ATC2015: Belatacept in Kidney Transplantation
There were several abstracts presented about outcomes in patients treated with belatacept, a recently FDA-approved immunosuppressive agent that blocks T-cell activation. Belatacept inhibits T cell activation by blocking the co-stimulatory molecules B7-1 and B7-2. These studies interest me as they challenge the current gold standard of immunosuppression, the calcineurin inhibitors (tacrolimus and cyclosporine). The calcineurin inhibitors, although excellent at preventing rejection, have numerous side effects and toxicities that contribute to morbidity in kidney transplant recipients. Below are two studies that compared belatacept and calcineurin inhibitors. In full disclosure, the studies were sponsored by Bristol Myers Squib.
Final Results from the BENEFIT EXT and BENEFIT Trial: A 7 Year Follow-Up
The BENEFIT trials were two large studies which compared 2 arms of belatacept (low intensity [LI] and medium intensity [MI]) to cyclosporine based immunosuppression. BENEFIT EXT was specifically using extended criteria kidney organs. In both trials, the groups received IL-2 inhibitor induction and were maintained on mycophenoate mofetil and prednisone. Three and 5 year results of the study revealed that belatacept-treated patients had higher GFR than cyclosporine-treated patients. However, the belatacept group also had more rejection episodes and a higher incidence of PTLD (post transplant lymphoproliferative disease) in patients who were EBV antibody negative. These two studies led the FDA to approve the use of low intensity belatacept for EBV positive patients.
Dr. Florman presented the final 7-year results of the BENEFIT EXT trial. Over 70% of patients were followed for the full 7 years of the study. What they found was very similar to the 3 and 5 year analysis. Belatacept-treated patients had better GFR at 7 years. There was no statistical difference in time to patient death or graft loss. They had more rejection episodes; however, this was not statistically significant. There were similar number of infections and cancers except for the EBV negative group treated with belatacept in which there were more cases of PTLD. To put it in perspective, the mean GFR was 57.6 in the MI group, 59.1 in LI group, and 44.6 in the cyclosporine group.
Dr. Vincenti presented the final 7 year results of the BENEFIT trial. The results were similar except that rejection episodes were higher in the belatacept groups. Most rejections occurred within 6 months of transplant. What was more impressive, however, was that both GFR and graft survival were better in the belatacept groups. He commented that this is the first time an immunosuppressive agent has shown better graft survival than a calcineurin inhibitor in a head-to-head trial.
Evaluation of Donor-Specific Antibodies Through 7 years with Belatacept in BENEFIT and BENEFIT-EXT
De novo donor-specific antibodies are a major cause of late allograft loss in kidney transplantation. They occur in about 15% of patients treated with calcineurin inhibitors (CNI) 5 years posttransplant and are often found in patients at the time of graft loss. They can result in both acute and chronic antibody mediated rejection which is very difficult to treat and portrays a dismal prognosis. Prior studies have shown that stopping CNI or converting to an mTOR inhibitor can even increase dn DSA production.
Dr. Bray presented data from the two large BENEFIT studies that compared cyclosporine-based immunosuppression to belatacept-based immunosuppression. During these studies, the authors prospectively tested for DN DSA at the following time points: 6, 12, 24, 36, 48, 60 and 84 months. Patients in the belatacept arms had less de novo DSA as compared to the cyclosporine arm. In the BENEFIT trial, DN DSA occurred in 2.2% of patients vs 11.3% of cyclosporine treated patients. In the BENEFIT EXT trial, DN DSA occurred in 2.7% of patients on belatacept vs. 11.9% of cyclosporine-treated patients.
Both studies were conducted in an intent-to-treat analysis therefore it is not known if changing treatment between groups affected the outcomes. In addition the BENEFIT and BENEFIT EXT studies used IL-2 blocking induction with belatacept or cyclosporine while most transplant centers in the USA use lymphocyte-depleting induction with tacrolimus. The question remains if the superiority of belatacept in preserving GFR is present over the more commonly used regiment of lymphocyte-depleting induction coupled with tacrolimus. Regardless the results are intriguing and suggest that blocking the co-stimulatory pathway may reduce formation of DN DSA and sustain transplant function without nephrotoxicity up to 7 years post transplantation.
Post written by Dr. Vinay Nair, AJKD Blog Advisory Board member.
Check out more AJKD blog coverage of the 2015 American Transplant Congress.
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