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.

Keywords: antibody biology; belatacept; clinical research/practice; clinical trial; cyclosporin A (CsA); immunosuppressant - calcineurin inhibitor; immunosuppressant - fusion proteins and monoclonal antibodies; kidney transplantation/nephrology.

Figure 1

Absolute percentage of patients who developed de novo DSAs by month 84 in (A) BENEFIT and (B) BENEFIT‐EXT. CI, confidence interval; CsA, cyclosporine; DSA, donor‐specific antibody; LI, less intense; MI, more intense

Figure 2

Kaplan‐Meier analysis of the cumulative rate of de novo DSA development in (A) BENEFIT and (B) BENEFIT‐EXT. CI, confidence interval; CsA, cyclosporine; DSA, donor‐specific antibody; HR, hazard ratio; LI, less intense; MI, more intense

Figure 3

MFI in the subset of patients in BENEFIT and BENEFIT‐EXT who developed de novo DSAs. CsA, cyclosporine; DSA, donor‐specific antibody; LI, less intense; MFI, mean fluorescence intensity; MI, more intense