Dipeptidyl Peptidase 4 Inhibition for Prophylaxis of Acute Graft-versus-Host Disease.

Abstract

BACKGROUND:

Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.

METHODS:

We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.

RESULTS:

A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.

CONCLUSIONS:

In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.).

• Authors: Sherif S Farag, Mohammad Abu Zaid, Jennifer E Schwartz, Teresa C Thakrar, Ann J Blakley, Rafat Abonour, Michael J Robertson, Hal E Broxmeyer, Shuhong Zhang
• Journal: The New England journal of medicine (N Engl J Med) Vol. 384 Issue 1 Pg. 11-19 (01 07 2021) ISSN: 1533-4406 [Electronic] United States
• PMID: 33406328 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Massachusetts Medical Society.

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Immunosuppressive Agents
• Sitagliptin Phosphate
• Sirolimus
• Tacrolimus

Topics

• Adult
• Dipeptidyl-Peptidase IV Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Drug Therapy, Combination
• Female
• Graft vs Host Disease (prevention & control)
• Hematopoietic Stem Cell Transplantation (adverse effects)
• Humans
• Immunosuppressive Agents (therapeutic use)
• Leukemia, Myeloid (therapy)
• Male
• Middle Aged
• Myelodysplastic Syndromes (therapy)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (therapy)
• Recurrence
• Sirolimus (therapeutic use)
• Sitagliptin Phosphate (administration & dosage, adverse effects, therapeutic use)
• Survival Analysis
• Tacrolimus (therapeutic use)
• Transplantation, Homologous
• Young Adult