In a phase II trial reported in The New England Journal of Medicine, Farag et al found that the addition of the dipeptidyl peptidase 4 (DPP-4; CD26) inhibitor sitagliptin to tacrolimus and sirolimus prophylaxis resulted in a low rate of acute graft-vs-host disease among patients with hematologic malignancies or myelodysplastic disorders undergoing allogeneic hematopoietic stem cell transplantation.

DPP-4 is a transmembrane receptor expressed on T cells; it acts as a costimulator in activation of T cells.

Study Details

The trial, conducted at Indiana University School of Medicine and Indiana University Simon Comprehensive Cancer Center, enrolled 36 evaluable patients between January 2016 and November 2018. Patients had to have acute myeloid leukemia; acute lymphoblastic leukemia; a myelodysplastic disorder with a score > 3 on the Revised International Prognostic Scoring System; or chronic myeloid leukemia refractory to more than two tyrosine kinase inhibitors or beyond first chronic phase. Patients underwent myeloablative conditioning followed by allogeneic hematopoietic stem cell transplant from related or unrelated donors and received prophylaxis with tacrolimus and sirolimus; both were started on day -3 before transplant, tapered at day 100 in the absence of graft-vs-host disease, and discontinued at 180 days. Oral sitagliptin was given at 600 mg every 12 hours, starting on the day before hematopoietic stem cell transplant and continuing until day 14. The primary endpoint was reduction in the incidence of grade II–IV acute graft-vs-host disease from 30% based on prior reports to ≤ 15% by day 100.

Acute Graft-vs-Host Disease

Engraftment occurred in all patients, with median times to neutrophil and platelet engraftment of 13 and 15 days, and all patients exhibited ≥ 95% donor chimerism in whole blood or bone marrow by day 30.

Acute graft-vs-host disease occurred in 2 (5%) of 36 patients by day 100; 1 patient had grade II graft-vs-host disease and 1 had grade IV graft-vs-host disease. Thus, the incidence of grade II to IV graft-vs-host disease was 5% (95% confidence interval [CI] = 1%–16%). The incidence of grade III or IV graft-vs-host disease was 3% (95% CI = 0%–12%).

During median follow-up among surviving patients of 700 days, 9 patients had relapse at a median of 243 days, with a 1-year cumulative incidence of 26% (95% CI = 13%–41%). Chronic graft-vs-host disease occurred in 15 of 34 surviving patients without relapse beyond day 100, with a 1-year cumulative incidence of 37% (95% CI = 22%–53%). Graft-vs-host disease–free, relapse-free survival at 1 year was 46% (95% CI = 29%–62%). Nonrelapse mortality was 0% at 1 year. Overall survival at 1 year was 94% (95% CI = 79%–98%).

Toxicity

Toxicity was similar to that observed in patients undergoing allogeneic hematopoietic stem cell transplant. No adverse events were considered to be related to sitagliptin (including hypoglycemia, which has been associated with the agent). The most common grade 3 or 4 nonhematologic adverse events were oropharyngeal mucositis (21%), gastrointestinal adverse events (anorexia, nausea, or vomiting; 11%), and acute kidney injury (9%). A total of 14 infection-related events were observed.

The investigators concluded, “In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute graft-vs-host disease by day 100 after myeloablative allogeneic hematopoietic stem cell transplantation.”

Disclosure: The study was funded by the National Heart, Lung, and Blood Institute. For full disclosures of the study authors, visit nejm.org.