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N Engl J Med. 2016 Jan 28;374(4):333-43. doi: 10.1056/NEJMoa1506027.
Belatacept and Long-Term Outcomes in Kidney Transplantation.
Vincenti F, Rostaing L, Grinyo J, Rice K, Steinberg S, Gaite L, Moal MC, Mondragon-Ramirez GA, Kothari J, Polinsky MS, Meier-Kriesche HU, Munier S, Larsen CP.
Free full text is available at the NEJM website
Pre-chat Summary
BELATACEPT AND LONG TERM KIDNEY TRANSPLANT OUTCOMES
Nephrology has made huge strides in improving short term kidney transplant outcomes. However, long term kidney transplants outcomes have not shared in the dramatic improvements. Why is this the case? The two leading culprits are calcineurin inhibitor toxicity and formation of donor specific antibodies leading to acute and chronic antibody mediated graft injury.
The current standard of care of long term maintenance immunosuppression includes calcineurin inhibitors, mycophenolate and steroids (OPTN/SRTR Report 2014). Introduction of calcineurin inhibitors dramatically improved short term graft survival at the expense of decreased graft function, increased diabetes mellitus, hypertension, dyslipidemia, and poorer cardiovascular outcomes (Naesens et al cJASN 2009, Stoumpas et al Transpl Int 2015). Unfortunately, the kidney transplant therapeutic pipeline for maintenance is dry. The last therapeutic agent to become mainstream for maintenance immunosuppression was mycophenolate.
Co-stimulation pathway and its blockade has been extensively studied in the realm of transplantation and autoimmunity. Blocking the signal 2 in T-cell activation via the co-stimulation blockade prevents adequate T-cell response leading to T-cell anergy. CTLA4 (Cytotoxic T-Lymphocyte Antigen-4) is a homologue of CD28 that binds B7. The first drug to exploit this was abatacept, used in Rheumatoid Arthritis and psoriasis, followed by belatacept (LEA29Y - fusion protein of the extracellular portion of CTLA-4 and Fc domain of human IgG1) approved for prevention of acute rejection in adult patients with renal transplant.
The BENEFIT (standard criteria kidneys) and BENEFIT-EXT (Extended criteria kidneys) Trials
BENEFIT was a worldwide multi-center randomized controlled trial. Patients were randomized to one of three arms: less intensive belatacept, more intensive belatacept or cyclosporine for maintenance immunosuppression. All patients received basiliximab for induction, along with maintenance immunosuppression with mycophenolate and steroids. The primary outcome was patient and graft survival at three years post transplant. There was no difference between the groups, however the belatacept groups had a mean GFR 13-15 ml/min higher than the cyclosporine group. This was despite a higher rate of acute rejection with belatacept in the first year:
Less intensive belatacept: 22%
Intensive belatacept: 17%
Cyclosporine: 7%
The BENEFIT EXT Trial which was an identical trial conducted in extended criteria donors which showed a more modest benefit in the GFR.
The subject of this week's #NephJC is the long term follow up of the original BENEFIT study.
Methods
3-year, international, randomized, single-blind, parallel-group study with an active control.
Patients were randomly assigned (in a 1:1:1 ratio) to a more-intensive belatacept-based regimen, a less intensive belatacept-based regimen, or cyclosporine.
Patients were eligible to continue the assigned therapy beyond 36 months if they provided consent.
Patients who provided consent were followed for up to 84 months.
Outcomes
Composite end points of Patient and Graft survival (also assessed individually), renal function and incidence of acute rejection.
Safety outcomes
Development of donor specific antibody (DSA)
Statistics
log-rank test to assess the time to death or graft loss
Hazard ratios and 95% confidence intervals for death or graft loss for the first 60 months and for the first 84 months were derived with the use of Cox regression
data were censored at month 60 and month 84
censoring rules
CAVEAT - if no date of death or graft-loss date was reported, the data were censored at the reported date of the last follow-up assessment.
Results
Discussion Points
Main BENEFITs - Why does belatacept make sense?
No calcineurin inhibitors and better GFR - GFR improving months after kidney transplant is unheard of in the calcineurin inhibitor era. With belatacept there is an improvement in the GFR whereas with cyclosporine there is the expected slow fall in GFR over the years.
Fig 3 from Vincenti et al, NEJM 2016
Decreased formation of donor specific antibody - Long term graft failures occur because of antibody mediated graft injury. The causes of graft failure in this study did not clearly indicate ABMR as a significant factor but there was a lower incidence of donor specific antibodies with belatacept.
Fig S1 from supplementary appendix, Vincenti et al NEJM 2016
Increased compliance? - Given than Belatacept is an IV infusion it is the first Directly Observed Therapy in transplantation. Cyclosporin and belatacept adherence were not different in this study. Like in all chronic therapies medication adherence plays a crucial role and may play a part in improving long term outcomes.
Better Graft and Mortality outcomes
Fig 2, panel A from Vincenti et al, NEJM 2016
Fig S2 from supplementary appendix, Vincenti et al, 2016
Serious adverse effects similar across all three therapies.
Table 1 from Vincenti et al NEJM 2016
Bones of Contention -
Tacrolimus - Graft outcomes are better with tacrolimus when compared to cyclosporine. (ELITE-SYMPHONY, NEJM 2007). Whether belatacept will stand tall when compared to tacrolimus is still unanswered.
Higher number of acute rejections - T-cell mediated acute rejection which is resistant to co-stimulatory blockade is a major hurdle. There was a small trial investigating the role of alemtuzumab, belatacept and rapamycin therapy to overcome this phenomenon. (Xu et al AJT 2016, Post Depletion Lymphocyte Reconstitution During Belatacept and Rapamycin Treatment in Kidney Transplant Recipients.)
PTLD - The occurrence of PTLD stopped many in their tracks when the data at 2 years was published. The risk is highest in EBV negative patients. Two cases were reported between year 1 and 2. The long term data is reassuring with no new subsequent cases. The overall risk remains low. The drug is contraindicated in EBV seronegative patients.
Cost - Belatacept is expensive $21,000 per year for the drug with administration costs adding to this. Calcineurins are less expensive, but need drug monitoring. Belatacept does not need monitoring, offsetting some of the costs.
In the long run, if a drug improves graft outcomes, the cost of a patient returning to dialysis and needing a second transplant needs to be considered.
My take
Belatacept is an exciting new kid on the block. It has potential and promise. Will it stand up to the scrutiny - only the future will tell. Until then prima facie we have a winner against cyclosporine-based kidney transplant immunosuppression.
Summary by Nikhil Shah, University of Alberta
#NephJC chat Tuesday Feb 23rd 9 pm Eastern
Wednesday Feb 24th 8 pm GMT, 12 noon Pacific