Dipeptidyl Peptidase 4 Inhibition For Prophylaxis Of Acute Graft-Versus-Host Disease

Dipeptidyl peptidase 4 (DPP-4 AKA CD26) is a T-cell transmembrane receptor, which acts as a costimulator for activated T cells.  Down-regulation of CD26 has been shown to prevent graft-versus-host disease in mouse models.  Importantly, graft versus tumor effect has been shown to be maintained.  Inhibition of this protein with sitagliptin was hypothesized to prevent acute GVHD in patients receiving allogeneic stem cell transplantation. 

Investigators conducted a two-stage phase 2 clinical trial to test this agent in combination with tacrolimus and sirolimus.  The anticipation of reductions in grade 2, 3 and 4 acute GVHD from 30% to no more than 15% by day 100 was anticipated.  Patients received myeloablative conditioning regimens. Sitagliptin was administered at 600 mg every 12 hours starting the day before transplantation until day 14. Sitagliptin is administered as an oral agent.

36 patients were evaluated.  The median age was 46.  Transplants were from matched related or unrelated donors.  Acute GVHD occurred in 2 of 36 patients by day 100, with a grade 2-4 GVHD incidence of 5%.  Incidence of grade 3 or 4 GVHD was 3%.  Nonrelapse mortality was 0 at 1 year.  The 1 year cumulative incidences of relapsing chronic GVHD were 26% and 37% respectively.  At 1 year, the GVHD-free, relaps- free survival was 46%.  The authors noted that the toxic effects were similar to other patients undergoing hematopoietic allogeneic stem cell transplantation.

The authors concluded “in this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a lower incidence of grade 2-4 acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem cell transplantation”

https://www.nejm.org/doi/full/10.1056/NEJMoa2027372?query=featured_home

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