In a phase II trial reported in The New England Journal of Medicine, Sherif S. Farag, MD, PhD, of Indiana University School of Medicine, and colleagues, 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 malignancy or myelodysplastic disorders undergoing allogeneic hematopoietic stem cell transplantation (HSCT).¹

DPP-4 is a transmembrane receptor expressed on T cells and acts as a co-stimulator in activation of T cells.

Sherif S. Farag, MD, PhD

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 HSCT with peripheral-blood stem cells from related or unrelated donors and received prophylaxis with tacrolimus and sirolimus; both were started on day -3 before HSCT, 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 HSCT and continuing until day 14. The primary endpoint was reduction in the incidence of grade 2 to 4 acute graft-vs-host disease, from 30% based on prior reports to ≤ 15% by day 100.

Among all patients, median age was 46 years (range = 20–59 years) and 19 (53%) were female. Karnofsky performance status was ≥ 90% in 34 (94%). Disease Risk Index group was low in 2 (6%), intermediate in 24 (67%), and high/very high in 10 (28%). Recipient/donor cytomegalovirus status was negative/negative in 9 (25%), positive/negative in 12 (33%), negative/positive in 4 (11%), and positive/positive in 4 (11%).

In total, 19 patients (53%) had acute myeloid leukemia, 9 (25%) acute lymphoblastic leukemia, 4 (11%) myelodysplastic syndrome, and 4 (11%) chronic myeloid leukemia. Matched donors were related for 13 patients (36%) and unrelated for 23 (64%).

Acute and Chronic Graft-vs-Host Disease and Survival Outcomes

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 with grade 2, and 1 with grade 4 graft-vs-host disease; thus, the incidence of grade 2 to 4 graft-vs-host disease was 5% (95% confidence interval [CI] = 1%– 16%). The incidence of grade 3 or 4 graft-vs-host disease was 3% (one patient; 95% CI = 0%–12%). Both patients with acute graft-vs-host disease had received transplants from unrelated donors. The case of grade 2 graft-vs-host disease had onset on day 81 and involved the gut (stage I), liver (stage I), and skin (stage III). The case of grade 4 graft-vs-host disease had onset on day 29 and involved the skin (stage III), gut (stage IV), and liver (stage IV). An additional patient, who had a related donor, had onset of grade 2 acute graft-vs-host disease on day 140 in association with termination of immunosuppression on day 110 due to low donor chimerism. No additional acute graft-vs-host disease was observed after day 100.

During median follow-up among surviving patients of 700 days, nine 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 (44%) of 34 surviving patients without relapse beyond day 100, with a 1-year cumulative incidence of 37% (95% CI = 22%–53%). Among these 15 patients, mild, moderate, and severe chronic graft-vs-host disease occurred in 5, 7, and 3, respectively, and 9 received systemic glucocorticoid treatment.

Overall, 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%). In subgroup analyses, graft-vs-host disease–free, relapse-free survival at 1 year was 38.1% among patients with acute lymphoblastic leukemia and 47.9% among those with myeloid malignancies and 1-year overall survival was 87.5% and 96.3%. According to donor status, graft-vs-host disease–free, relapse-free survival at 1 year was 58.3% among patients with related donors and 40.5% among those with unrelated donors and 1-year overall survival was 84.6% and 100%.

Toxicity

Toxicity was similar to that observed in patients undergoing allogeneic HSCT. 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 occurring within 30 days after HSCT 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.

Acute hemolysis due to passenger lymphocyte syndrome occurred in two patients, with one developing acute renal failure. Thrombotic microangiopathy was observed in one patient, with resolution after discontinuation of tacrolimus. Infections included cytomegalovirus viremia in six patients, BK virus cystitis in five patients, and bacteremia in three patients. Human herpesvirus 6 and Epstein-Barr virus reactivation occurred in the patient with grade 4 acute graft-vs-host disease.

The investigators concluded: “Our trial confirmed the safety of high-dose sitagliptin and showed a low incidence of grade 2 to 4 acute GVHD [graft-vs-host disease] by day 100 when used in combination with tacrolimus plus sirolimus after myeloablative allogeneic peripheral-blood stem-cell transplantation. Inhibition of DPP-4 should be further investigated in randomized trials that compare sitagliptin with current standard GVHD prophylaxis regimens.” 

DISCLOSURE: The study was funded by the National Heart, Lung, and Blood Institute. Dr. Farag has received honoraria from Jazz; has served in a consulting or advisory role for Jazz; and has received institutional research funding from Astellas Pharma, Bristol Myers Squibb, and Incyte.

REFERENCE

1. Farag SS, Abu Zaid M, Schwartz JE, et al: Dipeptidyl peptidase 4 inhibition for prophylaxis of acute graft-versus-host disease. N Engl J Med 384:11-19, 2021.