De novo donor-specific antibodies in belatacept-treated vs cyclosporine-treated kidney-transplant recipients: Post hoc analyses of the randomized phase III BENEFIT and BENEFIT-EXT studies

Abstract

Donor‐specific antibodies (DSAs) are associated with an increased risk of antibody‐mediated rejection and graft failure. In BENEFIT and BENEFIT‐EXT, kidney‐transplant recipients were randomized to receive belatacept more intense (MI)–based, belatacept less intense (LI)–based, or cyclosporine‐based immunosuppression for up to 7 years (84 months). The presence/absence of HLA‐specific antibodies was determined at baseline, at months 6, 12, 24, 36, 48, 60, and 84, and at the time of clinically suspected episodes of acute rejection, using solid‐phase flow‐cytometry screening. Samples from anti‐HLA‐positive patients were further tested with a single‐antigen bead assay to determine antibody specificities, presence/absence of DSAs, and mean fluorescence intensity (MFI) of any DSAs present. In BENEFIT, de novo DSAs developed in 1.4%, 3.5%, and 12.1% of belatacept MI‐treated, belatacept LI‐treated, and cyclosporine‐treated patients, respectively. The corresponding values in BENEFIT‐EXT were 3.8%, 1.1%, and 11.2%. Per Kaplan‐Meier analysis, de novo DSA incidence was significantly lower in belatacept‐treated vs cyclosporine‐treated patients over 7 years in both studies (P < .01). In patients who developed de novo DSAs, belatacept‐based immunosuppression was associated with numerically lower MFI vs cyclosporine‐based immunosuppression. Although derived post hoc, these data suggest that belatacept‐based immunosuppression suppresses de novo DSA development more effectively than cyclosporine‐based immunosuppression.

Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial

“…Importantly, DSA rates in the BENEFIT trial were no different at 1 year between belatacept and cyclosporine; however, significant differences were present at 7 years. Longer‐term follow‐up will be important in defining whether an advantage of belatacept in reducing DSA rates will occur under belatacept in the BEST trial similar to what was observed in BENEFIT and BENEFIT EXT trials …”

Tailored use of belatacept in adolescent kidney transplantation

“…It provides effective costimulatory blockade and has been used as maintenance immunosuppression in adult kidney transplantation . Belatacept has been shown to improve renal function, prolong allograft survival, and prevent dn DSA formation when compared to CNI‐based regimens . Its use has also, however, been associated with early rejection episodes that complicate its implementation in the first year of therapy.…”

The impact of belatacept on third-party HLA alloantibodies in highly sensitized kidney transplant recipients

“…18 Based on those data, belatacept was accepted as a safe immunosuppressive therapy. 10,11 Recent post hoc analyses of those studies revealed that belatacept also decreased preexisting DSA more effectively than cyclosporine. 10,11 Recent post hoc analyses of those studies revealed that belatacept also decreased preexisting DSA more effectively than cyclosporine.…”

“…5 However, the impact of belatacept on long-lived plasma cells (LLPC), which are likely responsible for the continuous production of preexisting antibodies (including HLA antibodies) has not been characterized. 9 Finally, recent studies revealed decreased production of de novo donor-specific HLA antibodies (DSA) 10,11 and elimination of preexisting DSA 12 in minimally sensitized recipients treated with belatacept compared to those patients treated with cyclosporine. 7,8 Furthermore, studies in healthy human volunteers demonstrated CD28 expression on approximately 30% of LLPC.…”