III. Alemtuzumab-based induction treatment versus basiliximab- based induction treatment in kidney transplantation (the 3C Study): a randomised trial
- In your own words, summarise this article.
- What are the weakness and strength of this study?
- Please reflect your practice if possible.
This study designed to assess the efficacy and safety of a lemtuzmab induction compared to basiliximab induction in renal transplanted patient s.
CNI can reduce attacks of acute rejection. But may also contribute to long term renal failure .The long term renal failure result from the drug innate side effect ,due to prolong CNI exposure .the interest to decrease the long term CNI dose is delivered . on e strategy is to use a potent induction therapy to help to reduce the subsequent doses of CNI . Alemtuzmab is one of the suggested induction therapy to achieve this target .
This study suggest that alemtuzmab induction therapy +low dose of CNI +low dose mmf + steroid avoidance is safe and effective in reducing acute rejection by 50% when compared to basiliximab .
This study show no overall excess of opportunistic or other serious infections with Alemtuzumab treatment versus basiliximab treatment.
There were non-significantly more deaths in those allocated to alemtuzumab-based treatment .
This study suggest that alemtuzumab-based induction treatment followed by CNI reduction and low-dose mycophenolate and steroid avoidance can substantially reduce the risk of acute rejection in the first 6 months after transplantation, without causing an excess of serious or opportunistic infections or other known complications of immunosuppression.
the important weakness of the 3C Study was its being an open-label trial .
To minimize any possible bias, however, all reports of transplant biopsies were reviewed by clinicians masked to treatment allocation to ensure episodes of rejection were not missed.
Alemtuzumab
•A recombinant , humanized ,monoclonal antibody , which target CD52 cell surface antigen present on T and B lymphocytes, natural killer cells, some monocytes and granulocytes .
•These cells will subsequently undergo a sustained complement-mediated lysis.
•Lymphocytes depletion is so marked from months to a year to make patient fully reconstituted (10).
Adverse reaction of alemtuzumab
•The depleting efficiency of alemtuzumab is so profound that it is invariably associated with side effects .
•Neutropenia ( 70%).
•Thrombocytopenia (52%).
•Anemia (47%).
Retrospective studies investigating the use of alemtuzumab versus antithymocyte globulin
•Induction with alemtuzumab versus ILr2a in low risk recipients and alemtuzumab versus ATG in high risk recipients of kidneys from donors after cardiac death. High risk was defined as PRA more or equal to 20 % ,retransplant and African American background. All patients received triple maintenance therapy with calcineurin inhibitors ,MMF and steroids (11).
Calcineurin inhibitors (CNI) are associated with better short-term graft results, but with long term nephrotoxicity being reported later in the years to come.
It was assumed that Alemtuzumab (antiCD52 monoclonal antibody) when used as an induction agent might help in reducing CNI exposure and hence improving graft outcomes, this study was conducted in the UK. It was a multi-center, open label, prospective randomized clinical trail.
This study was done at 18 transplant centers in UK from 2010 to 2013, with total 852 participants, who were randomized to either receive Alemtuzumab induction followed by low dose tacrolimus, MMF and steroid avoidance or Basiliximab induction with standard dose tacrolimus, MMF and steroids.
the results showed that there was a 58% reduction in biopsy proven acute rejection episodes in the alemtuzumab group. This benefit was seen in first few weeks post-transplant. The number of acute cellular rejection events were lower in the alemtuzumab group, but episodes of antibody mediated rejection were similar in both groups.
Alemtuzumab group had increased BK virus infections, although there was no difference from basiliximab group with respect to overall infection (opportunistic or serious) episodes, steroid resistant acute rejection, delayed graft function function at 6 months. Highly sensitized patients did not benefit from alemtuzumab therapy.
So the short term outcome of this 3 C study proved that alemtuzumab therapy as compared to basiliximab therapy proved to reduced the rate of biopsy proven acute rejection without increase in major opportunistic infections.
The Weakness of the study are
1) Open-label trial
2) Short follow-up: The data evaluated is regarding acute rejection in first 6 months post-transplant.
Strength:
1) Prospective, randomized trial
2) Multi-center trial
3) Although open-label, all reports of incidents like serious infections, cancers , rejection and death were reviewed by someone not knowing the treatment details of the patient
in our center we have not used alemtuzumab for induction agent in renal transplant
1- In your own words, summarise this article.
1- the incidence of acute rejection was 7% with Almetuzumab induction versus 16% with Basiliximab induction.
2- the incidence of graft failure was almost similar, 4% with Almentuzumab versus 3% with Basiliximab induction.
3- patient survival was almost similar, 3 % with Almetuzumab versus 1% with Basiliximab induction.
2- What are the weakness and strength of this study?
3- Please reflect your practice if possible
1-This a multicenter open label prospective study exploring if use of alemtuzumab could decrease CNI exposure to avoid hazardous effects and improve graft outcome.
At 18 centers in UK ,the study included 852 patients from 2010 to2013 .There was comparison of use of alemtuzumab as induction therapy with reduced Tac dose with MMF, to use of basiliximab and standard dose Tac and MMF with steroid.58 percent reduction in AR with alemtuzumab in first few weeks after transplantation .Incidence of ACR was also lower with alemtuzumab but AMR incidence was comparable in both groups.
Increased BK viral infection was higher with alemtuzumab. There was evidence that alemtuzumab induction could decrease CNI exposure with its adverse effects.
2-Being open-label trial and with short duration follow up are weak points .On the other hand ,randomization with multicenter exploring are strength points.
This study is an RCT that compares an alemtuzumab induction therapy followed by a steroid avoidance protocol based on low-dose tacrolimus and mycophenolic acid with induction therapy with basiliximab followed by triple therapy (tacrolimus, mycophenolic acid and prednisolone). Eight hundred and fifty two patients were included (426 in each treatment group). BPAR was significantly lower in alemtuzumab group compared to basiliximab group. There was no significant difference between the two groups. In terms of transplant failure, serious infection or mortality but BK compared to infection were common in alemtuzumab.
Weakness:
These results were obtained after six months of follow-up. It is a short duration to reach the aim of study which was using alemtuzumab to improve long-term outcome of TXs. The other weakness is that only primary short-term outcomes are evaluated in this study not secondary outcomes.
Strength of this study: high number of participants which increases power of study and perceptive RTC.
We didn’t use induction with alemtuzumab in our center.
Alemtuzumab-based induction treatment versus basiliximab based induction treatment in kidney transplantation (the 3C Study): a randomised trial
This is multicentred open label RCT which designed to assess the efficacy and safety in short term of an induction treatment strategy of alemtuzumab with reduced CNI compared with standard CNI with basiliximab induction.
The mean age was 52 and and were men and most patients were whites. Average trough tacrolimus concentration in alemtuzumab-based treatment was 6·9 ng/mL and in basiliximab-based treatment was 8·3 ng/mL.
7% alemtuzumab-based treatment had an episode of BPAR whereas 16%of patients allocated to basiliximab-based treatment.
Alemtuzumab-based treatment was associated with fewer cellular BPAR episodes and no difference in antibody-mediated BPAR.Alemtuzumab- based treatment showed no added benefit in higher-risk immunology group.
No statistically significant difference in the occurrence of steroid-resistant rejection (patients in the alemtuzumab group and in the basiliximab group.
No differences in delayed graft function after transplant.
No difference in the occurrence of transplant failure
No significant difference in graft function at 6 months
post-hoc analysis – BPAR during the first year after transplantation showed that the benefit of alemtuzumab-based treatment after
the first few weeks and was maintained at 1 year
No difference in the occurrence of any serious infection
Occurrence of any cytomegalovirus infections did not differ between groups
CMV infections, BK virus infections were more common in the alemtuzumab-based treatment
PTLD occurred in (<0·5% patient assigned alemtuzumab and 1% in basiliximab group
3% participants assigned to alemtuzumab group died during the first 6 months post-transplant vs 1% in basiliximab group
Alemtuzumab-based induction treatment followed by CNI reduction and low-dose mycophenolate and steroid avoidance can reduce the risk of acute rejection in the first 6 months after transplantation, without risk of serious or opportunistic infections or other known complications of IS
What are the weakness and strength of this study?
Weakness
This study is open label RCT, double blind RCT carries less risk of bias
The maintenance therapy is not standardised to evaluate the efficacy of alemtuzumab vs basiliximab induction alone
Short term outcome
CMV prophylaxis
Funding sources participated in discussions about the trial design, and had a right to comment on study reports- ? bias in developing trials
Concentrated on whites but not other ethnicity
Mostly not highly sensitised patients- why need alemtuzumab as induction therapy? Does alemtuzumab does better than placebo in low risk patients?
Strength
Evaluate minimisation of CNI vs standard dose CNI
Asses the efficacy of alemtuzumab at different mismatches
RCT, multicentred
Large number of patients
Please reflect your practice if possible
Our centre uses Basiliximab mostly as induction agent to avoid risk of infections. We do not have alemtuzumab but only rATG for high immunological risk patients.
Alemtuzumab-based induction treatment versus basiliximab- based induction treatment in kidney transplantation (the 3C Study): a randomised trial
1. In your own words, summarise this article.
This randomized controlled trial was conducted to evaluate induction therapy using Alemtuzimab (anti CD52 potent lymphocyte-depleting antibody ) (1) outcome on graft rejection and survival , and to assess the safety of its use in the view of associated infection and side effects. Lastly to determine if its possible to reduce mentainence immunesuppression protocols (specially CNIs, and steroids) in patients underwent induction therapy using Alemtuzumab without affecting graft outcome .
852 KTx participants were assigned : 426 underwent alemtuzum induction followed by reduced CNI and mycophenolate exposure and steroid avoidance , and 426 underwent basiliximab(non-depleting antibody )induction with standard CNI and steroids.
Patients follow up done thorough out one year duration at time of discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation.
As regard Bl pressure changes, lab kidney function, tacrolimus levels, evnts of Acute rejection episodes, possible infections, associated side effects, and cause specific mortality.
Results interpretation of this study suggested that Alemtuzimab arm showed roughly 50% reduction level in Acute rejection episodes than the Basiliximab arm though the first 6 months follow up posttransplant period.
Long term survival of the graft coudnt be assessed although we may consider Acute rejection episodes a prognostic factor for predicting poor graft outcome (3)
No significant change in the incidence of serious or oppertunistic infection (defined as an opportunistic infection or one requiring hospital admission) between both groups, except slight increase in CMV and BK viral infection episodes among the Alemtuzimab arm
As for Cancer and PTLDs, it was uncommon to develop within the first 6 months post Tx. And non significant difference of incidence of specific cause mortality
Finally , The study concluded that reduction in CNI exposure can be done without risking rejection after alemtuzumab-based induction. Yet this needs further evaluation over a longer period follow up.
1. What are the weakness and strength of this study?
Weakness:
(1) The study was of short follow up duration post transplantation and hence long-term follow-up will be crucial for assessment of the effi cacy of alemtuzumab-based induction treatment.
(2) most patients received CMV prophylaxis so any effect on CMV risk might not emerge until longer follow-up is available
(3) the necessity for an open-label trial because it was not possible to blind induction treatment strategies
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; 93: 1179–99
(2) Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made signifi cant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004; 4: 1289–95
(3) Opelz G, Döhler B. Infl uence of time of rejection on long-term graft survival in renal transplantation. Transplantation 2008; 85: 661–66
Alemtuzumab-based induction treatment versus basiliximabbased induction treatment in kidney transplantation (the 3C Study): a randomised trial
The aim is to assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants.
Methods
For this randomised trial, we enrolled patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK. Using minimised randomisation, we randomly assigned patients (1:1; minimised for age, sex, and immunological risk) to either alemtuzumab-based induction treatment (ie, alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids) or basiliximab-based induction
treatment (basiliximab followed by standard-dose tacrolimus, mycophenolate, and prednisolone).
Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation. The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat.
Findings
Between Oct 4, 2010, and Jan 21, 2013, we randomly assigned 852 participants to treatment: 426 to alemtuzumabbased treatment and 426 to basiliximab-based treatment. Overall, individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those allocated to basiliximab-based treatment [7%] patients in the alemtuzumab group vs 68 [16%] patients in the basiliximab group; hazard ratio (HR) 0·42,
95% CI 0·28–0·64; log-rank p<0·0001).
We detected no between-group difference in treatment effect on transplant failure during the first 6 months [4%] patients vs 13 [3%] patients; HR 1·23, 0·59–2·55; p=0·58) or serious infection [32%] patients vs 136 [32%] patients; HR 1·02, 0·80–1·29; p=0·88). During the first 6 months after transplantation, (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died (HR 1·79, 95% CI 0·66–4·83; p=0·25)
In your own words, summarise this article.
This a multi-center, open labelled randomized trial conducted in 18 UK transplant centers from 4/10/2010 till 21/1/2013.
Aim: assess the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants.
Alemtuzumab is an anti-CD52 monoclonal antibody, one of the lymphocyte depleting agents that is being used for induction to help lower acute rejection and reduce doses of CNIs.
The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat.
Results:
1- 58% reduction in biopsy proven acute rejection at 6 months in the Alemtuzumab group.
2- Lower incidence of ACR in Alemtuzumab group.
3- Similar incidence of ABMR in both groups.
4- Increased incidence of BK virus infection in Alemtuzumab group.
5- No difference between both groups regarding overall infections.
6- No difference between both groups regarding steroid resistant acute rejection at 6 months.
7- No difference between both groups regarding delayed graft function at 6 months.
8- No benefit of Alemtuzumab in high immunological risk group.
What are the weakness and strength of this study?
Weaknesses:
1- Open-label trial
2- Short follow-up: 6months
3- using different doses and regimen of maintenance IS between the two groups.
Strength:
1- Prospective, randomized trial
2- Multi-center trial
3- all serious infections, cancers, rejection and death were checked by a person who is not aware of the patient treatment.
Please reflect your practice if possible.
I know some patients who had induction with Alemtuzumab, with good outcome till now.
Dr Alaa’s Questions:
Are you aware of other RCTs of Alemtuzumab? Any comparison with rATG? What about use in high-risk patients?
Zheng et al 2017 published a meta-analysis of 6 RCTs of high-risk patients comparing Alemtuzumab vs ATG and concluded that there was no difference between 2 groups regarding acute rejection, delayed graft function, infections and graft/patient survival.
Reference:
Zheng J, Song W. Alemtuzumab versus Thymoglobulin induction therapies in kidney transplantation patients A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2017;96: e7551.
Do you think there is a bias of using different maintenance therapy in the study groups? For example, in Alemtuzumab, it is Low dose TAC, MMF, without steroids, whereas in the basiliximab, it is standard-dose TAC, MMF, and steroids!?
Different maintenance IS protocols will makes a bias.
I think this different dosage between the 2 groups because Alemtuzumab is more effective than Basiliximab as an induction agent.
What was the primary outcome of the study? Is it the rate of BPAR, or Graft function, or the ability to use less CNI dose?
The primary outcome was biopsy-proven acute rejection at 6 months, analysed by intention to treat.
What about the increased mortality in the Alemtuzumab group (3% vs.1%)?
Fatal infections or malignancy were not high in Alemtuzumab group. So mortality might be not related directly to Alemtuzumab.
According to the immunobiology of T-cells, what are the possible risks of Alemtuzumab?
Induces a profound and rapid effective depletion of peripheral and central lymphoid cells that may take months to return to pre-transplant levels. —-> infection, hematologic and lymphoma risks. Reference:Handbook of transplantation, Danovitch, 6thedition, chapter 6, page 102.
The 3C Study is Randomized trial compare efficacy and safety of Alemtuzumab-based
induction treatment compared with basiliximab-based induction treatment in patients
receiving kidney transplants.
Calcineurin inhibitors: As part of immune suppression protocols made a substantial
contribution to the reduction in early transplant failure, but these treatments might also
contribute to the subsequent decrease in transplant function and, ultimately, failure.
Interest in immunosuppression strategies that minimize CNI exposure to reduce the rate
of late transplant failure. One such strategy is to use more potent induction treatment at
the time of transplantation to allow CNI exposure to be minimized from the time of
transplantation without increasing the risk of rejection.
Alemtuzumab is a humanized monoclonal antibody directed against CD52 which is
expressed almost cause profound lymphocyte depletion.
Discussion:
Finding suggest that Alemtuzumab-based induction treatment (i.e., Alemtuzumab
followed by reduced CNI treatment, low dose mycophenolate, and steroid avoidance)
roughly halves the risk of acute rejection in the first 6 months after transplantation
compared with standard basiliximab-based induction treatment.
Detected no between-group difference in the occurrence of any serious infection.
a statistically significant reduction in tacrolimus exposure of 1·4 ng/mL (17%), showing
that CNI exposure can be reduced without risking rejection after Alemtuzumab-based
induction.
Cancer was uncommon in the first 6 months after transplantation.
What are the weakness and strength of this study?
it an open-label trial .
Only one year follow up LAR and CAN not assessed.
Reflect to practice:
We don’t have experience with Alemtuzumab-based induction therapy yet.
Although CNI have dramatically reduced risk of rejections following transplantation, yet their associated side effects still affect long term graft function.
And so came the idea of using an induction agent that allows using lower doses of CNIs and at same time not risking acute rejectio
The 3C study assesed the used of alemtuzumab followed by lower doses of CNIs ,MMF and steroid avoidance , with another group receiving basiliximab and the standard doses of maintenance IS .
The study included 852 patient with equally divided 2 groups , they ve been followed up to 12 month post transplant
They concluded that : alemtuzumab treatment followed by CNI reduction and low-dose MMF and steroid avoidance can
reduce the risk of acute rejection in the fi rst 6 months after
transplantation, without causing an extra risk of serious infections or malignancies.
Weaknesses of the 3C Study was the necessity
of making it an open-label trial .
Strengthes is that its a multicenter study
-Calcineurin inhibitors (CNI) reduce early transplant failure but lead to a subsequent decrease in transplant function and failure.
-Alemtuzumab is a CD52 humanized monoclonal antibody that leads to lymphocyte depletion.
-This study compared induction with alemtuzumab with reduced CNI exposure and induction with basiliximab with standard CNI exposure.
-participants were collected from 18 transplant centers in the UK.
– 852 Patients aged 18 years and older and scheduled to receive kidney transplant in the the next 24 h were included in the study and they were randomized equally.
-Follow-up at 1,3,6,9,12 month after transplant and at time of discharge.
-Leucopenia is more common in alemtuzumab–based treatment group but no difference between –groups in severe neutropenia.
-During the first 6 months basiliximab group have a high rate of biopsy-proven acute rejection(BPAR) than the alemtuzumab group.
-No difference between the 2 groups in the occurrence of either steroid-resistant rejection, transplant failure, serious infection, or delayed graft function.
-CMV and BK infections were more common in alemtuzumab–based treatment groups.
-Strength of this study: randomized .multicenter study.
-Weakness of the study :long –term outcome is pending.
-I have no experience with alemtuzumab.
This study evaluate the effect of short term outcomes of patients receiving alemtuzumab (with low dose CNI and MMF) and comparing it with patients receiving Basiliximab ( with standard dose of CNI and MMF) in the first 6 months after transplantation.
The risk of acute rejection was lower in patients receiving alemtuzumab than patients receiving Basiliximab but 6 months graft function was nearly equal.
The incidence of serious infections was similiar between the two groups but the incidence of BK virus infection was higher with alemtuzumab.
The strength of the study is that it enrolled patients from different centers .
The weakness of the study is that it was open labelled study.
In our center , Alemtuzumab is not available , we use ATG for high risk patients and basiliximab for low risk patients.
Random controlled study which compares Alemtuzumab low dose tacrolimus ,MMF, steroid free versus basiliximab with conventional therapy after standard dose tacrolimus,MMF, steroid, this comparison as regard biopsy proved acute rejection and graft survival.
Alemtuzumab is a Mab directed against CD52 receptor which is present on T and B lymphocytes so it cause marked depletion of lymphocytes.
Basiliximab is a Mab directed against CD25 which is present on T cell surface .
The incidence of BPAR at 6 months post-transplant is decreased by 50% with Alemtuzumab induction in comparison to basiliximab induction therapybut BK disease (nephritis) is increased in alemtuzumab group which may be related to more potent immunosuppression.
There is no significant increase in the incidence of cancer in the group of alemtuzumab, and no increase in mortality in this group as compared to basiliximab (mortality post transplant is due to infections or cancer).
in my practice: we don not use Campath , we only use basiliximab in standard risk patients and ATG in high risk patient .
-Strengths of the study
*randomized….computer based with very balanced distribution
-weakness
*not blinded but justified
*long term outcomes still pending
*conflict of interest
The Summary
The introduction of CNIs made a revolution in transplant field that reduce the rate of early graft rejections and failure. In the other side these treatments might also contribute to the subsequent decrease in transplant function and failure through the effect of CNI toxicity. In view of this fact there have been interest in immunosuppression strategies that minimise CNI exposure to reduce the rate of late transplant failure. One of these strategies to use a potent immunosuppressive agent as induction to allow use of reduced doses of conventional immunosuppression without risk of early graft rejection.
Alemtuzumab is a humanised monoclonal antibody directed against CD52 which is expressed almost exclusively on lymphocytes; monoclonal antibodies to CD52 cause profound and prolonged lymphocyte depletion for months.
The aim of the mentioned RCT to assess the efficacy and safety of an induction treatment strategy of alemtuzumab with reduced CNI exposure compared with non-depleting antibody induction (basiliximab) with standard CNI exposure. The primary outcome was biopsy-proven acute rejection at 6 months.
Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection in a broad range of patients receiving a kidney transplant. Long-term follow-up of this trial will assess whether these effects translate into differences in long-term transplant function and survival.
A potential limitation of the 3C Study it was an open-label trial because it was not possible to blind induction treatment strategies. To minimise any possible bias.
Strength of the study:
-randomized trial with big number of patients.
– These effects were consistent in the different types of participants studied and are applicable to the broad range of patients of receiving kidney transplants.
-Our experience with Alemtuzumab use: We are using Alemtuzumab as induction in situations where we can not use ATG as in cases of allergy or intolerable ATG side effects. We used Alemtuzumab recently in a patient with diagnosis of primary oxalosis underwent liver and renal transplantation and allergic to ATG, it causes prolonged lymphocyte depletion with absolute lymphocytic count of less than 200.
Strength of the study:
This study is a randomized controlled clinical trial with level 1 of evidence.
This study included a Wide range of different types of participants and recruited about a quarter of all kidney transplant recipients that were transplanted in the participating centers during the recruitment period. Therefore, the results may be relevant to most patients receiving a kidney transplant
Weakness of the study:
This study has no sufficient statistical power to allow reliable estimation of effects on acute rejection in different clinical circumstances.
It was the necessity of making this study an open-label trial because it was not possible to blind induction treatment strategies.
The main aim of treatment in kidney transplantation is improvement in long-term survival has not been achieved yet. Although the use of CNIs contributes to a reduction in early transplant failure, it may accompany nephrotoxicity and subsequent decrease in transplant function.
So, using induction therapy at the time of transplantation with the aim of minimization of CNIs exposure has been considered. Alemtuzumab that is a humanized monoclonal antibody directed against CD52, and causes profound lymphocyte depletion. This trial was designed to evaluate the efficacy and safety of an induction treatment strategy of Alemtuzumab with reduced CNI exposure compared with non-depleting antibody induction (Basiliximab) with standard CNI exposure.
Enrolled patients were allocated into two groups (Alemtuzumab-based treatment and Basiliximab-based treatment) by using minimized randomization.
Alemtuzumab-based treatment compared with Basiliximab-based treatment:
· Lower percentage receive prednisolone at discharge (8% vs 82%)
· Lower average trough Tacrolimus concentration (6.9 ng/ml vs 8.3 ng/ml with mean difference of 1.4 ng/ml)
· Leukopenia was more common (36% vs 10%), but not between group difference in neutropenia.
· Lower risk of acute rejection during the first 6 months (7% vs 16%), corresponding to a 58% proportional reduction with Alemtuzumab.
· Fewer acute cellular rejection but not between group difference in antibody mediated rejection. (Alemtuzumab might increase de novo DSA production)
· Proportional effects on acute rejection have no difference based on age, gender, or donor type.
· No increased benefit of alemtuzumab based treatment in immunologically higher-risk transplants
· No statistically significant difference in the occurrence of either steroid-resistant rejection or DGF or transplant failure.
· No between-group difference in the occurrence of any serious infection including CMV infection
· BK virus infections were more common in the alemtuzumab-based treatment group
· No statistically significant difference in the occurrence of PTLD or particular cause of death.
This study suggests that Alemtuzumab induction therapy with following lower doses of CNIs and MMF and steroid avoidance can essentially reduce the risk of acute rejection early post-transplant without an excess of serious infections or other complications.
3 C study assess the short term efficacy and safety of an induction treatment strategy of alemtuzumab with reduced CNIs exposure compared with basiliximab with standard CNI exposure
852 participants
426 to alemtuzumab -based treatment
426 to basiliximab -based treatment
During the first 6months after transplantation 58% reduction in BPAR to alemtuzumab based treatment compared with basiliximab based treatment
Allocation to alemtuzumab-based treatment was associated with fewer cellular BPAR than basiliximab-based treatment
No different in antibody mediated BPAR between the 2 groups
There is no benefit of alemtuzumab in immunologically higher-risk transplant
No between-group difference in occurrence of transplant failure
Increase benefit of alemtuzumab regarding decrease BPAR during the first year post transplant
No between-group difference in the occurrence of any serious infection
Occurrence of CMV infection did not differ between the 2 groups
By contrast, BK virus infections were more common in the alemtuzumab-based group
No between-group difference in the number of non -apportunistic serious infections
PTLD in alemtuzumab group is less than basiliximab group
Rate of death is less in alemtuzumab during the first 6moonths after transplantation
Limitations:
it is an open-label trial
Strength:
it is a randomized multi center study
The sample is big enough
1-In your own words ,summaries this aricle.
Alemtuzumab is a humanized monoclonal antibody directed against CD52 which is expressed almost exclusively on lymphocytes; monoclonal antibodies to CD52 cause profound lymphocyte depletion. The efficacy and safety of an induction treatment strategy of alemtuzumab with reduced CNI exposure compared with non-depleting antibody induction (basiliximab) with standard CNI exposure is therefore uncertain .
This study ( 3C study ) is used to asses efficacy and safety of alemtuzumab –based induction treatment compared with basiliximab –based induction treatment in patients receiving kidney transplants .
This study was conducted in UK and patients from 18 transplant centre with age of 18 years or above who were scheduled to receive a kidney transplant in the next 24 hours were enrolled in the study . Total number of patients was 852 . Patients were randomly assigned to either alemtuzumab-based induction treatment (alemtuzumab followed by low-dose tacrolimus and mycophenolate without steroids ) and they were 426 in number(only 412 received kidney transplant ) or basilixmab-based induction treatment (basiliximab followed by standard –dose tacrolimus , mycophenolate and prednisolone ) and they were 426 in number (only 408 received kidney transplant ) . Participant were reviewed at discharge from hospital and at 1,3,6,9 and 12 months after transplantation . The primary outcome was biopsy-proven acute rejection at 6months , analyzed by intension to treat .
Alemtuzumab –based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance is found to be associated with reduced risk of biopsy –proven acute rejection in comparison with standard basilixmab –based treatment in the first 6 months after transplantation . No overall excess of opportunistic or other serious infections with alemtuzumab-based therapy . longer-term follow up of the 3Cstudy cohort will allow the effect of avoidance of avoidance of acute rejection on graft survival to be assessed reliably .
3-What is weakness of this study ?
It is an open-label trial because it is not possible to blind induction treatment strategies.
2-What is strength of this study ?
1-All reports of transplant biopsies were reviewed by clinicians masked to treatment allocation (and using standardized , pre specified criteria; appendix pp 8–10) to ensure episodes of rejection were not missed.
2-all reports of serious infections, cancers, and deaths were also reviewed .
4- please reflect your practice if possible ?
we have not use alemtuzumab as an induction therapy
Alemtuzumab-based induction treatment versus basiliximab-based induction treatment in kidney transplantation. (the 3C Study): a randomised trial
Alemtuzumab is a humanised monoclonal antibody directed against CD52 on the lymphocytes. It causes profound lymphocyte depletion.
Aim: the 3C study aimed to address a question about the efficacy and safety of induction therapy with alemtuzumab with reduced CNI exposure compared with basiliximab with standard CNI exposure.
· The study reveals that alemtuzumab decreases the risk of acute rejection by about half in the first 6 months after transplantation compared with standard basiliximab-based induction.
· The study concludes that the alemtuzumab-based treatment shows no overall excess of opportunistic or other serious infections compared to basiliximab-based treatment.
· The beneficial effect (in regard to biopsy-proven acute rejection) of alemtuzumab-based treatment is in the first few weeks after transplantation, but then little effect.
· In this study, CNI dose can be reduced without an increase in the risk of rejection after alemtuzumab-based induction over 6 months posttransplantation. The long-term effect of the reduced dose of CNI still waiting for the future result of this study.
· There is no difference in the incidence of opportunistic infection (and CMV, between alemtuzumab and basiliximab, but alemtuzumab has a high incidence of BK infection.
Weakness point:
· Short period of follow up 6 months
Strength point:
Multicenter, includes different patients, so its result can be applied to many different patients.
Transplantation is improved in last year duto introduction of CNI which improve graft survival in short term .CNI may later contribute to decrease in graft function . Alemtuzumab is amonoclonal antibody directed against CD52 which cause profound lymphocyte depletion . The efficacy and safety of an induction treatment strategy of alemtuzumab with reduced CNI exposure and no steroid compared with non-depleting antibody induction (basiliximab) with standard CNI dose in a randomized open-label trial conducted at 18 transplant centers in UK from 2010 to 2013 . Results
-Individuals received alemtuzumab-based treatment had a 58% reduction in biopsy-proven acute rejection compared with those received basiliximab .
-There is no difference between two groups in graft failure or infection during the first 6 months .
– (3%) patients given alemtuzumab-based treatment and (1%) patients given basiliximab – based treatment died .
– TCR is higher in basiliximab group.
– CMV & BKV infection rate increased alemtuzumab group .
Weakness of this study :
-It is not a blind study .
-No assessment of long term outcome .
Strength :It is multicenter randomized trial .
In our practice we don’t use alemtuzumab it isn’t available in our country We use ATG in intermediate and high risk patient .
1. In your own words, summarise this article.
Alemtuzumab-based induction treatment versus basiliximab- based induction treatment in kidney transplantation (the 3C Study): a randomised trial
Kidney transplant is the treatment of choice for end stage renal disease which involves using immunosuppression to prevent graft rejection and hence prolong graft life. Calcineurin inhibitors (CNI) have been shown to be associated with better short-term graft results, but with increased graft failure in long-term.
Based on the premise that using Alemtuzumab (antiCD52 monoclonal antibody) as an induction agent might help in reducing CNI exposure and hence improving graft outcomes, this multi-center, open label, prospective trail was conducted.
This trial was conducted at 18 transplant centers in UK from 2010 to 2013, with total 852 participants, who were randomized to either receive Alemtuzumab induction followed by low dose tacrolimus and MMF or Basiliximab induction with standard dose tacrolimus, MMF and steroids.
The study revealed that there was a 58% reduction in biopsy proven acute rejection episodes in the alemtuzumab group. This benefit was seen in first few weeks post-transplant. The number of acute cellular rejection events were lower in the alemtuzumab group, but episodes of antibody mediated rejection were similar in both groups.
Alemtuzumab group had increased BK virus infections, although there was no difference from basiliximab group with respect to overall infection (opportunistic or serious) episodes, steroid resistant acute rejection, delayed graft function function at 6 months.
There was no benefit of alemtuzumab induction in high risk group (with history of prior transplant, sensitization or increased HLA mismatch).
So, the trial gave evidence that CNI exposure and its consequent ill-effects can be reduced with Alemtuzumab induction, and is associated with reduced acute rejection incidence without increasing infection risks.
2. What are the weakness and strength of this study?
Weaknesses:
1) Open-label trial
2) Short follow-up: The data evaluated is regarding acute rejection in first 6 months post-transplant.
Strength:
1) Prospective, randomized trial
2) Multi-center trial
3) Although open-label, all reports of incidents like serious infections, cancers , rejection and death were reviewed by someone not knowing the treatment details of the patient
3. Please reflect your practice if possible.
We have not used Alemtuzumab as an induction agent.
The strategy in transplantation is to use more potent induction therapy to minimise CNI exposure without increasing the risk of rejection as CNI can decrease transplant function
Alemtuzumab is a monoclonal antibody directed against CD52 expressed on lymphocytes leading to profound lymphocyte depletion
The 3C study addressed the efficacy of induction treatment using alemtuzumab with reduced CNI exposure compared with induction using basiliximab with standard CNI exposure .
They included patients from 18 UK transplant centers having certain inclusion and exclusion criteria they were followed at 1, 3, 6, 9, and 12 months after transplantation
They were randomised equally where 426 candidates were given alemtuzumab-based induction treatment followed by low-dose tacrolimus (target trough concentration 5–7 ng/mL), and mycophenolic acid without steroids; and the other 426 were given basiliximab-based induction treatment followed by standard-dose tacrolimus (target trough concentration 5–12 ng/mL), mycophenolic acid, and oral prednisolone.
The study found that alemtuzumab-based induction treatment (ie, alemtuzumab followed by reduced CNI treatment, low dose mycophenolate, and steroid avoidance) lowered the risk of acute rejection by nearly half the number in the first 6 months after transplantation compared with usual basiliximab-based induction treatment meanwhile long-term follow-up will be needed for evaluating the efficacy of alemtuzumab-based induction treatment
There was no increase in infection risk with CMV virus in alemtuzumab group in comparison to basilixmab group while BK infection was higher in alemtuzumab group than basiliximab group
They expressed that CNI exposure can be reduced without risking rejection after alemtuzumab-based induction.
Other studies suggested that antibody-mediated rejection was more common after alemtuzumab-based induction than after cellular rejection could be due to its effect on B cell
Cancer was uncommon in the first 6 months after transplantation.PLTD was discovered in four participants and the other cancers are likely to have been present before transplantation.
-Weakness of the study
is that it was not an open-label trial, excluding the few who are desensitised before transplantation for HLA- or blood group mismatch also did not provide reliable information about CNI reduction after alemtuzumab or the safety of alemtuzumab.
Due to short follow up period the evaluation of alemtuzumab efficacy on the long term need to be assessed
Also CMV infection on long term was not assessed as patients were recieving prophylaxis
Strength
Including different types of large number of patients
all reports of transplant biopsies were reviewed by clinicians masked to treatment allocation in order not to miss rejection episodes
All reports of serious infections, cancers, and deaths were reviewed.
According to the immunobiology of T-cells, what are the possible risks of Alemtuzumab?
There are side effects of alemtuzumab that mainly relate to induction of secondary autoimmunity like autoimmune thyroid disease, immune thrombocytopenic purpura and autoimmune nephropathies . Also, emergence of rare autoimmune diseases has been described after treatment with alemtuzumab in patients with MS such as ANCA-associated vasculitis as well as anti-GABAa receptor encephalitis .
Referance;
Horisberger A, Pantazou V, Cuendet G, Ribi C, Dunet V, Théaudin M. ANCA-associated life-threatening systemic vasculitis after alemtuzumab treatment for multiple sclerosis. Mult Scler (2020) 1352458519895449. doi: 10.1177/1352458519895449
Maniscalco GT, Mariotto S, Höftberger R, Capra R, Servillo G, Manzo V, et al. GABAa receptor autoimmunity after alemtuzumab treatment for multiple sclerosis. Neurology (2020) 2020(10):1212/WNL.0000000000010310. doi: 10.1212/WNL.0000000000010310
Are you aware of other RCTs of Alemtuzumab?
Any comparison with rATG?
What about use in high-risk patients?
almetuzemab is very potent monocolonal depleting agent for both T-and B cells , there is some RCT and obsrevational studies address its effacicy as induction immunotherapy compared to low dose rATG the INTAC study , randomized 139 high risk recipients recieved 30mg alemutuzemab or rATG 6mg /kg in 4 doses , ( high risk definition in this study including black race with PRA > 20%, the result of this study confrim no difference in AR rate betweeen the two groups at 6 , 12 , 36 months but late AR at 12 months was more in alemutizemab group and this again confirm the decrease effcicay of alemutzemab overtime. snother group of alemutemb induction followed by cni with mmf and early steriod withdraw in low risk recipients compared tobasiliximab induction froup with triple immunsuppression and assess the rejection rate at 6.12, 36 months again higher rate of late AR in alemtuzemab group so the study conculde that alemutzemab efficacy reduced over time in both high anf low immunological risk group .
1- ASN week , 2021 , lecture , update in kidney transplation .
2- update medicine 2021.
Dear Dr Alaa,
There are some RCT trials on the efficacy and safety of Alemtuzumab. However, they were published earlier than the 3C study and included a smaller number of patients.
Hanaway et al. 2011 presented the study mentioned earlier by Dr. saja Mohammed. He studied 139 high-risk patients (70 patients received Alemtuzumab and 69 patients received rATG) and 335 low-risk patients (164 patients received Alemtuzumab and 171 patients received basiliximab) (1).
The study confirmed that Alemtuzumab was comparable to ATG and superior to basiliximab induction in lowering the rate of biopsy-confirmed acute rejection, with no significant differences in the adverse effects between the studied groups (1).
Ciancio G. et al. 2005, published their RCT study, including 90 kidney transplant recipients from cadaveric donors assigned into three groups (group A received Thymoglobulin, group B received Alemtuzumab, and group C received Daclizumab) (2). The group B was kept on steroid-free maintenance immune suppression, MMF 500 mg twice daily and with lower target tacrolimus trough level (4-7 ng/ml), while groups A and C received standard steroid maintenance therapy, MMF 1 gm twice daily and with target tacrolimus trough level 8-10 ng/ml.
Despite the significantly lower maintenance immune suppression in group B, who received Alemtuzumab, the first-year acute rejection rate, patient and graft survival were comparable between the three groups. However, after follow-up for about 3 years, graft survival was worse in group B (78 versus 95 per cent) (3). This study’s worse long-term outcome should be interpreted carefully, as the confounding effect of the lower maintenance immune suppression should be considered.
Welberry Smith MP. et al. 2013, conducted a single-centre, prospective, open-label RCT comparing steroid-free protocol in 116 kidney transplant recipients. The patients were randomized to either basiliximab induction followed by tacrolimus and MMF maintenance or alemtuzumab induction followed by tacrolimus monotherapy (4). After follow up for one year, the patient and graft outcome were comparable in both groups with no significant increase in side effects or major complications (4).
References:
1) Hanaway MJ, Woodle ES, Mulgaonkar S, et al. Alemtuzumab induction in renal transplantation. N Engl J Med. 2011;364(20):1909.
2) Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of three renal transplant induction antibodies: early comparison of tacrolimus, mycophenolate mofetil, and steroid dosing, and newer immune-monitoring. Transplantation. 2005;80(4):457.
3) Ciancio G, Burke GW, Gaynor JJ, et al. A randomized trial of thymoglobulin vs. Alemtuzumab (with lower dose maintenance immunosuppression) vs. Daclizumab in renal transplantation at 24 months of follow-up. Clin Transplant. 2008;22(2):200.
4) Welberry Smith MP, Cherukuri A, Newstead CG, et al. Alemtuzumab induction in renal transplantation permits safe steroid avoidance with tacrolimus monotherapy: a randomized controlled trial. Transplantation. 2013 Dec 27;96(12):1082-8.
Other trials;
Systematic review;
The Centre for Evidence in Transplantation’s systematic review of alemtuzumab in kidney transplantation included five trials comparing alemtuzumab-based versus interleukin 2-receptor antagonist-based induction treatment. The findings showed that alemtuzumab reduced the risk of biopsy-proven acute rejection by about a half, but the trials reviewed did not provide reliable information about CNI reduction after
alemtuzumab or the safety of alemtuzumab.
Reference ;
Morgan RD, O’Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation 2012; 93: 1179–99.
Comparison of alemtuzumab with ATGr as induction therapy ;
This retrospective, single-center, cohort study evaluated cumulative incidence of one-yr biopsy-proven acute rejection (BPAR) among 200 consecutive primary non-sensitized kidney transplant recipients who received either alemtuzumab (n = 100) or rATG (n = 100) induction followed by rapid steroid taper, tacrolimus, and mycophenolate mofetil.
Protocol biopsies, plasma and urine BK virus PCR, serum creatinine and iothalamate glomerular filtration rate (iGFR), were obtained at 1, 4, and 12 months from transplantation.
The one-yr BPAR rates were similar between the alemtuzumab and rATG groups; however, rejection Banff IA and higher was more common in the alemtuzumab arm . After adjusting for confounding variables, alemtuzumab was still associated with Banff IA and higher rejection .
Despite similar rates of BK viremia, more patients in the alemtuzumab arm developed BK nephropathy .
One-year iGFR and three-yr graft survival were lower in the alemtuzumab group.
In low immunological risk kidney transplant recipients on steroid-free immunosuppression, alemtuzumab was associated with more severe rejection and BK nephropathy compared to rATG.
Reference;
Comparison of alemtuzumab vs. antithymocyte globulin induction therapy in primary non-sensitized renal transplant patients treated with rapid steroid withdrawal. Clin Transplant
2015 Jul;29(7):573-80. doi: 10.1111/ctr.12532. Epub 2015 Mar 24.
Comparison of alemtuzumab to ATGr in treatment of acute rejection ;
In comparison of alemtuzumab to ATGr regarding their effectiveness in treating acute rejection ,no difference in patient and graft survival with either of them . Infection-free survival after alemtuzumab treatment was superior compared with that of rATG-treated patients . Infusion-related adverse events occurred less frequently after alemtuzumab treatment. Alemtuzumab therapy may therefore be an alternative therapy for glucocorticoid-resistant, recurrent, or severe acute kidney transplant rejection.
Comparison of Alemtuzumab and Anti-thymocyte Globulin Treatment for Acute Kidney Allograft Rejection Front. Immunol., 03 July 2020 | https://doi.org/10.3389/fimmu.2020.01332
Are you aware of other RCTs of Alemtuzumab?
Any comparison with rATG?
A meta-analysis published in 2017, analysed 6 RCTs associated with Aletuzumab versus ATG use in kidney transplant. (1) The study revealed that there was no difference in outcomes between alemtuzumab and ATG groups with respect to graft and patient survial, acute rejection, DGF and infections.
What about use in high-risk patients?
All the 6 RCTs in the meta-analysis involved high risk patients.
Reference:
1) Zheng J, Song W. Alemtuzumab versus antithymocyte globulin induction therapies in kidney transplantation patients A systematic review and meta-analysis of randomized controlled trials. Medicine (Baltimore) 2017;96:e7551.
Comparing Thymoglobulin to Alemtuzumab
1. Farney and his colleagues 2009
· median follow-up of 2 years
· patients and graft survival were similar for both groups and incidence of infection and malignancy
· Thymoglobulin group- incidence of BPAR was higher (26%vs 14%)
2. Hanaway MJ et al
· randomly assigned to receive Alemtuzumab, basiliximab, thymoglobulin according to immunological risk
· high risk group- no diff thymol vs alemtuzumab in AR after 3 years f/up
· low risk group- alemtuzumab had therapeutic advantage over basiliximab – lower BPAR at 3 years f/up
3. Opelz et al
· showed a clear benefit of antibody induction in high-risk transplant
· fails to prove statistical benefit of this strategy in low-risk transplantation
· hospitalization secondary to infection was increased with both induction agents
there are some studies compared alemetuzumab with rATG
1- in 2011, a study by Hanawy et al, published in NEJM, revealed no difference in risk of acute rejection among patients who received almetuzumab compared to rATG. however,. the incidence of late acute rejection was more with alemtuzumab arm.
2- In 2014, results of the 3C study comparing almetuzumab vs basiliximab induction were released. there was no difference in graft failure nor infection. however, there was reduced biopsy documented rejections in the alemtuzumab arm.
references:
1- 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.
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.
Dear all
1. Do you think there is a bias of using different maintenance therapy in the study groups? For example, in Alemtuzumab, it is Low dose TAC, MMF, without steroids, whereas in the basiliximab, it is standard-dose TAC, MMF, and steroids!?
Yes. I think with these different maintenance protocols, the investigators accept that the effectiveness of alemtuzumab as an induction agent is much more than that of basiliximab and hence the investigators could device such a protocol with different maintenance immunosuppression.
2. What was the primary outcome of the study? Is it the rate of BPAR, or Graft function, or the ability to use less CNI dose?
The primary outcome of the study was to look for efficacy of alemtuzumab based induction treatment, BPAR and graft function both act as a marker of this efficacy.
3. What about the increased mortality in the Alemtuzuab group (3% vs.1%) !?
Although the mortality rate in alemtuzumab group was high, there was no increased incidence of fatal infections or malignancy in the alemtuzumab group, hence these deaths were probably unrelated to the molecule.
Do you think there is a bias of using different maintenance therapy in the study groups?
For example, in Alemtuzumab, it is Low dose TAC, MMF, without steroids, whereas in the basiliximab, it is standard-dose TAC, MMF, and steroids!?
I do not think there is bias in the study. Basiliximab with standard dose of CNI, MPA and steroids are standard practise in many countries including in my country.
The study intended to evaluate the role of alemtuzumab in reducing CNI dose yet without increasing the incidence of AR in 6 months.
What was the primary outcome of the study? Is it the rate of BPAR, or Graft function, or the ability to use less CNI dose?
The ability of use less CNI dose
What about the increased mortality in the Alemtuzumab group (3% vs.1%)
The mortality is more, but the causes of death not specified properly.
This is a randomized clinical trial in UK which aimed to compare the efficacy and safety between alemtuzumab(followed by reduced CNI , low dose mycophenolate, and no steroid )
and basiliximab (followed by standard-dose tacrolimus, mycophenolate, and prednisolone ) .
There was 852 participants : 426 got alemtuzumab and 426 got basiliximab. The participants were under follow up for one year with check up at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation .
Alemtuzumab group had more reduction in biopsy proven acute rejection (almost half the cases of bailiximab group) compared with basiliximab group. There was no difference between both group regarding serious infection((defined as an opportunistic infection or one requiring admission to hospital) despite the fact that alemtuzumab was associated with more BK virus infections in the study but less PTLD.
Mortality in the first 6 month was more in alemtuzumab group but with no statistical significance .
Strength of this study
· The sample is relevant to the population as it included quarter of all transplanted patients in the study area during the study period .
· Patients were comparable between both groups regarding demographics, underlying diseases, immunological level, donor type , ischemia time
Weakness
Making this study blind treatment is not applicable
In our country , we use basiliximab and ATG as induction agents. The first is no more available in our country due to financial burden. We do not use steroid avoidance regimen
This is randomized open label trail on patients from different kidney transplant centers comparing 2 group of patients first group received induction with alemtuzumab with CNI minimization, MMF and steroids avoidance,
second group received induction with basiliximab group with standard triple immunotherapy as maintenance.
Alemtuzumab is a monoclonal antibody with potent depleting effect on both T and B lymphocyte .
Results
1 individuals received alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection compared with those received basiliximab-based treatment.
2 no difference between both groups in graft failure or serious infection during the first 6 months .
3 During the first 6 months after transplantation, 11 (3%) patients given alemtuzumab-based treatment and six (1%) patients given basiliximab-based treatment died
4 more TCR in BASILIXIMAB group.
5 NO benefit with alemtuzumab induction in high immunological risk group .
6 more BKV in alemtuzemab gruop.
Strength of the study
It is a randomized trial on recipients form 18 centers
clinicians reviewing the biopsies were masked about treatment .
Limitation of the study
–short time of study no follow up at 12 month to assess the alemtuzumab effect on rejection rate and graft, patient survival over time.
–potential imitation of the 3C Study was the necessity of making it an open-label trial because it was not possible to blind induction treatment strategies. To minimise any possible bias, however, all reports of transplant biopsies were reviewed by clinicians masked to treatment allocation.
In my practice we dont use alemtuzumab .
W
Summary of the Article
This is a short term prospective cohort study, assessing over one year the efficacy and safety of alemtuzumab-based induction treatment compared with basiliximab-based induction treatment in patients receiving kidney transplants. In the arm of Basiliximab the exposure to CNIs is the standard one while they were minimized to low doses in the arm of Alemtuzumab.
CNIs contributes to substantial improvement in short-term graft survival but may adversely impact the long term graft survival, that’s why many studies were conducted to minimize the risk of CNIs. One of the strategies to minimize the lang-term adverse effects of CNIs is the use of potent induction therapy with subsequent minimization of CNIs doses.
Alemtuzumab and Basiliximab are humanised monoclonal antibodies directed against CD-52 and IL-2R respectively. Alemtuzumab causes profound lymphocyte depletion as CD-52 is expressed almost exclusively on lymphocytes. Basiliximab is a non-depleting antibody.
Study Results and Discussion :
What are the weakness and strength of this study?
Study Limitations:
Strength of this study:
Please reflect your practice if possible ?
We are using Basiliximab based treatment in induction beside TAC,MMF and Prednisolone. This protocol is commonly used in the centre I worked in whenever there’s sensitization issues.
It is a multicenter, open-label, randomized trial
This is a randomized open-label trial that includes One group receiving induction immunosuppressive medication while the other received maintenance immunosuppressive therapy. An initial steroid-free regimen of low-dose tacrolimus and mycophenolate was given to one group of patients, whereas an initial basiliximab-based induction regimen was given to the other.
It appears that alemtuzumab-based induction treatment followed by CNI reduction and low-dose mycophenolate and steroid avoidance can significantly reduce the risk of acute rejection in the first 6 months after transplantation without increasing the risk of serious or opportunistic infections or other known immunosuppression-associated complications. These effects were constant throughout the various kinds of participants who were evaluated, and they are relevant to a wide spectrum of individuals who are undergoing kidney transplantation.
Weakness of study:
No blind-label experiment.
could not measure AR and infection risk after 6 months.
In our clinical practice:
No alemtuzumab in our center.
Summary:
This is randomized open label trail from multiple kidney transplant centers in UK including adults above the age of 18 years with 1.1 randomization for alemtuzumab induction group with CNI minimization, MMF and early steroid withdraw, and basiliximab group with standard triple immunotherapy as maintenance Alemtuzumabs monoclonal AB have very potent both T and B lymphocyte cells depletion effect and have been proven its efficacy and safety as induction depletion agent in many RCT and observational studies but overall efficacy reduced overtime with increasing rate of late AR and more CAN ,and lower graft survival .
The aim of this study is to assess the potency and safety profile of alemtuzumab with CNI minimization group , by assessing the rejection rate frequency in first 6 months between the two groups and its effect on graft and patient survival.
Figer1 shows significant Lower rate of acute rejection (BPAR)in first 6 months in alemtuzumab group (p-value <0.0001), more TCR in BASILIXIMAB group and no difference in AMR between two groups.
Subgroup analysis shows no increased benefit with alemtuzumab induction in high immunological risk group (higher mismatch, sensitized recipients with retransplant)
No difference in infection rate including serious or opportunistic infection or transplant failure between the two groups, but more BKV in alemtuzemab gruop.
Low rate of malignancy without statistical significance between the two groups .
Limitation of the study
– Short FU we can’t assess the long term out come within 12 months need longer fu to assess the alemtuzumab effect on rejection rate and graft, patient survival over time.
-open label design as can’t blind the Induction treatment
-Please reflect your practice if possible.
I have no experience with the use of Alemtuzumab Cam path H as its not available, its used as induction IS limited to < 10% of the kidney transplantation as on long term alemtuzumab efficacy decreased and associated with more risk of late acute rejection, more death censored graft survival and CAN in both high and low risk kidney transplant candidates based on many studies (1).
Reference:
1- Up to date medicine, kidney transplantation in adults, induction immunosuppression 2021.
Alemtuzumab-based induction treatment versus basiliximab- based induction treatment in kidney transplantation (the 3C Study): a randomised trialshort graft survival improved in the era CNI but long term graft survival not improved
alemtuzumab induction followed by low dose CNI and steroid free regimen looks wise plan to decrease CNI nephrotoxicty and decrease steroid complications
the results showed the safety and efficacy of this regimen in 1st 6m post transplant n first 6 months post transplantation it was found the following:
Strength of the study
1/its randomised….computer based with very balanced distribution
2/its involving intension to treat
3/very clear 1ry end point.
weakness
1/not blinded but justified
2/long term outcomes still pending (the aim of study??? not done yet)
3/funded by pharmaceutical companies (conflict of interest)
To improve long-term graft & patient out-come, the induction regime is needed. Alemtuzumab ( CD52 Abs) can cause sever lymphocyte depletion ( CD52 exclusively expressed on lymphocytes) so it can be used to reduce CNI dose in maintenance regime.
The study included patients in 18 centers. They include all patients aged 18 years or more who schedules for transplantation in next 24 hours. It compare the efficacy of alemtuzumab as induction therapy with minimizing of CNI dose in reducing AR rate in comparison to basiliximab.
Exclusion criteria include:
In first 6 months post transplantation it was found the following:
Strength of the study is using of patients attend different center
Weakness of the study:
In our center we didn’t use alemtuzumab .
Summary:
The use of calcineurin inhibitors (CNI) as part of immunosuppressive therapy in kidney transplantation helped to improve the short term outcome and decreased the rate of early graft failure but may have adverse effect on the long term outcome and may cause late transplant failure.
So some strategies use potent induction therapy at time of transplant to allow reduction of CNI exposure without increasing the risk of rejection.
Alemtuzumab:
Humanized monoclonal antibodies against CD52 which is expressed only on lymphocytes.
cause profound lymphocyte depletion
Used as induction therapy to decrease CNI exposure
This study aims to compare the efficacy and safety of using Alemtuzumab with decreased CNI exposure with using Basiliximab with standard CNI exposure.
It included 852 patients randomly assigned to either Alemtuzumab followed by low dose Tacrolimus and mycophenolate without steroids or Basiliximab followed by standard dose Tacrolimus, mycophenolate and prednisolone.
The primary outcome was biopsy proven acute rejection at 6 months.
The study showed that:
In conclusion Alemtuzumab based induction with decreased CNI, low dose mycophenolate and steroid free can decrease risk of acute rejection in the first 6 months without increasing risk of serious or opportunistic infection.
Weakness:
Short follow up period so couldn’t assess the long-term outcome and the effect of decreasing CNI exposure on long term graft survival
couldn’t substantiate if Alemtuzumab is associated with increased risk of AMR or not
Strength:
randomized clinical trial
included large number of different types of participants in different centers recruited in the study so the results were relevant and could assess the effect on acute rejection rate.
transplant biopsies were assessed according to standardized prespecified criteria, so no rejection episode was missed
In our center, Basiliximab is used for standard risk and ATG for high risk patients
Do you think that being an RCT is a point of strength?
RCT minimizes bias and aims to make fair comparison
decreases clinicians or patients preference to certain treatment
used for clinically testing new interventions
allows direct comparison between 2 groups and provide a way to determine cause effect relationship between intervention and outcome.
Hariton E, Locascio JJ. Randomised controlled trials—the gold standard for effectiveness research. BJOG: an international journal of obstetrics and gynaecology. 2018 Dec;125(13):1716.
RCT compare Alemtuzumab as powerful induction therapy with conventional therapy after low dose tacrolimus ,MMF, steroid free versus basiliximab with conventional therapy after standard dose tacrolimus,MMF, steroid, this comparison as regard BPAR and graft survival.
Alemtuzumab is monoclonal antibody directed against CD52 receptor which is present on T and B lymphocytes, and also on natural killer and macrophage cells so it cause marked depletion of lymphocytes.
Basiliximab is monoclonal antibody directed against CD25 which is present on T cell surface so prevent its proliferation.
Alemtuzumab was given 30 mg day 0 and 30 mg day 1 , but if the recipient is old age more than 60 , one dose only was given at day 0…followed by conventional therapy low dose tacroloimus and MMF, steroid free regimen.
Basiliximab was given 20 mg at day 0 and day 4, with conventional therapy standard dose tacrolimus and MMF and steroid.
The incidence of BPAR at 6 months posttransplant is decreased by 50% with Alemtuzumab induction in comparison to basiliximab induction therapy, hence positive impact on graft outcome and survival with alemtuzumab without increased in opportunistic infections , and CMV infection incidence , but BK disease (nephritis) is increased in alemtuzumab group because of increase BK viremia in this group which may be related to more potent immunosuppression.
There is no significant increase in the incidence of cancer in the group of alemtuzumab, and no increase in mortality in this group as compared to basiliximab (mortality post transplant is due to infections or cancer).
in my practice: we don not use alemtuzumab, we only use basiliximab in standard risk patients and ATG in high risk patient
the strength of the study it is randomized control study with level of evidence 1
Alemtuzumab (Campath-1H) is a humanized panlymphocytic (both B and T cells) anti-CD52 antibody that can cause profound lymphopenia that can persists for months
This study addresses the safety and efficacy of the use of alemtuzumab for induction in combination with a reduced dose of CNI and MMF and steroid avoidance and compares this to basiliximab induction with a conventional dose of triple therapy.
It was found that in comparison to basiliximab group 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
Weakness
Strength
in our center we did not use Alemtuzumab for induction
This is a prospective study that evaluated the short term renal outcomes of 2 groups based on induction and maintenance immunosuppressive therapy. Two group of patients were randomly assigned to either alemtuzumab-based induction treatment followed by steroid free regimen consisting of low-dose tacrolimus and mycophenolate or basiliximab-based induction treatment followed by standard-dose tacrolimus, mycophenolate, and prednisolone.
The primary outcome was biopsy-proven acute rejection at 6 months.
Alemtuzumab is anti CD52 monoclonal antibody. CD52 are expressed almost exclusively on lymphocytes; monoclonal antibodies to CD52 cause profound B and Tlymphocyte depletion.
Results
Recipients who received alemtuzumab-based treatment had a 58% reduction in biopsy-proven acute rejection at 6 months compared with those allocated to basiliximab-based treatment, 7% vs 16%.
During the first 6 months after transplantation, mortality rate was higher in the alemtuzumab-based treatment 3% vs 1% in the basiliximab-based treatment.
No statistically significant difference in the occurrence of either steroid-resistant rejection or delayed graft function in both groups.
No difference in the occurrence of any serious infection requiring admission to hospital.
No difference in the occurrence of CMV infections.
BK virus infections were more common in the alemtuzumab-based treatment group compared with in the basiliximab-based.
In conclusion, fndings of this study suggest that alemtuzumab-based induction treatment followed by steroid free regimen consisting of low dose CNI and low-dose MMF can significantly reduce the risk of acute rejection in the first 6 months after transplantation, without leading to serious or opportunistic infections.
Please mention the strengths and limitations of the study according to the question above
A randomised trial was done to assess the efficacy and safety of Alemtuzumab based induction treatment compared with Basiliximab based induction in kidney transplant patients.
Participants from 18 UK centers were recruited .
Inclusion criteria:
patients of 18 years old and older if they scheduled to receive kidney transplant in the next 24 hr
Exclusion criteria:
A total number of 852 patients were included and are randomised to either Alemtuzumab induction 30 mg immediately after reperfusion and 24 hr later ( 426 patients)followed by low dose Tac ( trough level 5-7 ng/ml) & MMF 360 mg twice daily or Basiliximab based induction therapy 20 mg at day 0 and 4( 426 patients) followed by standard dose Tac ( trough level 5-12 ng/ml), MMF 540-720 mg twice daily and oral prednisolone.
The participants were reviewed at time of discharge from hospital and at 1,3,6,9 & 12 months post transplantation, each follow up visit, BP, weight, blood and urine analysis for creatinine, CBC, Tac level, and protein to creatinine ratio were chequed
Findings:
Individuals on the Alemtuzumab arm had 58% reduction in biopsy proven acute rejection as compared to Basiliximab induction.
No between group difference in treatment effect on transplant failure risk during the first 6 months or serious infection.
Death in the first 6 months was 3% in Alemtuzumab group and 1% in Basiliximab group.
Limitation of the study:
the necessity to make it open label trial because it was not possible to blind induction treatment strategies.
Strength of the study:
Avoidance of bias despite being open label study by reviewing the biopsies by clinicians masked to treatment allocation.
In my practice, we do not have Alemtuzumab at our center.
In your own words, summarise this article.
Aim –
To assess the effi cacy and safety of alemtuzumab-based induction treatment compared with
basiliximab-based induction treatment in patients receiving kidney transplants.
Methods-
Patients aged 18 years and older who were scheduled to receive a kidney transplant in the next 24 h from 18 transplant centres in the UK were enrolled.
Exclusion criteria –
multi-organ transplantation
previous treatment with alemtuzumab,
active infection,
history of malignancy in the past 5 years
Randomised to either alemtuzumab((30 mg immediately after reperfusion and 24 h later,
unless the participant was >60 years old, in which case the second dose was omitted)based induction treatment (alemtuzumab followed by low-dose tacrolimus(target trough concentration 5–7 ng/mL) and mycophenolate(360 mg twice daily) without steroids) or
basiliximab (20 mg on days 0 and 4) based induction treatment (basiliximab followed by standard-dose tacrolimus(target trough concentration 5–12 ng/mL), mycophenolate(540–720 mg twice daily), and prednisolone).
Participants were reviewed at discharge from hospital and at 1, 3, 6, 9, and 12 months after transplantation.
At each follow-up visit-
blood pressure
weight
obtained blood and urine samples for local analysis of creatinine, full blood count, tacrolimus
concentration, and urine protein-to-creatinine ratio were measured.
The primary outcome was biopsy-proven acute rejection at 6 months.
Findings –
Individuals allocated to alemtuzumab-based treatment had a 58% proportional reduction in biopsy-proven acute rejection.
No between-group difference in treatment effect on transplant failure during the first 6 months or serious infection.
Interpretation-
Compared with standard basiliximab-based treatment, alemtuzumab-based induction therapy followed by reduced CNI and mycophenolate exposure and steroid avoidance reduced the risk of biopsy-proven acute rejection. Also no overall excess of opportunistic or other serious infections with alemtuzumab-based treatment.
What are the weakness and strength of this study?
Weakness –
It was an open label trial prone to bias.
Strength –
All reports of transplant biopsies were reviewed by clinicians masked to treatment allocation.
All reports of serious infections, cancers, and deaths were reviewed.
Please reflect your practice if possible.
Alemtuzumab not used.
Basiliximab used in deceased donor with maintenance tacrolimus,MMF,prednisolone.
Live related donor- no induction used , maintenance tacrolimus,MMF,prednisolone