Three-Year Outcomes From BENEFIT-EXT: A Phase III Study of Belatacept Versus Cyclosporine in Recipients of Extended Criteria Donor Kidneys

Abstract

Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacepttreated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population.Key words: Belatacept, cyclosporine, extended criteria donor, kidney, renal function Abbreviations: BENEFIT-EXT, belatacept evaluation of nephroprotection and efficacy as first-line immunosupression trial-EXTended criteria donors; CI, confidence interval; CNS, central nervous system; DCD, donation after cardiac death; ECD, extended criteria donor; LI, less intensive; MI, more intensive; PTLD, posttransplant lymphoproliferative disorder; UNOS, United Network for Organ Sharing.

Long-Term Outcomes in Belatacept- Versus Cyclosporine-Treated Recipients of Extended Criteria Donor Kidneys: Final Results From BENEFIT-EXT, a Phase III Randomized Study

“…As in prior analyses 28, 29, 30, acute rejection was defined as central biopsy–proven rejection that was either clinically suspected for protocol‐defined reasons or clinically suspected for other reasons and treated. A combined end point comprising time to first occurrence of death, graft loss or estimated GFR (eGFR) <20 mL/min per 1.73 m 2 was examined post hoc .…”

“…The statistical approaches used in this 7‐year analysis differ from those used at 1, 3, and 5 years after transplant 28, 29, 30. First, in the present report, all evaluable patients were analyzed per the intent‐to‐treat principle; evaluable patients were alive and observable at 84 mo after randomization or died or experienced graft loss by month 84.…”

“…First, in the present report, all evaluable patients were analyzed per the intent‐to‐treat principle; evaluable patients were alive and observable at 84 mo after randomization or died or experienced graft loss by month 84. Similarly, the intent‐to‐treat population was analyzed at 1 and 3 years after transplant 28, 29, whereas a subgroup of patients corresponding to the long‐term extension cohort was analyzed at 5 years after transplant 30. The long‐term extension cohort represented a subset of the intent‐to‐treat population because it was composed of only those patients who completed 36 mo of study treatment and consented to continue the study beyond month 36 30.…”

“…The long‐term extension cohort represented a subset of the intent‐to‐treat population because it was composed of only those patients who completed 36 mo of study treatment and consented to continue the study beyond month 36 30. Second, rates of death and/or graft loss were presented as point estimates at 1 and 3 years after transplant 28, 29, but in the present analysis, the Kaplan–Meier method was used to derive estimated rates of death and/or graft loss. Third, renal function was assessed at 1, 3, and 5 years after transplant using analysis of variance, linear mixed modeling and analysis of covariance, respectively 28, 29, 30.…”

“…These randomized phase III studies compared two belatacept‐based immunosuppressive regimens (more intense [MI] and less intense [LI]) with CsA‐based immunosuppression in adult kidney transplant recipients. In BENEFIT‐EXT, analyses performed at 1, 3 and 5 years after transplant demonstrated that belatacept‐based immunosuppression was associated with similar rates of patient and graft survival and superior renal function versus CsA‐based immunosuppression; however, rates of acute rejection were numerically higher with belatacept‐based treatment 28, 29, 30.…”