Sitagliptin may prevent acute GVHD after peripheral blood stem cell transplantation
Sitagliptin significantly reduced incidence of acute graft-versus-host disease after myeloablative allogeneic peripheral blood stem cell transplantation, according to phase 2 study results published in The New England Journal of Medicine.
The agent, in combination with sirolumus and tacrolimus, also appeared safe.
“Acute GVHD is a major complication of allogeneic stem cell transplantation, which is a curative therapy for many patients with blood cancers. Reducing the incidence and severity of acute GVHD would make transplants safer and potentially improve survival of patients,” Sherif S. Farag, MD, PhD, FRACP, FRCPA, Lawrence H. Einhorn professor of oncology at Indiana University School of Medicine, told Healio.
As Healio previously reported, preclinical studies showed sitagliptin — a selective dipeptidyl peptidase 4 (DPP-4) inhibitor approved in the United States for treatment of type 2 diabetes — inhibits mixed-lymphocyte reactions in a dose-dependent manner.
The novel approach of targeting DPP-4 for prevention of acute GVHD was based on interest in DPP-4 among researchers at Indiana University Simon Comprehensive Cancer Center, according to Farag. Initial studies at the center indicated that inhibiting DPP-4 — a homodimeric type II transmembrane receptor that is identical to the leucocyte surface antigen CD26 — with sitagliptin could improve engraftment of cord blood cell transplants.
“We undertook a series of trials testing sitagliptin in cord blood transplant in patients with high-risk blood cancers. In these trials, we noted that while DPP-4 inhibition with sitagliptin could potentially enhance engraftment, an unexpected observation was that patients treated had a very low incidence of acute GVHD, much lower than would be expected,” Farag said.
In one pilot trial, Farag and colleagues found that only one of 16 patients developed grade 2 acute GVHD, suggesting sitagliptin may have a role in GVHD prevention.
In the current phase 2 trial, the investigators assessed whether inhibition of DPP-4 with sitagliptin could prevent acute GVHD among a cohort of 36 patients (median age, 46 years; range, 25-59; 53% women) who received peripheral blood stem-cell transplants from matched related or unrelated donors. Most (78%) had acute myeloid leukemia or acute lymphoblastic leukemia, 11% had myelodysplastic syndrome and 11% had chronic myeloid leukemia.
Patients received sitagliptin dosed at 600 mg every 12 hours beginning 1 day prior to transplant through day 14 after transplant, for a total of 32 doses. Tacrolimus and sirolimus were started 3 days prior to transplant and tapered at day 100 after transplant, with a plan to stop at approximately 180 days after transplant. Patients also routinely received antibiotic prophylaxis with ciprofloxacin, fluconazole and trimethoprim/sulfamethoxazole.
A reduction in grade 2 to grade 4 acute GVHD by day 100 from the historical rate of 30% to 15% or less served as the primary endpoint.
Median follow-up was 700 days (range, 327-1,313).
Results showed two patients developed acute GVHD by day 100, for a cumulative incidence of grade 2 to grade 4 GVHD of 5% (95% CI, 1-16) and cumulative incidence of grade 3 to grade 4 acute GVHD of 3% (95% CI, 0-12).
Cumulative incidence of chronic GVHD at 1 year was 37% (95% CI, 22-53) and cumulative incidence of relapse at 1 year was 26% (95% CI, 13-41).
Researchers also reported 1-year rates of zero for nonrelapse mortality, 46% (95% CI, 29-62) for GVHD-free RFS and 94% (95% CI, 79-98) for OS.
Clinically significant nonhematologic toxicities included grade 3 to grade 4 mucositis (n = 21) and acute hemolysis (n = 2) with subsequent renal failure in one patient. Infectious complications included cytomegalovirus viremia in six patients, BK virus cystitis in five patients and bacteremia in three patients.
“Sitagliptin was well-tolerated, safe and did not appear to increase complications of transplant or relapse of leukemia after transplant,” Farag said. “While a number of other agents are being tested, sitagliptin is an already-approved drug, is much simpler to administer and relatively inexpensive — possibly the least expensive intervention in the transplant process.”
If confirmed in phase 3 trials, the results could lead to safer allogeneic transplants with reduced mortality, according to Farag.
“The next steps should include a large phase 3 trial, as well a trial testing sitagliptin with other agents to reduce chronic GVHD. The findings might also have potential to prevent rejection of solid organ transplants,” he said.
Future studies also are needed to determine whether CD26 inhibition can prevent acute GVHD while preserving donor T-cell activity against recipient T cells and malignant cells when reduced-intensity regimens are used prior to allogeneic HSCT in older patients and those with co-existing conditions, according to an editorial accompanying the study by Paul J. Martin, MD, researcher in the division of clinical research at Fred Hutchinson Cancer Research Center and in the department of medicine at University of Washington.
“Whether sitagliptin can prevent GVHD after HSCT in HLA-mismatched recipients, as suggested by results with umbilical-cord blood cell grafts, and whether modifications of the immunosuppressive regimen could decrease the risk for chronic GVHD remain to be determined. Lastly, the current results encourage studies to test whether CD26 inhibition could prevent acute rejection of solid organ allografts,” Martin wrote.