Thank you All
Remember
Alemtuzumab can be given subcutaneously also. There is mortality reported following intravenous administration.
Professor Ahmed Halawa
Admin
3 years ago
Alemtuzumab is: A. Anti CD52 which is expressed on mature lymphocytes, natural killer cells (NK), eosinophils, neutrophils, monocytes/macrophages, and dendritic cells (DCs) B. It is used in renal transplantation “of label” (not licensed) C. CD52 is more expressed on B cells compared to T cells D. Associated with neutropenia E. Can be used is steroid-resistant rejection and can be given subcutaneously
A true
B true
c not true;
d true
E. true. can be given sc and this lowers the side effects of iv infusion, it can be an alternative to ATG with less side effects in treatment of acute rejection
Alemtuzumab is: A. Anti CD52 which is expressed on mature lymphocytes, natural killer cells (NK), eosinophils, neutrophils, monocytes/macrophages, and dendritic cells (DCs):
True. CD52 is expressed on mature lymphocytes, monocytes, macrophages, some granulocytes (neutrophils, eosinophils), natural killer cells, dendritic cells and mature sperm cells. B. It is used in renal transplantation “of label” (not licensed):
True. Alemtuzumab has been used ‘óff label’ for induction and steroid resistant rejection treatment. C. CD52 is more expressed on B cells compared to T cells:
False. CD52 is more expressed on T cells than B cells D. Associated with neutropenia:
False. Alemtuzumab is associated with lymphocytopenia, although mild neutropenia may be present. E. Can be used is steroid-resistant rejection and can be given subcutaneously:
True. Subcutaneous or IV Alemtuzumab has been used in steroid resistant rejection (off-label) cases in which ATG cannot be used.
C- False- CD52 is a 12 amino acid GLI linked protein with N linked glycan moiety and is expresses on T cells, B cells, monocytes, macrophages and eosinophils , NK cells ,Dendritic cells. It is expressed more on T cells as compared to B cells.
D-True- Usually associated with lymphopenia but neutropenia can be seen
A. Correct
B. Correct
C. Incorrect. CD 52 is expressed more in T cells than B cells. The T cell suppression is more profound than B cells
D. Incorrect. associated with lymphopenia
E. Correct
all are true except C , as it is expressed more on T cells and thus it is used in induction or treatment of steroid refractory TCMR (in stead of r ATG, when it is contraindicated as previous allergic reaction or excess consumption of rabbits.
1. Introduction
Alemtuzumab is an anti-CD52 depleting agent that is expressed on mature lymphocytes, natural killer cells , eosinophils, neutrophils, monocytes, macrophages, and dendritic cells. its effect lasts from 6-12 months.
2. The indications
Induction therapy in high risk patients
Resistant acute antibody mediated rejection
CLL
MS
3. Contraindications
Severe Allergic reaction to alemtuzumab
4. Dose used
Single intravenous dose of 30 mg at the time of transplantation
Available in 10 or 30 mg vials.
5. Route of administration
IV/SC; IV administered as infusion over 2 hours. Use normal saline
6. Side effects
Bone marrow suppression (pancytopenia; low WBC), autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia can occur.
Infusion reactions :
Alemtuzumab administration can result in serious, including fatal, infusion reactions. Careful monitosization required
Infections :
Serious, including fatal, bacterial, viral, fungal, and protozoan infections can occur in patients receiving alemtuzumab. Do not forget Bactrim and valgancyclovir prophylaxis
7. References
Van der Zwan, M., Groningen, C. V., Marian, C., van den Hoogen, M. W., Kho, M. M., Roodnat, J. I., … & Hesselink, D. A. (2020). Comparison of alemtuzumab and anti-thymocyte globulin treatment for acute kidney allograft rejection. Frontiers in immunology, 1332.
Betjes, M. G., Kho, M. M., Litjens, N. H., de Weerd, A. E., & Roodnat, J. I. (2021, September). Alemtuzumab as Second-Line Treatment for Late Antibody-Mediated Rejection of Transplanted Kidneys. In Transplantation Proceedings (Vol. 53, No. 7, pp. 2206-2211). Elsevier. https://doi.org/10.1016/j.transproceed.2021.07.005.
Hanaway, M. J., Woodle, E. S., Mulgaonkar, S., Peddi, V. R., Kaufman, D. B., First, M. R., … & Holman, J. (2011). Alemtuzumab induction in renal transplantation. New England Journal of Medicine, 364(20), 1909-1919.
Introduction:
Alemtuzumab anti CD52 (Campath1H), humanized monoclonal antibodies, potent depleting agent for both T-B cells, with rapid and profound depletion of central and peripheral lymphoid cells for months, its effective as induction agent in high immunological risk kidney transplantation and based on good evidence from many studies it’s not inferior to thymoglobulin in prevention of early acute rejection with similar graft and patient survival so can be used as alternative for thymoglobulin in certain cases with easier administration as single dose and allowed for the use of lower maintenance immunosuppression like early CNI minimization dose with early steroid withdraw protocol with the cost of increased risk of acute rejection overtime.
Indication:
1-Induction phase (high immunological risk kidney transplant recipient or low immunological risk with early steroid withdraw (off-label).
2-steriod resistant acute cellular rejection.
Dosing: available 20mg, 30mg, slow intravenous (IV) infusion or subcutaneous (SC). One or two doses. Side effect and warring:
1- infusion related allergic reaction like rigors, fever, nausea vomiting, hypotension, rash and urticaria, dyspnea preferred to be given SC with premedication
2- lymphopenia, close monitoring with FBC, wbc count and differential, platelet count
3- Increase risk of infections like viral infections herpes, cmv, BKV, PJP.
4- Hematological malignancy, Lymphoma, PTLD including aggressive type B cell lymphoma
5- Pregnancy: category C
Contraindication of campath1H:
Allergy, type 1 hypersensitivity reaction or allergic reaction to the component of alemtuzumab
Active systemic infection, Retroviral infection (HIV).
low dose 20mg or high dose 30mg intra-operative after reperfusionD0, Slow IV infusion or SC injection, preferred SC, second dose Day1.
2.PMP 500mg interoperative.
2-Maintenance Phase therapy:
A–Steroid with draw protocol, in low immunological risk, history of bone disease, cardiovascular disease, dyslipidemia
1-Tacrolimus (prograph), give in 12 hours split dose
0.15 -0.3mg /kg with target trough level initial phase 10-12ng first 3 months.
Then 5-7ng after 3months.
2-predsiolone 150mg oral, day 1, 2 then fast tapper with in 1week and stop
3- Mycophenolate sodium 360mg BID first two weeks then increased to full dose gradually 720mg BID, dose can be adjusted with AUC level alterative mycophenolate mofetil (MMF) 250, 500mg tablets.
B-Maintenance Phase therapy, in high immunological risk (as per local center definition of high immunological risk, autoimmune disease with high recurrence rate as primary glomerular disease
Tacrolimus 0.15-0.3 mg /kg with target trough level 10-12ng in first 3 months) then 7ng in 6 months, MMF 1gm bid, or myfortic 720mg BID plus oral prednisolone with gradually tapper over 2 months to 5 mg od.
monitor for lymphopenia with FBC , TLC , Platelets count.
All patients should receive CMV prophylaxis for 3 months and PJP prophylaxis for 6 months, avoid active vaccination.
References:
1-Kidney transplantation hand book 6th edition.
2-Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Lancet. 2014;384(9955):1684. Epub 2014 Jul 28. Induction Therapy for Kidney Transplant Recipients:
3-Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004759.
Last edited 3 years ago by saja Mohammed
Wee Leng Gan
2 years ago
Introduction Alemtuzumab is an anti-CD52 T-cell and B-cell–depleting monoclonal antibody, has been used for induction in renal transplantation. It is reported that renal allograft rejection rate was dramatically lower and alemtuzumab is not associated with an increased risk of infection.
The indications selected high immunologic risk subjects, to use as routine induction immunosuppression. Generally, its usage is limited. Steroid resistant allograft rejection.
Contraindications
1. Previous reaction to Alemtuzumab
2. Pregnancy or breast feeding.
3. Active infection.
4. Active malignancy.
Dose used
Pre med :
1. Paracetamol 1 g
2. Piriton 4mg
3. Prednisolone 30mg
Alemtuzumab dose 20-30mg depend on local guideline.
Route of administration
IV/SC Side effects
1. Allergy reaction.
2. Teratogenicity.
3. Fever, Vomiting, gastrointestinal symptoms.
4. Risk of malignancy need further evidence.
References Alemtuzumab in renal transplantation. Transplant Rev (Orlando). 2022 Apr;36(2):100686.
All True
AMAL Anan
2 years ago
Alemutzumab anti CD 52
Used as induction therapy in high risk patient
Given sc or IV
can cause bone marrow suppression
dina omar
2 years ago
Alemtuzumab is anti-CD52 highly expressed on the surface of T & B cells, thymocytes, monocytes, macrophage and NK cells. It can make marked lympho-penia which may continue for 6 months. Given as 2 doses of 30 mg doses given Sub-cutaneous 24 hours apart post-transplant , it can be given only one dose for patients more than 60 years. ITS given off-label in RTX , doses : First dose usually given intra-operatively before reperfusion. Late rejection may occur as T cells recover at ~ 6 months Can be used as rescue therapy to treat acute rejection Side effects include “cytokine-release syndrome” with IV given , neutropenia ,anemia , diarrhea ,increased risk of infection and autoimmune disorders .
Nandita Sugumar
2 years ago
Design for alemtuzumab protocol
Introduction
Alemtuzumab is an unconjugated, humanized, monoclonal antibody directed against the cell surface antigen CD52 on lymphocytes and monocytes.
Alemtuzumab is effective in preventing biopsy confirmed acute rejection in comparison with conventional induction therapy. It is as effective as ATG in high risk transplant recipients.
Indications
induction in kidney transplant
highly sensitized transplant recipient
steroid resistant rejection
B cell chronic lymphocytic leukemia
multiple sclerosis
Contraindications
allergy
type 1 hypersensitivity reaction
Infection
HIV patient
Malignancy
latent TB
Dose used
30 mg single dose at the time of kidney transplant
Farhad Ravandi & Susan O’Brien (2005) Alemtuzumab, Expert Review of Anticancer Therapy, 5:1, 39-51, DOI: 10.1586/14737140.5.1.39
Ahmed Fouad Omar
2 years ago
Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
· Introduction:
Alemtuzumab is a humanized depleting monoclonal antibody against CD52 which is expressed on mature lymphocytes(T>B cells), NK cells, DCs, macrophages, neutrophils and eosinophils.
It is Licensed for the treatment of multiple sclerosis and hematological malignancies and used off-label in kidney transplantation as induction and steroid resistant rejection therapy.
· Indications:
1-Induction phase (high immunological risk transplant recipient or low immunological risk with early steroid withdraw
2-steriod resistant acute cellular rejection when there is resistance or intolerance to rATG
· Contraindications:
Allergy, hypersensitivity to a component of Alemtuzumab, active systemic infection and malignancy
· Dose and method of administration: The dose used is similar to the dose used in CLL and multiple sclerosis.
– 20(low dose)- 30mg(high dose) intra-operative after reperfusion on Day 0, a second dose can be given on Day1.This is coupled with pulse methyl prednisolone 500 mg intraoperative.
– It is available as a solution for intravenous infusion over 2-4 hrs or subcutaneous administration.
– In high immunological risk: triple immunosuppression is given , keep TAC level 8-10 first 3 months the 5-8 ng/ml thereafter, MMF 1 gm BD, taper steroids to 5 mg within 2 M
– Steroid with draw protocol: : Early steroid withdrawal by day 7, continue on TAC +MMF
· Side effects:
1.infusion related reactions(cytokine release syndrome) , less if given SC
2.lymphopenia, close monitoring with FBC, WBC(total and differential)
3.Infections due to B and T cell depletion, BK infection is more common, prophylaxis against herpes virus , PCP(3 M prophylaxis) should be received. CMV(give 6 M prophylaxis) infection rate was similar to that of rATG
4.Data regarding malignancy is scarce, increased risk of non-hodgkins lymphoma, HPV related cancers, kaposi sarcoma.
5. It is teratogenic (class C) and expressed in breast milk
6. Autoimmunity: autoimmune hypo or hyperthyroidism and ITP
References:
1-Kidney transplantation hand book 6th edition.
2- Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Alemtuzumab-based induction treatment versus Basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Lancet. 2014;384(9955):1684.
Hamdy Hegazy
2 years ago
Introduction:
Kidney transplantation is considered the best modality of treatment that provide better quality of life and longer survival for ESRD patients.
Immunosuppressive medications are required to prevent rejection of renal graft.
Immunosuppression protocols in renal transplant recipients include induction protocol, maintenance and treatment of rejection episodes.
Alemtuzumab is a humanized monoclonal antibody against CD52 cell surface antigen, it is approved for use in some hematological malignancies and auto-immune diseases such as multiple sclerosis, it being used in some renal transplant centers as induction immunosuppressive agent in high risk recipients.
2. The indications: according to the available data from many trials, Alemtuzumab could be used in the following indications: 1- Low risk renal transplant recipients with early steroid withdrawal such as diabetic patients. 2- High risk renal transplant recipients who can’t use ATG because of contra-indications like hypersensitivity.
3. Contraindications Alemtuzumab is contra-indicated in the following situations: Active infection Active malignancies Hypersensitivity reaction Immunodeficiency such as HIV.
4. Dosage: Route: IV infusion (over 2-4 hours) or subcutaneous. Two doses, first dose at day 0, and second dose at day 1. Premedication should be given 30 minutes before, includes diphenhydramine 50 mg and paracetamol 1 gm IV. Dose: Alemtuzumab 30 mg IVI (over 2-4 hours) or SC.
5. Route of administration IVI in the majority of protocols. Subcutaneous has shown similar outcomes with less IV reactions, however, anti- Alemtuzumab antibody formation risk is higher. 6. Side effects The side-effects of Alemtuzumab include: Infusion associated reactions (in 70-80%), Infections, Increased risk of malignancy as compared to no induction, Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia. 7. References
1) 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014 Nov 8;384(9955):1684-90. doi: 10.1016/S0140-6736(14)61095-3. Epub 2014 Jul 28. PMID: 25078310. 2) Hill P, Cross NB, Barnett AN, Palmer SC, Webster AC. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD004759. doi: 10.1002/14651858.CD004759.pub2. PMID: 28073178; PMCID: PMC6464766. van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC57
ahmed saleeh
2 years ago
* Humanized rat monoclonal antibody against CD52 cell surface antigen, used in haematological malignancies and multiple sclerosis
*alemtuzumab (induction) in comparison to basliximab, revealed reduced rejection risks with similar delayed graft function, graft survival and patient survival rates.
*best to be used in following situations
¥ Tx patient with need of early withdrawal of steroids (and also if experienced complications of steroids
¥ if Hypersensitivity to ATG
*Can never be used in case of active infection , malignancy or previous hypersensitivity .
*dose used is similar to the dose used in CLL and multiple sclerosis.
*Injection Alemtuzumab 30 mg intravenous infusion over 2 to 4 hours
*maintenance triple therapy with early steroid withdrawal after 1st week .
*prophylaxis against CMV , PCP
Strict FU of the patient clinically and Lab wise
*precautions: take care of possibility of cytokine reaction and increased risk of malignancy and infections
MICHAEL Farag
3 years ago
Introduction
The best form of treatment for an end stage renal disease (ESRD) patient is a kidney transplant. Immunosuppression is an essential part of a kidney transplant patient management. Induction immunosuppression is required to decrease the risk of early rejections. Induction therapy involves use of T lymphocyte depleting and n-n-depleting antibody treatments. Alemtuzumab, a humanized rat monoclonal antibody against CD52 cell surface antigen, approved for use in haematological malignancies (B cell CLL) and autoimmune disease (multiple sclerosis), has been used as an induction agent in renal trasnplanation, although off-label. (1) 2. The indications
A systematic review regarding use of alemtuzumab as an induction agent, in comparison to basliximab, revealed reduced rejection risks with similar delayed graft function, graft survival and patient survival rates. (1) The 3C study compared alemtuzumab, low-dose tacrolimus and mycophenolate sodium without steroids with Basiliximab, standard-dose tacrolimus and mycophenolate sodium with steroids. The short-term results of this approach revealed lower biopsy proven acute rejection rates (BPAR) in the alemtuzumab arm with similar graft function, graft survival, infection and patient survival rates.(2)
Another trial comparing alemtuzumab with basiliximab in low-risk patient and with rabbit ATG in high risk patients revealed that alemtuzumab group had lower BPAR than basiliximab group in low-risk patients while the BPAR rates in the high-risk patients were similar to the rabbit ATG group.(3) Cochrane meta-analysis of induction therapy in kidney transplant patients also revealed similar BPAR rates in alemtuzumab based and ATG based induction therapies, but few studies showed reduced BPAR rates in alemtuzumab with early steroid withdrawal regimens.(4) Compared to ATG, Alemtuzumab with early steroid withdrawal had lower GFR at 6 months and 2 years.(4)
In the context of steroid minimisation, alemtuzumab prevented acute rejection at 1 year compared to ATG. CNI, MMF and steroid without induction therapy compared to alemtuzumab combined with early steroid withdrawal had similar rates of acute rejection. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple drug maintenance immunosuppression, in the absence of any clinical benefit. ATG and alemtuzumab use decreased risk of acute rejection, but with increased CMV disease with no change in patient-centred outcomes (reduced death or lower toxicity).(4)
In view of the data available, Alemtuzumab induction can be used in both low-risk and high-risk kidney transplant patients.(5)
a) Low-risk transplant recipients with early steroid withdrawal need (for example diabetic recipient)
b) High-risk transplant recipient with contraindication to ATG (hypersensitivity reaction). 3. Contraindications
Alemtuzumab should not be used in:
a) Active infection
b) Active malignancies
c) History of hypersensitivity reaction
d) Underlying immunodeficiency (e.g. HIV)
Although a patient being taken up for kidney transplant will not be having any active infection or malignancy at the time of transplantation. 4. Dose used
Dose of alemtuzumab used for induction in kidney transplantation is not based on any formal dose-finding studies in organ transplant recipients. The dose used is similar to the dose used in CLL and multiple sclerosis.
Injection Alemtuzumab 30 mg intravenous infusion over 2 to 4 hours, after pre-medication with diphenhydramine 50 mg and acetaminophen 500 mg intravenous 30 minutes prior to the infusion. Total 2 doses to be given on day 0 and day 1. Maintenance immunosuppression in form of a) Tacrolimus: 0.1 mg/kg/day. Target trough level 10 ng/ml initially, to be decreased to 7 ng/ml after 3 months. b) MMF: 1000 mg twice a day (dose to be withheld if leukopenia). c) Steroids: Early steroid withdrawal by day 7.
Prophylaxis:
a) CMV: Valgancyclovir 900 mg once day for minimum 2 months or until CD4 level>200
b) Pneumocystis: Tablet cotrimoxazole 480 mg once a day for 6 months.
c) Oral Candidiasis: Oral clotrimazole drops.
Post transplant regular CBC, creatinine, urine routine, DSA level monitoring. 5. Route of administration
Intravenous route has been used in majority of protocols, hence intravenous route being used. Although subcutaneous route has shown similar outcomes, there is increased risk of anti-alemtuzumab antibody formation.(5) 6. Side effects
The side-effects of Alemtuzumab includeL5)
a) Infusion associated reactions due to cytokine release (in 70-80%).
b) Infections due to prolonged lymphocyte depletion. Hence oral candidiasis, anti-herpes, CMV and pneumocystis prophylaxis to be given till CD4+ T lymphocyte count >200 or minimum 2 months. Watch for UTI.
c) Increased risk of malignancy as compared to no induction.
d) Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia. 7. References
1) Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012 Jun 27;93(12):1179-88. doi: 10.1097/TP.0b013e318257ad41. PMID: 22660659.
2) 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014 Nov 8;384(9955):1684-90. doi: 10.1016/S0140-6736(14)61095-3. Epub 2014 Jul 28. PMID: 25078310.
3) Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J; INTAC Study Group. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011 May 19;364(20):1909-19. doi: 10.1056/NEJMoa1009546. PMID: 21591943.
4) Hill P, Cross NB, Barnett AN, Palmer SC, Webster AC. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD004759. doi: 10.1002/14651858.CD004759.pub2. PMID: 28073178; PMCID: PMC6464766.
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC57 Influence on immunosuppression: 1) CNI exposure can be reduced by decreasing the target trough level to 4-7 ng/ml by 3 months
2) Similarly low dose MMF can be used
3) Rapid steroid tapering or early steroid withdrawal can be used in patients more prone to side-effects of steroids,
Autoimmune disease, particularly autoimmune thyroid disease and cytopenias.
Alemtuzumab may be associated with an increased risk of early graft thrombosi.
Administer by IV infusion over 2 hours.
Premedicate with diphenhydramine 50 mg and acetaminophen 500 to 1,000 mg 30
minutes before each infusion. IV glucocorticoids have been effective in decreasing
Start anti-infective prophylaxis.
How it influences the maintenance immunosuppression?
Low dose of maintenance IS can be used.
References:
Phuong-Th et al.The evolving role of alemtuzumab (Campath-1H) in renal transplantation.
Drug Des Devel Ther. 2009; 3: 41–49.
Ahmed Omran
3 years ago
Alemtuzumab ;Campath
_ _Used for treatment of CLL but utilized commonly in transplantation _ It is a humanized anti-CD52 antibodies ; CD52 is highly expressed on the surface of T & B cells in addition to other cells such as thymocytes, monocytes, macrophage and NK cells _It clears rapidly cells from the circulation leading to marked lymphopenia which may continue for 6 months( B cells recovers before T cells) _Dose ; Two of 30 mg doses given SQ 24 h apart post-transplant; some centers given only one dose for patients more than 60 years. _First dose usually given intraoperatively before reperfusion _Less marked infusion reaction and no cytokine release compared to ATG; SQ < IV. _Pre-medication is needed . _ Late rejection may occur as T cells recover at ~ 6 months
Can be used as rescue therapy to treat acute rejection with little experience and evidence.
Side effects include “cytokine-release syndrome” with IV infusion , characterized by fever, rash, hypotension, and bronchoconstriction ,neutropenia ,anemia ,rigors ,rash and allergy ,diarrhea ,increased risk of infection and autoimmune disorders like thyroiditis . Contraindications include: infection ,allergy ,fever ,malignancy and cytopenia.
Reference:Uptodate
CARLOS TADEU LEONIDIO
3 years ago
Introduction
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells. Ligation of alemtuzumab with CD52 induces apoptosis and lysis of immune cells through antibody- and complement-dependent cytotoxicity, which leads to profound and long-lasting lymphocyte depletion.
It´s used in immunosuppression strategies: A – induction treatment strategy; B- minimise CNI exposure to reduce the rate of late transplant failure. It has emerged as a promissing depletional MAb enabling a reversing steroid-resistant rejection.
The indications
– Perioperative depletion in combination with triple immunossppression;
– Early steroid or CNI weaning
Contraindications
– Patients with type 1 hypersensitivity or anaphylactic reactions to the active substance
– Patients with HIV
Dose used
30mg flat dose or at 0.3mg/Kg dose over 3 hours immediately after reperfusion and 24 h later
Route of administration
Through a peripheral intravenous cateter
Side effects
Mild to moderate infusion-associated reactions during administration for up to 24 hours, which frequently included headache, rash, pyrexia, nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, dysgeusia, discomfort chest, generalized rash, tachycardia, dyspepsia, dizziness and pain.
Serious reactions occurred in 3% of patients, including cases of pyrexia, urticaria, atrial fibrillation, nausea, chest discomfort, and hypotension.
In addition, anaphylaxis has been reported rarely.
Its use may result in the formation of autoantibodies and increased risk of autoimmunity-mediated conditions, including idiopathic thrombocytopenic purpura (ITP), thyroid disorders, or, rarely, nephropathies (eg, antiglomerular basement membrane disease).
7. References
– Kidney Transplantation: Principles and Practice – Eighth edition, ELSEVIER.
– Alemtuzumab-based induction treatment versus basiliximab based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet 2014; 384: 1684–90;
– Alemtuzumab as Antirejection Therapy: T Cell Repopulation and Cytokine Responsiveness. Bouvy et al. Transplantation Direct 2016;2: e83; doi: 10.1097/TXD.0000000000000595
– Lemtrada Genzyme – A Sanofi Company
Nasrin Esfandiar
3 years ago
Alemtuzumab is a humanized anti-CD52 monoclonal antibody pan lymphocytic (both B and T cell).
It is used as an anti-neoplastic agent, too.
In renal transplantation is used as an induction agent or treatment of renal transplant steroid resistant cellular rejection.
Labeled indication includes: B cell CLL, MS relapsing
OFF- label indications: steroid refractory GVHD, aplastic anemia, auto immune hemolytic anemia, conditioning regimen or GVHD prophylaxis induction and treatment of refractory TCMR in renal TX.
Contraindications hypersensitivity or anaphylactic reactions, HIV infection, active infection, latent TB, underlying immunodeficiency active secondary malignancies, current or history of progressive multifocal leukoencephalopathy (PMC)
Dosage:
As indication :30 mg as a single dose at the time of TX (immediately following reperfusion).
Followed by a second 30 mg dose 24 h later(for patientsfile:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png 60 years)
Followed by minimized maintenance immunosuppression or steroid-withdrawal. For steroid resistant TCMR: IV, SQ: 20-30 mg /dose on 2 subsequent days or 30mg /dose IV over 2-4 hours for1 to 2 dose.
Route of administration: IV or SQ. IV infusion over 2-4 hours with normal saline premedication used with acetaminophen and diphenhydramine and with control for V/S.
Side effects:
1) Infusion reactions
2) Infections: viral, fungal bacterial and protozoan infections that need prophylaxis with co-trimoxazole and valcyte.
3) Autoimmune effect (immune thrombocytopenia or anti- GBM)
4) Malignancies (thyroid cancer, melanoma and lymphoproliferative disorders
5) Stroke.
1.Asderakis, A., Sabah, T. K., Watkins, W. J., Khalid, U., Szabo, L., Stephens, M. R., Griffin, S., & Chavez, R. (2022). Thymoglobulin Versus Alemtuzumab Versus Basiliximab Kidney Transplantation From Donors After Circulatory Death. Kidney International Reports, 7(4), 732–740. https://doi.org/10.1016/J.EKIR.2022.01.1042
2.Guthoff, M., Berger, K., Althaus, K., Mühlbacher, T., Bakchoul, T., Steurer, W., Nadalin, S., Königsrainer, A., & Heyne, N. (2020). Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrology, 21(1). https://doi.org/10.1186/s12882-020-01767-z
3. Naesens, M., Berger, S., Biancone, L., Crespo, M., Djamali, A., Hertig, A., Öllinger, R., Portolés, J., Zuckermann, A., & Pascual, J. (2016). Lymphocyte-depleting induction and steroid minimization after kidney transplantation: A review. Nefrología, 36(5), 469–480. https://do i.org/10.1016/J.NEFRO.2016.03.019
4. uptodate 2022
Shereen Yousef
3 years ago
Introduction:
Alemtuzumab, a humanized monoclonal antibody directed against CD52 on B- and T-lymphocytes, monocytes and NK cells, is used in the treatment of lymphoma and multiple sclerosis
Alemtuzumab causes prolonged depletion of both T and B lymphocytes ,for up to 12 months, with profound immunosuppression and an associated risk of serious infections.
, it is used for induction in high immunological risk candidates .
Alemtuzumab has been used for induction in kidney transplantation since 1998 .
alemtuzumab,results in the same or even better results than ATG with regard to rejection episodes .
Complete B- and T-lymphocyte depletion, however, persists much longer than with ATG which is accompanied by an increased risk of infection.
Doses:
it is administred as single dose or two doses intraoperatively slow intravenous (IV) infusion or subcutaneous (SC)
standard dosing. With doses of 30–60 mg
Using a reduced dose of 20 mg, resulting in a median dose of 0.3 [0.26–0.34] mg/kg, time to lymphocyte recovery is markedly shorter than standard dosage .
With a median time to lymphocyte recovery of 77 days, the critical period of being prone to infections was kept short without putting the patients at immunological risk
Indication:
1-drug has been used off-label for both the prevention and treatment of acute allograft rejection in kidney, pancreas, intestinal, and lung transplantation.
2-Induction for high risk patients
3-steriod resistant acute cellular rejection.
4-treatment of lymphoma and multiple sclerosis.
Dose monitoring
measuring the serum or plasma concentration of alemtuzumab is possible. However, these assays are not widely available, technically demanding, and difficult to standardize.
Maintenance immunosuppression
Side effects
Fever, chills, dizziness, muscle stiffness, nausea, vomiting, headache, diarrhea, mild rash/itching, tiredness, flushing, or trouble breathing may occur during or after the infusion.
* in high risk patients inuction with alemtuzumab followed by triple immunosuppression with Tacrolimus, MMF and steroid
*Use of alemtuzumab allowed early
Steroid withdraw protocol, in low immunological risk
Triple immunosuppression with
Tacrolimus target trough level initial phase 8-10 ng first 3 months.
Then 5-7ng .
predsiolone 150mg oral, to be tapper with in 1week
Mycophenolate sodium 360mg BID first two weeks then increased to full dose gradually 720mg BID.
References:
1-Martina Guthoff, Kilian Berger,.Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients.BMC Nephrology volume 21,Article number: 178 (2020).
2-Kidney transplantation hand book 6th edition.
Ramy Elshahat
3 years ago
Induction means any drug used for inducing graft acceptance in the early postoperative period But it’s usually meant by induction the biological drugs. There are 2 types of induction therapy 1. Depleting induction w includes (ATG and alemtuzumab) 2. Nondepleting induction (basiliximab) alemtuzumab is depleting monoclonal biological drug formed by injection of cd52 antigen into rats then humanized. cd52 presented on lymphocytes, NK, eosinophils, neutrophils, monocytes/macrophages, and dendritic cells (DCs). so, it’s associated with the destruction of all the previous cells. Because its humanized, its allergic reaction is much better than chimeric drugs but still premedication is still needed (acetaminophen, methylprednisolone, and antihistaminic). Alemtuzumab is used at a dose of 30mg subcutaneous after reperfusion. Alemtuzumab was compared to rATG as regards efficacy and safety, results showed noninferiority. So, 1st step for any protocol is risk stratifications and with regard, to the risks patients should be divided into 3 categories High risk, intermediate risk, the low risk then 1. high-risk patients are for depleting induction using rATG or alemtuzumab 2. Low and intermediated risk studies showed that depleting induction didn’t show superiority to nondepleting induction using basiliximab so it’s better to be saved as a treatment and to decrease risks of complications but it can be used for the next reasons a. Immunosuppressive minimization b. Allow use of CNI sparing regimens: Like CNI avoidance and use mTOR as donovo IS or early conversion (6m) or late conversion (1y) c. Allow use of steroids sparing regimens: Like steroids avoidance, steroids early withdrawal, and steroids late withdrawal So, the best protocol to use Alemtuzumab is as induction therapy in high-risk patient It should be mentioned that there is no total agreement on the definition of high-risk patients but in general 1. Patients with +ve FXC and +ve DSA 2. Patients with +VE DSA and -ve FXC 3. Patients with 2 DR mismatch or 1DR mismatch and 2 B 4. Patients with cPRA > 80%
5. Patient 2nd,3th, and 4th kidney transplantation 6. Other parameters can be considered as risk factors for graft rejection and some centers give depleting inductions for those patients like (Young recipient, Recipient his 1ry kidney disease is GN, Black races. Finally, after establishing the protocol, patients should be randomized and studied in comparison to the control group to reach the best protocol for our patients special in the presence of big racial differences which exposes the urgent need for more studies on different races
nawaf yehia
3 years ago
Alemtuzumab
Alemtuzumab (Campath 1H) is a recombinant DNA-derived humanized monoclonal antibody directed against the cell surface glycoprotein CD52 .
USES 1): initially approved for use in Bcell chronic lymphocytic leukemia,
2) it is a depletional agent sometimes used in clinical transplantation, although off- label, where it is used as an induction agent and in the treatment of acute transplant rejection. 3) also used in relapsing form of Multiple sclerosis
When used at the time of transplantation as induction therapy :
1) alemtuzumab induces a profound, rapid, and effective depletion of peripheral and central lymphoid cells that maytake months to return to pretransplantation levels.
2) Used as a single agent, it does not induce tolerance and episodes of acute rejection can occur even in the absence of T cells.
3)Its use may facilitate minimization of maintenance immunosuppressive protocols and steroid sparing with monotherapy using sirolimus or low-dose calcineurin inhibitor.
MODE OF ADMINSTRATION & DOSE :
Although Alemtuzumab use in kidney transplantation is “off-label.” Its ease of administration has made it an attractive alternative to Thymoglobulin.
It is usually given as a single dose of 30 mg intraoperatively; a second dose is sometimes given. Because the drug is administered under general anesthesia, infusion-related events typically associated with the infusion of biologic agents are masked.
so it requires premedication with steroids , antihistamine and paracetamol along with close monitoring for infusion reaction till for 2 hours after infusion
When used as an induction agent, alemtuzumab reduces the risk of rejection compared to basiliximab in unsensitized patients. However, when compared to rATG in randomized clinical trials, alemtuzumab has not been shown to be superior. In trials of patients undergoing steroid withdrawal, those receiving alemtuzumab have a greater risk
of rejection.
SIDE EFFECTS :
1-Alemtuzumab induces profound lymphopenia, cytopenias ( including autoimmune thrombocytopenia , AIHA ) which may be prolonged requiring reduced doses of other myelosuppressive agents , so keep frequent monitoring of CBC and differential WBC count .
2- risk of oppurtunistic infections as PJP , CMV , herpes .give PJP prophylaxis for 2 months after last infusion , check VZV Ab and consider immunization prior to therapy 3- Malignancies 🙁 thyroid , melanoma , LPD ) , have baseline and regular skin exam
4- Anti GBM disease
CONTRAINDICATIONS
active infections
Baseline and later monitoring :
CBC and differential , TFT , RFT & urinalysis , skin exam , HIV , latent TB , oppurtunistic infections testing as mandated
# Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
# Alemtuzumab is a monoclonal anti-CD52 antibody, which has been used extensively off label in solid organ transplantation.
# Its use as induction agent at the time of organ transplantation
# There is limited experience for using it in steroid resistant rejection.
# Prolonged lymphocyte depletion can be expected following treatment wih Alemtuzumab even with one dose of 30mg IV
#Incomparison with ATG Alemtuzumab has benefits with lower cost, fewer side effects and no specific issues with i.v. access.
also with nondepleting agents, such as anti-CD25 induction therapy.
# Calne et al, conducted that recipients treated with alemtuzumab induction and cyclosporine maintenance therapy without azathioprine or steroids were described by profound lymphocyte depletion induce the immune system into a tolerogenic state when encountering a newly transplanted graft, or at least develop a state of ‘prope (almost) tolerance’ with minimal requirements for further immunosuppressive therapy.
# patients given alemtuzumab followed by one half of the usual dose of cyclosporine and no other agents, short term follow up on low dose cyclosporine monotherapy. their 5year followup of this recipient group and noted no significant difference in rejection episodes, graft function or graft and patient survival
#There were no differences in denovo malignancy or infection.
#They report more episodes of late rejection in the alemtuzumab treated group cause may be secondary to lower cyclosporine levels,
# Episodes of autoimmune disease were noted in alemtuzumab treated patients.
# With regard to the induction of tolerance, these patients were no more tolerant to renal grafts than controls at 5years.
#They demonstrate that alemtuzumab induction therapy could enable a steroid-free immunosuppressive regimen with low-dose cyclosporine with graft function equivalent to standard triple therapy
# Ciancio et al. described a similar experience with alemtuzumab induction their group received alemtuzumab induction followed by a steroid-free protocol including low-dose tacrolimus and low-dose mycophenolate, they found similar rates of acute rejection, graft and patient survival compared with earlier protocol.
# using alemtuzumab and low dose calcineurin inhibitors, this immunosuppressive protocol could be a means to completely avoid the toxicity associated with calcineurin inhibitors and possibly improve long-term graft function.
# Results of a pilot study noted an unacceptably high rate of acute humoral rejection (17%) compared with the10% using traditional, triple immunosuppressive therapy
# At the University of Wisconsin, a subsequent immunosuppressive protocol was then adopted consisting of two doses of alemtuzumab at the time of renal transplant in combination with low dose steroids (10mg methyprednisolone per day), MMF(1000mg) MMF, and either tacrolimus or cyclosporine compared with historical controls that received induction therapy with anti-CD25 antibody, Thymoglobulin or OKT3 followed by maintenance calcineurin inhibitor, MMF and steroids. It was noted that the alemtuzumab-treated group experienced less acute rejection, particularly in those patients experiencing delayed graft function (DGF).
#Shapiro et al. compared alemtuzumab with Thymoglobulin. Both groups received steroid-free maintenance immunosuppressive therapy and low-dose tacrolimus there were more episodes of acute cellular rejection in the Thymoglobulin group, the patient and graft survival rate was equivalent
# late rejection episodes (>6 months) in both depletional groups were increased, likely secondary to the aggressive calcineurin inhibitor weaning protocols.
# Calne et al. originally observed an acellular, ‘vascular’ type rejection in a single patient while Kirk et al. noted a marked macrophage infiltration in patients with early rejection who received alemtuzumab induction without maintenance immunosuppressive therapy.
#Several authors have now reported that a number of these rejection episodes demonstrate positive staining for C4d, indicative of acute humoral rejection It is unclear if the rates of C4d+ rejection are increased with alemtuzumab induction as this technique has only been employed for a relatively short period of time.
# Ciancio et al. observed that the incidence of C4d+ rejection was no different between patients undergoing induction with alemtuzumab or with other agents
# References
1 Waldmann H, Polliak A, Hale G, et al. Elimination of graft-versus-host disease by in-vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH-1). Lancet 1984; 2: 483.
CrossrefCASPubMedWeb of Science®Google Scholar
2 Heit W, Bunjes D, Wiesneth M, et al. Ex vivo T-cell depletion with the monoclonal antibody Campath-1 plus human complement effectively prevents acute graft-versus-host disease in allogeneic bone marrow transplantation. Br J Haematol 1986; 64: 479.
Wiley Online LibraryCASPubMedWeb of Science®Google Scholar
Zahid Nabi
3 years ago
A is true
B is true
C is false
D is true
E is true
Zahid Nabi
3 years ago
Introduction
Alemtuzumab is a humanized anti-CD52 panlymphocytic (both B and T cells) monoclonal antibody that is approved for treatment of chronic lymphocytic leukemia. Alemtuzumab induction therapy is used in approximately 10 percent of kidney transplant recipients in the United States.
Alemtuzumab binds to CD52, a nonmodulating antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. After binding to CD52+ cells, an antibody-dependent lysis of malignant cells occurs. In multiple sclerosis, alemtuzumab immunomodulatory effects may include alteration in the number, proportions, and properties of some lymphocyte subsets following treatment.
Although randomized trials comparing alemtuzumab with either rATG-Thymoglobulin or basiliximab have shown similar or lower rates of acute rejection , there are concerns that its benefits in reducing acute rejection may decrease over time Other long-term outcomes, including graft and patient survival and development of chronic allograft nephropathy, may also be worse in patients receiving alemtuzumab compared with rATG-Thymoglobulin and interleukin (IL) 2 receptor antagonists In addition, alemtuzumab is not readily available to all medical centers that perform kidney transplantation.
Some centers use alemtuzumab as induction therapy for recipients of a human leukocyte antigen (HLA)-incompatible kidney transplant following HLA desensitization.
Indications
The indications
Induction therapy in high risk patients
Resistant acute antibody mediated rejection
CHronic lymphocytic leukemia
MS
Contraindications
Hypersensitivity (eg, anaphylactic reactions) to alemtuzumab or any component of the formulation; HIV infection (due to prolonged reduction in CD4+ lymphocytes); active infection.
Canadian labeling:
Lemtrada: HIV infection; active or latent tuberculosis; severe active infections; active malignancies; concurrent anticoagulant, antiplatelet, antineoplastic, or immunosuppressive therapy; history of progressive multifocal leukoencephalopathy (PML); history of stroke and arterial dissection of cervicocephalic arteries infections; uncontrolled hypertension; history of arterial dissection of the cervicocephalic arteries; history of stroke; history of angina or myocardial infarction; known coagulopathy.
Side effects
>10%:
Dermatologic: Pruritus (14%), skin rash (53%), urticaria (16%)
Endocrine & metabolic: Thyroid disease (13% to 37%)
Gastrointestinal: Diarrhea (12%), nausea (21%)
Genitourinary: Urinary tract infection (19%)
Hematologic & oncologic: Lymphocytopenia (100%)
Immunologic: Antibody development (neutralizing: 5% to 94%; anti-alemtuzumab: 29% to 83%; no significant effect on drug efficacy)
Infection: Fungal infection (12% to 13%; including oral candidiasis, vulvovaginal candidiasis), herpes virus infection (16%), infection (71%; serious infection: 3%)
Nervous system: Fatigue (18%), headache (52%), insomnia (16%)
Neuromuscular & skeletal: Arthralgia (12%), back pain (12%), limb pain (12%)
Respiratory: Nasopharyngitis (25%), oropharyngeal pain (11%), sinusitis (11%), upper respiratory tract infection (16%)
Miscellaneous: Fever (29%), infusion related reaction (92%; severe infusion related reaction: 3%)
Alemtuzumab is administered as a single intravenous (IV) dose of 30 mg at the time of transplantation.
Ref: up to date
manal jamid
3 years ago
A+B+D+E ARE CORRECT
manal jamid
3 years ago
The origins of alemtuzumab date back to Campath-1 which was derived from the rat antibodies raised against human lymphocyte proteins by Herman Waldmann and colleagues in 1983. The name “Campath” derives from the pathology department of Cambridge University Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells, CD52 is not expressed on erythrocytes, platelets, and hematopoietic progenitor cells. The exact function of CD52 is unknown but it is suggested that the molecule may be involved in T lymphocyte co-stimulation, the induction of regulatory T lymphocytes, and T lymphocyte migration and adhesion. Ligation of alemtuzumab with CD52 induces apoptosis and lysis of immune cells through antibody- and complement-dependent cytotoxicity, Alemtuzumab causes a rapid and profound depletion of T and B lymphocytes, as well as various cells of the innate immune system. Reconstitution of cells from the innate immune system is faster (within 6 months) than that of T and B lymphocytes, which may take more than 1 year. Indication in general 1. solid organ transplantation as an induction agent in the prevention of rejection. 2. various autoimmune disorders, and has also shown potential as 3. treatment of chronic lymphocytic leukemia 4. Multiple sclerosis Clinical Use of Alemtuzumab in Kidney Transplantation
Alemtuzumab is not registered for SOT indications. However, the drug has been used off-label for both the prevention and treatment of acute allograft rejection in kidney, pancreas, intestinal, and lung transplantation. Alemtuzumab as Induction therapy at the time of transplantation allows for minimizationof CNI exposure without an increased risk of acute rejection. could potentially lead to better renal function and longer graft survival. Dose (30 mg on days 0 and 1, subcutaneously or intravenously) +low dose tacrolimus (target pre-dose concentrations 5–7 ng/mL) + and mycophenolate sodium (360 mg twice daily) steroid free. compared with basiliximab (20 mg intravenously on days 0 and 4) +standard-dose tacrolimus (target pre-dose concentrations 5–12 ng/mL), mycophenolate sodium (540–720 mg twice daily), and glucocorticoids (15–20 mg prednisone. Endpoint of the 3C study there was significant reduction in the incidence of BPAR: 26 (6.1%) vs respectively. compared induction therapy with alemtuzumab to rATG. There was no significant difference in graft loss and overall survival. Anti-rejection therapy Alemtuzumab used as anti-rejection therapy results in a comparable graft survival rate compared with rATG, although infusion-related side effects appear to be less.Alemtuzumab could be an alternative to rATG for the treatment of glucocorticoid-resistant, severe or recurrent AR. Compared to rATG, allograft- and patient survival of patients treated with alemtuzumab was not different. Moreover, adverse events and infections seemed to occur less frequently in patients treated with alemtuzumab compared with rATG-treated patients.
Contraindication 1.have active infections, underlying immunodeficiency (e.g., seropositive for HIV), 2. known type I hypersensitivity or anaphylactic reactions to the substance 3. Active malignancies
Dose used and rout of administration in renal transplantation . No formal dose-finding studies have been performed in SOT recipients. It is recommended that patients are pre-medicated with glucocorticoids, acetaminophen, and anti-histamines immediately prior to the administration of alemtuzumab to diminish infusion-related reactions.
The side effects of alemtuzumab?
1. Infusion associated reactions due to cytokine release. (Fever, chills, flushing, dizziness, shortness of breath, nausea, vomiting, or mild rash/itching may occur during or after the infusion. These reactions occur more often during the first week of treatment
2. Infections due to prolonged lymphocyte depletion. Hence oral candidiasis, anti-herpes, CMV and pneumocystis prophylaxis to be given till CD4+ T lymphocyte count >200 or minimum 2 months. Watch for UTI.
3. Increased risk of malignancy as compared to no induction.
4. Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia.
Comparison of Alemtuzumab and Anti-thymocyte Globulin Treatment for Acute Kidney Allograft Rejection
Mohamed Ghanem
3 years ago
Introduction : Alemtuzumab (Campath-1H) is a humanized rat monoclonal antibody directed against the CD52 antigen, Can cause profound B and T lymphocyte depletion. Alemtuzumab is now widely used in solid organ transplantation, principally as an induction agent, but also in the treatment of acute rejection.
mechanism of action it binds to CD52 on the surface of B and T lymphocytes, monocytes, macrophages, dendritic cells, and natural killer (NK) cells.
with subsequent lymphocytes lysis with complement activation and AB dependant cytotoxicity
rapid action: after 48 hrs.
Long-lasting T cell depletion may persist for years, B cells 2: 12 months
therapeutic uses: treatment of CLL GVHD in BM transplantation autoimmune diseases (including multiple sclerosis, rheumatoid arthritis, and vasculitis) solid organ transplantation in renal transplantation, alemtuzumab is used in the treatment of acute rejection Alemtuzumab is gaining increasing popularity as an induction agent since it allows the use of steroid-free maintenance regimens Side effects: Intravenous infusion is associated with a marked “cytokine-release syndrome”, characterized by fever, rash, hypotension, and bronchoconstriction Neutropenia Anemia Rigors Rash and allergy Diarrhea Increased risk of infection Autoimmune disorders ( thyroiditis ) Contraindication: Current infection Allergy fever malignancy Cytopenia
. Route of administration SC or IV infusion pre medication in IV route ( Paracetamol + Diphenhydramin + solumederol ) Monitor : CBC , CD4 count
Dosing : day 0 and day 1 of IV infusion of 30 mg Alemtuzumab
Reference :
Alemtuzumab as Induction Therapy in Renal Transplantation
Menna R. Clatworthy1 and Christopher J.E. Watson2
A True B Ture C False (more expression on T cells) D True E True
Sahar elkharraz
3 years ago
Alemutzumab (Campath) :
it’s monoclonal antibody against CD 52 inhibit B and T cell antibody, it’s expressed on lymphocytes and macrophage ; monocytes and natural killer cell and dentric cell.
it’s expressed more in T cell.
it’s used for treatment of chronic lymphocytic leukemia and multiple sclerosis. recently low dose of alemutzumab used in high sensitised patients to prevent AMR
it’s contraindicated in acute infection and bone marrow failure and hypersensitivity.
it’s side effects flu like illness, GIT upset, headache and dizziness and hypertension.
it’s can be used intravenous and subcutaneous which are less side effects than infusion
References
Michael J. et al, Alemtuzumab Induction in Renal Transplantation: N Engl J Med 2011; 364:1909-1919.
Balaji Kirushnan
3 years ago
Protocol for Alemtuzumab in Renal Transplantation
Introduction: Almetuzumab is an anti CD 52 monoclonal antibody. It is a depleting antibody. It is a fully humanized monoclonal antibody. It induces rapid depletion of circulating B and T cells within 24 to 48 hours of administration. B Cells remain suppressed for 12-24 months after one dose. T cells are suppressed further and may not even show an upward trend. Alemtuzumab is easy to administer with less side effects as compared to ATG. The ease of administration by a subcutaneous route has made it very convenient for use as an induction agent. It was initially used in the treatment of Steroid resistant cell mediated rejection, later it was used as an off label use for induction agent in various non randomized and randomized trials. Almetuzumab is a pro tolerogenic monoclonal antibody in that it induces more of CD4 CD25 FOXP3 T cells (Regulatory T Cells). It helps in inducing graft tolerance. There is evidence to show that a subset of T Cells namely CD4 CD45 RA T cells are resistant to alemtuzumab therapy, but these are suppressed when CNI are used as a downstream effect, hence most of the studies used almetuzumab with low dose CNI. It is useful in steroid avoidance protocols and even shown promise in pediatric transplants as induction agent.
Indications: In steroid free protocols, pediatric Transplants, Deceased donor renal transplant especially after DCD, steroid resistant cell mediated rejection, high risk transplant with risk of rejection. It is used as an off label indication in these group of patients. It is also used in Rheumatoid arthritis, multiple sclerosis and CLL
Contraindications: Previous allergic reaction to alemtuzumab
Dose: 30mg day 1 and Day 2 administered as a subcutaneous injection. Inj MPS 125mg IV is given as premedication to avoid allergic reaction
Low risk individuals: Maintain Tacrolimus level to 5 to 9ng/ml in the initial 3 months, with tapering dose of steroids over 1 month. MMF started in a low dose of 250mg twice a day and monitor absolute lymphocyte count; increase the dose of MMF when ALC >200 cells/microl.
High risk individuals: Maintain Tacrolimus level to 10 – 15 ng/ml in the initial 3 months with same dose of steroid taper and MMF dose escalation.
All patients would be on Tab cotrimoxazole 160/800mg once a day for 6 months and Valganciclovir 900mg per day depending on the differential count monitoring
Side effects: Initial retrospective cohorts report an increased incidence of PTLD and CMV infections with alemtuzumab owing to profound lymphocyte depletion. Later randomized studies did not demonstrate an increased incidence of the same. Reports of increased incidence of autoimmune thyroid diseases are quoted.
Mohamed Essmat
3 years ago
Induction therapy with alemtuzumab is implemented to reduce the Corticosteroids dose. Alemtuzumab ( Campath) is a humanized monoclonal anti CD52 antibody Indications. -CLL -Steroid resistant cellular rejection -As induction agent in high risk in high immunological risk patients and those with steroid withdrawal. Contraindications Hypersensitivity Active systemic infections HIV Dose: It is recommended that patients are given glucocorticoids, acetaminophen, and anti-histamines immediately prior to the administration. A Single IV dose of 30 mg as induction agent at the time of transplantation and second dose on day 1. Route of administration Intravenous or subcutaneous Side effects: – local injection-site reactions. – Infusion-Associated Reactions – Infection due to prolonged depletion of immune cells – Malignancy : EBV-positive large-cell lymphoma , non-Hodgkin lymphoma, Hodgkin lymphoma, Kaposi sarcoma, and liver cancer ,colorectal cancer and thyroid cancer· – Immune thrombocytopenia (idiopathic thrombocytopenic purpura) References -van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 F – alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients 2-Alemtuzumab Induction in Renal Transplantation by Michael J. Hanaway, M.D(INTAC study)eb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC5784003.
Manal Malik
3 years ago
References
Hirai T, Furusawa M, Omoto K, Ishida H, Tanabe K. Analysis of predictive and preventive factors for de novo DSA in kidney transplant recipients. Transplantation. 2014;98:443–
2- Brokhof MM, Sollinger HW, Hager DR, Muth BL, Pirsch JD, Fernandez LA, et al. Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients. Transplantation.
Manal Malik
3 years ago
Alemtuzumab introduction
is humanized monoclonal antibodies specific to T&B lymphocytes ,it recombinant DNA derived ,dirct against the 21 -28 kd cell surface glycoprotien CD52 ,.the campath-1 antibody is an IgG1kappa.
HLA sensitized patients were treated according to center protocol if their antibody (PRA equal or more than 15) in deceased donor transplant or if they had incompatible living donor transplant define by presence of DSA prior to transplant
single plasmapharsis performed in majority of patient prior to deceased donor transplant,
negative complement depend toxicity cross match require before transplant Protocol
for induction varies from centers so from literature review this protocol for Alemtuzumab induction:
low dose 20 mg i.v prior to perfusion and tailored immunosupression commencing with TAC trough level 10
pluse steroid 500 mg and 250 mg prednisone i.v at time of transplant and 12 hour later respectively.
followed by 100mg predislone given orally with taper to 5 mg within one month
MMF was suspended until lymphocytes count in peripheral blood reach >5% of leucocytes or >200/ul absoluate dose is 1000 mg po bid
pneumocytic Jiroveci prophylaxes for 6 month
CMV prophylaxes for 3-6 month
dose of ALemtuzumab is from 30 to 20 mg acorrding to protocol centre
protocol mention above as to minimize the side effects such as infection. indication of Alemtuzum
1-induction therapy in renal transplantation recipient
2- treatment of B-cell chronic lymphocytic leukemia.
3- kidney transplant rejection (steroid resistance)
4- leukemia( prolymphocytic Tcell.)..
5-relapsing remitting multiple sclerosis and secondary progressive M.S .
6-Refractory autoimmune heamolytic anemia.
7- refractory idiopathic thrombocytopanic purpura. reconstitution
30 mg /ml soluation for infusion with 100 ml of 0,9 N.S NACL or 5%dextrose in water as 12 mg /1.2ml soluation for infusion with draw 1,2 ml contraindication
1-HIV.
2-sever active infection
3- other autoimmune disease
4-coagulopathy
5-uncontrolled HTN
6- History of stroke .
7- History of angina pectoris ,MI or arterial dissection of cervico cephalic Artery.
8- antiplatlet and anticoagulant therapy.
Nazik Mahmoud
3 years ago
Alemtuzumab
It a monoclonal antibody directed against cell surface glycoprotein CD52.
Profound rapid depletion of peripheral and central lymphoid tissue and well take months to return back to pretransplant status,
It use as a single dose 30 mg interaoperatively. Side effects are masked cause the patient was under general Anathesia. Has superior effect when compared to basiliximab
But had no superiority to ATG. The incidence of cellular rejection was lower due to profound lymhopenia
The immune suppression effect of alemtuzmab called proper tolerance or near tolerance that allow minimal immune suppression mantance therapy as Low dose CNI or mTOR as mono therapy
Reference:
Kidney transplantation book 6 edition
Alemtuzumab: is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells.
It is registered for the treatment of multiple sclerosis and is also used in chronic lymphocytic leukaemia.
It’s used off-label in kidney transplantation as induction and anti-rejection therapy.
Indications:
Alemtuzumab is not registered for SOT indications. However, the drug has been used off-label for both the prevention and treatment of acute allograft rejection in kidney, pancreas, intestinal, and lung transplantation.
Induction therapy in kidney transplantation:
Alemtuzumab was first used as induction therapy in 1998 when 13 patients received it as induction therapy consisting of 2 doses of 20 mg IV on days 0 & 1. Only one patient had rejection on a 6-11 month follow up. Then the use of alemtuzumab as induction therapy was compared to basiliximab in an RCT and a reduced risk of rejection at 12 months in the alemtuzumab arm was confirmed but no significant difference was seen in graft loss, delayed graft function, or patient survival.
In the 3C study, No significant difference was seen in the occurrence of biopsy-proven antibody-mediated rejection in patients receiving alemtuzumab.
Simultaneous Pancreas-Kidney Transplantation:
In a single-centre RCT, alemtuzumab was compared to rATG, and no significant difference was seen in the frequency of rejection after 1 year.
Alemtuzumab as Anti-Rejection Therapy:
The main use is as a second line in steroid-resistant or severe cellular rejection when there is resistance or intolerance of rATG.The authors of a study including 40 patients concluded that the outcome after treatment with alemtuzumab is comparable to the outcome of other antibody preparations (indirect comparisons with RCTs). However, infectious complications were more frequent.
Alemtuzumab has incidentally been used as a treatment of biopsy-proven acute rejection after kidney transplantation. No RCTs investigating this application have been performed. In a study comparing the long term outcome of using alemtuzumab compared to MP in the treatment of acute rejection, the study found that the long-term transplant survival and allograft function were similar in both groups.
Complications;
infusion associated reaction: occur in 70–80% of patients during treatment with alemtuzumab when given intravenously. usually caused by cytokine release from lysed immune cells.
infections: a prolonged depletion of T and B lymphocytes (usually for over 12 months) will happen and predispose the patients to infections. Prophylaxis against herpes virus and Pneumocystis jirovecii should be started directly after administration of alemtuzumab and be continued for a minimum of 2 months. BK virus infection is more common after alemtuzumab induction, Cytomegalovirus and opportunistic and non-opportunistic infections were not more common when comparing alemtuzumab with ATG induction therapy.
malignancy: Long-term data are scarce and the risk of developing malignancy is poorly defined.
autoimmunity: Secondary autoimmune events have been reported after alemtuzumab treatment such as Autoimmune thyroid disorders, especially hypothyroidism and hyperthyroidism, also Immune thrombocytopenia, One case of Guillain–Barre syndrome was reported, four cases of glomerulopathy.
fertility and pregnancy: pregnancy category C, alemtuzumab, it crosses the placental barrier and may potentially affect the fetus. It is not known whether alemtuzumab can cause fetal harm when administered to pregnant women or whether it can affect reproductive capacity.
Dose and Administration:
Alemtuzumab is available as a solution for intravenous or subcutaneous administration.
The recommended dose depends on the indication for alemtuzumab.
A typical dosing scheme of alemtuzumab in SOT is 1 or 2 doses of 30 mg intravenously or subcutaneously.
No formal dose-finding studies have been performed on SOT recipients. It is recommended that patients are premedicated with glucocorticoids, acetaminophen, and antihistamines immediately prior to the administration of alemtuzumab to diminish infusion-related reactions.
Protocol:
Low-dose alemtuzumab for induction (20 mg intravenously prior to reperfusion)
tailored immunosuppression: tacrolimus (trough levels of 10 ng/ml initially and 7 ng/ml from month three on), corticosteroids (steroid pulse starting with 500 mg and 250 mg intravenously at the time of transplantation and 12 h later, respectively, followed by 100 mg given orally with a taper to 5 mg within 1 month), Mycophenolate mofetil is suspended until lymphocyte count in peripheral blood reached > 5% of leukocytes or > 200/μl absolute (dose increments aiming at 1000 mg b.i.d., depending on clinical tolerance).
Pneumocystis jiroveci prophylaxis for 6 months, prophylaxis for cytomegalovirus infection for 3–6 months (depending on mismatch constellation) post-transplantation.
References:
Zwan MVD, Baan CC, Gelder TV, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2017 July.
kidney transplantation principles and practice textbook by Knechtle SJ, Marson LP, Sir Peter Morris. Eighth Edition.
Guthoff M, Berger K, Althaus K, Mühlbacher Th, Bakchoul T, Steurer W, et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrology (2020) 21:178.
Amit Sharma
3 years ago
Review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
Introduction
The best form of treatment for an end stage renal disease (ESRD) patient is a kidney transplant. Immunosuppression is an essential part of a kidney transplant patient management. Induction immunosuppression is required to decrease the risk of early rejections. Induction therapy involves use of T lymphocyte depleting and n-n-depleting antibody treatments. Alemtuzumab, a humanized rat monoclonal antibody against CD52 cell surface antigen, approved for use in haematological malignancies (B cell CLL) and autoimmune disease (multiple sclerosis), has been used as an induction agent in renal trasnplanation, although off-label. (1)
2. The indications
A systematic review regarding use of alemtuzumab as an induction agent, in comparison to basliximab, revealed reduced rejection risks with similar delayed graft function, graft survival and patient survival rates. (1) The 3C study compared alemtuzumab, low-dose tacrolimus and mycophenolate sodium without steroids with Basiliximab, standard-dose tacrolimus and mycophenolate sodium with steroids. The short-term results of this approach revealed lower biopsy proven acute rejection rates (BPAR) in the alemtuzumab arm with similar graft function, graft survival, infection and patient survival rates.(2)
Another trial comparing alemtuzumab with basiliximab in low-risk patient and with rabbit ATG in high risk patients revealed that alemtuzumab group had lower BPAR than basiliximab group in low-risk patients while the BPAR rates in the high-risk patients were similar to the rabbit ATG group.(3) Cochrane meta-analysis of induction therapy in kidney transplant patients also revealed similar BPAR rates in alemtuzumab based and ATG based induction therapies, but few studies showed reduced BPAR rates in alemtuzumab with early steroid withdrawal regimens.(4) Compared to ATG, Alemtuzumab with early steroid withdrawal had lower GFR at 6 months and 2 years.(4)
In the context of steroid minimisation, alemtuzumab prevented acute rejection at 1 year compared to ATG. CNI, MMF and steroid without induction therapy compared to alemtuzumab combined with early steroid withdrawal had similar rates of acute rejection. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple drug maintenance immunosuppression, in the absence of any clinical benefit. ATG and alemtuzumab use decreased risk of acute rejection, but with increased CMV disease with no change in patient-centred outcomes (reduced death or lower toxicity).(4)
In view of the data available, Alemtuzumab induction can be used in both low-risk and high-risk kidney transplant patients.(5)
a) Low-risk transplant recipients with early steroid withdrawal need (for example diabetic recipient)
b) High-risk transplant recipient with contraindication to ATG (hypersensitivity reaction).
3. Contraindications
Alemtuzumab should not be used in:
a) Active infection
b) Active malignancies
c) History of hypersensitivity reaction
d) Underlying immunodeficiency (e.g. HIV)
Although a patient being taken up for kidney transplant will not be having any active infection or malignancy at the time of transplantation.
4. Dose used
Dose of alemtuzumab used for induction in kidney transplantation is not based on any formal dose-finding studies in organ transplant recipients. The dose used is similar to the dose used in CLL and multiple sclerosis.
Injection Alemtuzumab 30 mg intravenous infusion over 2 to 4 hours, after pre-medication with diphenhydramine 50 mg and acetaminophen 500 mg intravenous 30 minutes prior to the infusion. Total 2 doses to be given on day 0 and day 1.
Maintenance immunosuppression in form of a) Tacrolimus: 0.1 mg/kg/day. Target trough level 10 ng/ml initially, to be decreased to 7 ng/ml after 3 months. b) MMF: 1000 mg twice a day (dose to be withheld if leukopenia). c) Steroids: Early steroid withdrawal by day 7.
Prophylaxis:
a) CMV: Valgancyclovir 900 mg once day for minimum 2 months or until CD4 level>200
b) Pneumocystis: Tablet cotrimoxazole 480 mg once a day for 6 months.
c) Oral Candidiasis: Oral clotrimazole drops.
Post transplant regular CBC, creatinine, urine routine, DSA level monitoring.
5. Route of administration
Intravenous route has been used in majority of protocols, hence intravenous route being used. Although subcutaneous route has shown similar outcomes, there is increased risk of anti-alemtuzumab antibody formation.(5)
6. Side effects
The side-effects of Alemtuzumab includeL5)
a) Infusion associated reactions due to cytokine release (in 70-80%).
b) Infections due to prolonged lymphocyte depletion. Hence oral candidiasis, anti-herpes, CMV and pneumocystis prophylaxis to be given till CD4+ T lymphocyte count >200 or minimum 2 months. Watch for UTI.
c) Increased risk of malignancy as compared to no induction.
d) Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia.
7. References
1) Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012 Jun 27;93(12):1179-88. doi: 10.1097/TP.0b013e318257ad41. PMID: 22660659.
2) 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014 Nov 8;384(9955):1684-90. doi: 10.1016/S0140-6736(14)61095-3. Epub 2014 Jul 28. PMID: 25078310.
3) Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J; INTAC Study Group. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011 May 19;364(20):1909-19. doi: 10.1056/NEJMoa1009546. PMID: 21591943.
4) Hill P, Cross NB, Barnett AN, Palmer SC, Webster AC. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD004759. doi: 10.1002/14651858.CD004759.pub2. PMID: 28073178; PMCID: PMC6464766.
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC57
Influence on immunosuppression:
1) CNI exposure can be reduced by decreasing the target trough level to 4-7 ng/ml by 3 months
2) Similarly low dose MMF can be used
3) Rapid steroid tapering or early steroid withdrawal can be used in patients more prone to side-effects of steroids,
I must confess, I have never used alemtuzumab and never thought of using it as most of the patients in our transplant program are related living donors, managed well with triple drug immunosuppression and low dose ATG as induction, if needed.
Cost of ATG is low in our country, Alemtuzumab is not available.
Last edited 3 years ago by Amit Sharma
Dalia Eltahir
3 years ago
Alemtuzumab is a monoclonal antibody that targets CD52, a common antigen found on B and T cells. When the alemtuzumab antibody attaches to the CD52 antigen, the body’s immune system is activated to destroy these targeted cells in the blood and bone marrow. In phase 3 clinical trials, use has achieved steroid-sparing effects including improved glycemic stability Long-term follow-up results from the 3C trial regarding alemtuzumab’s role in reducing calcineurin inhibitor exposure by using a more potent induction regimen .-In steroid resistant TCMR.-Chronic Lymphocytic Leukemia-Multiple SclerosisDosing : Alentuzumab 30mg -IV or SC .Contraindication hypersensitivity reaction .Side effects : Fever, chills, flushing, dizziness, shortness of breath, nausea, vomiting, or mild rash/itching may occur during or after the infusion. These reactions occur more often during the first week of treatment.
Mohamed Mohamed
3 years ago
2. Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
Alemtuzumab (Campath-1H) is an anti-CD52 T-cell and B-cell–depleting monoclonal antibody that has been used for induction in renal transplantation. Alemtuzumab-induced lymphocyte depletion is rapid (within 24-48 hours of administration) & long-lasting. B cells return within 2-12 months, but the number of circulating T lymphocytes (particularly CD4+ T-cells) may remain depressed for many years after treatment.
Randomised trials of alemtuzumab in solid organ transplantation: 1. Margreiter et al(Am J Transplant. 2008;2:1480–1485. doi: 10.1111/j.1600-6143.2008.02273.x.): A 131 recipients received induction with alemtuzumab (2 × 20 mg) vs no induction. All patients treated with Tac & those who had not received induction therapy also received MMF. Results: – Significant reduction of acute rejection at 6 months (29% vs. 15%, P = 0.05), but not at 12 months (32% vs. 30%). – No difference in renal function between the 2 groups. – Apart from an increase in the incidence of CMV infection, there was no other A/E of induction therapy. ====================================================================
2.Chan et al (Kidney transplantation with minimized maintenance: alemtuzumab induction with tacrolimus monotherapy – an open label, randomized trial. Transplantation. 2011;2:774–780. doi: 10.1097/TP.0b013e31822ca7ca.) 82 alemtuzumab-treated patients (with Tac monotherapy) vs 42 controls (receiving dacluzimab, Tac, MMF), all patients having a rapid steroid taper. Results: – Lower incidence of rejection in the alemtuzumab-treated group at 6 months but not 12 months – No difference in graft survival or function. – Confirmed that alemtuzumab therapy does enable simple & effective Tac mono-therapy with a very low rate of rejection. ====================================================================
3.Hanaway MJ et al INTAC Study Group: Alemtuzumab induction in renal transplantation. N Engl J Med 2011, 364:1909-1919.
A randomised trial involving 474 recipients divided into high-risk patients (defined as PRA>20%, black race, re-transplant; n = 139) & low-risk patients (all others). High-risk group was treated with either ATG (1.5 mg/ kg × 4, n = 70) or alemtuzumab (30 mg × 1, n = 69). Low-risk group of patients was treated with basiliximab (20 mg × 2, n = 171) or alemtuzumab (30 mg × 1, n = 164). All patients received Tac8 to 14 ng/ml, MMF 2 g/day, & steroids for 5 days. Followed up for 3 years. Results – Patients treated with alemtuzumab had a significantly lower incidence of cellular rejection at 6, 12 & 36 months (3% vs. 15%, 5% vs. 17% & 13% vs. 20% respectively). – The incidence of rejection in the high-risk patients was similar between the alemtuzumab & ATG groups. – No significant difference in graft or patient survival. – There was no effect on renal function. – Alemtuzumab-treated patients are more liable to late rejection episodes (after 12 months). ====================================================================
4. Calne R et al : Prope tolerance, perioperative Campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 1998, 351:1701-1702.18. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR: The natural history of chronic allograft nephropathy. N Engl JMed 2003, 349:2326-233
– Tested the use of alemtuzumab induction (2 × 20 mg) followed by low-dose cyclosporin monotherapy (75 to 125 mg/ml). – This study demonstrated the capability of a low-dose monotherapy IS regimen to achieve low levels of rejection & good levels of graft survival & function. ====================================================================
5.Michael J. et al(N Engl J Med 2011;364:1909-19.) – BPAR is significantly lower in the alemtuzumab vs conventional induction (basiliximab or rATG ) at both 6 months (3% vs.15%, P<0.001) & 12 months (5% vs. 17%, P<0.001). – At 3 years, the rate of BPAR in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P = 0.003), but in high-risk patients, no significant difference was seen between alemtuzumab & rATG (18% vs. 15%, P = 0.63). – Adverse-event rates were similar among all four treatment groups. – Minor differences were found between the alemtuzumab & conventional IS groups in the trough levels of tacrolimus, doses of MMF or MPA, & serum creatinine levels over the 3-year study period. Conclusion Alemtuzumab induction with early GC withdrawal is superior to conventional IS in preventing BPAR in the 1st year after transplantation. This benefit was primarily realized in recipients at low immunologic risk. ====================================================================
6.Martina Guthoff et al (BMC Nephrology volume 21, Article number: 178 (2020)) Between 01/2007 & 04/2017, 48 kidney transplants were treated with low-dose alemtuzumab induction (a single dose of 20 mg intra-op), followed by Tac & corticosteroids for initial IS, with MMFsuspended until a TLC >5% or 200/μl was reached. Median PRAmax was 43 %; all patients had -ve CDC-XM. Results
– Low-dose alemtuzumab was well tolerated.
– Median time to TLC recovery was 77 days.
– Within a median follow-up of 3.3 years, 12 (25%) patients developed BPAR, 10 of which were AMR (3 acute, 7 chronic ABMR).
– Death-censored 5-year allograft survival was 79.2%, with an excellent allograft function at the end of follow-up.
– There was no increased rate of infections, in particular viral infections. Conclusion: Low-dose alemtuzumab induction, initial suspension of MMF & triple maintenance IS, provides excellent patient & allograft outcome in sensitized renal allograft recipients.
=============================================================
Alemtuzumab & mammalian target of rapamycin inhibitors
1. Knechtle SJ et al : Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am JTransplant 2003, 3:722-730. 29 patients were treated with alemtuzumab (20 mg × 2) followed by low-dose maintenance sirolimus. Results 8 patients required treatment for rejection One graft was lost. Conclusion Sirolimus monotherapy was inadequate. ====================================================================
2. Flechner SM et al : Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI
and steroid-free kidney transplant immunosuppression. Am J Transplant 2005, 5:3009-3014. 22 patients were treated with alemtuzumab induction (30 mg × 2) & maintenance therapy sirolimus (8 to 12 mg/ml) & MMF (500 mg/twice daily). Results Acute rejection in 36% Leukopaenia in 27% ARDS in 2 patients. Conclusion Combination of alemtuzumab, sirolimus & MMF, was associated with a high rejection rate & a high incidence of other complications. Another protocol used alemtuzumab induction plus short course of CNI therapy, before switching to sirolimus maintenance therapy for the longer term: In 30 patients, alemtuzumab (30 mg × 2) induction was followed by MMF(500 mg BID for 12 months), Tac(5 to 8 ng/ml for 6 months) &, after tacrolimus withdrawal, sirolimus (5 to 8 ng/ml) (data submitted for publication). Results
– A number of rejections occurred after MMF withdrawal at 12 months (all reversible with steroids)
– The protocol was therefore amended to continue MMF 250 mg BID thereafter;
– This protocol was associated with a low incidence of rejection (6.6% at 12 months).
– Following the change of protocol to maintain low-dose MMF after 12 months, there were no acute rejection episodes after 12 months.
– 2 patients were withdrawn due to respiratory side effects of sirolimus.
– 85 % of patients remained steroid & CNI free 5 years postoperatively.
Conclusion Use of alemtuzumab enabled CNI-free therapy. This strategy eliminated the potential CNI nephrotoxicity & consequently improve long-term graft life.
Abdul Rahim Khan
3 years ago
Introduction
Alemtuzumab is human monoclonal antibody against CD52 and is a 12 amino acid GLI linked protein with N linked glycan moiety and is expresses on T cells, B cells, monocytes, macrophages and eosinophils , NK cells ,Dendritic cells. It is expressed more on T cells as compared to B cells. It causes central and peripheral lymphoid depletion by Compliment depletion, antibody dependent cellular toxicity or Compliment dependent cytotoxicity.
Indications.
CLL
Multiple sclerosis
Steroid resistant cellular rejection
As induction agent in high risk in high immunological risk patients and those with steroid withdrawal- Off Label.
Contraindications
Hypersensitivity
Active systemic infections
HIV
Dose used
It is recommended that patients are pre-medicated with glucocorticoids, acetaminophen, and anti-histamines immediately prior to the administration .prophylaxis against herpes and pneumocystis jirovecii should be given.
Single IV dose of 30 mg as induction agent at the time of transplantation and second dose on day 1, followed by the maintenance with TAc, MMF and steroids.
Tacrolimus can be given at 0.1-0.2 mg/kg per day in 2 divided doses. The target trough level of 7-14 ng/ml for first 3 months followed by 4-12 ng/ml. MMF- 2gram per day and steroids for five days. Prednisolone is given as 150 mh day 1 and 2 followed by tapper in first week.
Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207.
kumar avijeet
3 years ago
Alemtuzumab is monoclonal anti- CD52 Ab,which acts on CD52 receptor present on T-cell,B-cell, NK cell,Dendritic cell and causes central and peripheral lymphoid tissue depletion by-
1.complement dependant cytotoxicity
2.antibody dependant cytotoxicity
3.anergy leading to apoptosis.
Hence its lymphoparalytic activity starts within 5-7days and persists for 6-12mnth,which decides its mammoth potential than ATG as immunosuppression which paves the bright way towards early steroid withdrwal, early cni withdrawl without risk of rejection but with a cost of infection.
Contraindication-
1.hypersensitivity reaction to campath.
Dose-it is used as a single dose of 30mg IV/sc.
Side-effects-
1.Infusion reaction-mostly due to release of cytokines,urticaria,fever,rash,hypotension,etc.
2.lymphopenia, some times pancytopenia due to bonemarrow suppression
3.hematological malignancy
4.viral infections like bkv,cmv,pcc
5.autoimmunity-thyroid graves disease
It is category-c in pregnancy.
Theepa Mariamutu
3 years ago
Alemtuzumab
Introduction
is a humanised monoclonal antibody against CD52
causes T and B lymphocyte, monocytes and NK cell depletion by 3 mechanisms
Complement dependant cytotoxicity -through C1q activation and subsequent generation of the MAC
Antibody -dependant cellular cytotoxicity
Induction of apoptosis
Indications
Treatment of CLL
Treatment of Multiple sclerosis (RRMS)
Treatment for Non hodgkin’s lymphoma
Dose used
3C study – Alentuzumab 30mg on Day 0 and 1 -IV or SC VS basiliximab
Hanawey et al (INTAC study) – Alentuzumab single dose of 30mg IV vs Basiliximab in low risk and VS ATG in high risk
LaMattina et al- Alentuzumab 30mg once or 2 times has better outcome in graft survival and rejection
Martina Guthoff et al – Low-dose alemtuzumab induction consisted of a single dose of 20 mg intraoperatively, followed by tacrolimus and corticosteroids for initial immunosuppression, with mycophenolate mofetil suspended until a total lymphocyte count (TLC) >5% or 200/μl was reached.
Route of administration
Available for intravenous or subcutaneous administration
Available in 30mg in 1 ml or Lemtrada 12mg in 10mls
Side effects
1- infusion related reactions – 70-80% patients such as headache, rash, nausea, hypotension, rigours and pyrexia
a. while given IV, but can be less if given SC
2- Infections – due to depletion of T and B cell but not neutrophilic granulocytes – so reconstitution of the cells of the innate immune system is faster
Prophylaxis with herpes and PCP should be started
BK virus infection is common
3- Malignancy -data scarce and poorly defined
US transplantation showed : risk of non-hodgkins lymphoma, HPV related cancers, kaposi sarcoma and liver cancer
4- Autoimmunity -secondary autoimmunity has been reported
More common if used with IL-21
Most commonly thyroid gland is affected -graves’ disease or hypothyroidism
ITP also reported -1-2%
5- Fertility and Pregnancy
Category C for pregnancy
IgG of alentuzumab crosses placenta and has teratogenic effect
CD52 is expressed in maple reproductive system – it inactivate sperm in vitro but clinically not reported
Alentuzumab expressed in breast milk within 4 months
References
1-Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients by Martina Guthoff2-Alemtuzumab Induction in Renal Transplantation by Michael J. Hanaway, M.D(INTAC study)
3-Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the clinical pharmacokinetics and pharmacodynamics of Alemtuzumab and its use in kidney transplantation. Clin Pharmacokinet. 2018;57:191–207
Last edited 3 years ago by Theepa Mariamutu
Dalia Ali
3 years ago
Monoclonal Lymphocyte Depleting Antibodies
Alemtuzumab [Campath-1 H]
it’s is humanized anti-CD 52 antibody that causes depleting of both T and B cell
• Current practice is to give to give 30mg intra-operatively and a second 30mg dose 24 hours later.
*Can be used in steroid resistant cellular rejection
Administration of alemtuzumab
Infusion reactions and cytopaenias are common
Intravenous infusion is associated with a marked “cytokine-release syndrome”, characterized by fever, rash, hypotension, and bronchoconstriction.
• Do not give alemtuzumab if there is :-
1-untreated infection
2-platelets <100×10 /L or WBC <3×10 /L.
Give pre-medication 30 minutes before each dose:
• IV hydrocortisone 100mg
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• prophylaxis against PCP, CMV and oral candidiasis.
For IV administration
• Dilute 30mg alemtuzumab in 100ml 0.9% NaCl
• Infuse over 2 hours into a central or peripheral vein
For
SC administration
SC administration is as effective as IV, but eliminates infusion-related reactions.
• Give pre-medication
• Alemtuzumab is supplied as a solution of 30mg in 1ml
• Withdraw 15mg (0.5ml) into 2×1ml syringes
• Administer each 15mg dose as a slow (1 minute) SC injection over the deltoid or anterior chest wall
Used as a single agent, it does not induce tolerance and episodes of acute rejection can occur even in the absence of T cells. Its use may facilitate minimization of maintenance immunosuppressive protocols and steroid sparing with monotherapy using sirolimus or low-dose calcineurin inhibitor.
Alemtuzumab
plus low-dose cyclosporin
low-dose cyclosporin monotherapy with trough levels of 75-125 ng/ml.
gives low rates of acute rejection
Alemtuzumab plus sirolimus
sirolimus monotherpy (target level: 8-12 ng/ml) but rates of early acute rejection were high, particularly humoral rejection.
Alemtuzumab
plus tacrolimus and MMF
low-dose tacrolimus (target trough concentration: 5-7 ng/ml) and MMF (500 mg twice daily
gives low rates of acute rejection
Alemtuzumab allows the use of a steroid-free maintenance regimen
Alemtuzumab induces profound lymphopenia, which may be prolonged requiring reduced doses of other
myelosuppressive agents.
There may be delayed incidence of cell-mediated acute rejection and possibly a higher incidence of antibody-mediated rejection that occurs as lymphocyte counts return to baseline.
The hematologic, infection, and lymphoma risks are similar to those described for other depletional agents, and infection prophylaxis is mandatory.
Reference
1- Menna R. Clatworthy1 and Christopher J.E. Watson2 1Division of Renal Medicine, Department of Medicine and 2Department of Surgery, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK. Alemtuzumab as Induction Therapy in Renal Transplantation.
Trends in transplantation 2008;2:12-23
2- Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation. SIXTH EDITION.
3-up to date
4- Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, and David Talbot. OSH Renal Transplantation. Published online: Oct 2011.
Hinda Hassan
3 years ago
Induction therapy is used to reduce early rejection rates . Induction therapy with alemtuzumab has been propsed mainly to avoid glucocorticoids and to reduce calcineurin inhibitor exposure . Alemtuzumab is a humanized monoclonal anti CD52 antibody which deplete of T and B lymphocytes , monocytes, and NK cells. Indications:
1- Patients planned for CNI minimization protocols
2- Patients planned for steroid free regimen
3- Patients planned for early steroid withdrawal (day 5) Doses and route of administration:
1- Patients planned for CNI minimization or steroid free regimen
· alemtuzumab (30 mg on days 0 and 1, subcutaneously or intravenously) + tacrolimus (trough level5–7 ng/mL) + mycophenolate sodium (360 mg twice daily)
· Do protocol biopsy after 6 month
2- Patients planned for early steroid withdrawal (day 5)
a)High risk patients intolerant of ATG (PRA (historical or current) above 20%, repeat transplantation, or black ethnicity)
b) low risk patients intolerant of basiliximab
c) Simultaneous Pancreas-Kidney Transplantation with low immunological risk who are intolerant of ATG or basiliximab
· a single shot of 30 mg, intravenously + tacrolimus (target pre-dose concentration of 7–14 ng/mL in the first 3 months after transplantation, and 4–12 ng/mL after month 3), mycophenolate mofetil (1000 mg twice daily), Side effects:
· local injection-site reactions.
· Infusion-Associated Reactions : are more if given intravenously than subcutaneously (headache, rash, nausea, hypotension, rigors, and pyrexia. ) · Infection due to prolonged depletion of immune cells( T and B lymphocytes recover usually for over 12 months, monocytes after 3 months and NK cells after 6 months).
· Malignancy : EBV-positive large-cell lymphoma, all virus-related tumors such as non-Hodgkin lymphoma, Hodgkin lymphoma, human papilloma virus-related cancers, Kaposi sarcoma, and liver cancer ,colorectal cancer and thyroid cancer. Alemtuzumab induction was not associated with an increased risk of lung or kidney cancer, or melanoma · Autoimmunity due to high Interleukin-21 causing 1- autoimmune thyroid disorders, especially Graves’ disease 2- Immune thrombocytopenia (idiopathic thrombocytopenic purpura) 3- Glomerulopathy anti-glomerular basement membrane disease and membranous glomerulopathy. The onset of kidney disease ranged from 4 to 39 months after alemtuzumab administration 4- Guillain–Barre syndrome Precautions : · Prophylaxis with an oral anti-herpes agent and prophylaxis against Pneumocystis jirovecii should be started directly after administration of alemtuzumab and be continued for a minimum of 2 months after the last alemtuzumab gift or until the CD4+ T lymphocyte count is C200 cells/lL · Routinely screen kidney transplant recipients for BK virus. · It is advised that thyroid function tests should be obtained prior to initiation of treatment and tested on a regular basis until 48 months after the last
· infusion plasmapheresis : can reduce the plasma concentration of alemtuzumab.
· It is recommended that patients are premedicated with glucocorticoids, acetaminophen, and antihistamines immediately prior to the administration of alemtuzumab to diminish infusion-related reactions.
References van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC5784003.
Batool Butt
3 years ago
Introduction: Alemtuzumab- a humanized monoclonal antibody against CD52 on T- and B-cell leading to prolonged lymphocyte depletion for up to 12 months. Indications: Alemtuzumab is used mainly in highly sensitized patients and also as an induction therapy. Dose used : Low-dose alemtuzumab for induction 20 mg intravenously followed by tacrolimus (aiming at trough levels of 10 ng/ml initially and 7 ng/ml from month three on) and corticosteroids (steroid pulse starting with 500 mg and 250 mg prednisolone intravenously at time-point of transplantation and 12 h later, followed by 100 mg given orally with taper to 5 mg within 1 month). Mycophenolate mofetil (MMF) can be suspended till lymphocyte count reaches > 5% of leukocytes or > 200/μl absolute count. Premedication with diphenhydramine 50 mg and acetaminophen 0.5-1gm 30 minutes before dose is usually sufficient Prophylaxis:Pneumocystis jirovecii prophylaxis administered for 6 months,
Cytomegalovirus infection prophylaxis for 3–6 months (after transplantation.) Standard dose: Alemtuzumab given as induction as a single intravenous dose of 30 mg at the time of transplantation for high and low risk rejection groups followed by maintenance with Tacrolimus at dose of 0.10 to 0.20 mg per kilogram per day in two divided doses, with a target whole-blood trough level of 7 to 14 ng /ml for the first 90 days after transplantation and 4 to 12 ng /ml after 90 days. MMF orally or intravenously daily at a dose of 2 g per day. and steroids which can be discontinued by day 5 after transplantation, with prophylaxis against infection with cytomegalovirus, Pneumocystis carinii, fungi, or bacteria Route of administration: Intravenous.Subcutaneous Side effects :Increased risk of infection, Infusion reactions including fever, rigors, headache, nausea, vomiting, urticaria, pruritus, dyspnoea, hypotension and diarrhea .Anti GBM disease and crevice cephalic arterial dissection Thrombocytopenia most commonly occur during 2 – 4 weeks and Neutropenia common between 4 – 8 weeks. Efficacy: Efficacy of Alemtuzumab is comparable to ATG in term of incidence of acute rejection , graft survival and incidence of malignancy and infection in high risk groups. One study addresses the safety and efficacy of the use of Alemtuzumab for induction in combination with reduced dose of CNI and MMF and steroid avoidance and compare this to basiliximab induction with conventional dose of triple therapy, and found that Alemtuzumab based induction reduced the incidence of acute rejection in the first 6 months by 50 % with no significant increase in serious and opportunistic infections, CMV infection or malignancy but may be an increase in BK viremia and BK nephritis
Alemtuzumab induction is associated with lower incidence of acute rejection when compared to basiliximab in low risk group References:
1-Michael J. Hanaway, M.D., E. Steve Woodle,et al. Alemtuzumab Induction in Renal Transplantation.N Engl J Med 2011; 364:1909-1919
2-Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the clinical pharmacokinetics and pharmacodynamics of Alemtuzumab and its use in kidney transplantation. Clin Pharmacokinet. 2018;57:191–207
Tahani Ashmaig
3 years ago
☆Alemtuzumab (Campath1H)
___________________________
▪︎Is a huminized monoclonal antibody that has a profound lymphocyte-depleting effect, targeting the CD52 antigen that is present on all lymphocytes.
☆Mechanism of action:
_________________________
▪︎It bind to CD52 cells which are rapidly cleared from the circulation by complement mediated lysis or removed of opsonized cells in lymphoid organs.
☆Role Induction therapy:
_________________________
▪︎It has shown potential as an induction agent in the prevention of rejection following solid organ transplantation.[1]
▪︎It has not been compared to other induction agents in any large, randomised controlled trial [2].
▪︎ Experience is limited to case series, often exploiting the profound T cell depletion induced by alemtuzumab to minimize other IS agents [2].
▪︎Studies have shown that alemtuzumab enables the use of lower calcineurin inhibitor (CNI) maintenance drugs; however, this reduction in nephrotoxic immunosuppression has not consistently been matched by an improvement in renal function.
▪︎The hypothesis has been suggested that alemtuzumab might allow the development of immunosuppressive regimens that avoid CNIs completely
▪︎Studies have investigated the combination of alemtuzumab with mammalian target of rapamycin-inhibitor maintenance therapy, and, in particular, sirolimus. Initial studies with this combination showed that regimens of sirolimus alone and of sirolimus with mycophenolate mofetil were unsuccessful, with a high rate of rejection and complications.
▪︎Subsequent studies have targeted the combination of alemtuzumab induction with a short course of a CNI, before switching to maintenance therapy with sirolimus. This regimen might combine good protection from acute cellular rejection and chronic nephrotoxicity.
☆Dose of alemtuzumab in induction:
______________________________________
▪︎Current practice is to give either a single 30mg intraoperative/ post operative dose, or to give 30 mg intraoperatively and a second 30mg dose 24hrs later [2].
☆Side effects:
________________
1. Infusion reaction from cytokine release
2. Increase autoimmune disease( haeolytic anemia, ITP, etc)
But, both CMV infection and PTLD is less significant with alemtuzumab.
__________________
Ref:
[1] Peter J Friend “Alemtuzumab induction therapy in solid organ transplantation”
[2] Oxford- renal transplantation.
Please review the literatures and design protocols for alemtuzumab induction.
In immunosuppressive regimen, balancing the need for immunosuppression and the risk of associated infections is challenging.The dosage of alemtuzumab given for induction in kidney transplantation varies between 30 and 60 mg . With doses of 30–60 mg of alemtuzumab, prolonged leukocytopenia and lymphopenia have been reported .
The success of protocol is based on three factors:
1-A reduced dose of alemtuzumab .
2-Suspension of MMF until lymphocyte recovery .
3- Triple maintenance immunosuppression.
The following studies addressed the outcome of a different regimen and doses of Alemtuzumab in the induction therapy .
1-Two doses of alemtuzumab 20 mg intravenously on day 0 and 1;
This dose was used in induction therapy in a case series of 13 kidney transplant recipient . The patients received induction therapy with alemtuzumab two doses of alemtuzumab 20 mg intravenously on day 0 and 1followed by low-dose ciclosporin as maintenance therapy. In the 6- to 11-month follow-up, only one patient experienced acute rejection .
2- Alemtuzumab 30 mg on days 0 and 1, subcutaneously or intravenously;
In the 3C study, induction therapy with alemtuzumab (30 mg on days 0 and 1, subcutaneously or intravenously) was compared with basiliximab (20 mg intravenously on days 0 and 4). Induction therapy with alemtuzumab in combination with low-dose tacrolimus and mycophenolate sodium without glucocorticoids significantly reduced the incidence of BPAR at 6 months follow up .
3- alemtuzumab as a single shot of 30 mg, intravenously ;
Hanaway et al. compared alemtuzumab induction therapy (a single shot of 30 mg, intravenously) with basiliximab induction therapy (in patients with low risk of acute rejection) or with rabbit ATG (rATG) induction therapy in high-risk patients. No significant difference in BPAR after month 12 was observed between alemtuzumab and rATG in the high-risk group .
4- comparison of one to two doses 30 mg of alemtuzumab ;
LaMattina et al. compared in a retrospective study induction therapy with alemtuzumab (n = 632), basiliximab (n = 690), or rATG (n = 125). Alemtuzumab was given one or two times (30 mg), basiliximab was administered on postoperative day 0 and 4 (20 mg), and the total dose of rATG was 6–8 mg/kg. Maintenance immunosuppression consisted of tacrolimus or ciclosporin in combination with mycophenolate mofetil and glucocorticoids (tapered to 5–10 mg/day after the first post-operative month). No significant difference was seen in overall frequency of BPAR.
How it influences the maintenance immunosuppression?
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells. Leukocyte depletion at the time of transplantation with alemtuzumab (Campath-1H) has been demonstrated to be one of the ways of reducing immunosuppressive drug load without increasing the rate of acute rejection . The following immunological effects had been demonstrated in patient received alemtuzumab as induction therapy ;
1- The CD8+ T cell compartment was repopulated predominantly by immunosenescent CD28−CD8+ cells with suppressive capacity, while classical Treg cells (CD25hiCD4+) remained low .
2-An increase in Treg cells after alemtuzumab induction has been demonstrated ..
3- An increase in IL-17A producing cells with IL-17A expression compensated for by increase in Treg cell frequency and number. Th17 cells have been demonstrated to be protective against extracellular pathogens but detrimental in autoimmune conditions .
Reference ;
1. Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, et al. Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet. 1998;351(9117):1701–1702. doi: 10.1016/S0140-6736(05)77739-4. [PubMed] [CrossRef] [Google Scholar]
2. Group CSC, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, et al. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014;384(9955):1684–1690. doi: 10.1016/S0140-6736(14)61095-3. [PubMed] [CrossRef] [Google Scholar]
3. Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364(20):1909–1919. doi: 10.1056/NEJMoa1009546. [PubMed] [CrossRef] [Google Scholar]
4. LaMattina JC, Mezrich JD, Hofmann RM, Foley DP, D’Alessandro AM, Sollinger HW, et al. Alemtuzumab as compared to alternative contemporary induction regimens. Transpl Int. 2012;25(5):518–526. doi: 10.1111/j.1432-2277.2012.01448.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
5. Calne R, Moffatt SD, Friend PJ, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation. 1999;68(10):1613. [PubMed] [Google Scholar]
6. Watson CJ, Bradley JA, Friend PJ, et al. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation–efficacy and safety at five years. Am J Transplant. 2005;5(6):1347. [PubMed] [Google Scholar]
7. Bloom DD, Chang Z, Fechner JH, et al. CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant. 2008;8(4):793. [PubMed] [Google Scholar]
8. Knechtle SJ, Pascual J, Bloom DD, et al. Early and limited use of tacrolimus to avoid rejection in an alemtuzumab and sirolimus regimen for kidney transplantation: clinical results and immune monitoring. Am J Transplant. 2009;9(5):1087. [PubMed] [Google Scholar]
9. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009 [PubMed] [Google Scholar
Ala Ali
Admin
3 years ago
Check;
Guthoff, M., Berger, K., Althaus, K. et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrol21, 178 (2020). https://doi.org/10.1186/s12882-020-01767-z Comment on the study protocol and how can you implement it?
This protocol designed by local Centre with heterogenous group of sensitized patients even some of them underwent desensitization with no standardization of desensitization protocol, using small dose of alemtuzumab with triple tacrolimus IS and targeting higher level of tacrolimus upon FU ( 7ng ), so the question to be addressed here the finding of less rejection rate compared to other studies ( 25% vs > 36%) is it due to the efficacy of alemtuzumab induction or the effect of potent triple maintenance IS and not the alemtuzumab alone ,i think for better design of such protocol we need to add another group to compare the efficacy and safety like adding group with low dose ATG as induction IS with same homogenous triple IS and get prospective design with more homogenous patients characteristics longer FU to address graft and patient survival outcome
also in this limited study they have higher rate of PTDM which again indicate the CNI effect and steriod in maintenance rather than induction with low dose alemtuzumab alone .
Ala Ali
Admin
3 years ago
Dear all, please check: van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC5784003.
Alemtuzumab is a depleting CD52-specific antibody with T- and B-cell activity, leading to prolonged lymphocyte depletion up to 12 months, with profound immunosuppression and an associated risk of severe infections.
-Alemtuzumab use as an induction for sensitised recipients :
low-dose alemtuzumab for induction 20 mg intravenously and for maintenance , starting by tacrolimus (aiming at trough levels of 10 ng/ml initially and 7 ng/ml from month three on) and corticosteroids (steroid pulse starting with 500 mg and 250 mg prednisolone intravenously at time-point of transplantation and 12 h later, followed by 100 mg u.i.d given orally with taper to 5 mg u.i.d. within 1 month). Mycophenolate mofetil (MMF) can be suspended till lymphocyte count reaches > 5% of leukocytes or > 200/μl absolute count. Pneumocystis jirovecii prophylaxis administered for 6 months, prophylaxis for cytomegalovirus infection for 3–6 months (depending on mismatch constellation) after transplantation.(1)
-Alemtuzumab given as induction as a single intravenous dose of 30 mg at the time of transplantation for high and low risk rejection groups followed by maintenance with
Tacrolimus at dose of 0.10 to 0.20 mg per kilogram per day in two divided doses, with a target whole-blood trough level of 7 to 14 ng /ml for the first 90 days after transplantation and 4 to 12 ng /ml after 90 days ,
MMF orally or intravenously daily at a dose of 2 g per day.
and steroids which can be discontinued by day 5 after transplantation,
with prophylaxis against infection with cytomegalovirus, Pneumocystis carinii, fungi, or bacteria
For high risk group ;the overall outcome , rejection risk and graft survival are similar to conventional induction with r ATG .
For low risk group it had superior outcomes and lower rejection risk when compared with induction with non depleting agent basiliximab .
Alemtuzumab was more effective in preventing biopsy-confirmed acute rejection than conventional induction therapy in low risk transplant recipients and was as effective as rabbit anti thymocyte globulin in high-risk transplant recipients.
Alemtuzumab induction with early glucocorticoid withdrawal is superior to conventional immunosuppression in preventing biopsy-confirmed acute rejection in the first year after transplantation for recipients at low immunologic risk.(2)
Reference:
1-Guthoff, M., Berger, K., Althaus, K. et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrol 21,178 (2020).
2-Hanaway M. J. etal,Alemtuzumab Induction in Renal Transplantation.N Engl J Med 2011; 364:1909-1919.
_ alemtizumab is a monoclonal antibody against CD 52 , present on both B and T cells ..it is depleting antibody which can be used in either:
a- induction protocol for highly sensitized or HLA incompatible transplantation.
b. Treatment of steroid refractory acute rejection.
_ it is alternative to r ATG as induction therapy with comparable efficacy. However, it is more potent than non depleting antibody ( basiliximab).
_ pros:
a. prolonged immense depletion which lasts for 12 months that allow for either CNI minimization protocols ( to limit their nephrotoxicity) or steroid withdrawal or avoidance protocols ( may be beneficial especially in pediatric population. To alleviate the steroid effect on growth and height).
b. Use of CNI monotherapy with steroid avoidance
c. Early steroid withdrawal after 1 st week protocol.
d. Less infusion reaction than with r ATG, but also premedicate with diphenhydramine and solumedrol.
_Cons:
It is expensive drug.
Prolonged immunodifficency which increases risk of infection and malignancy.
_ so, chemoprophylaxis against pneumocystis jiroveci and valcyte against CMV are crucial.
1. Aref A, Bridson M Julie BM, Sharma A, Halawa A. Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and the Beast. Journal of Nephrology and Urology.2016
2. Haynes R, Harden PN, Judge P, Blackwell L. Alemtuzumab-based induction treatment versus basiliximab- based induction treatment in kidney transplantation (the 3C Study): a randomised trial. The Lancet 2014; 384, 1684-1690
Indication:
1-Induction in immunologically high risk or HLA incompatible transplant.
2-Steriod refractory acute TCMR.
3. Induction when we need steroid avoidance or CNI minimization maintenance protocols.
Mainly it is used when r ATG is contraindicated, as it has similar efficacy to it. Contraindication
previous allergic reaction to the component of alemtuzumab
HIV infection Route of administration; either slow IV infusion or SC to minimize allergic reaction. Adverse effects:
1- infusion reaction like rigors, fever, nausea vomiting, hypotension, rash and urticaria, dyspnea preferred to be given SC with premedication with solumedrol and diphenhydramine.
2- lymphopenia, close monitoring differential leucocytic count to guide 2nd dose
3- Increase risk of infections as CMV, BKV, PJP.
4- increase risk of malignancy, Lymphoma, PTLD including aggressive type B cell lymphoma
ü Induction phase therapy:
low dose 20mg or high dose 30 mg D 0, 1.1st dose given intra-operative after reperfusion
2.PMP 500mg interoperative.
3. followed by maintenance therapy:
· Tacrolimus 0.1-0.3 mg/kg/day and guided by trough level ( target is 10 in 1st 3 months then 5-7 therafter.
· Steroids either rapid tapering over 1 week (steroid avoidance protocol) or over 2 months and keep lowest maintenance doe at 5 mg eod.
· MMF
v Steroid avoidance or steroid-free regimens is defined as no i.v. or oral steroids after the first 2 weeks post Tx and steroid withdrawal defined as discontinuation of steroids either early after 3-6 months or late more than 6 months after Tx Steroid withdrawal at 6 months post Tx was associated with improved height velocity without increased AR risk compared to those who continued on low-dose steroids. Also, late steroids discontinuation after (12–24 months after KT) in those with stable graft function seems to be safe and improve growth and decrease the cardiovascular risk
· References:
Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Lancet. 2014;384(9955):1684. Epub 2014 Jul 28. Induction Therapy for Kidney Transplant Recipients.
· Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004759.
· PAPE, L. J. P. N. 2019. State-of-the-art immunosuppression protocols for pediatric renal transplant recipients. 34, 187-194.
· HALLER, M. C., KAMMER, M., KAINZ, A., BAER, H. J., HEINZE, G. & OBERBAUER, R. J. B. M. 2017. Steroid withdrawal after renal transplantation: a retrospective cohort study. 15, 1-9.
Ban Mezher
3 years ago
Previously 78% renal transplant recipients receive induction either by T cell depleted agent( ATG), or non depleted agent ( basiliximb). But recently new depleted agent used for induction( alemtuzumab).
Alemtuzumab is a humanized monoclonal antibodies directed against CD52 that present on B cells, T cells, monocytes & NK cells. It used as induction agent at 1998. There are 2 regime of alemtuzumab:
standard dose of alemtuzumab ( 30-60 mg): used for recipients with early steroid withdrawal & low dose of maintenance CNI & MFF. Its efficacy was similar or better than ATG, & better than basiliximab in prevention of acute graft rejection with out increasing risk of serious infections or malignancy.
Low dose alemtuzumab( 20 mg IV prior to reperfusion) with triple maintenance immunosuppression ( CNI, MMF & steroids) mainly used for sensitized recipients . This regime associated with shorter time of lymphocytes recovery( 77 days) than standard alemtuzumab regime without increasing risk of rejection. MMf introduced when lymphocytes >200.
It was noted that the risk of malignancy not increased with using of alemtuzumab but there was an increased in risk of autoimmune diseases(e.g. Graves, hypothyroidism & hemolytic anemia). Also it was noted that rejection episodes occur late (>6months post transplantation) among patients receive induction with alemtuzumab.
References:
Hanaway M., Woodle S., Mulgaonkar S., Peddi V., et al. Alemtuzumab Induction in Renal Transplantation. N.Engl.J.Med. 2011; 364:1909-1919.
Guthoff M., Berger K., Althaus K.,Muhlbacher T., Bakchoul T. et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrology.2020; 21:178.
Clatworthy M and Watson J. Alemtuzumab as Induction Therapy in Renal Transplantation. Trends in Transplant.2008; 2:12-23.
Alemtuzumab is a humanized depleting monoclonal antibody against CD52 on B- and T-lymphocytes, monocytes and NK cells, that produces prolonged depletion of both B and T lymphocytes up to 12 months Standard dose : 20 -30 mg infusion over 4 h on day 0 and 1 of the operation Efficaacy:
1- More effective than conventional therapy in reducing rejection episodes but only in low risk patients
2- More prolonged immunesuppressive effect than ATG SE:
1- Complete and prolonged B- and T-lymphocyte depletion is accompanied by an increased risk of infection
Maintenance IS : several maintenance regimens were investigated with alemtizumab
1- Standard dose of alemtizumab induction followed by early steroid withdrawal regimen : Tac , MMF and a 5-day glucocorticoid taper 2- Low-dose alemtizumab : 20 mg followed by triple IS ( TAC , MMF and steroid)
1- Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012;93(12):1179-1188. doi:10.1097/TP.0b013e318257ad41 2- Guthoff M, Berger K, Althaus K, et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrol. 2020;21(1):178. Published 2020 May 13. doi:10.1186/s12882-020-01767-z
Alemtuzumab is a humanized anti-CD52 pan-lymphocytic (both B and T cells) monoclonal antibody that is approved for the treatment of chronic lymphocytic leukaemia. Alemtuzumab induction therapy is used in approximately 10 per cent of kidney transplant recipients in the United States.
We do not routinely use alemtuzumab as induction therapy in most patients undergoing kidney transplantation. Although randomized trials comparing alemtuzumab with either rATG-Thymoglobulin or basiliximab have shown similar or lower rates of acute rejection [ there are concerns that its benefits in reducing acute rejection may decrease over time. Other long-term outcomes, including graft and patient survival and development of chronic allograft nephropathy, may also be worse in patients receiving alemtuzumab compared with rATG-Thymoglobulin and interleukin (IL) 2 receptor antagonists. In addition, alemtuzumab is not readily available to all medical centres that perform kidney transplantation.
Some centres use alemtuzumab as induction therapy for recipients of a human leukocyte antigen (HLA)-incompatible kidney transplant following HLA desensitization, as discussed separately. Alemtuzumab is administered as a single intravenous (IV) dose of 30 mg at the time of transplantation.
Preferably before administration, the patient should be immunized against encapsulated organisms and counselled about the risk of exposure to opportunistic organisms such as PCP, or the risk of developing viral infections such as varicella-zoster (which requires the use of sulfamethoxazole and trimethoprim as well as antiviral medications), as well as the importance of frequent monitoring for CMV.
There are a variety of procedures that may be utilized for alemtuzumab induction, including:
-in low-risk patients treated with tacrolimus as monotherapy following induction treatment, it was discovered that graft survival was much greater with alemtuzumab.
-patients were treated with low-dose cyclosporine alone as maintenance therapy, which resulted in excellent patient and graft survival; however, some patients developed AR.
-The use of a steroid-free approach combined with CNI and MMF as maintenance treatment resulted in higher graft and patient survival than alternative induction methods
Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
Alemtuzumab (Campath 1H) is a recombinant DNA-derived humanized monoclonal antibody directed against the cell surface glycoprotein CD52 initially approved for use in chronic lymphocytic leukemia, it is a depletional agent sometimes used in clinical transplantation, although it has not been formally approved for such use
When used at the time of transplantation as induction therapy, alemtuzumab induces a profound, rapid, and effective depletion of peripheral and central lymphoid cells that may take months to return to pretransplantation levels.
Alemtuzumab use in kidney transplantation is “off-label.” Its ease of administration has made it an attractive alternative to Thymoglobulin. It is usually given as a single dose of 30 mg intraoperatively; a second dose is sometimes given. Because the drug is administered under general anesthesia, infusion-related events typically associated with the infusion of biologic agents are masked.
When used as an induction agent, alemtuzumab reduces the risk of rejection compared to basiliximab in unsensitized patients. However, when compared to rATG in randomized clinical trials, alemtuzumab has not been shown to be superior. In trials of patients undergoing steroid withdrawal, those receiving alemtuzumab have a greater risk of rejection.
Clinical studies evaluating the safety and efficacy of antibody pre-conditioning with alemtuzumab in conjunction with reduction in maintenance immunosuppression have yielded variable and conflicting results.
Maintenance Immunosuppressant: After the usage of Alemtuzumab for induction a triple immunosuppressant should be used which includes: Tacrolimus 0.1mg/kg in two divided doses keeping serum trough level 5 – 10 ng/ml for the next six months. Mycophenolate Mofetil (MMF) might be used in high immunological risk patients but is not mandatory, if used a dose of 500mg twice daily and can be delayed for three months. In case of Basiliximab then MMF dose of 750mg BD should be used. Finally, Prednisolone 20mg once daily with tapering of 5mg evert week until dose of 5mg once daily.
Its use may facilitate minimization of maintenance immunosuppressive protocols and steroid sparing with monotherapy using sirolimus or low-dose calcineurin inhibitor.
References Pham, P. T., Lipshutz, G. S., Pham, P. T., Kawahji, J., Singer, J. S., & Pham, P. C. (2009). The evolving role of alemtuzumab (Campath-1H) in renal transplantation. Drug design, development and therapy, 3, 41–49.
Handbook of Kidney Transplantation, 6th Ed,Lippincott Williams & Wilkins (LWW) 2017
One of the main challenges that associated with the use of induction therapy , including standardized protocols not yet available , cost and availability of drugs ,immediate and long term side effects like infection and cancer risk , also long term efficacy of certain agents reduced overtime with increasing shift to higher rate of subclinical rejection and subsequent chronic graft dysfunction however the use of induction therapy is widely increased and effective in reduction of early graft rejection and they are very effective with over all favorable kidney transplant outcome especially in high immunological risk like pre-sensitized patients and ABOi transplantation.
Anti-thymocyte-globulin polyclonal antibody act as T cell depleting agent and alemtuzumab monoclonal antibody anti CD52 which is more potent depleting agent for both T and B cells.Both are used as induction IS in high immunological risk kidney transplant and associated with lower risk of acute rejection at 6 months and 12 months based on good evidence from RCT and meta-analysis. Also, systematic review of RCT comparing low dose ATG vs alemtuzumab as induction antibodies in high immunological risk which again confirmed that there is no difference between the two agents on the rate of BPAR and also have similar graft and patient survival upon long term follow up both agents associated with increased rate of infection and PTLD.
also both can be used for treatment of steriod resistant acute rejection .
Alemtuzumab use is limited to less than 10% in USA as off-labile monoclonal induction agent with early steroid withdraw and CNI minimization protocol of 1 or two doses of 30mg and its use associated with lower rate of early acute rejection this report from 3c RCT comparing alemtuzumab vs basiliximab induction therapy in high immunological risk and showed that alemtuzumab group have lower rate biopsy proven acute rejection (BPAR) compared to basiliximab group in the first 6 months as primary outcome as well as by number of event still in favor alemtuzumab arm but its effect on long-term still questionable and need more research.
There is some RCT and observational studies address the efficacy of alemtuzumab as induction immunotherapy compared to low dose rATG , the intact study a randomized trail included 139 high risk recipients received 30mg alemtuzumab or rATG 6mg /kg in 4 doses , in high risk group including black race with PRA > 20%, the result of this study confirm no difference in AR rate between the two groups at 6 , 12 , 36 months but late AR at 12 months was more in alemtuzumab group and this again confirm the decrease efficacy of alemtuzumab overtime. over all graft and patient survival were similar among both arms in both low and high-risk groups, the same applied for the mean lymphocytes count reduction which was comparable in both groups with no difference in the adverse side effects like infection rate and malignancy.
One important observation is the shift of maintenance IS from cyclosporine based to tacrolimus and MMF may explain in part the marked reduction in 1-year acute rejection rates from 50% in the early 1990s to 10–15% nowadays regardless to the type of induction therapy so still we need in the future more studies to identify the effect of the current inductions antibodies with tacrolimus and MMF based conventional therapy especially with growing evidence of increasing rate of subclinical rejections up to 25% as per studies.
To design protocol using alemtuzumab as induction IS should be individualized and tailored to type of immunological risk and other medical factors like the primary disease, associated comorbid like DM and underlying bone disease osteoporosis will be preferred induction agent and choice tacrolimus-based maintenance IS. I don’t have experience with the use alemtuzumab as its not available in our center
References:
1–Alemtuzumab induction in renal transplantation. AU Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J, INTAC Study Group SO N Engl J Med. 2011;364(20):1909.
2– A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow-up. AU Ciancio G, Burke GW, Gaynor JJ, Roth D, Kupin W, Rosen A, Cordovilla T, Tueros L, Herrada E, Miller J SO Clin Transplant. 2008;22(2):200.
3-Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Lancet. 2014;384(9955):1684. Epub 2014 Jul 28. Induction Therapy for Kidney Transplant Recipients:
4- 4-Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004759.
Thank you, Dr. Saja; this is an excellent review.
Could you design a possible IS a protocol using Alemtuzumab?
Reem Younis
3 years ago
-High –risk recipients need more intense immunosuppression.
-Induction therapies should be used in addition to maintenance triple therapy consisting of a CNI combined with an anti proliferative drug and steroids .
– Lymphocyte-depleting induction therapy was recommended in high-risk patients. -Induction protocol using biological antibodies proved to be effective and safe and allow better graft and the patient survival . Biological antibodies divided into:
1.Depletive antibodies : e.g. alemtuzumab and anti-thymocyte globulin.
2.No depletive antibodies : e.g. basiliximab. Alemtuzumab (Campath )
-It is humanized anti-CD52 antibody.
-It is the recombinant DNA-derived drug.
-CD52 is a glycoprotein antigen found on the surface of B and T cells , thymocyte, monocyte, macrophage and NK cells .
– It used for both transplantation and B- CLL .
-When used as induction therapy in the kidney transplantation leads to severe, rapid, and effective depletion of peripheral and central lymphoid cells .
-When used as induction, alemtuzumab reduces the risk of rejection compared to basiliximab in unsensitized patients and when compared to rATG, alemtuzumab isn’t superior (7). Dose :
-30mg,a single dose intra-operative ,a second dose sometime is given(day 0 and day 1 post-transplant). Pre-medications :
–Methylprednisolone 30 mg and diphenhydramine hydrochloride 50mg given 30 min before injection. Acetaminophen should be given before and 4 hours after commencement of the infusion for fever control. Side effects :
-Anaemia ,leucopenia ,and thrombocytopenia
-Nausea ,vomiting , and diarrhea.
-It increases the risk of infection .
-Autoimmune phenomena .
-Alemtuzumab induction therapy followed by reduced maintenance immunosuppression is associated with a better kidney function compared to no induction and ATG. Survival rate as well as freedom from ACR were comparable between alemtuzumab and ATG. References
1. Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the clinical pharmacokinetics and pharmacodynamics of Alemtuzumab and its use in kidney transplantation. Clin Pharmacokinet. 2018;57:191–207.
2.Sageshima J, Ciancio G, Guerra G, Gaynor JJ, Cova D, Zarak A, et al. Prolonged lymphocyte depletion by single-dose rabbit anti-thymocyte globulin and alemtuzumab in kidney transplantation. Transpl Immunol. 2011;25:104–11 3.Steddon S,Ashman N .Oxford handbook of nephrology and hypertension . 2ed edition. Oxford :University Press:2017
4.Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. Am J Transplant. 2009; 9 Suppl 3: S1.
Thank you All
Remember
Alemtuzumab can be given subcutaneously also. There is mortality reported following intravenous administration.
Alemtuzumab is:
A. Anti CD52 which is expressed on mature lymphocytes, natural killer cells (NK), eosinophils, neutrophils, monocytes/macrophages, and dendritic cells (DCs)
B. It is used in renal transplantation “of label” (not licensed)
C. CD52 is more expressed on B cells compared to T cells
D. Associated with neutropenia
E. Can be used is steroid-resistant rejection and can be given subcutaneously
A, B, D, E
A true
B true
c not true;
d true
E. true. can be given sc and this lowers the side effects of iv infusion, it can be an alternative to ATG with less side effects in treatment of acute rejection
all correct
It is expressed more on the T cells. C is incorrect
A, B,D and E are true
A True
B Ture
C False
D True
E True
Alemtuzumab is:
A. Anti CD52 which is expressed on mature lymphocytes, natural killer cells (NK), eosinophils, neutrophils, monocytes/macrophages, and dendritic cells (DCs):
True. CD52 is expressed on mature lymphocytes, monocytes, macrophages, some granulocytes (neutrophils, eosinophils), natural killer cells, dendritic cells and mature sperm cells.
B. It is used in renal transplantation “of label” (not licensed):
True. Alemtuzumab has been used ‘óff label’ for induction and steroid resistant rejection treatment.
C. CD52 is more expressed on B cells compared to T cells:
False. CD52 is more expressed on T cells than B cells
D. Associated with neutropenia:
False. Alemtuzumab is associated with lymphocytopenia, although mild neutropenia may be present.
E. Can be used is steroid-resistant rejection and can be given subcutaneously:
True. Subcutaneous or IV Alemtuzumab has been used in steroid resistant rejection (off-label) cases in which ATG cannot be used.
A.true
B.true
C.false
D.false
E.true
A, B,E are true
C- False- CD52 is a 12 amino acid GLI linked protein with N linked glycan moiety and is expresses on T cells, B cells, monocytes, macrophages and eosinophils , NK cells ,Dendritic cells. It is expressed more on T cells as compared to B cells.
D-True- Usually associated with lymphopenia but neutropenia can be seen
all correct
correct answer
A,
B
D
E
All are true
Sorry, C is incorrect as alemtuzumab is expressed more on T cells, not on B cells
A,B,D and E are true
All are correct except C ( as it’s more expressed on T then B cells )
A. Correct
B. Correct
C. Incorrect. CD 52 is expressed more in T cells than B cells. The T cell suppression is more profound than B cells
D. Incorrect. associated with lymphopenia
E. Correct
all are true except C , as it is expressed more on T cells and thus it is used in induction or treatment of steroid refractory TCMR (in stead of r ATG, when it is contraindicated as previous allergic reaction or excess consumption of rabbits.
A,B,D & E
A,B,D,E
A, B,D,E
A true
B true
C false
D true
E true
A. True
B. True
C. False
D. False
E. True
A,B,D,AND E.
A true
B true
C false
D true
E true
all true except c
all true except C
A true
B true
C false
D true
E true
all correct except for c as cd 52 more expressed on t cells not b cells
a: True
b:True
c:True
d:True
e:True
Dear All
Many of you made it difficult for themselves.
You need to write the following to design a protocol:
At some stage you will be asked to design a protocol for your unit.
Renal Trasnplantation UNIT
Alemtuzumab (CAMPATH)
1. Introduction
Alemtuzumab is an anti-CD52 depleting agent that is expressed on mature lymphocytes, natural killer cells , eosinophils, neutrophils, monocytes, macrophages, and dendritic cells. its effect lasts from 6-12 months.
2. The indications
Induction therapy in high risk patients
Resistant acute antibody mediated rejection
CLL
MS
3. Contraindications
Severe Allergic reaction to alemtuzumab
4. Dose used
Single intravenous dose of 30 mg at the time of transplantation
Available in 10 or 30 mg vials.
5. Route of administration
IV/SC; IV administered as infusion over 2 hours. Use normal saline
6. Side effects
Bone marrow suppression (pancytopenia; low WBC), autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia can occur.
Infusion reactions :
Alemtuzumab administration can result in serious, including fatal, infusion reactions. Careful monitosization required
Infections :
Serious, including fatal, bacterial, viral, fungal, and protozoan infections can occur in patients receiving alemtuzumab. Do not forget Bactrim and valgancyclovir prophylaxis
7. References
Van der Zwan, M., Groningen, C. V., Marian, C., van den Hoogen, M. W., Kho, M. M., Roodnat, J. I., … & Hesselink, D. A. (2020). Comparison of alemtuzumab and anti-thymocyte globulin treatment for acute kidney allograft rejection. Frontiers in immunology, 1332.
Betjes, M. G., Kho, M. M., Litjens, N. H., de Weerd, A. E., & Roodnat, J. I. (2021, September). Alemtuzumab as Second-Line Treatment for Late Antibody-Mediated Rejection of Transplanted Kidneys. In Transplantation Proceedings (Vol. 53, No. 7, pp. 2206-2211). Elsevier. https://doi.org/10.1016/j.transproceed.2021.07.005.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/alemmil050701LB.htm
Hanaway, M. J., Woodle, E. S., Mulgaonkar, S., Peddi, V. R., Kaufman, D. B., First, M. R., … & Holman, J. (2011). Alemtuzumab induction in renal transplantation. New England Journal of Medicine, 364(20), 1909-1919.
Introduction:
Alemtuzumab anti CD52 (Campath1H), humanized monoclonal antibodies, potent depleting agent for both T-B cells, with rapid and profound depletion of central and peripheral lymphoid cells for months, its effective as induction agent in high immunological risk kidney transplantation and based on good evidence from many studies it’s not inferior to thymoglobulin in prevention of early acute rejection with similar graft and patient survival so can be used as alternative for thymoglobulin in certain cases with easier administration as single dose and allowed for the use of lower maintenance immunosuppression like early CNI minimization dose with early steroid withdraw protocol with the cost of increased risk of acute rejection overtime.
Indication:
1-Induction phase (high immunological risk kidney transplant recipient or low immunological risk with early steroid withdraw (off-label).
2-steriod resistant acute cellular rejection.
Dosing: available 20mg, 30mg, slow intravenous (IV) infusion or subcutaneous (SC). One or two doses.
Side effect and warring:
1- infusion related allergic reaction like rigors, fever, nausea vomiting, hypotension, rash and urticaria, dyspnea preferred to be given SC with premedication
2- lymphopenia, close monitoring with FBC, wbc count and differential, platelet count
3- Increase risk of infections like viral infections herpes, cmv, BKV, PJP.
4- Hematological malignancy, Lymphoma, PTLD including aggressive type B cell lymphoma
5- Pregnancy: category C
Contraindication of campath1H:
Allergy, type 1 hypersensitivity reaction or allergic reaction to the component of alemtuzumab
Active systemic infection, Retroviral infection (HIV).
Alemtuzumab (campath1H) proposed induction protocol:
1- Induction phase therapy:
low dose 20mg or high dose 30mg intra-operative after reperfusionD0, Slow IV infusion or SC injection, preferred SC, second dose Day1.
2.PMP 500mg interoperative.
2-Maintenance Phase therapy:
A–Steroid with draw protocol, in low immunological risk, history of bone disease, cardiovascular disease, dyslipidemia
1-Tacrolimus (prograph), give in 12 hours split dose
0.15 -0.3mg /kg with target trough level initial phase 10-12ng first 3 months.
Then 5-7ng after 3months.
2-predsiolone 150mg oral, day 1, 2 then fast tapper with in 1week and stop
3- Mycophenolate sodium 360mg BID first two weeks then increased to full dose gradually 720mg BID, dose can be adjusted with AUC level alterative mycophenolate mofetil (MMF) 250, 500mg tablets.
B-Maintenance Phase therapy, in high immunological risk (as per local center definition of high immunological risk, autoimmune disease with high recurrence rate as primary glomerular disease
Tacrolimus 0.15-0.3 mg /kg with target trough level 10-12ng in first 3 months) then 7ng in 6 months, MMF 1gm bid, or myfortic 720mg BID plus oral prednisolone with gradually tapper over 2 months to 5 mg od.
monitor for lymphopenia with FBC , TLC , Platelets count.
All patients should receive CMV prophylaxis for 3 months and PJP prophylaxis for 6 months, avoid active vaccination.
References:
1-Kidney transplantation hand book 6th edition.
2-Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Lancet. 2014;384(9955):1684. Epub 2014 Jul 28. Induction Therapy for Kidney Transplant Recipients:
3-Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004759.
Introduction
Alemtuzumab is an anti-CD52 T-cell and B-cell–depleting monoclonal antibody, has been used for induction in renal transplantation. It is reported that renal allograft rejection rate was dramatically lower and alemtuzumab is not associated with an increased risk of infection.
The indications
selected high immunologic risk subjects, to use as routine induction immunosuppression. Generally, its usage is limited.
Steroid resistant allograft rejection.
Contraindications
1. Previous reaction to Alemtuzumab
2. Pregnancy or breast feeding.
3. Active infection.
4. Active malignancy.
Dose used
Pre med :
1. Paracetamol 1 g
2. Piriton 4mg
3. Prednisolone 30mg
Alemtuzumab dose 20-30mg depend on local guideline.
Route of administration
IV/SC
Side effects
1. Allergy reaction.
2. Teratogenicity.
3. Fever, Vomiting, gastrointestinal symptoms.
4. Risk of malignancy need further evidence.
References
Alemtuzumab in renal transplantation. Transplant Rev (Orlando). 2022 Apr;36(2):100686.
All True
Alemutzumab anti CD 52
Used as induction therapy in high risk patient
Given sc or IV
can cause bone marrow suppression
Alemtuzumab is anti-CD52 highly expressed on the surface of T & B cells, thymocytes, monocytes, macrophage and NK cells.
It can make marked lympho-penia which may continue for 6 months.
Given as 2 doses of 30 mg doses given Sub-cutaneous 24 hours apart post-transplant , it can be given only one dose for patients more than 60 years.
ITS given off-label in RTX , doses :
First dose usually given intra-operatively before reperfusion.
Late rejection may occur as T cells recover at ~ 6 months
Can be used as rescue therapy to treat acute rejection
Side effects include “cytokine-release syndrome” with IV given , neutropenia ,anemia , diarrhea ,increased risk of infection and autoimmune disorders .
Design for alemtuzumab protocol
Introduction
Alemtuzumab is an unconjugated, humanized, monoclonal antibody directed against the cell surface antigen CD52 on lymphocytes and monocytes.
Alemtuzumab is effective in preventing biopsy confirmed acute rejection in comparison with conventional induction therapy. It is as effective as ATG in high risk transplant recipients.
Indications
Contraindications
Dose used
Route of administration
Side effects
References
Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
· Introduction:
Alemtuzumab is a humanized depleting monoclonal antibody against CD52 which is expressed on mature lymphocytes(T>B cells), NK cells, DCs, macrophages, neutrophils and eosinophils.
It is Licensed for the treatment of multiple sclerosis and hematological malignancies and used off-label in kidney transplantation as induction and steroid resistant rejection therapy.
· Indications:
1-Induction phase (high immunological risk transplant recipient or low immunological risk with early steroid withdraw
2-steriod resistant acute cellular rejection when there is resistance or intolerance to rATG
· Contraindications:
Allergy, hypersensitivity to a component of Alemtuzumab, active systemic infection and malignancy
· Dose and method of administration: The dose used is similar to the dose used in CLL and multiple sclerosis.
– 20(low dose)- 30mg(high dose) intra-operative after reperfusion on Day 0, a second dose can be given on Day1.This is coupled with pulse methyl prednisolone 500 mg intraoperative.
– It is available as a solution for intravenous infusion over 2-4 hrs or subcutaneous administration.
– In high immunological risk: triple immunosuppression is given , keep TAC level 8-10 first 3 months the 5-8 ng/ml thereafter, MMF 1 gm BD, taper steroids to 5 mg within 2 M
– Steroid with draw protocol: : Early steroid withdrawal by day 7, continue on TAC +MMF
· Side effects:
1.infusion related reactions(cytokine release syndrome) , less if given SC
2. lymphopenia, close monitoring with FBC, WBC(total and differential)
3.Infections due to B and T cell depletion, BK infection is more common, prophylaxis against herpes virus , PCP(3 M prophylaxis) should be received. CMV(give 6 M prophylaxis) infection rate was similar to that of rATG
4.Data regarding malignancy is scarce, increased risk of non-hodgkins lymphoma, HPV related cancers, kaposi sarcoma.
5. It is teratogenic (class C) and expressed in breast milk
6. Autoimmunity: autoimmune hypo or hyperthyroidism and ITP
References:
1-Kidney transplantation hand book 6th edition.
2- Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Alemtuzumab-based induction treatment versus Basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Lancet. 2014;384(9955):1684.
Kidney transplantation is considered the best modality of treatment that provide better quality of life and longer survival for ESRD patients.
Immunosuppressive medications are required to prevent rejection of renal graft.
Immunosuppression protocols in renal transplant recipients include induction protocol, maintenance and treatment of rejection episodes.
Alemtuzumab is a humanized monoclonal antibody against CD52 cell surface antigen, it is approved for use in some hematological malignancies and auto-immune diseases such as multiple sclerosis, it being used in some renal transplant centers as induction immunosuppressive agent in high risk recipients.
2. The indications:
according to the available data from many trials, Alemtuzumab could be used in the following indications:
1- Low risk renal transplant recipients with early steroid withdrawal such as diabetic patients.
2- High risk renal transplant recipients who can’t use ATG because of contra-indications like hypersensitivity.
3. Contraindications
Alemtuzumab is contra-indicated in the following situations:
Active infection
Active malignancies
Hypersensitivity reaction
Immunodeficiency such as HIV.
4. Dosage:
Route: IV infusion (over 2-4 hours) or subcutaneous.
Two doses, first dose at day 0, and second dose at day 1.
Premedication should be given 30 minutes before, includes diphenhydramine 50 mg and paracetamol 1 gm IV.
Dose: Alemtuzumab 30 mg IVI (over 2-4 hours) or SC.
5. Route of administration
IVI in the majority of protocols.
Subcutaneous has shown similar outcomes with less IV reactions, however, anti- Alemtuzumab antibody formation risk is higher.
6. Side effects
The side-effects of Alemtuzumab include: Infusion associated reactions (in 70-80%), Infections, Increased risk of malignancy as compared to no induction, Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia.
7. References
1) 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014 Nov 8;384(9955):1684-90. doi: 10.1016/S0140-6736(14)61095-3. Epub 2014 Jul 28. PMID: 25078310.
2) Hill P, Cross NB, Barnett AN, Palmer SC, Webster AC. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD004759. doi: 10.1002/14651858.CD004759.pub2. PMID: 28073178; PMCID: PMC6464766.
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC57
* Humanized rat monoclonal antibody against CD52 cell surface antigen, used in haematological malignancies and multiple sclerosis
*alemtuzumab (induction) in comparison to basliximab, revealed reduced rejection risks with similar delayed graft function, graft survival and patient survival rates.
*best to be used in following situations
¥ Tx patient with need of early withdrawal of steroids (and also if experienced complications of steroids
¥ if Hypersensitivity to ATG
*Can never be used in case of active infection , malignancy or previous hypersensitivity .
*dose used is similar to the dose used in CLL and multiple sclerosis.
*Injection Alemtuzumab 30 mg intravenous infusion over 2 to 4 hours
*maintenance triple therapy with early steroid withdrawal after 1st week .
*prophylaxis against CMV , PCP
Strict FU of the patient clinically and Lab wise
*precautions: take care of possibility of cytokine reaction and increased risk of malignancy and infections
The best form of treatment for an end stage renal disease (ESRD) patient is a kidney transplant. Immunosuppression is an essential part of a kidney transplant patient management. Induction immunosuppression is required to decrease the risk of early rejections. Induction therapy involves use of T lymphocyte depleting and n-n-depleting antibody treatments. Alemtuzumab, a humanized rat monoclonal antibody against CD52 cell surface antigen, approved for use in haematological malignancies (B cell CLL) and autoimmune disease (multiple sclerosis), has been used as an induction agent in renal trasnplanation, although off-label. (1)
2. The indications
A systematic review regarding use of alemtuzumab as an induction agent, in comparison to basliximab, revealed reduced rejection risks with similar delayed graft function, graft survival and patient survival rates. (1) The 3C study compared alemtuzumab, low-dose tacrolimus and mycophenolate sodium without steroids with Basiliximab, standard-dose tacrolimus and mycophenolate sodium with steroids. The short-term results of this approach revealed lower biopsy proven acute rejection rates (BPAR) in the alemtuzumab arm with similar graft function, graft survival, infection and patient survival rates.(2)
Another trial comparing alemtuzumab with basiliximab in low-risk patient and with rabbit ATG in high risk patients revealed that alemtuzumab group had lower BPAR than basiliximab group in low-risk patients while the BPAR rates in the high-risk patients were similar to the rabbit ATG group.(3) Cochrane meta-analysis of induction therapy in kidney transplant patients also revealed similar BPAR rates in alemtuzumab based and ATG based induction therapies, but few studies showed reduced BPAR rates in alemtuzumab with early steroid withdrawal regimens.(4) Compared to ATG, Alemtuzumab with early steroid withdrawal had lower GFR at 6 months and 2 years.(4)
In the context of steroid minimisation, alemtuzumab prevented acute rejection at 1 year compared to ATG. CNI, MMF and steroid without induction therapy compared to alemtuzumab combined with early steroid withdrawal had similar rates of acute rejection. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple drug maintenance immunosuppression, in the absence of any clinical benefit. ATG and alemtuzumab use decreased risk of acute rejection, but with increased CMV disease with no change in patient-centred outcomes (reduced death or lower toxicity).(4)
In view of the data available, Alemtuzumab induction can be used in both low-risk and high-risk kidney transplant patients.(5)
a) Low-risk transplant recipients with early steroid withdrawal need (for example diabetic recipient)
b) High-risk transplant recipient with contraindication to ATG (hypersensitivity reaction).
3. Contraindications
Alemtuzumab should not be used in:
a) Active infection
b) Active malignancies
c) History of hypersensitivity reaction
d) Underlying immunodeficiency (e.g. HIV)
Although a patient being taken up for kidney transplant will not be having any active infection or malignancy at the time of transplantation.
4. Dose used
Dose of alemtuzumab used for induction in kidney transplantation is not based on any formal dose-finding studies in organ transplant recipients. The dose used is similar to the dose used in CLL and multiple sclerosis.
Injection Alemtuzumab 30 mg intravenous infusion over 2 to 4 hours, after pre-medication with diphenhydramine 50 mg and acetaminophen 500 mg intravenous 30 minutes prior to the infusion. Total 2 doses to be given on day 0 and day 1.
Maintenance immunosuppression in form of
a) Tacrolimus: 0.1 mg/kg/day. Target trough level 10 ng/ml initially, to be decreased to 7 ng/ml after 3 months.
b) MMF: 1000 mg twice a day (dose to be withheld if leukopenia).
c) Steroids: Early steroid withdrawal by day 7.
Prophylaxis:
a) CMV: Valgancyclovir 900 mg once day for minimum 2 months or until CD4 level>200
b) Pneumocystis: Tablet cotrimoxazole 480 mg once a day for 6 months.
c) Oral Candidiasis: Oral clotrimazole drops.
Post transplant regular CBC, creatinine, urine routine, DSA level monitoring.
5. Route of administration
Intravenous route has been used in majority of protocols, hence intravenous route being used. Although subcutaneous route has shown similar outcomes, there is increased risk of anti-alemtuzumab antibody formation.(5)
6. Side effects
The side-effects of Alemtuzumab includeL5)
a) Infusion associated reactions due to cytokine release (in 70-80%).
b) Infections due to prolonged lymphocyte depletion. Hence oral candidiasis, anti-herpes, CMV and pneumocystis prophylaxis to be given till CD4+ T lymphocyte count >200 or minimum 2 months. Watch for UTI.
c) Increased risk of malignancy as compared to no induction.
d) Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia.
7. References
1) Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012 Jun 27;93(12):1179-88. doi: 10.1097/TP.0b013e318257ad41. PMID: 22660659.
2) 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014 Nov 8;384(9955):1684-90. doi: 10.1016/S0140-6736(14)61095-3. Epub 2014 Jul 28. PMID: 25078310.
3) Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J; INTAC Study Group. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011 May 19;364(20):1909-19. doi: 10.1056/NEJMoa1009546. PMID: 21591943.
4) Hill P, Cross NB, Barnett AN, Palmer SC, Webster AC. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD004759. doi: 10.1002/14651858.CD004759.pub2. PMID: 28073178; PMCID: PMC6464766.
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC57
Influence on immunosuppression:
1) CNI exposure can be reduced by decreasing the target trough level to 4-7 ng/ml by 3 months
2) Similarly low dose MMF can be used
3) Rapid steroid tapering or early steroid withdrawal can be used in patients more prone to side-effects of steroids,
Alemtuzumab :
is a recombinant anti-CD52 pan-lymphocyte depleting monoclonal antibody that has
been in use for kidney transplantation since the late1990. (1).
Evidence suggests that Alemtuzumab is associated with a lower risk of acute
rejection within the first year of transplantation while exhibiting a comparable safety
profile to non-lymphocyte depleting agents.
Mechanism of action:
CD52, the antigen to which Alemtuzumab binds, is found on the surface of B and T
lymphocytes, monocytes, macrophages, dendritic cells (DC), and natural killer (NK)
cells, as well as on cells lining the male reproductive system.
INDICATION:
Hematologic malignancies (particularly chronic lymphocytic leukemia).
In bone marrow transplantation for graft versus host disease.
Autoimmune diseases (including multiple sclerosis, rheumatoid arthritis, and vasculitis).
In solid organ transplantation (induction and treatment for AR).
Alemtuzumab at induction protocol:
Alemtuzumab plus low-dose cyclosporine:
Two 20 mg doses of Alemtuzumab on days 0 and 1, and maintained on low-dose
cyclosporine monotherapy, aiming for trough levels of 75-125 ng/ml.
Alemtuzumab plus tacrolimus and MMF:
Two doses of Alemtuzumab on days 0 and 4, followed by low-dose tacrolimus
monotherapy (target trough concentration: 5-7 ng/ml) and MMF (500 mg twice daily).
Side effect:
Infusion associated reactions.
Infections.
Autoimmune disease, particularly autoimmune thyroid disease and cytopenias.
Alemtuzumab may be associated with an increased risk of early graft thrombosi.
Administer by IV infusion over 2 hours.
Premedicate with diphenhydramine 50 mg and acetaminophen 500 to 1,000 mg 30
minutes before each infusion. IV glucocorticoids have been effective in decreasing
Start anti-infective prophylaxis.
How it influences the maintenance immunosuppression?
Low dose of maintenance IS can be used.
References:
Phuong-Th et al.The evolving role of alemtuzumab (Campath-1H) in renal transplantation.
Drug Des Devel Ther. 2009; 3: 41–49.
Alemtuzumab ;Campath
_ _Used for treatment of CLL but utilized commonly in transplantation
_ It is a humanized anti-CD52 antibodies ; CD52 is highly expressed on the surface of T & B cells in addition to other cells such as thymocytes, monocytes, macrophage and NK cells
_It clears rapidly cells from the circulation leading to marked lymphopenia which may continue for 6 months( B cells recovers before T cells)
_Dose ; Two of 30 mg doses given SQ 24 h apart post-transplant; some centers given only one dose for patients more than 60 years.
_First dose usually given intraoperatively before reperfusion
_Less marked infusion reaction and no cytokine release compared to ATG; SQ < IV.
_Pre-medication is needed .
_ Late rejection may occur as T cells recover at ~ 6 months
Can be used as rescue therapy to treat acute rejection with little experience and evidence.
Side effects include “cytokine-release syndrome” with IV infusion , characterized by fever, rash, hypotension, and bronchoconstriction ,neutropenia ,anemia ,rigors ,rash and allergy ,diarrhea ,increased risk of infection and autoimmune disorders like thyroiditis .
Contraindications include: infection ,allergy ,fever ,malignancy and cytopenia.
Reference:Uptodate
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells. Ligation of alemtuzumab with CD52 induces apoptosis and lysis of immune cells through antibody- and complement-dependent cytotoxicity, which leads to profound and long-lasting lymphocyte depletion.
It´s used in immunosuppression strategies: A – induction treatment strategy; B- minimise CNI exposure to reduce the rate of late transplant failure. It has emerged as a promissing depletional MAb enabling a reversing steroid-resistant rejection.
– Perioperative depletion in combination with triple immunossppression;
– Early steroid or CNI weaning
– Patients with type 1 hypersensitivity or anaphylactic reactions to the active substance
– Patients with HIV
30mg flat dose or at 0.3mg/Kg dose over 3 hours immediately after reperfusion and 24 h later
Through a peripheral intravenous cateter
Mild to moderate infusion-associated reactions during administration for up to 24 hours, which frequently included headache, rash, pyrexia, nausea, urticaria, pruritus, insomnia, chills, flushing, fatigue, dyspnea, dysgeusia, discomfort chest, generalized rash, tachycardia, dyspepsia, dizziness and pain.
Serious reactions occurred in 3% of patients, including cases of pyrexia, urticaria, atrial fibrillation, nausea, chest discomfort, and hypotension.
In addition, anaphylaxis has been reported rarely.
Its use may result in the formation of autoantibodies and increased risk of autoimmunity-mediated conditions, including idiopathic thrombocytopenic purpura (ITP), thyroid disorders, or, rarely, nephropathies (eg, antiglomerular basement membrane disease).
7. References
– Kidney Transplantation: Principles and Practice – Eighth edition, ELSEVIER.
– Alemtuzumab-based induction treatment versus basiliximab based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet 2014; 384: 1684–90;
– Alemtuzumab as Antirejection Therapy: T Cell Repopulation and Cytokine Responsiveness. Bouvy et al. Transplantation Direct 2016;2: e83; doi: 10.1097/TXD.0000000000000595
– Lemtrada Genzyme – A Sanofi Company
Alemtuzumab is a humanized anti-CD52 monoclonal antibody pan lymphocytic (both B and T cell).
It is used as an anti-neoplastic agent, too.
In renal transplantation is used as an induction agent or treatment of renal transplant steroid resistant cellular rejection.
Labeled indication includes: B cell CLL, MS relapsing
OFF- label indications: steroid refractory GVHD, aplastic anemia, auto immune hemolytic anemia, conditioning regimen or GVHD prophylaxis induction and treatment of refractory TCMR in renal TX.
Contraindications hypersensitivity or anaphylactic reactions, HIV infection, active infection, latent TB, underlying immunodeficiency active secondary malignancies, current or history of progressive multifocal leukoencephalopathy (PMC)
Dosage:
As indication :30 mg as a single dose at the time of TX (immediately following reperfusion).
Followed by a second 30 mg dose 24 h later(for patientsfile:///C:/Users/user/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png 60 years)
Followed by minimized maintenance immunosuppression or steroid-withdrawal. For steroid resistant TCMR: IV, SQ: 20-30 mg /dose on 2 subsequent days or 30mg /dose IV over 2-4 hours for1 to 2 dose.
Route of administration: IV or SQ. IV infusion over 2-4 hours with normal saline premedication used with acetaminophen and diphenhydramine and with control for V/S.
Side effects:
1) Infusion reactions
2) Infections: viral, fungal bacterial and protozoan infections that need prophylaxis with co-trimoxazole and valcyte.
3) Autoimmune effect (immune thrombocytopenia or anti- GBM)
4) Malignancies (thyroid cancer, melanoma and lymphoproliferative disorders
5) Stroke.
1.Asderakis, A., Sabah, T. K., Watkins, W. J., Khalid, U., Szabo, L., Stephens, M. R., Griffin, S., & Chavez, R. (2022). Thymoglobulin Versus Alemtuzumab Versus Basiliximab Kidney Transplantation From Donors After Circulatory Death. Kidney International Reports, 7(4), 732–740. https://doi.org/10.1016/J.EKIR.2022.01.1042
2.Guthoff, M., Berger, K., Althaus, K., Mühlbacher, T., Bakchoul, T., Steurer, W., Nadalin, S., Königsrainer, A., & Heyne, N. (2020). Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrology, 21(1). https://doi.org/10.1186/s12882-020-01767-z
3. Naesens, M., Berger, S., Biancone, L., Crespo, M., Djamali, A., Hertig, A., Öllinger, R., Portolés, J., Zuckermann, A., & Pascual, J. (2016). Lymphocyte-depleting induction and steroid minimization after kidney transplantation: A review. Nefrología, 36(5), 469–480. https://do i.org/10.1016/J.NEFRO.2016.03.019
4. uptodate 2022
Introduction:
Alemtuzumab, a humanized monoclonal antibody directed against CD52 on B- and T-lymphocytes, monocytes and NK cells, is used in the treatment of lymphoma and multiple sclerosis
Alemtuzumab causes prolonged depletion of both T and B lymphocytes ,for up to 12 months, with profound immunosuppression and an associated risk of serious infections.
, it is used for induction in high immunological risk candidates .
Alemtuzumab has been used for induction in kidney transplantation since 1998 .
alemtuzumab,results in the same or even better results than ATG with regard to rejection episodes .
Complete B- and T-lymphocyte depletion, however, persists much longer than with ATG which is accompanied by an increased risk of infection.
Doses:
it is administred as single dose or two doses intraoperatively slow intravenous (IV) infusion or subcutaneous (SC)
standard dosing. With doses of 30–60 mg
Using a reduced dose of 20 mg, resulting in a median dose of 0.3 [0.26–0.34] mg/kg, time to lymphocyte recovery is markedly shorter than standard dosage .
With a median time to lymphocyte recovery of 77 days, the critical period of being prone to infections was kept short without putting the patients at immunological risk
Indication:
1-drug has been used off-label for both the prevention and treatment of acute allograft rejection in kidney, pancreas, intestinal, and lung transplantation.
2-Induction for high risk patients
3-steriod resistant acute cellular rejection.
4-treatment of lymphoma and multiple sclerosis.
Dose monitoring
measuring the serum or plasma concentration of alemtuzumab is possible. However, these assays are not widely available, technically demanding, and difficult to standardize.
Maintenance immunosuppression
Side effects
Fever, chills, dizziness, muscle stiffness, nausea, vomiting, headache, diarrhea, mild rash/itching, tiredness, flushing, or trouble breathing may occur during or after the infusion.
* in high risk patients inuction with alemtuzumab followed by triple immunosuppression with Tacrolimus, MMF and steroid
*Use of alemtuzumab allowed early
Steroid withdraw protocol, in low immunological risk
Triple immunosuppression with
Tacrolimus target trough level initial phase 8-10 ng first 3 months.
Then 5-7ng .
predsiolone 150mg oral, to be tapper with in 1week
Mycophenolate sodium 360mg BID first two weeks then increased to full dose gradually 720mg BID.
References:
1-Martina Guthoff, Kilian Berger,.Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients.BMC Nephrology volume 21,Article number: 178 (2020).
2-Kidney transplantation hand book 6th edition.
Induction means any drug used for inducing graft acceptance in the early postoperative period
But it’s usually meant by induction the biological drugs.
There are 2 types of induction therapy
1. Depleting induction w includes (ATG and alemtuzumab)
2. Nondepleting induction (basiliximab)
alemtuzumab is depleting monoclonal biological drug formed by injection of cd52 antigen into rats then humanized.
cd52 presented on lymphocytes, NK, eosinophils, neutrophils, monocytes/macrophages, and dendritic cells (DCs). so, it’s associated with the destruction of all the previous cells.
Because its humanized, its allergic reaction is much better than chimeric drugs but still premedication is still needed (acetaminophen, methylprednisolone, and antihistaminic).
Alemtuzumab is used at a dose of 30mg subcutaneous after reperfusion.
Alemtuzumab was compared to rATG as regards efficacy and safety, results showed noninferiority.
So, 1st step for any protocol is risk stratifications and with regard, to the risks patients should be divided into 3 categories
High risk, intermediate risk, the low risk then
1. high-risk patients are for depleting induction using rATG or alemtuzumab
2. Low and intermediated risk studies showed that depleting induction didn’t show superiority to nondepleting induction using basiliximab so it’s better to be saved as a treatment and to decrease risks of complications but it can be used for the next reasons
a. Immunosuppressive minimization
b. Allow use of CNI sparing regimens: Like CNI avoidance and use mTOR as donovo IS or early conversion (6m) or late conversion (1y)
c. Allow use of steroids sparing regimens: Like steroids avoidance, steroids early withdrawal, and steroids late withdrawal
So, the best protocol to use Alemtuzumab is as induction therapy in high-risk patient
It should be mentioned that there is no total agreement on the definition of high-risk patients but in general
1. Patients with +ve FXC and +ve DSA
2. Patients with +VE DSA and -ve FXC
3. Patients with 2 DR mismatch or 1DR mismatch and 2 B
4. Patients with cPRA > 80%
5. Patient 2nd,3th, and 4th kidney transplantation
6. Other parameters can be considered as risk factors for graft rejection and some centers give depleting inductions for those patients like (Young recipient, Recipient his 1ry kidney disease is GN, Black races.
Finally, after establishing the protocol, patients should be randomized and studied in comparison to the control group to reach the best protocol for our patients special in the presence of big racial differences which exposes the urgent need for more studies on different races
Alemtuzumab
Alemtuzumab (Campath 1H) is a recombinant DNA-derived humanized monoclonal antibody directed against the cell surface glycoprotein CD52 .
USES 1): initially approved for use in Bcell chronic lymphocytic leukemia,
2) it is a depletional agent sometimes used in clinical transplantation, although off- label, where it is used as an induction agent and in the treatment of acute transplant rejection.
3) also used in relapsing form of Multiple sclerosis
When used at the time of transplantation as induction therapy :
1) alemtuzumab induces a profound, rapid, and effective depletion of peripheral and central lymphoid cells that maytake months to return to pretransplantation levels.
2) Used as a single agent, it does not induce tolerance and episodes of acute rejection can occur even in the absence of T cells.
3)Its use may facilitate minimization of maintenance immunosuppressive protocols and steroid sparing with monotherapy using sirolimus or low-dose calcineurin inhibitor.
MODE OF ADMINSTRATION & DOSE :
Although Alemtuzumab use in kidney transplantation is “off-label.” Its ease of administration has made it an attractive alternative to Thymoglobulin.
It is usually given as a single dose of 30 mg intraoperatively; a second dose is sometimes given. Because the drug is administered under general anesthesia, infusion-related events typically associated with the infusion of biologic agents are masked.
so it requires premedication with steroids , antihistamine and paracetamol along with close monitoring for infusion reaction till for 2 hours after infusion
When used as an induction agent, alemtuzumab reduces the risk of rejection compared to basiliximab in unsensitized patients. However, when compared to rATG in randomized clinical trials, alemtuzumab has not been shown to be superior. In trials of patients undergoing steroid withdrawal, those receiving alemtuzumab have a greater risk
of rejection.
SIDE EFFECTS :
1-Alemtuzumab induces profound lymphopenia, cytopenias ( including autoimmune thrombocytopenia , AIHA ) which may be prolonged requiring reduced doses of other myelosuppressive agents , so keep frequent monitoring of CBC and differential WBC count .
2- risk of oppurtunistic infections as PJP , CMV , herpes .give PJP prophylaxis for 2 months after last infusion , check VZV Ab and consider immunization prior to therapy
3- Malignancies 🙁 thyroid , melanoma , LPD ) , have baseline and regular skin exam
4- Anti GBM disease
CONTRAINDICATIONS
active infections
Baseline and later monitoring :
CBC and differential , TFT , RFT & urinalysis , skin exam , HIV , latent TB , oppurtunistic infections testing as mandated
references :
1- Handbook of kidney transplantation , 6th edition
2- Medscape
# Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
# Alemtuzumab is a monoclonal anti-CD52 antibody, which has been used extensively off label in solid organ transplantation.
# Its use as induction agent at the time of organ transplantation
# There is limited experience for using it in steroid resistant rejection.
# Prolonged lymphocyte depletion can be expected following treatment wih Alemtuzumab even with one dose of 30mg IV
#Incomparison with ATG Alemtuzumab has benefits with lower cost, fewer side effects and no specific issues with i.v. access.
also with nondepleting agents, such as anti-CD25 induction therapy.
# Calne et al, conducted that recipients treated with alemtuzumab induction and cyclosporine maintenance therapy without azathioprine or steroids were described by profound lymphocyte depletion induce the immune system into a tolerogenic state when encountering a newly transplanted graft, or at least develop a state of ‘prope (almost) tolerance’ with minimal requirements for further immunosuppressive therapy.
# patients given alemtuzumab followed by one half of the usual dose of cyclosporine and no other agents, short term follow up on low dose cyclosporine monotherapy. their 5year followup of this recipient group and noted no significant difference in rejection episodes, graft function or graft and patient survival
#There were no differences in denovo malignancy or infection.
#They report more episodes of late rejection in the alemtuzumab treated group cause may be secondary to lower cyclosporine levels,
# Episodes of autoimmune disease were noted in alemtuzumab treated patients.
# With regard to the induction of tolerance, these patients were no more tolerant to renal grafts than controls at 5years.
#They demonstrate that alemtuzumab induction therapy could enable a steroid-free immunosuppressive regimen with low-dose cyclosporine with graft function equivalent to standard triple therapy
# Ciancio et al. described a similar experience with alemtuzumab induction their group received alemtuzumab induction followed by a steroid-free protocol including low-dose tacrolimus and low-dose mycophenolate, they found similar rates of acute rejection, graft and patient survival compared with earlier protocol.
# using alemtuzumab and low dose calcineurin inhibitors, this immunosuppressive protocol could be a means to completely avoid the toxicity associated with calcineurin inhibitors and possibly improve long-term graft function.
# Results of a pilot study noted an unacceptably high rate of acute humoral rejection (17%) compared with the10% using traditional, triple immunosuppressive therapy
# At the University of Wisconsin, a subsequent immunosuppressive protocol was then adopted consisting of two doses of alemtuzumab at the time of renal transplant in combination with low dose steroids (10mg methyprednisolone per day), MMF(1000mg) MMF, and either tacrolimus or cyclosporine compared with historical controls that received induction therapy with anti-CD25 antibody, Thymoglobulin or OKT3 followed by maintenance calcineurin inhibitor, MMF and steroids. It was noted that the alemtuzumab-treated group experienced less acute rejection, particularly in those patients experiencing delayed graft function (DGF).
#Shapiro et al. compared alemtuzumab with Thymoglobulin. Both groups received steroid-free maintenance immunosuppressive therapy and low-dose tacrolimus there were more episodes of acute cellular rejection in the Thymoglobulin group, the patient and graft survival rate was equivalent
# late rejection episodes (>6 months) in both depletional groups were increased, likely secondary to the aggressive calcineurin inhibitor weaning protocols.
# Calne et al. originally observed an acellular, ‘vascular’ type rejection in a single patient while Kirk et al. noted a marked macrophage infiltration in patients with early rejection who received alemtuzumab induction without maintenance immunosuppressive therapy.
#Several authors have now reported that a number of these rejection episodes demonstrate positive staining for C4d, indicative of acute humoral rejection It is unclear if the rates of C4d+ rejection are increased with alemtuzumab induction as this technique has only been employed for a relatively short period of time.
# Ciancio et al. observed that the incidence of C4d+ rejection was no different between patients undergoing induction with alemtuzumab or with other agents
# References
1 Waldmann H, Polliak A, Hale G, et al. Elimination of graft-versus-host disease by in-vitro depletion of alloreactive lymphocytes with a monoclonal rat anti-human lymphocyte antibody (CAMPATH-1). Lancet 1984; 2: 483.
CrossrefCASPubMedWeb of Science®Google Scholar
2 Heit W, Bunjes D, Wiesneth M, et al. Ex vivo T-cell depletion with the monoclonal antibody Campath-1 plus human complement effectively prevents acute graft-versus-host disease in allogeneic bone marrow transplantation. Br J Haematol 1986; 64: 479.
Wiley Online LibraryCASPubMedWeb of Science®Google Scholar
A is true
B is true
C is false
D is true
E is true
Introduction
Alemtuzumab is a humanized anti-CD52 panlymphocytic (both B and T cells) monoclonal antibody that is approved for treatment of chronic lymphocytic leukemia. Alemtuzumab induction therapy is used in approximately 10 percent of kidney transplant recipients in the United States.
Alemtuzumab binds to CD52, a nonmodulating antigen present on the surface of B and T lymphocytes, a majority of monocytes, macrophages, NK cells, and a subpopulation of granulocytes. After binding to CD52+ cells, an antibody-dependent lysis of malignant cells occurs. In multiple sclerosis, alemtuzumab immunomodulatory effects may include alteration in the number, proportions, and properties of some lymphocyte subsets following treatment.
Although randomized trials comparing alemtuzumab with either rATG-Thymoglobulin or basiliximab have shown similar or lower rates of acute rejection , there are concerns that its benefits in reducing acute rejection may decrease over time Other long-term outcomes, including graft and patient survival and development of chronic allograft nephropathy, may also be worse in patients receiving alemtuzumab compared with rATG-Thymoglobulin and interleukin (IL) 2 receptor antagonists In addition, alemtuzumab is not readily available to all medical centers that perform kidney transplantation.
Some centers use alemtuzumab as induction therapy for recipients of a human leukocyte antigen (HLA)-incompatible kidney transplant following HLA desensitization.
Indications
The indications
Induction therapy in high risk patients
Resistant acute antibody mediated rejection
CHronic lymphocytic leukemia
MS
Contraindications
Hypersensitivity (eg, anaphylactic reactions) to alemtuzumab or any component of the formulation; HIV infection (due to prolonged reduction in CD4+ lymphocytes); active infection.
Canadian labeling:
Lemtrada: HIV infection; active or latent tuberculosis; severe active infections; active malignancies; concurrent anticoagulant, antiplatelet, antineoplastic, or immunosuppressive therapy; history of progressive multifocal leukoencephalopathy (PML); history of stroke and arterial dissection of cervicocephalic arteries infections; uncontrolled hypertension; history of arterial dissection of the cervicocephalic arteries; history of stroke; history of angina or myocardial infarction; known coagulopathy.
Side effects
>10%:
Dermatologic: Pruritus (14%), skin rash (53%), urticaria (16%)
Endocrine & metabolic: Thyroid disease (13% to 37%)
Gastrointestinal: Diarrhea (12%), nausea (21%)
Genitourinary: Urinary tract infection (19%)
Hematologic & oncologic: Lymphocytopenia (100%)
Immunologic: Antibody development (neutralizing: 5% to 94%; anti-alemtuzumab: 29% to 83%; no significant effect on drug efficacy)
Infection: Fungal infection (12% to 13%; including oral candidiasis, vulvovaginal candidiasis), herpes virus infection (16%), infection (71%; serious infection: 3%)
Nervous system: Fatigue (18%), headache (52%), insomnia (16%)
Neuromuscular & skeletal: Arthralgia (12%), back pain (12%), limb pain (12%)
Respiratory: Nasopharyngitis (25%), oropharyngeal pain (11%), sinusitis (11%), upper respiratory tract infection (16%)
Miscellaneous: Fever (29%), infusion related reaction (92%; severe infusion related reaction: 3%)
Alemtuzumab is administered as a single intravenous (IV) dose of 30 mg at the time of transplantation.
Ref: up to date
A+B+D+E ARE CORRECT
The origins of alemtuzumab date back to Campath-1 which was derived from the rat antibodies raised against human lymphocyte proteins by Herman Waldmann and colleagues in 1983. The name “Campath” derives from the pathology department of Cambridge University
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells, CD52 is not expressed on erythrocytes, platelets, and hematopoietic progenitor cells. The exact function of CD52 is unknown but it is suggested that the molecule may be involved in T lymphocyte co-stimulation, the induction of regulatory T lymphocytes, and T lymphocyte migration and adhesion. Ligation of alemtuzumab with CD52 induces apoptosis and lysis of immune cells through antibody- and complement-dependent cytotoxicity, Alemtuzumab causes a rapid and profound depletion of T and B lymphocytes, as well as various cells of the innate immune system. Reconstitution of cells from the innate immune system is faster (within 6 months) than that of T and B lymphocytes, which may take more than 1 year.
Indication in general
1. solid organ transplantation as an induction agent in the prevention of rejection.
2. various autoimmune disorders, and has also shown potential as 3. treatment of chronic lymphocytic leukemia
4. Multiple sclerosis
Clinical Use of Alemtuzumab in Kidney Transplantation
Alemtuzumab is not registered for SOT indications. However, the drug has been used off-label for both the prevention and treatment of acute allograft rejection in kidney, pancreas, intestinal, and lung transplantation.
Alemtuzumab as Induction therapy at the time of transplantation allows for minimization of CNI exposure without an increased risk of acute rejection. could potentially lead to better renal function and longer graft survival.
Dose (30 mg on days 0 and 1, subcutaneously or intravenously) +low dose tacrolimus (target pre-dose concentrations 5–7 ng/mL) + and mycophenolate sodium (360 mg twice daily) steroid free. compared with basiliximab (20 mg intravenously on days 0 and 4) +standard-dose tacrolimus (target pre-dose concentrations 5–12 ng/mL), mycophenolate sodium (540–720 mg twice daily), and glucocorticoids (15–20 mg prednisone.
Endpoint of the 3C study there was significant reduction in the incidence of BPAR: 26 (6.1%) vs respectively.
compared induction therapy with alemtuzumab to rATG. There was no significant difference in graft loss and overall survival.
Anti-rejection therapy
Alemtuzumab used as anti-rejection therapy results in a comparable graft survival rate compared with rATG, although infusion-related side effects appear to be less. Alemtuzumab could be an alternative to rATG for the treatment of glucocorticoid-resistant, severe or recurrent AR. Compared to rATG, allograft- and patient survival of patients treated with alemtuzumab was not different. Moreover, adverse events and infections seemed to occur less frequently in patients treated with alemtuzumab compared with rATG-treated patients.
Contraindication
1.have active infections, underlying immunodeficiency (e.g., seropositive for HIV),
2. known type I hypersensitivity or anaphylactic reactions to the substance
3. Active malignancies
Dose used and rout of administration in renal transplantation
. No formal dose-finding studies have been performed in SOT recipients. It is recommended that patients are pre-medicated with glucocorticoids, acetaminophen, and anti-histamines immediately prior to the administration of alemtuzumab to diminish infusion-related reactions.
The side effects of alemtuzumab?
1. Infusion associated reactions due to cytokine release. (Fever, chills, flushing, dizziness, shortness of breath, nausea, vomiting, or mild rash/itching may occur during or after the infusion. These reactions occur more often during the first week of treatment
2. Infections due to prolonged lymphocyte depletion. Hence oral candidiasis, anti-herpes, CMV and pneumocystis prophylaxis to be given till CD4+ T lymphocyte count >200 or minimum 2 months. Watch for UTI.
3. Increased risk of malignancy as compared to no induction.
4. Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia.
1“LEMTRADA® (alemtuzumab) injection, for intravenous use Prescribing Information”. products.sanofi.us. Retrieved 11 October 2021.
2.. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation
Marieke van der Zwan,file:///C:/Users/dell/AppData/Local/Temp/msohtmlclip1/01/clip_image001.gif1 Carla C. Baan,1 Teun van Gelder,1,2 and Dennis A. Hesselink1
Author information Copyright and License information Disclaimer
3.ORIGINAL RESEARCH article
Front. Immunol., 03 July 2020 | https://doi.org/10.3389/fimmu.2020.01332
Comparison of Alemtuzumab and Anti-thymocyte Globulin Treatment for Acute Kidney Allograft Rejection
Introduction :
Alemtuzumab (Campath-1H) is a humanized rat monoclonal antibody directed against the CD52 antigen,
Can cause profound B and T lymphocyte depletion. Alemtuzumab is now widely used in solid organ transplantation, principally as an induction agent, but also in the treatment of acute rejection.
mechanism of action
it binds to CD52 on the surface of B and T lymphocytes, monocytes, macrophages, dendritic cells, and natural killer (NK) cells.
with subsequent lymphocytes lysis with complement activation and AB dependant cytotoxicity
rapid action: after 48 hrs.
Long-lasting T cell depletion may persist for years, B cells 2: 12 months
therapeutic uses:
treatment of CLL
GVHD in BM transplantation
autoimmune diseases (including multiple sclerosis, rheumatoid arthritis, and vasculitis)
solid organ transplantation
in renal transplantation, alemtuzumab is used in the treatment of acute rejection
Alemtuzumab is gaining increasing popularity as an induction agent since it allows the use of steroid-free maintenance regimens
Side effects:
Intravenous infusion is associated with a marked “cytokine-release syndrome”, characterized by fever, rash, hypotension, and bronchoconstriction
Neutropenia
Anemia
Rigors
Rash and allergy
Diarrhea
Increased risk of infection
Autoimmune disorders ( thyroiditis )
Contraindication:
Current infection
Allergy
fever
malignancy
Cytopenia
. Route of administration
SC or IV infusion
pre medication in IV route ( Paracetamol + Diphenhydramin + solumederol )
Monitor : CBC , CD4 count
Dosing :
day 0 and day 1 of IV infusion of 30 mg Alemtuzumab
Reference :
Alemtuzumab as Induction Therapy in Renal Transplantation
Menna R. Clatworthy1 and Christopher J.E. Watson2
Alemtuzumab in kidney-transplant recipients
James F Markmann, Jay A Fishman
A True
B Ture
C False (more expression on T cells)
D True
E True
Alemutzumab (Campath) :
it’s monoclonal antibody against CD 52 inhibit B and T cell antibody, it’s expressed on lymphocytes and macrophage ; monocytes and natural killer cell and dentric cell.
it’s expressed more in T cell.
it’s used for treatment of chronic lymphocytic leukemia and multiple sclerosis. recently low dose of alemutzumab used in high sensitised patients to prevent AMR
it’s contraindicated in acute infection and bone marrow failure and hypersensitivity.
it’s side effects flu like illness, GIT upset, headache and dizziness and hypertension.
it’s can be used intravenous and subcutaneous which are less side effects than infusion
References
Michael J. et al, Alemtuzumab Induction in Renal Transplantation: N Engl J Med 2011; 364:1909-1919.
Protocol for Alemtuzumab in Renal Transplantation
Induction therapy with alemtuzumab is implemented to reduce the Corticosteroids dose. Alemtuzumab ( Campath) is a humanized monoclonal anti CD52 antibody
Indications.
-CLL
-Steroid resistant cellular rejection
-As induction agent in high risk in high immunological risk patients and those with steroid withdrawal.
Contraindications
Hypersensitivity
Active systemic infections
HIV
Dose:
It is recommended that patients are given glucocorticoids, acetaminophen, and anti-histamines immediately prior to the administration. A Single IV dose of 30 mg as induction agent at the time of transplantation and second dose on day 1.
Route of administration
Intravenous or subcutaneous
Side effects:
– local injection-site reactions.
– Infusion-Associated Reactions
– Infection due to prolonged depletion of immune cells
– Malignancy : EBV-positive large-cell lymphoma , non-Hodgkin lymphoma, Hodgkin lymphoma, Kaposi sarcoma, and liver cancer ,colorectal cancer and thyroid cancer·
– Immune thrombocytopenia (idiopathic thrombocytopenic purpura)
References
-van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 F
– alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients 2-Alemtuzumab Induction in Renal Transplantation by Michael J. Hanaway, M.D(INTAC study)eb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC5784003.
References
2- Brokhof MM, Sollinger HW, Hager DR, Muth BL, Pirsch JD, Fernandez LA, et al. Antithymocyte globulin is associated with a lower incidence of de novo donor-specific antibodies in moderately sensitized renal transplant recipients. Transplantation.
Alemtuzumab
introduction
is humanized monoclonal antibodies specific to T&B lymphocytes ,it recombinant DNA derived ,dirct against the 21 -28 kd cell surface glycoprotien CD52 ,.the campath-1 antibody is an IgG1kappa.
HLA sensitized patients were treated according to center protocol if their antibody (PRA equal or more than 15) in deceased donor transplant or if they had incompatible living donor transplant define by presence of DSA prior to transplant
single plasmapharsis performed in majority of patient prior to deceased donor transplant,
negative complement depend toxicity cross match require before transplant
Protocol
for induction varies from centers so from literature review this protocol for Alemtuzumab induction:
low dose 20 mg i.v prior to perfusion and tailored immunosupression commencing with TAC trough level 10
pluse steroid 500 mg and 250 mg prednisone i.v at time of transplant and 12 hour later respectively.
followed by 100mg predislone given orally with taper to 5 mg within one month
MMF was suspended until lymphocytes count in peripheral blood reach >5% of leucocytes or >200/ul absoluate dose is 1000 mg po bid
pneumocytic Jiroveci prophylaxes for 6 month
CMV prophylaxes for 3-6 month
dose of ALemtuzumab is from 30 to 20 mg acorrding to protocol centre
protocol mention above as to minimize the side effects such as infection.
indication of Alemtuzum
1-induction therapy in renal transplantation recipient
2- treatment of B-cell chronic lymphocytic leukemia.
3- kidney transplant rejection (steroid resistance)
4- leukemia( prolymphocytic Tcell.)..
5-relapsing remitting multiple sclerosis and secondary progressive M.S .
6-Refractory autoimmune heamolytic anemia.
7- refractory idiopathic thrombocytopanic purpura.
reconstitution
30 mg /ml soluation for infusion with 100 ml of 0,9 N.S NACL or 5%dextrose in water as 12 mg /1.2ml soluation for infusion with draw 1,2 ml
contraindication
1-HIV.
2-sever active infection
3- other autoimmune disease
4-coagulopathy
5-uncontrolled HTN
6- History of stroke .
7- History of angina pectoris ,MI or arterial dissection of cervico cephalic Artery.
8- antiplatlet and anticoagulant therapy.
Alemtuzumab
It a monoclonal antibody directed against cell surface glycoprotein CD52.
Profound rapid depletion of peripheral and central lymphoid tissue and well take months to return back to pretransplant status,
It use as a single dose 30 mg interaoperatively. Side effects are masked cause the patient was under general Anathesia. Has superior effect when compared to basiliximab
But had no superiority to ATG. The incidence of cellular rejection was lower due to profound lymhopenia
The immune suppression effect of alemtuzmab called proper tolerance or near tolerance that allow minimal immune suppression mantance therapy as Low dose CNI or mTOR as mono therapy
Reference:
Kidney transplantation book 6 edition
Alemtuzumab: is a humanized monoclonal antibody against CD52 and causes depletion of T and B lymphocytes, monocytes, and NK cells.
It is registered for the treatment of multiple sclerosis and is also used in chronic lymphocytic leukaemia.
It’s used off-label in kidney transplantation as induction and anti-rejection therapy.
Indications:
Alemtuzumab is not registered for SOT indications. However, the drug has been used off-label for both the prevention and treatment of acute allograft rejection in kidney, pancreas, intestinal, and lung transplantation.
Alemtuzumab was first used as induction therapy in 1998 when 13 patients received it as induction therapy consisting of 2 doses of 20 mg IV on days 0 & 1. Only one patient had rejection on a 6-11 month follow up. Then the use of alemtuzumab as induction therapy was compared to basiliximab in an RCT and a reduced risk of rejection at 12 months in the alemtuzumab arm was confirmed but no significant difference was seen in graft loss, delayed graft function, or patient survival.
In the 3C study, No significant difference was seen in the occurrence of biopsy-proven antibody-mediated rejection in patients receiving alemtuzumab.
In a single-centre RCT, alemtuzumab was compared to rATG, and no significant difference was seen in the frequency of rejection after 1 year.
The main use is as a second line in steroid-resistant or severe cellular rejection when there is resistance or intolerance of rATG.The authors of a study including 40 patients concluded that the outcome after treatment with alemtuzumab is comparable to the outcome of other antibody preparations (indirect comparisons with RCTs). However, infectious complications were more frequent.
Alemtuzumab has incidentally been used as a treatment of biopsy-proven acute rejection after kidney transplantation. No RCTs investigating this application have been performed. In a study comparing the long term outcome of using alemtuzumab compared to MP in the treatment of acute rejection, the study found that the long-term transplant survival and allograft function were similar in both groups.
Complications;
Dose and Administration:
Alemtuzumab is available as a solution for intravenous or subcutaneous administration.
The recommended dose depends on the indication for alemtuzumab.
A typical dosing scheme of alemtuzumab in SOT is 1 or 2 doses of 30 mg intravenously or subcutaneously.
No formal dose-finding studies have been performed on SOT recipients. It is recommended that patients are premedicated with glucocorticoids, acetaminophen, and antihistamines immediately prior to the administration of alemtuzumab to diminish infusion-related reactions.
Protocol:
References:
Review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
The best form of treatment for an end stage renal disease (ESRD) patient is a kidney transplant. Immunosuppression is an essential part of a kidney transplant patient management. Induction immunosuppression is required to decrease the risk of early rejections. Induction therapy involves use of T lymphocyte depleting and n-n-depleting antibody treatments. Alemtuzumab, a humanized rat monoclonal antibody against CD52 cell surface antigen, approved for use in haematological malignancies (B cell CLL) and autoimmune disease (multiple sclerosis), has been used as an induction agent in renal trasnplanation, although off-label. (1)
2. The indications
A systematic review regarding use of alemtuzumab as an induction agent, in comparison to basliximab, revealed reduced rejection risks with similar delayed graft function, graft survival and patient survival rates. (1) The 3C study compared alemtuzumab, low-dose tacrolimus and mycophenolate sodium without steroids with Basiliximab, standard-dose tacrolimus and mycophenolate sodium with steroids. The short-term results of this approach revealed lower biopsy proven acute rejection rates (BPAR) in the alemtuzumab arm with similar graft function, graft survival, infection and patient survival rates.(2)
Another trial comparing alemtuzumab with basiliximab in low-risk patient and with rabbit ATG in high risk patients revealed that alemtuzumab group had lower BPAR than basiliximab group in low-risk patients while the BPAR rates in the high-risk patients were similar to the rabbit ATG group.(3) Cochrane meta-analysis of induction therapy in kidney transplant patients also revealed similar BPAR rates in alemtuzumab based and ATG based induction therapies, but few studies showed reduced BPAR rates in alemtuzumab with early steroid withdrawal regimens.(4) Compared to ATG, Alemtuzumab with early steroid withdrawal had lower GFR at 6 months and 2 years.(4)
In the context of steroid minimisation, alemtuzumab prevented acute rejection at 1 year compared to ATG. CNI, MMF and steroid without induction therapy compared to alemtuzumab combined with early steroid withdrawal had similar rates of acute rejection. Alemtuzumab plus steroid withdrawal would cause one additional patient experiencing CMV disease for every six patients treated compared to no induction and triple drug maintenance immunosuppression, in the absence of any clinical benefit. ATG and alemtuzumab use decreased risk of acute rejection, but with increased CMV disease with no change in patient-centred outcomes (reduced death or lower toxicity).(4)
In view of the data available, Alemtuzumab induction can be used in both low-risk and high-risk kidney transplant patients.(5)
a) Low-risk transplant recipients with early steroid withdrawal need (for example diabetic recipient)
b) High-risk transplant recipient with contraindication to ATG (hypersensitivity reaction).
3. Contraindications
Alemtuzumab should not be used in:
a) Active infection
b) Active malignancies
c) History of hypersensitivity reaction
d) Underlying immunodeficiency (e.g. HIV)
Although a patient being taken up for kidney transplant will not be having any active infection or malignancy at the time of transplantation.
4. Dose used
Dose of alemtuzumab used for induction in kidney transplantation is not based on any formal dose-finding studies in organ transplant recipients. The dose used is similar to the dose used in CLL and multiple sclerosis.
Injection Alemtuzumab 30 mg intravenous infusion over 2 to 4 hours, after pre-medication with diphenhydramine 50 mg and acetaminophen 500 mg intravenous 30 minutes prior to the infusion. Total 2 doses to be given on day 0 and day 1.
Maintenance immunosuppression in form of
a) Tacrolimus: 0.1 mg/kg/day. Target trough level 10 ng/ml initially, to be decreased to 7 ng/ml after 3 months.
b) MMF: 1000 mg twice a day (dose to be withheld if leukopenia).
c) Steroids: Early steroid withdrawal by day 7.
Prophylaxis:
a) CMV: Valgancyclovir 900 mg once day for minimum 2 months or until CD4 level>200
b) Pneumocystis: Tablet cotrimoxazole 480 mg once a day for 6 months.
c) Oral Candidiasis: Oral clotrimazole drops.
Post transplant regular CBC, creatinine, urine routine, DSA level monitoring.
5. Route of administration
Intravenous route has been used in majority of protocols, hence intravenous route being used. Although subcutaneous route has shown similar outcomes, there is increased risk of anti-alemtuzumab antibody formation.(5)
6. Side effects
The side-effects of Alemtuzumab includeL5)
a) Infusion associated reactions due to cytokine release (in 70-80%).
b) Infections due to prolonged lymphocyte depletion. Hence oral candidiasis, anti-herpes, CMV and pneumocystis prophylaxis to be given till CD4+ T lymphocyte count >200 or minimum 2 months. Watch for UTI.
c) Increased risk of malignancy as compared to no induction.
d) Diarrhea, nausea, fatigue, headache, insomnia, back pain and arthralgia.
7. References
1) Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012 Jun 27;93(12):1179-88. doi: 10.1097/TP.0b013e318257ad41. PMID: 22660659.
2) 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014 Nov 8;384(9955):1684-90. doi: 10.1016/S0140-6736(14)61095-3. Epub 2014 Jul 28. PMID: 25078310.
3) Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J; INTAC Study Group. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011 May 19;364(20):1909-19. doi: 10.1056/NEJMoa1009546. PMID: 21591943.
4) Hill P, Cross NB, Barnett AN, Palmer SC, Webster AC. Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database Syst Rev. 2017 Jan 11;1(1):CD004759. doi: 10.1002/14651858.CD004759.pub2. PMID: 28073178; PMCID: PMC6464766.
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC57
Influence on immunosuppression:
1) CNI exposure can be reduced by decreasing the target trough level to 4-7 ng/ml by 3 months
2) Similarly low dose MMF can be used
3) Rapid steroid tapering or early steroid withdrawal can be used in patients more prone to side-effects of steroids,
I must confess, I have never used alemtuzumab and never thought of using it as most of the patients in our transplant program are related living donors, managed well with triple drug immunosuppression and low dose ATG as induction, if needed.
Cost of ATG is low in our country, Alemtuzumab is not available.
Alemtuzumab is a monoclonal antibody that targets CD52, a common antigen found on B and T cells. When the alemtuzumab antibody attaches to the CD52 antigen, the body’s immune system is activated to destroy these targeted cells in the blood and bone marrow.
In phase 3 clinical trials, use has achieved steroid-sparing effects including improved glycemic stability
Long-term follow-up results from the 3C trial regarding alemtuzumab’s role in reducing calcineurin inhibitor exposure by using a more potent induction regimen .-In steroid resistant TCMR.-Chronic Lymphocytic Leukemia-Multiple SclerosisDosing : Alentuzumab 30mg -IV or SC .Contraindication hypersensitivity reaction .Side effects :
Fever, chills, flushing, dizziness, shortness of breath, nausea, vomiting, or mild rash/itching may occur during or after the infusion. These reactions occur more often during the first week of treatment.
2. Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
Alemtuzumab (Campath-1H) is an anti-CD52 T-cell and B-cell–depleting monoclonal antibody that has been used for induction in renal transplantation.
Alemtuzumab-induced lymphocyte depletion is rapid (within 24-48 hours of administration) & long-lasting.
B cells return within 2-12 months, but the number of circulating T lymphocytes (particularly CD4+ T-cells) may remain depressed for many years after treatment.
Randomised trials of alemtuzumab in solid organ transplantation:
1. Margreiter et al(Am J Transplant. 2008;2:1480–1485. doi: 10.1111/j.1600-6143.2008.02273.x.):
A 131 recipients received induction with alemtuzumab (2 × 20 mg) vs no induction.
All patients treated with Tac & those who had not received induction therapy also received MMF.
Results:
– Significant reduction of acute rejection at 6 months (29% vs. 15%, P = 0.05), but not at 12 months (32% vs. 30%).
– No difference in renal function between the 2 groups.
– Apart from an increase in the incidence of CMV infection, there was no other A/E of induction therapy.
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2.Chan et al (Kidney transplantation with minimized maintenance: alemtuzumab induction with tacrolimus monotherapy – an open label, randomized trial. Transplantation. 2011;2:774–780. doi: 10.1097/TP.0b013e31822ca7ca.)
82 alemtuzumab-treated patients (with Tac monotherapy) vs 42 controls (receiving dacluzimab, Tac, MMF), all patients having a rapid steroid taper.
Results:
– Lower incidence of rejection in the alemtuzumab-treated group at 6 months but not 12 months
– No difference in graft survival or function.
– Confirmed that alemtuzumab therapy does enable simple & effective Tac mono-therapy with a very low rate of rejection.
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3.Hanaway MJ et al INTAC Study Group: Alemtuzumab induction in renal transplantation. N Engl J Med 2011, 364:1909-1919.
A randomised trial involving 474 recipients divided into high-risk patients (defined as PRA>20%, black race, re-transplant; n = 139) & low-risk patients (all others).
High-risk group was treated with either ATG (1.5 mg/ kg × 4, n = 70) or alemtuzumab (30 mg × 1, n = 69).
Low-risk group of patients was treated with basiliximab (20 mg × 2, n = 171) or alemtuzumab (30 mg × 1, n = 164).
All patients received Tac8 to 14 ng/ml, MMF 2 g/day, & steroids for 5 days. Followed up for 3 years.
Results
– Patients treated with alemtuzumab had a significantly lower incidence of cellular rejection at 6, 12 & 36 months (3% vs. 15%, 5% vs. 17% & 13% vs. 20% respectively).
– The incidence of rejection in the high-risk patients was similar between the alemtuzumab & ATG groups.
– No significant difference in graft or patient survival.
– There was no effect on renal function.
– Alemtuzumab-treated patients are more liable to late rejection episodes (after 12 months).
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4. Calne R et al : Prope tolerance, perioperative Campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet 1998, 351:1701-1702.18. Nankivell BJ, Borrows RJ, Fung CL, O’Connell PJ, Allen RD, Chapman JR: The natural history of chronic allograft nephropathy. N Engl J Med 2003, 349:2326-233
– Tested the use of alemtuzumab induction (2 × 20 mg) followed by low-dose cyclosporin monotherapy (75 to 125 mg/ml).
– This study demonstrated the capability of a low-dose monotherapy IS regimen to achieve low levels of rejection & good levels of graft survival & function.
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5.Michael J. et al(N Engl J Med 2011;364:1909-19.)
– BPAR is significantly lower in the alemtuzumab vs conventional induction (basiliximab or rATG ) at both 6 months (3% vs.15%, P<0.001) & 12 months (5% vs. 17%, P<0.001).
– At 3 years, the rate of BPAR in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P = 0.003), but in high-risk patients, no significant difference was seen between alemtuzumab & rATG (18% vs. 15%, P = 0.63).
– Adverse-event rates were similar among all four treatment groups.
– Minor differences were found between the alemtuzumab & conventional IS groups in the trough levels of tacrolimus, doses of MMF or MPA, & serum creatinine levels over the 3-year study period.
Conclusion
Alemtuzumab induction with early GC withdrawal is superior to conventional IS in preventing BPAR in the 1st year after transplantation.
This benefit was primarily realized in recipients at low immunologic risk.
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6.Martina Guthoff et al (BMC Nephrology volume 21, Article number: 178 (2020))
Between 01/2007 & 04/2017, 48 kidney transplants were treated with low-dose alemtuzumab induction (a single dose of 20 mg intra-op), followed by Tac & corticosteroids for initial IS, with MMF suspended until a TLC >5% or 200/μl was reached. Median PRAmax was 43 %; all patients had -ve CDC-XM.
Results
– Low-dose alemtuzumab was well tolerated.
– Median time to TLC recovery was 77 days.
– Within a median follow-up of 3.3 years, 12 (25%) patients developed BPAR, 10 of which were AMR (3 acute, 7 chronic ABMR).
– Death-censored 5-year allograft survival was 79.2%, with an excellent allograft function at the end of follow-up.
– There was no increased rate of infections, in particular viral infections.
Conclusion:
Low-dose alemtuzumab induction, initial suspension of MMF & triple maintenance IS, provides excellent patient & allograft outcome in sensitized renal allograft recipients.
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Alemtuzumab & mammalian target of rapamycin inhibitors
1. Knechtle SJ et al : Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant 2003, 3:722-730.
29 patients were treated with alemtuzumab (20 mg × 2) followed by low-dose maintenance sirolimus.
Results
8 patients required treatment for rejection
One graft was lost.
Conclusion
Sirolimus monotherapy was inadequate.
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2. Flechner SM et al : Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI
and steroid-free kidney transplant immunosuppression. Am J Transplant 2005, 5:3009-3014.
22 patients were treated with alemtuzumab induction (30 mg × 2) & maintenance therapy sirolimus (8 to 12 mg/ml) & MMF (500 mg/twice daily).
Results
Acute rejection in 36%
Leukopaenia in 27%
ARDS in 2 patients.
Conclusion
Combination of alemtuzumab, sirolimus & MMF, was associated with a high rejection rate & a high incidence of other complications.
Another protocol used alemtuzumab induction plus short course of CNI therapy, before switching to sirolimus maintenance therapy for the longer term:
In 30 patients, alemtuzumab (30 mg × 2) induction was followed by MMF(500 mg BID for 12 months), Tac(5 to 8 ng/ml for 6 months) &, after tacrolimus withdrawal, sirolimus (5 to 8 ng/ml) (data submitted for publication).
Results
– A number of rejections occurred after MMF withdrawal at 12 months (all reversible with steroids)
– The protocol was therefore amended to continue MMF 250 mg BID thereafter;
– This protocol was associated with a low incidence of rejection (6.6% at 12 months).
– Following the change of protocol to maintain low-dose MMF after 12 months, there were no acute rejection episodes after 12 months.
– 2 patients were withdrawn due to respiratory side effects of sirolimus.
– 85 % of patients remained steroid & CNI free 5 years postoperatively.
Conclusion
Use of alemtuzumab enabled CNI-free therapy.
This strategy eliminated the potential CNI nephrotoxicity & consequently improve long-term graft life.
Introduction
Alemtuzumab is human monoclonal antibody against CD52 and is a 12 amino acid GLI linked protein with N linked glycan moiety and is expresses on T cells, B cells, monocytes, macrophages and eosinophils , NK cells ,Dendritic cells. It is expressed more on T cells as compared to B cells. It causes central and peripheral lymphoid depletion by Compliment depletion, antibody dependent cellular toxicity or Compliment dependent cytotoxicity.
Indications.
CLL
Multiple sclerosis
Steroid resistant cellular rejection
As induction agent in high risk in high immunological risk patients and those with steroid withdrawal- Off Label.
Contraindications
Hypersensitivity
Active systemic infections
HIV
Dose used
It is recommended that patients are pre-medicated with glucocorticoids, acetaminophen, and anti-histamines immediately prior to the administration .prophylaxis against herpes and pneumocystis jirovecii should be given.
Single IV dose of 30 mg as induction agent at the time of transplantation and second dose on day 1, followed by the maintenance with TAc, MMF and steroids.
Tacrolimus can be given at 0.1-0.2 mg/kg per day in 2 divided doses. The target trough level of 7-14 ng/ml for first 3 months followed by 4-12 ng/ml. MMF- 2gram per day and steroids for five days. Prednisolone is given as 150 mh day 1 and 2 followed by tapper in first week.
Route of administration
Intravenous or subcutaneous
Side effects
Nausea, Vomiting, urticaria, pruritis, headache, dyspnoea, hypotension, infections, allergic reactions, thrombocytopenia, neutopenia, GB syndrome, Graves disease, ITP, membranus glomerulopathy and anti glomerular basement membrane disease
References
Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207.
Alemtuzumab is monoclonal anti- CD52 Ab,which acts on CD52 receptor present on T-cell,B-cell, NK cell,Dendritic cell and causes central and peripheral lymphoid tissue depletion by-
1.complement dependant cytotoxicity
2.antibody dependant cytotoxicity
3.anergy leading to apoptosis.
Hence its lymphoparalytic activity starts within 5-7days and persists for 6-12mnth,which decides its mammoth potential than ATG as immunosuppression which paves the bright way towards early steroid withdrwal, early cni withdrawl without risk of rejection but with a cost of infection.
Indication-
1.steroid resistant cell mediated rejection(off label)
2.induction agent(off label)
3.CLL
4.Multiple sclerosis.
Contraindication-
1.hypersensitivity reaction to campath.
Dose-it is used as a single dose of 30mg IV/sc.
Side-effects-
1.Infusion reaction-mostly due to release of cytokines,urticaria,fever,rash,hypotension,etc.
2.lymphopenia, some times pancytopenia due to bonemarrow suppression
3.hematological malignancy
4.viral infections like bkv,cmv,pcc
5.autoimmunity-thyroid graves disease
It is category-c in pregnancy.
Alemtuzumab
Introduction
is a humanised monoclonal antibody against CD52
causes T and B lymphocyte, monocytes and NK cell depletion by 3 mechanisms
Indications
Dose used
Route of administration
Side effects
1- infusion related reactions – 70-80% patients such as headache, rash, nausea, hypotension, rigours and pyrexia
a. while given IV, but can be less if given SC
2- Infections – due to depletion of T and B cell but not neutrophilic granulocytes – so reconstitution of the cells of the innate immune system is faster
3- Malignancy -data scarce and poorly defined
4- Autoimmunity -secondary autoimmunity has been reported
5- Fertility and Pregnancy
References
1-Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients by Martina Guthoff2-Alemtuzumab Induction in Renal Transplantation by Michael J. Hanaway, M.D(INTAC study)
3-Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the clinical pharmacokinetics and pharmacodynamics of Alemtuzumab and its use in kidney transplantation. Clin Pharmacokinet. 2018;57:191–207
Monoclonal Lymphocyte Depleting Antibodies
Alemtuzumab [Campath-1 H]
it’s is humanized anti-CD 52 antibody that causes depleting of both T and B cell
• Current practice is to give to give 30mg intra-operatively and a second 30mg dose 24 hours later.
*Can be used in steroid resistant cellular rejection
Administration of alemtuzumab
Infusion reactions and cytopaenias are common
Intravenous infusion is associated with a marked “cytokine-release syndrome”, characterized by fever, rash, hypotension, and bronchoconstriction.
• Do not give alemtuzumab if there is :-
1-untreated infection
2-platelets <100×10 /L or WBC <3×10 /L.
Give pre-medication 30 minutes before each dose:
• IV hydrocortisone 100mg
• IV H antagonist, for example chlorpheniramine 10mg
• PO paracetamol 1000mg
• prophylaxis against PCP, CMV and oral candidiasis.
For IV administration
• Dilute 30mg alemtuzumab in 100ml 0.9% NaCl
• Infuse over 2 hours into a central or peripheral vein
For
SC administration
SC administration is as effective as IV, but eliminates infusion-related reactions.
• Give pre-medication
• Alemtuzumab is supplied as a solution of 30mg in 1ml
• Withdraw 15mg (0.5ml) into 2×1ml syringes
• Administer each 15mg dose as a slow (1 minute) SC injection over the deltoid or anterior chest wall
Used as a single agent, it does not induce tolerance and episodes of acute rejection can occur even in the absence of T cells. Its use may facilitate minimization of maintenance immunosuppressive protocols and steroid sparing with monotherapy using sirolimus or low-dose calcineurin inhibitor.
Alemtuzumab
plus low-dose cyclosporin
low-dose cyclosporin monotherapy with trough levels of 75-125 ng/ml.
gives low rates of acute rejection
Alemtuzumab plus sirolimus
sirolimus monotherpy (target level: 8-12 ng/ml) but rates of early acute rejection were high, particularly humoral rejection.
Alemtuzumab
plus tacrolimus and MMF
low-dose tacrolimus (target trough concentration: 5-7 ng/ml) and MMF (500 mg twice daily
gives low rates of acute rejection
Alemtuzumab allows the use of a steroid-free maintenance regimen
Alemtuzumab induces profound lymphopenia, which may be prolonged requiring reduced doses of other
myelosuppressive agents.
There may be delayed incidence of cell-mediated acute rejection and possibly a higher incidence of antibody-mediated rejection that occurs as lymphocyte counts return to baseline.
The hematologic, infection, and lymphoma risks are similar to those described for other depletional agents, and infection prophylaxis is mandatory.
Reference
1- Menna R. Clatworthy1 and Christopher J.E. Watson2 1Division of Renal Medicine, Department of Medicine and 2Department of Surgery, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK. Alemtuzumab as Induction Therapy in Renal Transplantation.
Trends in transplantation 2008;2:12-23
2- Gabriel M. Danovitch, MD. Handbook of Kidney Transplantation. SIXTH EDITION.
3-up to date
4- Nicholas Torpey, Nadeem E Moghal, Evelyn Watson, and David Talbot. OSH Renal Transplantation. Published online: Oct 2011.
Induction therapy is used to reduce early rejection rates . Induction therapy with alemtuzumab has been propsed mainly to avoid glucocorticoids and to reduce calcineurin inhibitor exposure . Alemtuzumab is a humanized monoclonal anti CD52 antibody which deplete of T and B lymphocytes , monocytes, and NK cells.
Indications:
1- Patients planned for CNI minimization protocols
2- Patients planned for steroid free regimen
3- Patients planned for early steroid withdrawal (day 5)
Doses and route of administration:
1- Patients planned for CNI minimization or steroid free regimen
· alemtuzumab (30 mg on days 0 and 1, subcutaneously or intravenously) + tacrolimus (trough level5–7 ng/mL) + mycophenolate sodium (360 mg twice daily)
· Do protocol biopsy after 6 month
2- Patients planned for early steroid withdrawal (day 5)
a)High risk patients intolerant of ATG (PRA (historical or current) above 20%, repeat transplantation, or black ethnicity)
b) low risk patients intolerant of basiliximab
c) Simultaneous Pancreas-Kidney Transplantation with low immunological risk who are intolerant of ATG or basiliximab
· a single shot of 30 mg, intravenously + tacrolimus (target pre-dose concentration of 7–14 ng/mL in the first 3 months after transplantation, and 4–12 ng/mL after month 3), mycophenolate mofetil (1000 mg twice daily),
Side effects:
· local injection-site reactions.
· Infusion-Associated Reactions : are more if given intravenously than subcutaneously (headache, rash, nausea, hypotension, rigors, and pyrexia. )
· Infection due to prolonged depletion of immune cells( T and B lymphocytes recover usually for over 12 months, monocytes after 3 months and NK cells after 6 months).
· Malignancy : EBV-positive large-cell lymphoma, all virus-related tumors such as non-Hodgkin lymphoma, Hodgkin lymphoma, human papilloma virus-related cancers, Kaposi sarcoma, and liver cancer ,colorectal cancer and thyroid cancer. Alemtuzumab induction was not associated with an increased risk of lung or kidney cancer, or melanoma
· Autoimmunity due to high Interleukin-21 causing
1- autoimmune thyroid disorders, especially Graves’ disease
2- Immune thrombocytopenia (idiopathic thrombocytopenic purpura)
3- Glomerulopathy anti-glomerular basement membrane disease and membranous glomerulopathy. The onset of kidney disease ranged from 4 to 39 months after alemtuzumab administration
4- Guillain–Barre syndrome
Precautions :
· Prophylaxis with an oral anti-herpes agent and prophylaxis against Pneumocystis jirovecii should be started directly after administration of alemtuzumab and be continued for a minimum of 2 months after the last alemtuzumab gift or until the CD4+ T lymphocyte count is C200 cells/lL
· Routinely screen kidney transplant recipients for BK virus.
· It is advised that thyroid function tests should be obtained prior to initiation of treatment and
tested on a regular basis until 48 months after the last
· infusion plasmapheresis : can reduce the plasma concentration of alemtuzumab.
· It is recommended that patients are premedicated with glucocorticoids, acetaminophen, and antihistamines immediately prior to the administration of alemtuzumab to diminish infusion-related reactions.
References
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC5784003.
Introduction: Alemtuzumab- a humanized monoclonal antibody against CD52 on T- and B-cell leading to prolonged lymphocyte depletion for up to 12 months.
Indications: Alemtuzumab is used mainly in highly sensitized patients and also as an induction therapy.
Dose used : Low-dose alemtuzumab for induction 20 mg intravenously followed by tacrolimus (aiming at trough levels of 10 ng/ml initially and 7 ng/ml from month three on) and corticosteroids (steroid pulse starting with 500 mg and 250 mg prednisolone intravenously at time-point of transplantation and 12 h later, followed by 100 mg given orally with taper to 5 mg within 1 month). Mycophenolate mofetil (MMF) can be suspended till lymphocyte count reaches > 5% of leukocytes or > 200/μl absolute count. Premedication with diphenhydramine 50 mg and acetaminophen 0.5-1gm 30 minutes before dose is usually sufficient
Prophylaxis:Pneumocystis jirovecii prophylaxis administered for 6 months,
Cytomegalovirus infection prophylaxis for 3–6 months (after transplantation.)
Standard dose: Alemtuzumab given as induction as a single intravenous dose of 30 mg at the time of transplantation for high and low risk rejection groups followed by maintenance with Tacrolimus at dose of 0.10 to 0.20 mg per kilogram per day in two divided doses, with a target whole-blood trough level of 7 to 14 ng /ml for the first 90 days after transplantation and 4 to 12 ng /ml after 90 days. MMF orally or intravenously daily at a dose of 2 g per day. and steroids which can be discontinued by day 5 after transplantation, with prophylaxis against infection with cytomegalovirus, Pneumocystis carinii, fungi, or bacteria
Route of administration: Intravenous.Subcutaneous
Side effects :Increased risk of infection, Infusion reactions including fever, rigors, headache, nausea, vomiting, urticaria, pruritus, dyspnoea, hypotension and diarrhea .Anti GBM disease and crevice cephalic arterial dissection Thrombocytopenia most commonly occur during 2 – 4 weeks and Neutropenia common between 4 – 8 weeks.
Efficacy: Efficacy of Alemtuzumab is comparable to ATG in term of incidence of acute rejection , graft survival and incidence of malignancy and infection in high risk groups. One study addresses the safety and efficacy of the use of Alemtuzumab for induction in combination with reduced dose of CNI and MMF and steroid avoidance and compare this to basiliximab induction with conventional dose of triple therapy, and found that Alemtuzumab based induction reduced the incidence of acute rejection in the first 6 months by 50 % with no significant increase in serious and opportunistic infections, CMV infection or malignancy but may be an increase in BK viremia and BK nephritis
Alemtuzumab induction is associated with lower incidence of acute rejection when compared to basiliximab in low risk group
References:
1-Michael J. Hanaway, M.D., E. Steve Woodle,et al. Alemtuzumab Induction in Renal Transplantation.N Engl J Med 2011; 364:1909-1919
2-Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the clinical pharmacokinetics and pharmacodynamics of Alemtuzumab and its use in kidney transplantation. Clin Pharmacokinet. 2018;57:191–207
☆Alemtuzumab (Campath1H)
___________________________
▪︎Is a huminized monoclonal antibody that has a profound lymphocyte-depleting effect, targeting the CD52 antigen that is present on all lymphocytes.
☆Mechanism of action:
_________________________
▪︎It bind to CD52 cells which are rapidly cleared from the circulation by complement mediated lysis or removed of opsonized cells in lymphoid organs.
☆Role Induction therapy:
_________________________
▪︎It has shown potential as an induction agent in the prevention of rejection following solid organ transplantation.[1]
▪︎It has not been compared to other induction agents in any large, randomised controlled trial [2].
▪︎ Experience is limited to case series, often exploiting the profound T cell depletion induced by alemtuzumab to minimize other IS agents [2].
▪︎Studies have shown that alemtuzumab enables the use of lower calcineurin inhibitor (CNI) maintenance drugs; however, this reduction in nephrotoxic immunosuppression has not consistently been matched by an improvement in renal function.
▪︎The hypothesis has been suggested that alemtuzumab might allow the development of immunosuppressive regimens that avoid CNIs completely
▪︎Studies have investigated the combination of alemtuzumab with mammalian target of rapamycin-inhibitor maintenance therapy, and, in particular, sirolimus. Initial studies with this combination showed that regimens of sirolimus alone and of sirolimus with mycophenolate mofetil were unsuccessful, with a high rate of rejection and complications.
▪︎Subsequent studies have targeted the combination of alemtuzumab induction with a short course of a CNI, before switching to maintenance therapy with sirolimus. This regimen might combine good protection from acute cellular rejection and chronic nephrotoxicity.
☆Dose of alemtuzumab in induction:
______________________________________
▪︎Current practice is to give either a single 30mg intraoperative/ post operative dose, or to give 30 mg intraoperatively and a second 30mg dose 24hrs later [2].
☆Side effects:
________________
1. Infusion reaction from cytokine release
2. Increase autoimmune disease( haeolytic anemia, ITP, etc)
But, both CMV infection and PTLD is less significant with alemtuzumab.
__________________
Ref:
[1] Peter J Friend “Alemtuzumab induction therapy in solid organ transplantation”
[2] Oxford- renal transplantation.
This is not a protocol Tahani
Ok I will revise it. Thanks
Please review the literatures and design protocols for alemtuzumab induction.
In immunosuppressive regimen, balancing the need for immunosuppression and the risk of associated infections is challenging.The dosage of alemtuzumab given for induction in kidney transplantation varies between 30 and 60 mg . With doses of 30–60 mg of alemtuzumab, prolonged leukocytopenia and lymphopenia have been reported .
The success of protocol is based on three factors:
1-A reduced dose of alemtuzumab .
2-Suspension of MMF until lymphocyte recovery .
3- Triple maintenance immunosuppression.
The following studies addressed the outcome of a different regimen and doses of Alemtuzumab in the induction therapy .
1-Two doses of alemtuzumab 20 mg intravenously on day 0 and 1;
This dose was used in induction therapy in a case series of 13 kidney transplant recipient . The patients received induction therapy with alemtuzumab two doses of alemtuzumab 20 mg intravenously on day 0 and 1followed by low-dose ciclosporin as maintenance therapy. In the 6- to 11-month follow-up, only one patient experienced acute rejection .
2- Alemtuzumab 30 mg on days 0 and 1, subcutaneously or intravenously;
In the 3C study, induction therapy with alemtuzumab (30 mg on days 0 and 1, subcutaneously or intravenously) was compared with basiliximab (20 mg intravenously on days 0 and 4). Induction therapy with alemtuzumab in combination with low-dose tacrolimus and mycophenolate sodium without glucocorticoids significantly reduced the incidence of BPAR at 6 months follow up .
3- alemtuzumab as a single shot of 30 mg, intravenously ;
Hanaway et al. compared alemtuzumab induction therapy (a single shot of 30 mg, intravenously) with basiliximab induction therapy (in patients with low risk of acute rejection) or with rabbit ATG (rATG) induction therapy in high-risk patients. No significant difference in BPAR after month 12 was observed between alemtuzumab and rATG in the high-risk group .
4- comparison of one to two doses 30 mg of alemtuzumab ;
LaMattina et al. compared in a retrospective study induction therapy with alemtuzumab (n = 632), basiliximab (n = 690), or rATG (n = 125). Alemtuzumab was given one or two times (30 mg), basiliximab was administered on postoperative day 0 and 4 (20 mg), and the total dose of rATG was 6–8 mg/kg. Maintenance immunosuppression consisted of tacrolimus or ciclosporin in combination with mycophenolate mofetil and glucocorticoids (tapered to 5–10 mg/day after the first post-operative month). No significant difference was seen in overall frequency of BPAR.
How it influences the maintenance immunosuppression?
Alemtuzumab (Campath-1H) is a humanized monoclonal antibody directed against the cell surface antigen CD52, which is expressed not only by T cells but also by B cells, NK cells, monocytes, macrophages, and dendritic cells. Leukocyte depletion at the time of transplantation with alemtuzumab (Campath-1H) has been demonstrated to be one of the ways of reducing immunosuppressive drug load without increasing the rate of acute rejection . The following immunological effects had been demonstrated in patient received alemtuzumab as induction therapy ;
1- The CD8+ T cell compartment was repopulated predominantly by immunosenescent CD28−CD8+ cells with suppressive capacity, while classical Treg cells (CD25hiCD4+) remained low .
2-An increase in Treg cells after alemtuzumab induction has been demonstrated ..
3- An increase in IL-17A producing cells with IL-17A expression compensated for by increase in Treg cell frequency and number. Th17 cells have been demonstrated to be protective against extracellular pathogens but detrimental in autoimmune conditions .
Reference ;
1. Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, et al. Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet. 1998;351(9117):1701–1702. doi: 10.1016/S0140-6736(05)77739-4. [PubMed] [CrossRef] [Google Scholar]
2. Group CSC, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, et al. Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomised trial. Lancet. 2014;384(9955):1684–1690. doi: 10.1016/S0140-6736(14)61095-3. [PubMed] [CrossRef] [Google Scholar]
3. Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364(20):1909–1919. doi: 10.1056/NEJMoa1009546. [PubMed] [CrossRef] [Google Scholar]
4. LaMattina JC, Mezrich JD, Hofmann RM, Foley DP, D’Alessandro AM, Sollinger HW, et al. Alemtuzumab as compared to alternative contemporary induction regimens. Transpl Int. 2012;25(5):518–526. doi: 10.1111/j.1432-2277.2012.01448.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
5. Calne R, Moffatt SD, Friend PJ, et al. Campath IH allows low-dose cyclosporine monotherapy in 31 cadaveric renal allograft recipients. Transplantation. 1999;68(10):1613. [PubMed] [Google Scholar]
6. Watson CJ, Bradley JA, Friend PJ, et al. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation–efficacy and safety at five years. Am J Transplant. 2005;5(6):1347. [PubMed] [Google Scholar]
7. Bloom DD, Chang Z, Fechner JH, et al. CD4+ CD25+ FOXP3+ regulatory T cells increase de novo in kidney transplant patients after immunodepletion with Campath-1H. Am J Transplant. 2008;8(4):793. [PubMed] [Google Scholar]
8. Knechtle SJ, Pascual J, Bloom DD, et al. Early and limited use of tacrolimus to avoid rejection in an alemtuzumab and sirolimus regimen for kidney transplantation: clinical results and immune monitoring. Am J Transplant. 2009;9(5):1087. [PubMed] [Google Scholar]
9. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009 [PubMed] [Google Scholar
Check;
Guthoff, M., Berger, K., Althaus, K. et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrol 21, 178 (2020). https://doi.org/10.1186/s12882-020-01767-z
Comment on the study protocol and how can you implement it?
This protocol designed by local Centre with heterogenous group of sensitized patients even some of them underwent desensitization with no standardization of desensitization protocol, using small dose of alemtuzumab with triple tacrolimus IS and targeting higher level of tacrolimus upon FU ( 7ng ), so the question to be addressed here the finding of less rejection rate compared to other studies ( 25% vs > 36%) is it due to the efficacy of alemtuzumab induction or the effect of potent triple maintenance IS and not the alemtuzumab alone ,i think for better design of such protocol we need to add another group to compare the efficacy and safety like adding group with low dose ATG as induction IS with same homogenous triple IS and get prospective design with more homogenous patients characteristics longer FU to address graft and patient survival outcome
also in this limited study they have higher rate of PTDM which again indicate the CNI effect and steriod in maintenance rather than induction with low dose alemtuzumab alone .
Dear all, please check:
van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the Clinical Pharmacokinetics and Pharmacodynamics of Alemtuzumab and Its Use in Kidney Transplantation. Clin Pharmacokinet. 2018 Feb;57(2):191-207. doi: 10.1007/s40262-017-0573-x. PMID: 28669130; PMCID: PMC5784003.
Thanks
Alemtuzumab is a depleting CD52-specific antibody with T- and B-cell activity, leading to prolonged lymphocyte depletion up to 12 months, with profound immunosuppression and an associated risk of severe infections.
-Alemtuzumab use as an induction for sensitised recipients :
low-dose alemtuzumab for induction 20 mg intravenously and for maintenance , starting by tacrolimus (aiming at trough levels of 10 ng/ml initially and 7 ng/ml from month three on) and corticosteroids (steroid pulse starting with 500 mg and 250 mg prednisolone intravenously at time-point of transplantation and 12 h later, followed by 100 mg u.i.d given orally with taper to 5 mg u.i.d. within 1 month). Mycophenolate mofetil (MMF) can be suspended till lymphocyte count reaches > 5% of leukocytes or > 200/μl absolute count. Pneumocystis jirovecii prophylaxis administered for 6 months, prophylaxis for cytomegalovirus infection for 3–6 months (depending on mismatch constellation) after transplantation.(1)
-Alemtuzumab given as induction as a single intravenous dose of 30 mg at the time of transplantation for high and low risk rejection groups followed by maintenance with
Tacrolimus at dose of 0.10 to 0.20 mg per kilogram per day in two divided doses, with a target whole-blood trough level of 7 to 14 ng /ml for the first 90 days after transplantation and 4 to 12 ng /ml after 90 days ,
MMF orally or intravenously daily at a dose of 2 g per day.
and steroids which can be discontinued by day 5 after transplantation,
with prophylaxis against infection with cytomegalovirus, Pneumocystis carinii, fungi, or bacteria
For high risk group ;the overall outcome , rejection risk and graft survival are similar to conventional induction with r ATG .
For low risk group it had superior outcomes and lower rejection risk when compared with induction with non depleting agent basiliximab .
Alemtuzumab was more effective in preventing biopsy-confirmed acute rejection than conventional induction therapy in low risk transplant recipients and was as effective as rabbit anti thymocyte globulin in high-risk transplant recipients.
Alemtuzumab induction with early glucocorticoid withdrawal is superior to conventional immunosuppression in preventing biopsy-confirmed acute rejection in the first year after transplantation for recipients at low immunologic risk.(2)
Reference:
1-Guthoff, M., Berger, K., Althaus, K. et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrol 21, 178 (2020).
2-Hanaway M. J. etal, Alemtuzumab Induction in Renal Transplantation. N Engl J Med 2011; 364:1909-1919.
Well done, thank you
_ alemtizumab is a monoclonal antibody against CD 52 , present on both B and T cells ..it is depleting antibody which can be used in either:
a- induction protocol for highly sensitized or HLA incompatible transplantation.
b. Treatment of steroid refractory acute rejection.
_ it is alternative to r ATG as induction therapy with comparable efficacy. However, it is more potent than non depleting antibody ( basiliximab).
_ pros:
a. prolonged immense depletion which lasts for 12 months that allow for either CNI minimization protocols ( to limit their nephrotoxicity) or steroid withdrawal or avoidance protocols ( may be beneficial especially in pediatric population. To alleviate the steroid effect on growth and height).
b. Use of CNI monotherapy with steroid avoidance
c. Early steroid withdrawal after 1 st week protocol.
d. Less infusion reaction than with r ATG, but also premedicate with diphenhydramine and solumedrol.
_Cons:
It is expensive drug.
Prolonged immunodifficency which increases risk of infection and malignancy.
_ so, chemoprophylaxis against pneumocystis jiroveci and valcyte against CMV are crucial.
1. Aref A, Bridson M Julie BM, Sharma A, Halawa A. Induction with Thymoglobulin in High-Risk Renal Transplant Patients; Beauty and the Beast. Journal of Nephrology and Urology.2016
2. Haynes R, Harden PN, Judge P, Blackwell L. Alemtuzumab-based induction treatment versus basiliximab- based induction treatment in kidney transplantation (the 3C Study): a randomised trial. The Lancet 2014; 384, 1684-1690
This is a theoretical review, not a protocol
Agree with Dr Ala
Ok dear professor I will revise it
Ok dear professor I will revise that.
Indication:
1-Induction in immunologically high risk or HLA incompatible transplant.
2-Steriod refractory acute TCMR.
3. Induction when we need steroid avoidance or CNI minimization maintenance protocols.
Mainly it is used when r ATG is contraindicated, as it has similar efficacy to it.
Contraindication
previous allergic reaction to the component of alemtuzumab
HIV infection
Route of administration; either slow IV infusion or SC to minimize allergic reaction.
Adverse effects:
1- infusion reaction like rigors, fever, nausea vomiting, hypotension, rash and urticaria, dyspnea preferred to be given SC with premedication with solumedrol and diphenhydramine.
2- lymphopenia, close monitoring differential leucocytic count to guide 2nd dose
3- Increase risk of infections as CMV, BKV, PJP.
4- increase risk of malignancy, Lymphoma, PTLD including aggressive type B cell lymphoma
ü Induction phase therapy:
low dose 20mg or high dose 30 mg D 0, 1.1st dose given intra-operative after reperfusion
2.PMP 500mg interoperative.
3. followed by maintenance therapy:
· Tacrolimus 0.1-0.3 mg/kg/day and guided by trough level ( target is 10 in 1st 3 months then 5-7 therafter.
· Steroids either rapid tapering over 1 week (steroid avoidance protocol) or over 2 months and keep lowest maintenance doe at 5 mg eod.
· MMF
v Steroid avoidance or steroid-free regimens is defined as no i.v. or oral steroids after the first 2 weeks post Tx and steroid withdrawal defined as discontinuation of steroids either early after 3-6 months or late more than 6 months after Tx Steroid withdrawal at 6 months post Tx was associated with improved height velocity without increased AR risk compared to those who continued on low-dose steroids. Also, late steroids discontinuation after (12–24 months after KT) in those with stable graft function seems to be safe and improve growth and decrease the cardiovascular risk
· References:
Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Lancet. 2014;384(9955):1684. Epub 2014 Jul 28. Induction Therapy for Kidney Transplant Recipients.
· Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004759.
· PAPE, L. J. P. N. 2019. State-of-the-art immunosuppression protocols for pediatric renal transplant recipients. 34, 187-194.
· HALLER, M. C., KAMMER, M., KAINZ, A., BAER, H. J., HEINZE, G. & OBERBAUER, R. J. B. M. 2017. Steroid withdrawal after renal transplantation: a retrospective cohort study. 15, 1-9.
Previously 78% renal transplant recipients receive induction either by T cell depleted agent( ATG), or non depleted agent ( basiliximb). But recently new depleted agent used for induction( alemtuzumab).
Alemtuzumab is a humanized monoclonal antibodies directed against CD52 that present on B cells, T cells, monocytes & NK cells. It used as induction agent at 1998. There are 2 regime of alemtuzumab:
It was noted that the risk of malignancy not increased with using of alemtuzumab but there was an increased in risk of autoimmune diseases(e.g. Graves, hypothyroidism & hemolytic anemia). Also it was noted that rejection episodes occur late (>6months post transplantation) among patients receive induction with alemtuzumab.
References:
New depleting agents.
Alemtuzumab is a humanized depleting monoclonal antibody against CD52 on B- and T-lymphocytes, monocytes and NK cells, that produces prolonged depletion of both B and T lymphocytes up to 12 months
Standard dose : 20 -30 mg infusion over 4 h on day 0 and 1 of the operation
Efficaacy:
1- More effective than conventional therapy in reducing rejection episodes but only in low risk patients
2- More prolonged immunesuppressive effect than ATG
SE:
1- Complete and prolonged B- and T-lymphocyte depletion is accompanied by an increased risk of infection
Maintenance IS : several maintenance regimens were investigated with alemtizumab
1- Standard dose of alemtizumab induction followed by early steroid withdrawal regimen : Tac , MMF and a 5-day glucocorticoid taper
2- Low-dose alemtizumab : 20 mg followed by triple IS ( TAC , MMF and steroid)
1- Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation. 2012;93(12):1179-1188. doi:10.1097/TP.0b013e318257ad41
2- Guthoff M, Berger K, Althaus K, et al. Low-dose alemtuzumab induction in a tailored immunosuppression protocol for sensitized kidney transplant recipients. BMC Nephrol. 2020;21(1):178. Published 2020 May 13. doi:10.1186/s12882-020-01767-z
This is much better Fatima
See my question above
Alemtuzumab is a humanized anti-CD52 pan-lymphocytic (both B and T cells) monoclonal antibody that is approved for the treatment of chronic lymphocytic leukaemia. Alemtuzumab induction therapy is used in approximately 10 per cent of kidney transplant recipients in the United States.
We do not routinely use alemtuzumab as induction therapy in most patients undergoing kidney transplantation. Although randomized trials comparing alemtuzumab with either rATG-Thymoglobulin or basiliximab have shown similar or lower rates of acute rejection [ there are concerns that its benefits in reducing acute rejection may decrease over time. Other long-term outcomes, including graft and patient survival and development of chronic allograft nephropathy, may also be worse in patients receiving alemtuzumab compared with rATG-Thymoglobulin and interleukin (IL) 2 receptor antagonists. In addition, alemtuzumab is not readily available to all medical centres that perform kidney transplantation.
Some centres use alemtuzumab as induction therapy for recipients of a human leukocyte antigen (HLA)-incompatible kidney transplant following HLA desensitization, as discussed separately.
Alemtuzumab is administered as a single intravenous (IV) dose of 30 mg at the time of transplantation.
Preferably before administration, the patient should be immunized against encapsulated organisms and counselled about the risk of exposure to opportunistic organisms such as PCP, or the risk of developing viral infections such as varicella-zoster (which requires the use of sulfamethoxazole and trimethoprim as well as antiviral medications), as well as the importance of frequent monitoring for CMV.
There are a variety of procedures that may be utilized for alemtuzumab induction, including:
-in low-risk patients treated with tacrolimus as monotherapy following induction treatment, it was discovered that graft survival was much greater with alemtuzumab.
-patients were treated with low-dose cyclosporine alone as maintenance therapy, which resulted in excellent patient and graft survival; however, some patients developed AR.
-The use of a steroid-free approach combined with CNI and MMF as maintenance treatment resulted in higher graft and patient survival than alternative induction methods
-Up-to-date.
This is a summary rather than a protocol
Week V
Assignment II
Please review the literatures and design protocols for alemtuzumab induction. How it influences the maintenance immunosuppression?
Alemtuzumab (Campath 1H) is a recombinant DNA-derived humanized monoclonal antibody directed against the cell surface glycoprotein CD52 initially approved for use in chronic lymphocytic leukemia, it is a depletional agent sometimes used in clinical transplantation, although it has not been formally approved for such use
When used at the time of transplantation as induction therapy, alemtuzumab induces a profound, rapid, and effective depletion of peripheral and central lymphoid cells that may take months to return to pretransplantation levels.
Alemtuzumab use in kidney transplantation is “off-label.” Its ease of administration has made it an attractive alternative to Thymoglobulin. It is usually given as a single dose of 30 mg intraoperatively; a second dose is sometimes given. Because the drug is administered under general anesthesia, infusion-related events typically associated with the infusion of biologic agents are masked.
When used as an induction agent, alemtuzumab reduces the risk of rejection compared to basiliximab in unsensitized patients. However, when compared to rATG in randomized clinical trials, alemtuzumab has not been shown to be superior. In trials of patients undergoing steroid withdrawal, those receiving alemtuzumab have a greater risk of rejection.
Clinical studies evaluating the safety and efficacy of antibody pre-conditioning with alemtuzumab in conjunction with reduction in maintenance immunosuppression have yielded variable and conflicting results.
Maintenance Immunosuppressant: After the usage of Alemtuzumab for induction a triple immunosuppressant should be used which includes: Tacrolimus 0.1mg/kg in two divided doses keeping serum trough level 5 – 10 ng/ml for the next six months. Mycophenolate Mofetil (MMF) might be used in high immunological risk patients but is not mandatory, if used a dose of 500mg twice daily and can be delayed for three months. In case of Basiliximab then MMF dose of 750mg BD should be used. Finally, Prednisolone 20mg once daily with tapering of 5mg evert week until dose of 5mg once daily.
Its use may facilitate minimization of maintenance immunosuppressive protocols and steroid sparing with monotherapy using sirolimus or low-dose calcineurin inhibitor.
References
Pham, P. T., Lipshutz, G. S., Pham, P. T., Kawahji, J., Singer, J. S., & Pham, P. C. (2009). The evolving role of alemtuzumab (Campath-1H) in renal transplantation. Drug design, development and therapy, 3, 41–49.
Handbook of Kidney Transplantation, 6th Ed,Lippincott Williams & Wilkins (LWW) 2017
This is a scenario, Not an assignment.
If it is not superior to ATG, why do some centers prefer to use it? What are the justifications?
Yes, it is “off-label.”
One of the main challenges that associated with the use of induction therapy , including standardized protocols not yet available , cost and availability of drugs ,immediate and long term side effects like infection and cancer risk , also long term efficacy of certain agents reduced overtime with increasing shift to higher rate of subclinical rejection and subsequent chronic graft dysfunction however the use of induction therapy is widely increased and effective in reduction of early graft rejection and they are very effective with over all favorable kidney transplant outcome especially in high immunological risk like pre-sensitized patients and ABOi transplantation.
Anti-thymocyte-globulin polyclonal antibody act as T cell depleting agent and alemtuzumab monoclonal antibody anti CD52 which is more potent depleting agent for both T and B cells.Both are used as induction IS in high immunological risk kidney transplant and associated with lower risk of acute rejection at 6 months and 12 months based on good evidence from RCT and meta-analysis. Also, systematic review of RCT comparing low dose ATG vs alemtuzumab as induction antibodies in high immunological risk which again confirmed that there is no difference between the two agents on the rate of BPAR and also have similar graft and patient survival upon long term follow up both agents associated with increased rate of infection and PTLD.
also both can be used for treatment of steriod resistant acute rejection .
Alemtuzumab use is limited to less than 10% in USA as off-labile monoclonal induction agent with early steroid withdraw and CNI minimization protocol of 1 or two doses of 30mg and its use associated with lower rate of early acute rejection this report from 3c RCT comparing alemtuzumab vs basiliximab induction therapy in high immunological risk and showed that alemtuzumab group have lower rate biopsy proven acute rejection (BPAR) compared to basiliximab group in the first 6 months as primary outcome as well as by number of event still in favor alemtuzumab arm but its effect on long-term still questionable and need more research.
There is some RCT and observational studies address the efficacy of alemtuzumab as induction immunotherapy compared to low dose rATG , the intact study a randomized trail included 139 high risk recipients received 30mg alemtuzumab or rATG 6mg /kg in 4 doses , in high risk group including black race with PRA > 20%, the result of this study confirm no difference in AR rate between the two groups at 6 , 12 , 36 months but late AR at 12 months was more in alemtuzumab group and this again confirm the decrease efficacy of alemtuzumab overtime. over all graft and patient survival were similar among both arms in both low and high-risk groups, the same applied for the mean lymphocytes count reduction which was comparable in both groups with no difference in the adverse side effects like infection rate and malignancy.
One important observation is the shift of maintenance IS from cyclosporine based to tacrolimus and MMF may explain in part the marked reduction in 1-year acute rejection rates from 50% in the early 1990s to 10–15% nowadays regardless to the type of induction therapy so still we need in the future more studies to identify the effect of the current inductions antibodies with tacrolimus and MMF based conventional therapy especially with growing evidence of increasing rate of subclinical rejections up to 25% as per studies.
To design protocol using alemtuzumab as induction IS should be individualized and tailored to type of immunological risk and other medical factors like the primary disease, associated comorbid like DM and underlying bone disease osteoporosis will be preferred induction agent and choice tacrolimus-based maintenance IS. I don’t have experience with the use alemtuzumab as its not available in our center
References:
1–Alemtuzumab induction in renal transplantation. AU Hanaway MJ, Woodle ES, Mulgaonkar S, Peddi VR, Kaufman DB, First MR, Croy R, Holman J, INTAC Study Group SO N Engl J Med. 2011;364(20):1909.
2– A randomized trial of thymoglobulin vs. alemtuzumab (with lower dose maintenance immunosuppression) vs. daclizumab in renal transplantation at 24 months of follow-up. AU Ciancio G, Burke GW, Gaynor JJ, Roth D, Kupin W, Rosen A, Cordovilla T, Tueros L, Herrada E, Miller J SO Clin Transplant. 2008;22(2):200.
3-Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation (the 3C Study): a randomized trial. AU 3C Study Collaborative Group, Haynes R, Harden P, Judge P, Blackwell L, Emberson J, Landray MJ, Baigent C, Friend PJ SO Lancet. 2014;384(9955):1684. Epub 2014 Jul 28. Induction Therapy for Kidney Transplant Recipients:
4- 4-Polyclonal and monoclonal antibodies for induction therapy in kidney transplant recipients. Cochrane Database of Systematic Reviews 2017, Issue 1. Art. No.: CD004759.
Thank you, Dr. Saja; this is an excellent review.
Could you design a possible IS a protocol using Alemtuzumab?
-High –risk recipients need more intense immunosuppression.
-Induction therapies should be used in addition to maintenance triple therapy consisting of a CNI combined with an anti proliferative drug and steroids .
– Lymphocyte-depleting induction therapy was recommended in high-risk patients. -Induction protocol using biological antibodies proved to be effective and safe and allow better graft and the patient survival .
Biological antibodies divided into:
1.Depletive antibodies : e.g. alemtuzumab and anti-thymocyte globulin.
2.No depletive antibodies : e.g. basiliximab.
Alemtuzumab (Campath )
-It is humanized anti-CD52 antibody.
-It is the recombinant DNA-derived drug.
-CD52 is a glycoprotein antigen found on the surface of B and T cells , thymocyte, monocyte, macrophage and NK cells .
– It used for both transplantation and B- CLL .
-When used as induction therapy in the kidney transplantation leads to severe, rapid, and effective depletion of peripheral and central lymphoid cells .
-When used as induction, alemtuzumab reduces the risk of rejection compared to basiliximab in unsensitized patients and when compared to rATG, alemtuzumab isn’t superior (7).
Dose :
-30mg,a single dose intra-operative ,a second dose sometime is given(day 0 and day 1 post-transplant).
Pre-medications :
–Methylprednisolone 30 mg and diphenhydramine hydrochloride 50mg given 30 min before injection. Acetaminophen should be given before and 4 hours after commencement of the infusion for fever control.
Side effects :
-Anaemia ,leucopenia ,and thrombocytopenia
-Nausea ,vomiting , and diarrhea.
-It increases the risk of infection .
-Autoimmune phenomena .
-Alemtuzumab induction therapy followed by reduced maintenance immunosuppression is associated with a better kidney function compared to no induction and ATG. Survival rate as well as freedom from ACR were comparable between alemtuzumab and ATG.
References
1. Van der Zwan M, Baan CC, van Gelder T, Hesselink DA. Review of the clinical pharmacokinetics and pharmacodynamics of Alemtuzumab and its use in kidney transplantation. Clin Pharmacokinet. 2018;57:191–207.
2.Sageshima J, Ciancio G, Guerra G, Gaynor JJ, Cova D, Zarak A, et al. Prolonged lymphocyte depletion by single-dose rabbit anti-thymocyte globulin and alemtuzumab in kidney transplantation. Transpl Immunol. 2011;25:104–11 3.Steddon S,Ashman N .Oxford handbook of nephrology and hypertension . 2ed edition. Oxford :University Press:2017
4.Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. Am J Transplant. 2009; 9 Suppl 3: S1.
Depleting agents, NOT Depletive!!??