Adding the selective, oral dipeptidyl peptidase-4 inhibitor, sitagliptin, to antithymocyte globulin–based prophylaxis significantly reduced the incidence of grade 2 to 4 acute graft-vs-host disease (GVHD) among patients undergoing alternative donor hematopoietic stem-cell transplantation, according to findings from a randomized phase III trial in China reported by Qiao et al in the Journal of Clinical Oncology. The study also identified potential reductions in severe and intestinal acute GVHD, although long-term survival outcomes did not differ significantly between treatment groups.
Study Details
The prospective, open-label trial enrolled 190 adults aged 18 to 60 years with hematologic malignancies who were undergoing myeloablative haploidentical or unrelated donor transplantation. Patients were randomly assigned to receive standard prophylaxis consisting of antithymocyte globulin, a calcineurin inhibitor, methotrexate, and mycophenolate mofetil, either alone (n = 95) or with the antidiabetic agent sitagliptin (n = 95). Sitagliptin was administered at 600 mg every 12 hours from day −1 through day +14.
Enrollment occurred between December 2021 and June 2023 at five centers in China. The median patient age was 38.5 years; 56% had acute myeloid leukemia, and approximately 76% underwent haploidentical transplantation. The primary endpoint was the cumulative incidence of grade 2 to 4 acute GVHD by day 100. Median follow-up was 29.8 months.
Key Results
By day 100, the cumulative incidence of grade 2 to 4 acute GVHD was 14.7% in the sitagliptin group vs 31.6% in the control group, meeting the primary endpoint (subdistribution hazard ratio [sHR] = 0.41, 95% confidence interval [CI] = 0.22–0.76; P = .005). The findings were consistent in the per-protocol analysis and after adjustment for baseline differences in remission status.
Exploratory analyses also favored sitagliptin. Grade 3 to 4 acute GVHD occurred in 6.3% vs 18.9% of patients, respectively (sHR = 0.30; P = .010), with no grade 4 cases in the sitagliptin group. Intestinal acute GVHD occurred in 12.6% vs 29.5% of patients (P = .004). At 6 months, GVHD-free, relapse-free survival was 86.3% vs 72.6% (HR = 0.44; P = .016).
At 2 years, overall survival was 86.2% with sitagliptin vs 83.0% with standard prophylaxis (HR = 0.79; P = .531), and relapse-free survival was 81.9% vs 78.6% (HR = 0.82; P = .559). The 2-year incidence of chronic GVHD was 10.6% vs 18.1% (P = .142).
Median neutrophil and platelet recovery occurred on days 11 and 14, respectively, in both groups. Grade 3 to 5 adverse events within 42 days after transplantation occurred in 32.6% of sitagliptin recipients vs 54.7% of controls. Five patients discontinued sitagliptin because of adverse events, primarily gastrointestinal discomfort.
The investigators concluded: “In this randomized trial, adjunct sitagliptin to [antithymocyte globulin]–containing prophylaxis significantly reduced the incidence of grade 2 to 4 [acute] GVHD. Reductions in severe and intestinal [acute] GVHD, as well as improved day +180 [GVHD-free, relapse-free survival], were exploratory observations; no significant benefits were detected for long-term [GVHD-free, relapse-free survival], overall survival, or [relapse-free survival], and treatment did not alter the engraftment, relapse, or infection risk.”
Yang Xu, MD, of National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, Jiangsu Key Laboratory of Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China and Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China, is the corresponding author for the Journal of Clinical Oncology article.
DISCLOSURE: The study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project, Key Program of the National Natural Science Foundation of China, and others. For full disclosures of the study authors, visit ascopubs.org.
