Sitagliptin, combined with sirolimus plus tacrolimus, shows feasibility in small phase II trial

A novel combination of two immunosuppressive agents plus sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor used to treat diabetes, resulted in a low rate of acute graft-versus-host disease (GVHD) in patients who had undergone allogeneic hematopoietic stem-cell transplantation (HSCT), a phase II, non-randomized trial found.

In a small sample of 36 evaluable patients, acute GVHD occurred in only two patients 100 days post-HSCT, Sherif Farag, MD, PhD, Indiana University School of Medicine in Indianapolis, and colleagues reported in The New England Journal of Medicine.

Chronic GVHD occurred in 15 out of 34 patients who survived without relapse beyond day 100, for a one-year cumulative incidence rate of 37% (95% CI, 22-53%), the investigators noted. “Acute graft-versus-host disease (GVHD) remains a major complication and cause of death after allogeneic hematopoietic stem-cell transplantation (HSCT),” they wrote.

“Our trial confirmed the safety of high-dose sitagliptin and showed a low incidence of grade II to IV acute GVHD by day 100 when used in combination with tacrolimus plus sirolimus after myeloablative allogeneic peripheral-blood stem-cell transplantation,” Farag and colleagues added.

Study Design

Patients had undergone allogeneic HSCT for the treatment of acute myeloid (AML) or acute lymphoblastic leukemia (ALL).

The prophylactic regimen used in the study consisted of intravenous tacrolimus at a dose of 0.02 mg/kg/day which was started on day minus 3 and which was later switched to an oral formulation when the patient could comfortably swallow. Sirolimus was also initiated on day minus 3 at a dose of 4 mg day; the doses of both drugs later were modified to target serum trough levels of 5 to 10 ng/mL.

If patients did not develop GVHD, both tacrolimus and sirolimus were tapered at day 100 and discontinued by about day 180. Sitagliptin was initiated on day minus one at a dose of 600 mg, every 12 hours, and was continued until day 14.

“The primary end point was grade II to IV acute GVHD by day 100,” the authors wrote, and the median follow-up of surviving patients was 700 days (range, 327-1313 days).

“Overall, 9 patients had a relapse at a median of 243 days (range, 71-322) after transplantation with a cumulative incidence of relapse at 1 year of 26% (95% CI, 13 to 41),” Farag and colleagues wrote, adding that the one-year, GVHD-free, relapse-free survival rate was 46% (95% CI, 29-62%) while 94% of patients (95% CI, 79-98%) were still alive one year post-HSCT.

There was no control group included in the trial. Nevertheless, the risk of grade II to IV acute GVHD in the current trial was “substantially lower” than previously reported rates with sirolimus plus tacrolimus alone.

Moreover, even if a number of newer agents including vorinostat and vedolizumab have shown “promising” results in single group trials, “none appears to achieve a lower level of acute GVHD than sitagliptin,” the study authors pointed out.

Indeed, even with the use of standard prophylaxis regimens, grade II to IV acute GVHD occurs in somewhere between one-third to about half of patients by day 100 after patients undergo allogeneic transplantation.

Sitagliptin is also easy to administer, has very mild adverse effects, and is relatively inexpensive compared with the newer agents, all of which make the drug a clinically attractive candidate for the prophylaxis of acute GVHD in the setting of HSCT.

Preclinical studies have shown that DPP-4 inhibitors reduce T-cell activation. Thus, the authors hypothesized that DPP-4 inhibition with sitagliptin might reduce the incidence of acute GVHD in the post- allogeneic HSCT setting.

As pointed out in an editorial by Paul Martin, MD, Fred Hutchinson Cancer Research Center, University of Washington in Seattle, sitagliptin inhibits DPP-4 activity of CD26, a multifunctional, cell-surface glycoprotein expressed in many tissues throughout the body. “Many types of cells can present alloantigens that stimulate donor T cells to cause GVHD,” Martin noted.

Since effective T-cell immune responses require other stimulatory signals in addition to T-cell receptor interactions with antigens on antigen-presenting cells, “[s]timulation of T-cell receptors by antigen in the absence of costimulatory signals leads to a specific antigen nonresponsive rate of anergy that is perpetuated by continued antigen exposure,” he explained, noting that using an inexpensive medication to target interactions between T cells and antigen-presenting cells opens up a whole new channel of investigation although many questions remained unanswered.

“The current results first require confirmation in a controlled trial,” he said.

The most effective duration of sitagliptin administration remains to be determined as does the extent to which prevention of acute GVHD depends on concurrent treatment with sirolimus and tacrolimus.

Nevertheless, Martin wrote that the current trial should encourage studies testing the hypothesis as to whether or not inhibition of CD26 might prevent acute rejection of solid-organ allografts. He also suggested that outcomes could potentially be improved by having a parenteral formulation of sitagliptin as use of the oral formulation was limited by severe mucositis in some patients in the current study.

  1. A novel combination of standard immunosuppression plus the DPP-4 inhibitor, sitagliptin, resulted in an impressively low rate of acute GVHD in the post-HSCT setting.

  2. The antidiabetic agent is easy to give and relatively inexpensive, making sitagliptin an attractive candidate for the prophylaxis of GVHD in patients who have undergone HSCT.

Pam Harrison, Contributing Writer, BreakingMED™

The study was funded by the National Heart, Lung, and Blood Institute.

Farag reported receiving grants from Bristol-Myers Squibb and Incyte Corporation.

Martin reported receiving personal fees from Pfizer, Genentech, Pharmacyclics, Neovii, Enlivex Therapeutics, Mesoblast, Rigel, Talaris, and from Janssen.

Cat ID: 118

Topic ID: 78,118,730,118,119,717,935,192,925