Sitagliptin for Acute Graft-Versus-Host Disease Prevention in Alternative Donor Transplantation: A Randomized Phase III Trial

PURPOSE This trial evaluated whether the addition of sitagliptin to antithymocyte globulin (ATG)–based prophylaxis reduces the incidence of acute graft-versus-host disease (aGVHD) after alternative donor hematopoietic stem-cell transplantation. METHODS This prospective, multicenter, open-label, randomized trial enrolled patients age 18-60 years with hematologic malignancies who received myeloablative conditioning haploidentical or unrelated donor transplantation. Participants were randomly assigned in a 1:1 ratio to ATG-based prophylaxis (ATG + calcineurin inhibitor + methotrexate + mycophenolate mofetil) with or without sitagliptin (600 mg orally once every 12 hours, days –1 to +14). The primary end point was the cumulative incidence of grade Ⅱ-Ⅳ aGVHD by day +100. RESULTS From December 22, 2021, to June 16, 2023, 190 of the 251 screened patients were enrolled, with a median follow-up of 29.8 (0.7-41.3) months. The sitagliptin group had a significantly lower incidence of grade Ⅱ-Ⅳ aGVHD on day +100 (14.7% v 31.6%; subdistribution hazard ratio [sHR] = 0.41; P = .005). Reduced grade Ⅲ-Ⅳ (6.3% v 18.9%; sHR = 0.30; P = .010) and intestinal aGVHD (12.6% v 29.5%; P = .004) and superior day +180 GVHD-free, relapse-free survival (GRFS; 86.3% v 72.6%; HR = 0.44; P = .016) were also observed. No between-group disparities were detected in 2-year chronic GVHD, nonrelapse mortality, relapse-free/overall survival, or cytomegalovirus/Epstein-Barr virus reactivation; the adverse event profiles were similar. CONCLUSION In this randomized trial, adjunct sitagliptin to ATG-containing prophylaxis significantly reduced the incidence of grade Ⅱ-Ⅳ aGVHD. Reductions in severe and intestinal aGVHD, as well as improved day +180 GRFS, were exploratory observations; no significant benefits were detected for long-term GRFS, overall survival, or RFS, and treatment did not alter the engraftment, relapse, or infection risk.