CD40 Ligand Blockade for Prevention of Graft-Versus-Host Disease

PURPOSE This phase I-Ib trial evaluated a novel CD40L blocking antibody, BMS-986004, for the prevention of graft-versus-host disease (GVHD) after unrelated donor allogeneic hematopoietic cell transplantation (HCT). PATIENTS AND METHODS A total of 34 patients were treated at three centers. The safety and biologic activity of single-dose BMS-986004 (675 mg [n = 6] and 1,500 mg [n = 6]; one-time dose) were evaluated. Safety of prolonged dosing was then examined in separate cohorts (drug administration every 2 weeks × 3 [n = 3], 5 [n = 3] or 7 doses [n = 16]). Included patients received 8/8 HLA-matched unrelated donor peripheral blood stem-cell HCT and sirolimus/tacrolimus GVHD prophylaxis. Comprehensive HCT outcome data were collected through 2 years, inclusive of GVHD outcomes, immune reconstitution and infections, and biologic correlative studies. RESULTS BMS-986004, a single, one-time dose of 1,500 mg was identified as the safe and biologically active single-dose regimen, and prolonged dosing cohorts demonstrated safety through the seven-dose duration regimen. In phase Ib (n = 16), grade II-IV acute GVHD was 25% with no grade III or IV acute GVHD. Moderate-severe chronic GVHD at 2 years was 18.4%. Considering all patients (n = 34), a total of five deep venous thrombosis (DVT) events occurred and no significant association was detected between DVT and serial D-dimer and TAT levels. There was no evidence for excess infectious complications or cytomegalovirus reactivation. Two-year estimates were the following: Non-relapse mortality 15.3% (95% CI, 5.4% to 29.8%), relapse 22% (95% CI, 9.5% to 37.8%), and overall survival 77.8% (95% CI, 58.7% to 88.8%). CONCLUSION This trial demonstrates that next-generation CD40L blocking antibodies can be used safely in HCT recipients and supports initial clinical efficacy in the prevention of GVHD. Further study is needed in larger populations to verify these outcomes.