Diabetes Drug Shines as GVHD Prophylaxis

Patients undergoing matched allogeneic stem-cell transplantation (SCT) had a low incidence of graft-versus-host disease (GVHD) with the addition of the diabetes drug sitagliptin (Januvia) to standard prophylaxis, a small prospective study showed.

Two of 36 evaluable patients developed acute GVHD by day 100, one of which was grade III/IV. The cohort had a 1-year relapse incidence of 26% and chronic GVHD incidence of 37%. Non-relapse mortality was 0% at 1 year.

Toxicities were consistent with known adverse effects associated with allogeneic SCT, reported Sherif S. Farag, MD, PhD, of Indiana University School of Medicine in Indianapolis, and colleagues.

“The incidence of acute GVHD in our trial appears to be lower than in other trials testing other agents,” the researchers wrote in their study online in the New England Journal of Medicine. “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 regimens.

“Our results also compare favorably with other approaches, including post-transplantation cyclophosphamide in combination with tacrolimus and mycophenolate,” the team continued. “A number of new agents, including abatacept (Orencia), atorvastatin (for treatment of donor and recipient), vorinostat (Zolinza), and vedolizumab (Entyvio), also have shown promising results in single-group trials, although none appears to achieve a lower level of acute GVHD than sitagliptin.”

Ready availability, ease of administration, safety, and relatively inexpensive cost as compared with other new agents make the dipeptidyl peptidase 4 (DPP-4) inhibitor clinically attractive, the investigators added.

The results require validation, but hold promise for future development of strategies to prevent GVHD, according to the author of an accompanying editorial.

“The innovative testing of an inexpensive medication repurposed to prevent a major complication of allogeneic hematopoietic cell transplantation by targeting interactions between T cells and APCs [antigen-presenting cells] opens a whole new avenue of investigations with many important questions yet to be answered,” wrote Paul J. Martin, MD, of Fred Hutchinson Cancer Research Center and the University of Washington in Seattle.

“From a clinical perspective, outcomes could theoretically be improved by having a parenteral formulation, since oral administration of sitagliptin was limited by severe mucositis. The most effective duration of sitagliptin administration remains to be determined, and the extent to which prevention of acute GVHD depends on concurrent treatment with sirolimus and tacrolimus is not known. On the one hand, conventional immunosuppression with T-cell-targeted agents might be needed to supplement the activities of sitagliptin, but on the other hand, immunosuppressive drugs that inhibit biochemical pathways after T-cell receptor signaling could interfere with induction of anergy,” he said.

Whether sitagliptin can prevent GVHD in mismatched recipients also remains to be seen, Martin added.

DPP-4 (also known as CD26) contributes to a variety of biological processes, including insulin release, stromal-cell-derived factor 1-inducing homing of stem cells, hematopoietic cytokine activity, and T-cell immune function.

The rationale for evaluating sitagliptin as GVHD prophylaxis evolved from recognition that DPP-4 acts as a co-stimulatory factor for T-cell activation. In a preclinical model, down-regulation of DDP-4 expression prevented acute GVHD and preserved graft-versus-tumor effects.

The phase II trial involved patients who underwent allo-SCT following myeloablative conditioning and mobilization of peripheral-blood stem cells. Patients received stem cells from matched related or unrelated donors. All patients received sitagliptin beginning the day before transplantation and continuing to day 14, along with tacrolimus and sirolimus. The primary endpoint was the incidence of grade II-IV acute GVHD at day 100.

The 36 evaluable patients had a median age of 46, and most underwent SCT for acute myeloid leukemia (19 patients, 53%) or acute lymphoblastic leukemia (nine, 25%). Most patients (24, 67%) were categorized as intermediate risk. Thirteen patients had matched related donors, and the remaining 23 had matched unrelated donors.

The results showed an overall incidence of grade II-IV acute GVHD at day 100 of 5.6%, which included a single case of grade III-IV GVHD. Both patients who developed acute GVHD by day 100 had unrelated donors.

All but eight patients received at least 80% of the planned 32 doses of sitagliptin. The eight patients received fewer doses because of mucositis-related swallowing difficulty. Both patients who developed grade II-IV acute GVHD by day 100 received fewer than 80% of planned doses.

There were no toxic effects attributable to sitagliptin, and in particular, no patient developed hypoglycemia, Farag and co-authors noted.