Sitagliptin may reduce acute graft-versus-host disease following allogeneic stem-cell transplantation

1. While standard prophylaxis regimens against acute graft-versus-host disease (GVHD) are ineffective in a substantial portion of patients, less than 10% of patients who also received sitagliptin had such an event at the end of follow-up.

2. Adverse events were frequent but reversible, and none were attributed to the dipeptidyl peptidase 4 (DPP-4) inhibitor.

Evidence Rating Level: 2 (Good)

Study Rundown: Acute graft-versus-host disease (GVHD) occurs in one-third to one-half of patients who receive allogeneic hematopoietic stem-cell transplantation (HSCT) despite the use of immunosuppressive regimens involving various calcineurin inhibitors and antimetabolites. Sitagliptin is a selective inhibitor of dipeptidyl peptidase 4 (DPP-4), a transmembrane and secreted protein that is involved in numerous biologic processes including glucose metabolism, hematopoietic cytokine activity, and T-cell activation. Disruption of DPP-4 activity was found to reduce the incidence of acute GVHD in a murine model as well as in a clinical study of cord-blood transplantation, suggesting that sitagliptin may be a promising candidate for prophylaxis. In this present study, patients with preleukemia or leukemia received a two-week course of sitagliptin in conjunction with standard prophylactic treatment after myeloablative conditioning and stem cell infusion. Sitagliptin was found to promote engraftment and dramatically reduce the incidence of moderate- to life-threatening acute GVHD while preserving graft-versus-leukemia effects. Only 2 of over 35 patients had acute GVHD at 100 days, and nearly half of the study population remained GVHD-free and relapse-free at 1 year. While gastrointestinal adverse events were fairly common, no toxic effects could be directly attributed to sitagliptin. Overall, sitagliptin appeared to be both safe and highly efficacious in lowering the incidence of acute GVHD after HSCT. Larger, randomized controlled trials should be conducted to verify these findings as well as determine the optimal dosing strategy.

Click here to read the study in NEJM

Relevant Reading: High-dose sitagliptin for systemic inhibition of dipeptidylpeptidase-4 to enhance engraftment of single cord umbilical cord blood transplantation

In-Depth [prospective cohort]: This phase II trial conducted from January 2016 to October 2019 involved 36 patients between 18 and 60 years of age who had acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), refractory or advanced chronic myeloid leukemia (CML), or a myelodysplastic disorder of at least intermediate risk according to the Revised International Prognostic Scoring System. These patients first received myeloablative conditioning consisting of high-dose cyclophosphamide (120 mg per kilogram of body weight) and either fractionated total body irradiation (total dose, 13.5 Gy) or thiotepa (15 mg per kilogram); both combinations were followed by infusion of filgrastim-mobilized peripheral-blood stem cells. For prophylaxis of acute graft-versus-host disease (GVHD), sitagliptin was administered at a dosage of 600 mg orally per 12 hours from day −1 until day 14 in addition to a regimen of tacrolimus and sirolimus adjusted to target serum trough levels of 5 to 10 ng per milliliter. Plasma DPP-4 inhibition was greatest between 2-4 hours after dosing (nadir activity, 22±5%), and inhibition was sustained with a mean trough residual activity of 29±8%. Neutrophil and platelet engraftment were achieved in all patients in a median time of 13 days (range, 10 to 20) and 15 days (range, 13 to 114), respectively. Acute GVHD occurred in 2 patients by day 100, both of which received transplants from unrelated donors and received ≤70% of the planned total dose of sitagliptin. One patient had grade II GVHD involving the gut (stage 1), liver (stage 1), and skin (stage 3); the other had grade IV GVHD involving the skin (stage 3), gut (stage 4), and liver (stage 4). Together, the cumulative incidence of grade II to IV acute GVHD was 5% (95% confidence interval [CI], 1 to 16), and that of grade III or IV acute GVHD was 3% (CI, 0 to 12). At 1 year, the cumulative incidence of relapse was 26% (CI, 13 to 41), overall survival was 94% (CI, 79 to 98), and GVHD- and relapse-free survival was 46% (95% CI, 29 to 62).

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