BACKGROUND: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem-cell transplant (HSCT). The rate of GVHD is between 34% to 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, 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.
METHODS: This single-group, open-label, phase 2 clinical trial included 36 patients who underwent HSCT for 1 of several hematologic malignancies. 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.
RESULTS: 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 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.
Source: Farag SS, Zaid MA, Schwartz JE, et al. Dipeptidyl peptidase 4 inhibition for prophylaxis of acute graft-versus-host disease. N Engl J Med. 2021;384:11-19.
Commentary by Robert J. Ignoffo
Sitagliptin is approved for the treatment of type 2 diabetes. With its ability to inhibit DPP-4 activity, sitagliptin is effective in preventing acute GVHD, but the effective dose is 1200 mg daily versus the 100 mg daily used for the treatment of diabetes. Despite this high dose, sitagliptin did not have more adverse events than the sirolimus-tacrolimus immunomodulatory regimen. Adding sitagliptin produced a substantially lower incidence (5%) of grade II to IV acute GVHD versus 26% to 47% with tacrolimus-sirolimus, and 3% for grade III to IV versus 7% to 19% with tacrolimus-sirolimus. Treatment with sitagliptin also lowered the incidence of chronic GVHD to 37% versus 59% with tacrolimus-sirolimus.
The question arises whether we should wait for a randomized clinical trial before sitagliptin is approved for the prevention of GVHD. Further studies are needed to compare it with other standard prophylactic regimens. Farag and colleagues spent 2.5 years to obtain and publish their results; it may take twice as long to obtain enough patients to conduct a randomized study.
Another issue is that sitagliptin’s dosing was studied at 600 mg twice daily. Sitagliptin is sold as 100-mg oral tablets and costs approximately $500. Without a larger study, the manufacturer may not produce a dosage as high as 600 mg that could easily be administered. It is also questionable whether insurance companies would pay for sitagliptin without FDA approval. It remains to be seen if this very promising study will result in the off-label use of sitagliptin for the prevention of acute GVHD.