Acute graft-versus-host disease (GVHD) is a potentially deadly complication after allogeneic hematopoietic stem cell transplantation (HSCT), occurring in 30% to 50% of patients within 100 days of transplantation.
A new study shows that adding the diabetes drug sitagliptin (Januvia) to the usual immunosuppression therapies substantially reduces the risk of this adverse event.
“Because acute GVHD is a major complication of allogeneic stem cell transplantation, the study results have the potential to make transplants safer and improve the quality of life and overall survival of transplant patients,” first author Sherif Farag, MD, PhD, from the Division of Hematology and Oncology, Indiana University School of Medicine, Indianapolis, Indiana, said Medscape Medical News.
The discoveries were Published on January 7 in The new English medical journal.
On a accompanying editorial, Paul J. Martin, MD, Division of Clinical Research, Fred Hutchinson Cancer Research Center, and the Department of Medicine, Washington University School of Medicine, Seattle, Washington, expresses cautious optimism.
“The innovative test of an inexpensive drug adapted to prevent a major complication of allogeneic hematopoietic cell transplantation … opens up a new path of investigation,” he writes, although he adds that there are “many important questions yet to be answered.”
“Current results first require confirmation in a controlled test,” 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 increases the secretion of endogenous insulin through this mechanism led to its approval for the treatment of Type 2 diabetes in 2006, explains Martin.
DPP-4 is identical to the CD26 leukocyte surface antigen and is also involved in the immune function of T cells. DDP-4 inhibitors, such as sitagliptin, have been shown to decrease T cell activation. The hypothesis has been raised that this would be useful in preventing acute GVHD after transplantation.
Better than newer investigational drugs
The new results come from an open clinical trial conducted on 36 adult patients undergoing HSCT at Indiana University Health for conditions that included acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemiaand myelodysplastic syndrome.
All patients received oral sitagliptin at a dose of 600 mg every 12 hours, starting on the day before the transplant and continuing until day 14 after the transplant.
The dose of sitagliptin used in transplant patients is about 16 times the recommended dose for patients with diabetes (ranging from 25 mg to 100 mg once a day), noted the first author Farag. There were no additional toxic effects beyond those commonly seen in patients with allogeneic stem cell transplantation, he said.
“In fact, the death rate without relapse was 0% in 1 year, confirming the safety and tolerability of the drug. There was no apparent increase in the relapse rate over what is seen with standard immune suppression drugs, ”he said.
However, in his editorial, Martin notes that oral administration of sitagliptin has been 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 study, two developed acute GVHD on day 100. The incidence of grade II-IV GVHD was 5%; the incidence of grade III or IV GVHD was 3%.
After one year, the cumulative incidence of relapse was 26% and the incidence of chronic GVHD was 37%; 46% of patients had GVHD-free survival and recurrence.
Although this study does not have a control group, the authors note that the risks of GVHD were substantially less than those seen historically. As usual immunosuppression with sirolimus plus tacrolimus, the incidence rates of acute grades II to IV GVDH range from 26% to 47%; for grades III or IV, they vary from 7% to 19%.
Encouraging reductions in GVHD rates have been seen with newer drugs, including abatacept, atorvastatinand vorinostat. However, none demonstrated risk reductions that exceed those seen in the new sitagliptin study, Farag said Medscape Medical News.
“The discovery of only a 5% cumulative incidence of acute grade III to IV GVHD was very important,” said Farag.
“In the absence of methods that deplete graft T cells, usually by means of antibodies or cell selection, the new pharmacological agents currently being evaluated have not demonstrated such a low rate of acute GVHD in early-stage studies,” he said.
The most recent agents being investigated have not yet been approved by the U.S. Food and Drug Administration and many need to be taken for several weeks after transplantation, including after discharge. In contrast, sitagliptin has already been approved and was administered for only 16 days during the transplant, explained Farag.
Faraq noted that the results need to be confirmed in a randomized study. The next important steps include assessing the effects of sitagliptin under different conditions and possibly for preventing organ rejection, he said.
“Other directions in the research will be to test sitagliptin in the low-intensity transplant environment, in combination with other agents, to further improve the outcome, and may play a role in preventing rejection of solid organ transplantation,” he said.
In his editorial, Martin notes: “Future studies are needed to determine whether inhibition of CD26 can prevent acute GVHD while preserving donor T cell activity against recipient T cells and malignant cells when low intensity preparatory regimens are used. to allow allogeneic HSCT in older patients and those with coexisting conditions.
“Whether sitagliptin can prevent GVHD after HSCT in incompatible HLA receptors, as suggested by results with umbilical cord cell grafts and whether changes in the immunosuppressive regimen could decrease the risk of chronic GVHD, has not yet been determined.”
The study was supported by grants from the National Heart, Lung and Blood Institute of the National Institutes of Health. Farag received financial support from Bristol-Myers Squibb and Incyte. The full disclosures of the authors are detailed in the published study.