenia indicated by ANC <500/μL.
3- The next therapeutic step for WBC count correction would be administration of “colony- stimulating” factors if there is no accepted responseto the previous maneuvers.
4- Neutropenia ;G-CSF OR GM-CSF used in onocology ,this agents can be utilazed in solid organ transplant,but no consensus.
5- The prophylactic adminstration of these agent is suggested in pateints with febrail neutropenia and with diminshed bone marrow reserves with extended radiotherapy and AIDS human and older age more than 65 years .
References
1-Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literatur
2-In ,Meyler’s Side Effects of Drugs (Sixteenth Edition) 2016
3-Delate T, Hansen ML, Gutierrez AC, Le KN. Indications for Rituximab Use in an Integrated Health Care Delivery System. J Manag Care Spec Pharm. 2020 Jul;26(7):832-838.
4- Pierpont TM, Limper CB, Richards KL. Past, Present, and Future of Rituximab-The World’s First Oncology Monoclonal Antibody Therapy. Front Oncol. 2018;8:163
5- Anja De Rycke, Daan Dierickx and Dirk R. Kuypers
CJASN March 2011, 6 (3) 690-694; DOI: https://doi.org/10.2215/CJN.07320810
Myelosuppression is commonely encountered in the context of maintenance anti -rejection threrapy. Its always a challenging condition as modifying the doses of medicines is often linked to triggering the immunological rejection in one hand and might pave the way for opportunistic infections consequent to that change of medications.
Medications that can precipitate leukopenia , anemia , thrombocytopenia and pancytopenia are Mycophenolate mofetil and enteric coated Mycophenolate sodium, CNI, ATG, Alemtuzumab, Gancyclovir, valgancyclovir and trimethoprim-sulfamethoxasol TMS.
Myelosuppression is either broad with resultant pancytopenia or selective , affecting one of the cellular line .Incidence of Myelosuppression is variable between 20-60 % of Kidney transplant recipients KTR.
neutropenia is another descriptive entity , that is not interchangeable with leukopenia.
Its used to address the level of deficiency of neutrophil count as follows:
1000-1500 mild
500-1000 moderate
Below 500 severe.
The risk of infection is manifold when neutropenia is overwhelming .
particularly gram negative bacteria , like E.coli and more intra-abdomenal infection.
There is no consensus on the management of myelosuppression secondary to anti-rejection therapy. But,in general, precocious down adjustment of the dose of immune-suppressants is the rule of thumb in managing this condition, which portend gradual reduction of the dose or cessation of the medicine alltogether.
This modification of therapy might harbor an escalated risk of acute rejection.
Similarly reducing the dose of prophylactic antibiotic TMS or antiviral valgancyclovir might potentially escalate the risk of pneumocystis jiruvici pneumonia PJP and CMV infection.
other causes of Myelosuppression are common post transplantation and have to be precluded, like viral infection Parvo virus.
Combination of certain induction and maintenance medications might be potentiating the myelosuppressant outcome. such as induction with ATG or Alemtezumab and maintaining with MMF and Tacrolimus.
Special considerations:
MMF:up to 40 % of KTR might develop hematoxicity . It is causing dose dependent myelosuppresion. therefore , reducing the dose might be reversing the suppression.
On some occasions it might be masked by Alemtuzumab or ATG induced myelosuppression.
prescribing Gancyclovir , Valgancyclovir ot TMS might augment the hematoxicity of MMF..
And adjustment of MMF dose after ATG and Alemtuzumab induction, and similarly the antiviral ganvalcyclovir to 450 mg per day might lessen the risk of hematoxicity.
Tacrolimus:
Incidence is less with up to 10 % risk, augmented by combining with MMF and induction with ATG. and Alemtuzumab.Reduction or withdrawal of the dose can improve the myelosuppression.
Its a narrative review with level of evidence 4
III. Drug-Induced Myelosuppression in Kidney Transplant Patients
Briefly summarise this article
Definitions
Pancytopenia: all 3 cells lines involved (WBCs, RBCs, & platelets).
Bicytopenia involves 2 of 3 cell lines.
Leucopenia graded according to the CTCAE into 4 levels:
3000 cells/mm3 (normal)
2000 to 3000 WBCs/mm3(mild)
1000 to 2000 WBCs/mm3(moderate)
<1000 WBC/mm3 (severe).
Absolute neutrophil count (ANC):
ANC<1500/μL is termed neutropenia.
Mild neutropenia is ANC level of 1000 to 1500/μL
Moderate neutropenia is ANC level of
500 to 999/μL
Severe neutropenia (agranulocytosis)is ANC level of <500/μL
Thrombocytopenia is graded into:
Grade I or subnormal (75 000-150,000 cells/mm3)
Grade II or low (50000-75000 cells/mm3 Grade III or moderate (25 000-50 000 cells/mm3)
Grade IV or critical (<25 000/mm3).
Consequences of Hematological Cytopenia
When ANC is <1000 cells/μL, susceptibility to opportunistic infection increases.
Both tacrolimus & MMF are common causes of neutropenia.
Withdrawal of prophylactic agents for CMV or PJP leads to their spread.
Reduction or withdrawal of tacrolimus or MMF will result in rise of WBC counts, but will increase risk of rejection(Zafrani et al, Vanhove).
Caution should be entertained in the treatment of patients with high immunological risk, especially in the 1st 3 months after transplant.
Drug-induced Leukopenia & Neutropenia
Rituximab:(anti-CD20 monoclonal antibody).
Uses:
– Induction in ABO-I transplant.
– Treatment of acute rejection.
– Attempted treatment of CAMR.
– Resolution therapy of PTLD.
It results in B-cell depletion & thus affects phagocytosis by macrophages, complement -mediated cytotoxicity, & antibody dependent cell-mediated toxicity by natural killer cells.
Late-onset neutropenia (after the 6th rituximab dose) in KTRs occurs in 37.5% to 48%.
Dose reduction or drug withdrawal is the ideal method for hematological recovery.
Antithymocyte globulin (ATG)
Its activity is not confined to T cells.
T cells, B cells, NK cells, monocytes, neutrophils, platelets, & RBCs are all affected.
Leukopenia incidence is variable in different studies; the highest incidence (50%), reported by Gaber et al, may be explained by the concurrent use of azathioprine.
ATG dose halved if platelet count is 50 000 -75 000 /mm3 or WBC count 2000 to 3000 / mm3.
Hold dose if platelet count is < 50 000 / mm3 or when WBC count is <2000 /mm3.
MMF might need to be held with concurrent ATG-induced cytopenia.
Alemtuzumab (an anti-CD52 humanized monoclonal Ig G1 antibody).
CD52 is expressed on mononuclear cells (T & B lymphocytes), monocytes, & NK cells.
Used as an induction agent or as anti-rejection.
Leucopenia occurs in 33.3%-42%.
More severe myelotoxicity compared with ATG ; however, infectious events are usually not life threatening.
Dose modification of MMF or valganciclovir or cotrimoxazole is required.
Interleukin receptor antagonists
(basiliximab & daclizumab)
Leucopenia & thrombocytopenia are rare compared with ATG & alemtuzumab (b/c anti-IL-2R activity is confined to activated T cells).
Anti-IL-2R agents are optimum therapeutic option for leukopenic KTRs with low/ moderate risk of rejection.
MMF & enteric-coated MPA
Are inosine monophosphate dehydro –
genase inhibitors; inhibit both cell-mediated & humoral immune responses.
Leucopenia occurs in 11.8% to 40% of KTRs.
ATG-related & alemtuzumab related cytopenia may mask the diagnosis of MMF
myelotoxicity, as they may require MMF dose reduction.
Myelosuppression is the most common cause requiring MMF dose reduction.
Concomitant use of valganciclovir, valacyclovir, & fenofibrate may aggravate MMFrelated leukopenia.
Treatment approaches for MMF-induced neutropenia:
– Dose reduction or complete withdrawal; however, this would trigger the risk of acute rejection, with subsequent high risk of graft loss (many retrospective reports).
– Preemptive dose reduction of MMF after ATG & alemtuzumab induction
– Shifting to a suitable mTOR inhibitor (eg, sirolimus or everolimus may reverse cytopenia)
– Halving the CMV prophylactic dose of valganciclovir. Valganciclovir 450 mg daily is as effective as 900 mg daily for CMV prophylaxis.
– Cessation of both MMF & valganciclovir may be needed in resistant cases.
Tacrolimus
May intensify MMF myelotoxicity. Combination MMF with induce neutropenia in 28% of KTRs.
In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels.
Neutropenia can be observed within the 1st 3 months after transplant.
No particular test for diagnosis, apart from count normalization after the withdrawal of
tacrolimus. A dose reduction of MMF is suggested in patients on dual IS therapy.
Azathioprine
Is largely replaced by the more potent MMF
May induce leukopenia & neutropenia in almost half of KTRs, particularly with higher doses.
Most cases present in the 1st month after transplant. A dose reduction or transient drug withdrawal is usually sufficient.
Patients with low or lack of thiopurine S-methyl transferase (TPMT) activity are likely to develop severe, life-threatening myelo-toxicity.
Methods to ameliorate the risk of myelo-suppression:
– Monitoring of 6-thioguanine nucleotide in RBC (more beneficial than monitoring of 6-mercaptopurine in plasma)
– Genotyping & phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
Concomitant use with allopurinol necessitates dose reduction of azathioprine (allopurinol inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid).
Mammalian target of rapamycin inhibitors
(sirolimus and everolimus)
Severity of myelotoxicity is dose dependent. A trough level of >12 ng/dL is highly associated with development of leukopenia & thrombocytopenia.
Sirolimus & MMF combination therapy after
alemtuzumab induction in steroid & CNI-free regimens may result in severe leukopenia.
Everolimus can be also be complicated by leukopenia (11%-19%).
In mTORi-induced leucopenia usually resolves spontaneously. If it persists, then a reduction of the MMF dose with reduction of mTORi to a lower therapeutic range is required.
Drug cessation may be the last resort for resistant cases.
Valganciclovir
Leucopenia in 4.9% to 37.5% of patients. The cytopenia may be potentiated by:
– Higher doses of the drug (900 mg or more).
– Low BMI
– Concomitant MMF use.
Dose reduction to 450 mg/day or transient cessation may be enough for reversal of cytopenias.
Ganciclovir
Used for anti-CMV therapy & prophylaxis.
Given IV.
Modest myelosuppression Compared with valganciclovir.
Valacyclovir
Used for CMV prophylaxis & treatment of herpes simplex.
Mild myelotoxicity compared with valganciclovir & ganciclovir.
Combination with MMF may aggravate the myelotoxicity.
Trimethoprim-sulfamethoxazole
Commonly used for PJP prophylaxis.
Can cause neutropenia, leukopenia & megaloblastic anemia.
Combination with azathioprine therapy can aggravate drug-induced myelosuppression.
Dapsone
Used for PJP prevention.
Causes many hematological complications, e.g. neutropenia.
Drug-induced Lymphopenia
Result of induction therapy with ATG.
Posttransplant Drug-induced Thrombocytopenia
Implicated medications include:
Rituximab
ATG
Alemtuzumab
IL2 receptor antagonists
MMF & enteric-coated MPA
MTOR inhibitors
Ganciclovir
Trimethoprim-sulfamethoxazole
Differential Diagnosis of Drug-induced Leukopenia & Thrombocytopenia:
EBV-induced PTLD
CMV
ParvovirusB19
HHV 6
Influenza viruses
Ehrlichiosis (a tick-borne bacterial infection)
Hemophagocytic Syndrome
Is associated with cytopenia.
Incriminated infections include:
CMV, EBV, HHV 8, parvovirus B19, & BKV.
Therapy for Drug-induced Hematological Cytopenia.
1st step: detailed history to reveal the cause. Dose reduction or hold the suspected agent.
Next step is use of “colonystimulating” factors (GM-CSF, G-CSF).
==================
What is the level of evidence provided by this article?
Level V
Cytopenia can be identified as follows:
1-Pancy-topenia;
involves all 3 cells lines, that is, white blood cells (WBCs), red blood cells (RBCs), and platelets.
2-Bicytopenia ;
involves 2 of 3 cell lines
3-Thrombocytopenia ;involves low platelet count
Platelet count of 150 000/mm 3 is considered the lower limit of normal level in many laboratories.
The CTCAE has graded thrombocytopenia into 4 levels;
A- grade I or subnormal (75 000-150,000 cells//mm 3)
B- grade II orlow (50000-75000 cells/mm 3
C- grade III or moderate (25 000-50 000 cells/mm 3)
D- grade IV or critical(<25 000/mm3) .
3- Leukopenia;
Absolute neutrophil count (ANC); is used to assess the magnitude of neutropenic severity as follows :
ANC = (WBCs/μL) × (percentage of polymorphonuclear cells + bands)/100.
An ANC of <1500/μL or <1.5 × 109/L can be termed neutropenia and graded as ;
1-Mild neutropenia is ANC level of 1000 to 1500/μL or 1 to 1.5 × 10 9/L .
2-moderate neutropenia is ANC level of 500 to 999/μL or 0.5 to 0.99 × 10 9 /L .
3- severe neutropenia (agranulocytosis) is ANC level of <500/μL or <0.5 × 109/L .
Consequences of Hematological Cytopenia;
The predisposition to frequency and severity of infection is related to duration of neutropenia and magnitude of neutropenic decline.
Infection with Escherichia coli is also more prevalent in neutropenic KTRs.
Neutropenic KTRs commonly experience more intra-abdominal infections (22.5%) than those with normal neutrophil counts (7%-10%).
Withdrawal of prophylactic agents for CMV or Pneumocystis jirovecii opens the door to their spread.
leukopenia augments the risk of infection by disrupting immunogenic integrity and liability of ubiquitous and opportunistic infections.
In an attempt to reduce the severity of neutropenia, transplant physicians often reduce or withhold MMF.Despite the expected rise in WBC counts, risk of rejection increases, which is usually evident in the first year post transplant.
Drug-induced Leukopenia and Neutropenia;
A number of agents have been implicated in posttransplant leukopenia and neutropenia development; Through clinical assessments, culprit medications in
cytopenia have been identified, including MMF, trimethoprim-sulfamethoxazole, valganciclovir, ganciclovir, alemtuzumab, and ATG.
Differential Diagnosis of Drug-induced Leukopenia and Thrombocytopenia;
1- medication-induced myelotoxicity.
2-B12, folic acid, zinc, and copper deficiencies.
3-Epstein-Barr virus-induced post transplant proliferative disorders invade bone marrow of recipients, causing cytopenia .
4-Cytomegalovirus, parvovirus B19, human herpesvirus 6, influenza viruses, and
ehrlichiosis (a tick-borne bacterial infection) can lead to myelosuppression-induced cytopenia.
Hemophagocytic Syndrome;
Hemophagocytic syndrome can be associated with cytopenia.
Several viral infections (CMV, adenovirus, pstein-Barr virus, human herpesvirus 8, human herpesvirus 6, parvovirus B19, and BK polyomavirus) have been incriminated in hemophagocytic syndrome evolution.
Thrombocytic microangiopathy with consequent thrombocytopenia can develop in the following situations:
1-renal ischemic events,
2-antibody-mediated rejection
3-viral infection (CMV, human immunodeficiency virus, and parvovirus B19).
Drugs induced cytopenia ;
1-Rituximab;
Cytopenia can occur 4 weeks after start of rituximab therapy (late-onset neutropenia).
Late-onset neutropenia can be defined as neutropenia that is observed 4 weeks after the last dose of rituximab after exclusion of other causes (ie, use of ganciclovir, valganciclovir, or MMF).
2-Antithymocyte globulin;
The dose of ATG should be halved when;
1- platelet count reaches 50 000 to 75 000 per mm3
2-WBC count reaches 2000 to 3000 per mm .
Treatment with ATG should be held when;
1- platelet count declines to less than 50 000 per mm .
2- 2- WBC count is less than 2000 per mm 3 . CD3 + T-cell count should be monitored when less than 0.05 × 10 9 /L (<50/μL; normal range, 128-131/μL) to avoid unnecessary higher doses.
This approach is successful in reducing the incidence of acute rejection episodes, infections, and cytopenia.
Total lymphocyte count should be maintained as less than 0.3 × 10 9 /L, which is a suitable alternative if CD3 monitoring is not available.
3-Alemtuzumab;
With alemtuzumab, the leukopenic incidence in KTRs ranges from 33.3% to 42% in various reports.
Compared with ATG, the myelotoxic effects of alemtuzumab are more severe with the lowest WBC counts observed 130 days after the last given dose. However, infectious episodes are usually not life-threatening.
A dose reduction of MMF, in response to alemtuzumab-induced leukopenia, may reach 14 mg/kg, a dose that is much less than that required for ATG-induced leukopenia.
Subsequently, a strict monitoring of allograft function at that time is mandated, particularly in high-risk KTRs.
4-Interleukin receptor antagonists;
Considering all these observations, the anti-IL-2R agents would be an optimum therapeutic option for leukopenic KTRs with low/moderate risk of rejection.
5-Mycophenolic mofetil and enteric-coated mycophenolate sodium;
The myelotoxic impact of MMF is dose dependent and is usually related to the trough levels of MPA.
Concomitant administration of valganciclovir,valacyclovir, and fenofibrate59 may exaggerate MMF- related leukopenia.
Several approaches could be added for the management of this type of leukopenia, including;
1-preemptive dose reduction of MMF after ATG and alemtuzumab induction
2-shifting to a suitable mammalian target of rapamycin inhibit
3-halving the CMV prophylactic dose of valganciclovir, which could also be another preventive measure.
4-For resistant cases, cessation of both MMF and valganciclovir may be the last resort for cytopenia reversal .
6-Tacrolimus;
Mechanisms of tacrolimus-induced neutropenia include;
1-direct suppression of myeloid cells, with bone marrow hypoplasia ,However, tacrolimus-induced direct myeloid inhibition has not been observed in vitro.
Direct inhibition of myeloid precursors may not be a convincing mechanism for tacrolimus-induced neutropenia and leukopenia.
2-altered cytokine production by T lymphocytes and monocytes,
3-production of antimyeloid precursors and anti-mature neutrophil antibodies.
4-Tacrolimus has been shown to prevent MPA glucuronidation that results in intensification of blood levels.
In contrast to cyclosporine, tacrolimus does not interfere with MMF enterohepatic circulation, leading to augmented MPA levels.
A combination of tacrolimus and MMF expands the area under the curve for MMF within 3 months by pproximately 20% to 30%.
A dose reduction of MMF is suggested in patients on dual immunosuppression therapy. In such patients, other alternatives include everolimus, belatacept, or eculizumab.
7-Azathioprine;
An important factor to determine the magnitude of azathioprine-induced myelotoxicity is thiopurine S-methyl transferase (TPMT) activity.
Moderately active TPMT may lead to higher risk of myelotoxicity with conventional doses of azathioprine.
Patients with complete lack or low TPMT activity are vulnerable to developing severe, life-threatening myelotoxicity.
To ameliorate the risk of myelosuppression, techniques have been proposed.;
1-The first is monitoring of 6-thioguanine nucleotide in RBCs, which is an efficacious and more beneficial method than monitoring of 6-mercaptopurine in plasma.
2-Genotyping and phenotyping of TPMT may also help to recognize KTRs at higher risk for myelotoxicity.
3-Drugs that interact with azathioprine include allopurinol, which inhibits xanthine oxidase activity leading to decline in purine metabolism to uric acid.
Therefore, concomitant administration with allopurinol necessitates dose reduction of azathioprine by 25% to 50% .
Azathioprine levels should be monitored weekly, with full blood count monitoring in the first month, then twice per month during the second and third months, and then monthly or less according to dose adjustment.
8-Mammalian target of rapamycin inhibitors;
Severity of myelotoxicity is dose dependent,with involvement of about 20% of
KTRs on sirolimus.
A trough level of >12 ng/dL has been shown to be highly associated with development of leukopenia and thrombocytopenia ,although it can commonly occur even with lower drug levels.
Sirolimus and MMF combination therapy after alemtuzumab induction in steroid and CNI-free regimens may result in severe leukopenia.
The development of cytopenia with mTORi agents can be usually observed within the first 4 to 8 weeks.
For patients with sirolimus-induced cytopenia, 7% need dose reduction, 4% need drug withdrawal, and 89% resolve spontaneously.
In most patients, mTORi-induced leucopenia resolves spontaneously. If it persists, then a reduction of the MMF dose with simultaneous reduction of mTORi to a lower therapeutic range is required.
However, drug cessation may be the last resort for resistant cases.
9-Valganciclovir;
The higher bioavailability of this agent (70% vs 7% for oral ganciclovir) has also affected its myelotoxicity profile
The resultant cytopenia may be potentiated by several factors, including ;
1-higher doses of the drug (900 mg or more)having a significant impact on leukopenia and neutropenia development.
2-low body mass index, which is a significant potentiating factor for leucopenia.
3-concomitant MMF administration, which can also aggravate valganciclovir myelotoxicity.
Although leukopenia can develop within 3 months, resolution of leukopenia can occur spontaneously with or without treatment.
Risk of infection is usually low.
The need for G-CSF administration may be required with prolonged
periods of prophylaxis.
Dose reduction to 450 mg/day or transient drug cessation may be sufficient for cytopenia reversal.
10-Ganciclovir;
The bioavailability of this drug is rather poor when given orally; therefore, it is
always given intravenously.
Compared with valganciclovir, ganciclovir exerts modest myelosuppression.
Although patients (23%) on ganciclovir therapy respond to dose reduction, some (2.4%) require ganciclovir cessation.
11- Valacyclovir;
Compared with valganciclovir and ganciclovir, myelotoxicity with valacyclovir is relatively mild. However, combined MMF and valacyclovir therapy may aggravate drug-
induced myelotoxicity. Moreover, MMF may aggravate bone marrow toxicity by increasing the intracellular concentration of valacyclovir.
When compared with ganciclovir, dose modification is less frequently employed with valacyclovir.
12-Trimethoprim-sulfamethoxazole;
Several types of cytopenia are associated with use of trimethoprim-sulfamethoxazole; these include; neutropenia and leukopenia and megaloblastic
anemia.
Trimethoprim per se can cause dose- dependent inhibition of granulopoiesis in vitro.
combined azathioprine therapy with trimethoprim- sulfamethoxazole can aggravate drug-induced myelosuppression
Folinic acid can reverse this side effect.
13-Dapsone;
Many hematological complications, including neutropenia.
Moreover, the neutropenic effects of dapsone may be aggravated by development of agranulocytosis
Therapy for Drug-induced Hematological Cytopenia;
In addition to the aforementioned protocols, there are a number of other specific interventions, as detailed below.
1-Specific treatment of neutropenia;
therapeutic step for WBC count correction would be administration of “colony-
stimulating” factors if there is no accepted response to the previous maneuvers.
The prophylactic administration of these agents is suggested in patients with;
1-febrile neutropenia .
2-those with diminished bone marrow reserves (eg, ANC <1.5 × 10 9/L) d
3-extensive radiotherapy
4-patients with AIDS/human immunodeficiency virus infection, and
5-patients older than 65 years.
Therapeutic indications include ;
1-sepsis, hypotension, neutropenic pyrexia of >7 days,
2-pneumonia or fungal infections, and adjunctive therapy along with antibiotics in the aforementioned indications.
3-Some conditions constitute medical emergencies of worse outcome that necessitate prophylactic administration of these agents, including prolonged pyrexia, severe neutropenia with ANC <500/μL, 94 and prolonged
neutropenia of more than 7 days.
2-Thrombocytopenia in kidney transplant;
can be attributed to either bone marrow suppression or to an idiosyncratic drug reaction.
The following steps in care are suggested:
1-if thrombocytopenia is due to idiosyncratic reaction ( due to trimethoprimulfamethoxazole), then immediate withdrawal of the suspected agent is required.
2-if bone marrow suppression is the underlying mechanism, dose reduction or complete drug cessation is required for correction of platelet decline.
3-Occasionally, platelet transfusion may be required, such as;
A- in life-threatening bleeding risk, serious decline of platelet count (<20 000/mm 3 ).
B- before an invasive procedure .
The recommended cut-off therapeutic level for platelet transfusion should be;
1->50 000/mm3 withcommencement of invasive maneuvers (eg, allograft
biopsy, gastroscopic studies, indwelling catheter application, transbronchial biopsy, and laparotomy).
2-Before ocular and neurosurgical invasive procedures, a minimum platelet count of ≥100 000/mm3is usually advised.
3-For lumbar puncture procedures, a platelet count of ≥50 000/ mm3 is recommended.
4- Because of the high vascularity of renal tissue, a minimum level of 100 000/mm3 is usually recommended for renal invasive procedures.
What is the level of evidence provided by this article?
Level v