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Sitagliptin may cut risk of graft-versus-host disease

The New England Journal of Medicine
Reuters Health - 06/01/2021 - Adding the type-2 diabetes drug sitagliptin to tacrolimus and sirolimus appears to lower the risk of graft-versus-host disease in people who receive peripheral-blood stem-cell transplants, according to the results of a nonrandomized phase-2 study.

At the 100-day mark, the rate of grades II to IV acute graft-versus-host disease (GVHD) was 5% among the 36 volunteers. The rate of grades III to IV disease was 3%. The usual risk historically ranges from 34% to 51%, researchers note in the New England Journal of Medicine.

After one year, 26% had suffered a relapse and 37% had developed chronic GVHD. Relapse-free survival was 46%.

The researchers said they didn't see any side effects attributable to the drug, although it was given at a much higher dose of 600 mg twice daily, and there were no instances of hypoglycemia.

"This is a novel target for prevention of acute graft-versus-host disease and the results look really promising," chief author Dr. Sherif Farag of Indiana University School of Medicine, in Indianapolis, told Reuters Health by phone. "It's an inexpensive and simple drug to give compared to other drugs being tested that are not yet approved for this complication. It may actually end up being the least expensive intervention in a transplant."

In a linked editorial, Dr. Paul Martin of the Fred Hutchinson Cancer Research Center in Seattle characterized the incidence of GVHD in the patients with allogeneic hematopoietic cell transplantation as "impressively low."

A phase-3 test of the treatment is still in the planning stages.

The idea for the therapy came from research attempting to enhance engraftment of cord blood transplants, where the Indiana researchers were unexpectedly seeing a much lower rate of GVHD.

In the new study, the 36 volunteers had acute or chronic myeloid leukemia, acute lymphoblastic leukemia, or a myelodysplastic disorder. None were taking insulin or insulin secretagogues for diabetes. They received their cells from matched related or unrelated donors.

Sitagliptin was given for 16 days.

Two patients died but "there was no mortality related to treatment whatsoever by one year after transplant. If we were expecting this to cause problems, we would have seen some mortality," said Dr. Farag. The typical one-year mortality rate is 10% to 15% "and we didn't see that, so it was really well tolerated."

Among those who survived, the median follow-up was 700 days. Nine of the 36 patients had a relapse after a median of 243 days.

Of the 34 patients who survived for at least 100 days without a relapse, chronic GVHD developed in 15, including three severe cases, seven moderate cases and five mild ones.

"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, for which the incidence has varied from 26 to 47% and from 7 to 19%, respectively," the researchers write.

Sitagliptin's "ready availability, ease of administration, safety, and relatively inexpensive cost as compared with the new agents make sitagliptin a clinically attractive candidate" for preventing GVHD, they say.

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

SOURCE: https://bit.ly/2KIK0Eb and https://bit.ly/2KIY28N The New England Journal of Medicine, online January 6, 2021.

By Gene Emery

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