Lessons Learned: Early Termination of a Randomized Trial of Calcineurin Inhibitor and Corticosteroid Avoidance Using Belatacept

Abstract

The intent of this NIH-sponsored study was to compare a belatacept-based immunosuppressive regimen with a maintenance regimen of tacrolimus and mycophenolate (MMF). Nineteen primary, EBV-immune renal transplant recipients with a negative cross-match were randomized to one of three groups. All patient groups received perioperative steroids and maintenance MMF. Patients in groups 1 and 2 were induced with alemtuzumab and maintained on tacrolimus or belatacept, respectively. Patients in group 3 were induced with basiliximab, received 3 months of tacrolimus, and maintained on belatacept. There was one death with a functioning allograft due to endocarditis (group 1). There were three graft losses due to vascular thrombosis (all group 2) and one graft loss due to glomerular disease (group 1). Biopsy-proven acute cellular rejection was more frequent in the belatacept treated groups, with 10 treated episodes in 7 subjects compared to 1 episode in group 1. However, eGFR was similar between groups at week 52. There were no episodes of PTLD or opportunistic infections in any group. Protocol enrollment was halted prematurely due to high rate of serious adverse events. Such negative outcomes pose challenges to clinical investigators who ultimately must weigh the risk and benefit in randomized trials.

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

“…Two large‐scale trials, CTOT 10 and CTOT 16, were designed to evaluate belatacept‐based CNIA/ESW regimens but were terminated prematurely for high renal allograft loss rates (CTOT 10) and high acute rejection rates (CTOT 16). The reasons for differences between CTOT 10/CTOT 16 and the BEST trial are not immediately clear, but the authors’ impressions from the BEST trial are that rejection and viral infections respond more slowly to traditional therapy under belatacept than they do under CNI therapy in the presence of depleting T cell induction.…”

Co-inhibitory profile and cytotoxicity of CD57+PD-1− T cells in end-stage renal disease patients

“…However, these findings were not confirmed in recent randomized controlled clinical trials in which belataceptbased immunosuppressive therapy was compared with tacrolimus-based immunosuppressive therapy [21][22][23]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21]. In the study by de Graav et al [23], no association between rejection and higher frequencies of CD4 1 CD57 1 PD-1was found.…”

“…These authors also demonstrated that, after polyclonal stimulation, CD4 1 CD57 1 PD-1 -T cells produced high levels of the effector cytokines interferon (IFN)-g or tumour necrosis factor (TNF)-a, or exhibited cytotoxicity [20]. However, these findings were not confirmed in recent randomized controlled clinical trials in which belataceptbased immunosuppressive therapy was compared with tacrolimus-based immunosuppressive therapy [21][22][23]. However, these findings were not confirmed in recent randomized controlled clinical trials in which belataceptbased immunosuppressive therapy was compared with tacrolimus-based immunosuppressive therapy [21][22][23].…”

“…CD4 1 CD57 1 T cells were also found to infiltrate the kidney allograft during rejection, and genes involved in allograft rejection were up-regulated in this T cell subset [20]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21]. In the study by de Graav et al, 11 of the 20 (55%) belatacepttreated patients experienced biopsy-proven acute rejection (BPAR) compared with two of 20 in the control arm [12,23], while in another study patient enrolment was even halted because of a high rate of acute cellular rejection [21].…”

Alemtuzumab induction and belatacept maintenance in marginal pathology renal allografts

“…the basiliximab induction arm. 23 A review of the events suggested that technical issues may have contributed to at least two of the thromboses, but authors stated that it was not possible to rule out the concern of infusing two biologic medications around reperfusion placing a patient in a higher thrombotic risk, although this has not been substantiated.…”