Medicine is a constant balance of risks and benefits. The importance of maintaining this balance is especially evident in kidney transplantation. While methods of immunosuppression in kidney transplantation have improved substantially since the use of total body irradiation to induce tolerance in the 1950s, current immunosuppressive agents such as calcineurin inhibitors still come with clinically significant side effects and potential for harm. One of the most worrisome side effects of calcineurin inhibitors, ironically, is nephrotoxicity, which can prematurely lead to graft dysfunction and even loss.
Thus, research efforts have focused on finding alternative immunosuppressive agents that do not confer nephrotoxicity. One such study, the BENEFIT trial , previously published 3 year outcomes comparing death and graft loss in patients receiving belatacept, a selective costimulation blocker, to those outcomes in patients receiving cyclosporine A, a calcineurin inhibitor. Initial trial results showed equivalent rates of death and graft loss between the 2 groups but a higher glomerular filtration rate (GFR) and a higher incidence of acute rejection in the belatacept group. The authors now report 7 year outcomes of belatacept versus cyclosporine A in this week’s issue of NEJM.
The BENEFIT trial randomized 666 patients transplanted with a living or deceased standard donor criteria kidney in a 1:1:1 ratio to receive either high intensity betalacept-based therapy, low intensity belatacept-based therapy or cyclosporine A- based therapy for 36 months. All patients received basiliximab induction, and adjunctive maintenance therapy with mycophenolate mofetil and glucocorticoids. About 60-70% of the patients in each treatment arm remained on the assigned treatment through 7 years of follow-up.
While there was no statistically significant difference in the composite primary outcome of death or graft loss after 36 months of follow-up, differences emerged after prolonged follow-up. At 84 months (7 years) of follow-up, Kaplan–Meier estimated rates of death or graft loss with more intense belatacept, less intense, belatacept, and cyclosporine A were about 13%, 13%, and 22%, respectively. This corresponds to an HR of 0.57 comparing both the more intense betalacept to cyclosporine A (P=0.0225), and the less intense belatacept with cyclosporine A (P=0.0210). There was equal contribution from both endpoints- death and graft failure.
Both belatacept regimens also appeared to have an advantage over the cyclosporine A regimen with respect to GFR over time. After 7 years follow-up there was a significant difference in GFR, with GFR increasing over time in both belatacept groups and decreasing over time for the cyclosporine A group. Additionally, fewer patients on belatacept developed donor-specific antibodies. Acute rejection was, however, more common with belatacept with rates of about 25% vs. 18% vs. 11% for high belatacept, low belatacept, and cyclosporine A regimens, respectively. Frequencies of all other adverse events, including infection, malignancy and post-transplant lymphoproliferative disorder, were similar across all treatment groups.
The study indicates that belatacept, a relatively new immunosuppressive agent used in kidney transplantation, has long-term efficacy despite the higher rates of acute rejection with the agent. Belatacept may offer a promising alternative to cyclosporine, given the possibility of longer preservation of graft function. Belatacept may also increase adherence, as it is administered as a monthly infusion rather than a twice daily pill and does not require frequent venipunctures for drug level monitoring. However, the monthly infusion may be seen as a barrier by some patients, and belatacept is more costly than cyclosporine.
Limitations of the study are addressed in the accompanying editorial by Drs. Eliot Heher and James Markmann. They state, “Looking forward, several lines of inquiry beckon. First, we must define how best to combine belatacept with other available immunosuppressive agents to lower the risk of rejection mediated by memory T Cells resistant to costimulatory blockade. Second, head-to-head comparisons of belatacept to tacrolimus are needed, as tacrolimus itself is associated with better transplant survival compared to cyclosporine.” Despite such limitations, the editorialists are optimistic about belatacept’s future concluding, “as is typical with clinical research, we’re at the end of the beginning for belatacept, but with a lucky seven years of experience to guide us in answering the next set of critical questions.”
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Andrea Merrill, MD
Andrea was a 2015-2016 NEJM Group Editorial Fellow. She is currently in the middle of her General Surgery residency at Massachusetts General Hospital and is also conducting research focusing on improvements in breast cancer surgery. She plans to pursue a fellowship in Surgical Oncology at the completion of her residency.