Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem-cell transplant (HSCT). The rate of GVHD is between 34% and 51% within 100 days of undergoing transplant.
Dipeptidyl peptidase (DPP)-4 acts as a co-stimulatory factor for T-cell activation. In a preclinical model, down-regulation of DDP-4 expression prevented the incidence of acute GVHD and preserved graft-versus-tumor effects. In addition, a previous study of sitagliptin (Januvia), a selective DPP-4 inhibitor, in core-blood transplants in adults with hematologic malignancies had an acceptable side-effect profile and decreased incidence of acute GVHD.
This led researchers to investigate the efficacy of adding sitagliptin to standard prophylaxis after allogeneic HSCT for the prevention of acute GVHD (Farag SS, et al. N Engl J Med. 2021;384:11-19).
This single-group, open-label, phase 2 clinical trial included 36 patients who underwent HSCT for 1 of several conditions, including acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome. In all, 13 patients had matched-related donors, and the remaining 23 had unmatched-related donors.
All patients received sitagliptin 600 mg every 12 hours beginning the day before the transplant and continuing until day 14 after transplant, along with a standard immunosuppressive regimen of tacrolimus and sirolimus. The primary end point was grade II to IV acute GVHD by day 100. Secondary end points included mortality not related to disease relapse, disease relapse, and the incidence of chronic GVHD.
Of the 36 patients enrolled in the study, 2 patients had acute GVHD by day 100; 1 patient had grade II acute GVHD involving the gut (stage 1), liver (stage 1), and skin (stage 3) on day 81. Yet another patient had grade IV acute GVHD involving the skin (stage 3), gut (stage 4), and liver (stage 4) on day 29.
Overall, the incidence of grade II to grade IV GVHD was 5%, and the incidence of grade III to IV acute GVHD was 3%. A total of 28 patients received 80% or more of the planned 32 doses of sitagliptin.
The rate of disease relapse was 0% at 1 year, confirming the safety and tolerability of the drug. After 1 year, the incidence of disease relapse was 26% (95% confidence interval [CI], 13-41), and the incidence of chronic GVHD was 37% (95% CI, 22-53).
A total of 46% (95% CI, 29-62) of the patients had GVHD-free, relapse-free survival. No additional side effects were reported beyond those observed in patients undergoing allogeneic HSCT; in particular, no episodes of hyperglycemia were noted.
“The incidence of acute GVHD in our trial appears to be lower than in other trials testing other agents,” the researchers observed. “Although a control group was not included, the risks of grade II to IV and grade III or IV acute GVHD were substantially lower than previously observed with sirolimus plus tacrolimus alone…even when other agents such as methotrexate, mycophenolate, or antithymocyte globulin were added to the backbone regimen.”
The researchers noted that these results need to be confirmed in randomized clinical trials comparing sitagliptin with current standard GVHD prophylaxis regimens.