Blog entry by Arif Khwaja
The 3C study presented at this weeks’ World Transplant Congress and published online in the Lancet is an important study, which may in the future inform clinical practice in transplantation. In essence there are two parts to the study. The first part looks at induction therapy and compares induction with alemtuzumab (and anti-CD52 monoclonal antibody that depletes mature lymphocytes and is licensed for the treatment of multiple sclerosis and CLL) vs basiliximab – an IL2- receptor antagonist. Those randomised to alemtuzumab also received tacrolimus (targeting a lower therapeutic 5-7 ng/ml) and low dose mychphenolic acid (MPA 360mg bd) but no steroids. In contrast those randomised to basiliximab received steroids, higher dose tacrolimus (5-12ng/ml) and higher dose MPA (540mg bd). The second part of the study looks at switching patients 6 months post transplant from tacrolimus to sirolimus or continuing tacrolimus.
The data presented this week is very early data from the induction part of the study and looks at the impact of a standard basiliximab-based regime vs the steroid-free alemtuzumab-based regime with lower-dose tacrolimus and MPA on biopsy proven acute rejection (BPAR) at 6 months. Groups were well matched though on the whole were of low immunological risk – 92% were first transplants and 4% highly sensitised
The key findings are as follows:
i) There was a significant, 58% proportional reduction in BPAR in the alemtuzumab group (7% of patients) vs the Basiliximab group (16% of patients). Graft function at 6 months was the same in both groups.
ii) The reduction in BPAR was driven by a significant reduction in early cellular rejection. Antibody mediated rejection incidence was 1.9% in the alemtuzumab group but 1.2 % in in the basiliximab group – this was non significant.
iii) There was no difference in CMV viraemia, CMV disease and other opportunistic infections between both groups but BK viraemia was significantly higher in the alemtuzumab group (8% vs 4%). There was no difference in the number of serious infections or hospitalisations
iv) 11 patients died in the alemtuzumab arm compared to 6 in the basiliximab arm. This was not statistically significant but perhaps a little concerning.
v) Leucopaenia was much commoner in the alemtuzumab group – 36% vs 10%.
Like many other clinicians in the UK I have consented patients into the study. To me the interesting points so far are:
i) the 3C study represents a huge success for the UK transplant community in general but in particular for the Oxford Clinical Trials Unit that ran the study. To have recruited so many patients into a study in a relatively short period of time is incredibly difficult and happened because clinicians up and down the country ‘bought’ into the study and the trials unit made it logistically as easy as possible for all investigators
ii) The data is broadly in line with the results of the previous INTAC study which showed that alemtuzumab reduced BPAR in low risk transplant recipients compared to basiliximab whilst enabling an early steroid taper.
iii) The authors emphasise in the discussion that reducing BPAR does not necessarily translate into better graft survival. However the study is powered to detect long-term outcomes and this data will come out in a few years time and we will then be in a position to determine the impact of alemtuzumab induction is on more meaningful outcomes than BPAR.
iv) The results do suggest alemtuzumab-induction does allow for the delivery of steroid-free immunosuppression regimes using lower doses of MPA and tacrolimus – albeit in relatively low risk transplant recipients
v) Although infection rates were broadly similar the ‘big hassle’ of the patients randomised to alemtuzumab was leucopenia which affected a third of patients. There maybe scope to attenuate this by introducing MPA a little later once the lymphocyte count recovers or using a lower dose of alemtuzumab.
vi) Previous retrospective data suggests that alemtuzumab use is associated with an increased risk of antibody-mediated rejection. In the previous INTAC study late acute rejection occurred in 10% of patients in the high-risk group on alemtuzumab vs 2% in the ATG group. Whilst not statistically significant such a difference is worrying. The longer term 3C data will hopefully be able to tease out whether this risk of late rejection (perhaps associated with repopulation of lymphocytes) is a real concern.
In summary the data presented so far are interesting and may clarify a role for alemtuzumab in the delivery of steroid-free immunosuppression once the longer-term outcome data is presented.