Acute graft-vs-host disease (GVHD) is a potentially deadly complication after allogeneic hematopoietic stem cell transplant (HSCT), occurring in 30% to 50% of patients within 100 days of transplant.
A new study shows that adding the diabetes drug sitagliptin (Januvia) to usual immunsuppression therapies substantially reduces the risk for this adverse event.
“As acute GVHD is a major complication of allogeneic stem cell transplantation, the findings of the study have the potential to make transplants safer and improve overall the quality of life and survival of patients transplanted,” first author Sherif Farag, MD, PhD, of the Division of Hematology and Oncology at Indiana University School of Medicine, Indianapolis, Indiana, told Medscape Medical News.
The findings were published on January 7 in The New England Journal of Medicine.
In an accompanying editorial, Paul J. Martin, MD, of the Division of Clinical Research, Fred Hutchinson Cancer Research Center, and the Department of Medicine, University of Washington School of Medicine, Seattle, Washington, expresses cautious optimism.
“The innovative testing of an inexpensive medication repurposed to prevent a major complication of allogeneic hematopoietic cell transplantation…opens a whole new avenue of investigations,” he writes, although he adds that there are “many important questions yet to be answered.”
“The current results first require confirmation in a controlled trial,” he adds.
Sitagliptin is an oral drug that acts as an inhibitor of dipeptidyl peptidase 4 (DPP-4).
Sitagliptin inhibits DPP-4–mediated degradation of hormones that stimulate insulin secretion. The fact that sitagliptin enhances endogenous insulin secretion through this mechanism led to its approval for treatment of type 2 diabetes in 2006, Martin explains.
DPP-4 is identical to the leukocyte surface antigen CD26 and is also involved in T-cell immune function. DDP-4 inhibitors such as sitagliptin have been shown to lessen T-cell activation. It has been hypothesized that this would be useful in preventing acute GVHD after transplant.
Better Than Newer Investigational Drugs
The new results come from an open-label trial conducted in 36 adult patients who underwent HSCT at Indiana University Health for conditions that included acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome.
All patients received oral sitagliptin at a dose of 600 mg every 12 hours beginning the day before transplant and continuing until day 14 post transplant.
Patients also received a standard immunosuppressive regimen of tacrolimus and sirolimus.
The dose of sitagliptin used in the transplant patients is about 16 times the recommended dose for patients with diabetes (which ranges from 25 mg to 100 mg once daily), noted first author Farag. There were no additional toxic effects beyond those commonly observed in allogeneic stem cell transplant patients, he said.
“In fact, the nonrelapse death rate was 0% at 1 year, confirming the safety and tolerability of the drug. There was no apparent increase in relapse rate to what is observed with standard immune suppression drugs,” he said.
However, in his editorial, Martin notes that oral administration of sitagliptin was limited by severe mucositis, and he wonders whether a parenteral formulation of the drug may be preferable for this patient population.
Of the 36 patients in the trial, two developed acute GVHD by day 100. The incidence of grade II–IV GVHD was 5%; the incidence of grade III or IV GVHD was 3%.
After a year, the cumulative incidence of relapse was 26%, and the incidence of chronic GVHD was 37%; 46% of patients experienced GVHD-free, relapse-free survival.
Although this study lacked a control group, the authors note that the risks for GVHD were substantially lower than have been seen historically. With usual immunosuppression with sirolimus plus tacrolimus, incidence rates of acute GVDH of grades II–IV range from 26% to 47%; for grades III or IV, they range from 7% to 19%.
GVHD rates with other agents, including methotrexate, mycophenolate, or antithymocyte globulin, are similar to those with sirolimus and tacrolimus, the authors note.
Encouraging reductions in GVHD rates have been seen with newer drugs, including abatacept, atorvastatin, and vorinostat. However, none have demonstrated risk reductions that exceed those seen in the new study with sitagliptin, Farag told Medscape Medical News.
“The finding of only a 5% cumulative incidence of grade III to IV acute GVHD was very important,” Farag said.
“Short of methods that deplete T cells from the graft, usually through antibodies or cell selection, newer pharmacological agents currently being evaluated have not demonstrated such a low rate of acute GVHD in early phase trials,” he said.
Newer agents that are being investigated have not yet been approved by the US Food and Drug Administration, and many need to be taken for several weeks after transplant, including after discharge. By contrast, sitagliptin has already been approved, and it was administered for only 16 days during the transplant, Farag explained.
Faraq noted that the results need to be confirmed in a randomized trial. Important next steps include evaluating sitagliptin’s effects under different conditions and possibly for the prevention of organ rejection, he said.
“Other directions of research will be to test sitagliptin in the reduced-intensity transplant setting, in combination with other agents, to further improve outcome, and it may potentially have a role in prevention of solid organ transplant rejection,” he said.
In his editorial, Martin notes, “Future studies 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 preparative regimens are used to enable allogeneic HSCT in older patients and in those with coexisting conditions.
“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 of chronic GVHD remain to be determined.”
The study was supported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health. Farag has received grant support from Bristol-Myers Squibb and Incyte. The authors’ full disclosures are detailed in the published study.
N Engl J Med. Published January 7, 2021. Abstract, Editorial
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