Meeting NewsPerspective

Sitagliptin reduces acute GVHD after peripheral blood stem cell transplantation

Sherif S. Farag, MD, PhD, FRACP, FRCPA
Sherif S. Farag

ORLANDO — The anti-diabetic medication sitagliptin significantly reduced incidence of acute graft-versus-host disease after myeloablative allogeneic peripheral blood stem cell transplantation, according to results of a prospective phase 2 study presented at TCT | Transplantation & Cellular Therapy Meetings.

“Reduction in acute GVHD is extremely important for patients because it is one of the major complications after allogeneic transplants,” Sherif S. Farag, MD, PhD, FRACP, FRCPA, Lawrence H. Einhorn professor of oncology at Indiana University School of Medicine, told Healio. “This trial, which really was repurposing a drug used for diabetes, shows very promising results. Hopefully we can take this investigation further, perhaps into a randomized trial.”

Approximately 34% to 51% of patients who undergo allogeneic stem cell transplant develop acute GVHD.

Dipeptidyl peptidase (DPP)-4 is a homodimeric type II transmembrane glycoprotein receptor that is identical to the leucocyte surface antigen CD26. It is expressed on a variety of cells and circulates in an enzymatically active form in plasma. It is involved in a multiple biological processes, including insulin release and metabolism, homing and engraftment, and T-cell activation and migration, according to study background.

Results from a mouse xenograft model of GVHD showed an anti-CD26 monoclonal antibody downregulated CD26 expression and protected against acute GVHD while preserving graft-versus-leukemia effects, Farag said.

Preclinical studies showed sitagliptin — a small-molecule specific DPP-4 inhibitor approved in the United States for treatment of type 2 diabetes — inhibits mixed-lymphocyte reactions in a dose-dependent manner. The agent typically is dosed at 50 mg/day to 100 mg/day.

Farag and colleagues previously conducted a pilot trial to evaluate sitagliptin for enhancement of cord blood engraftment, and results showed only one of 16 patients developed grade 2 acute GVHD, suggesting the agent may have a role in GVHD prevention.

They conducted the prospective phase 2 trial to evaluate whether CD26/DPP-4 inhibition with sitagliptin in combination with tacrolimus and sirolimus could reduce the rate of grade 2 to grade 4 acute GVHD after myeloablative allogeneic peripheral blood stem cell transplant.

The study included 36 patients (median age, 46 years; range, 25-59; 19 women). The majority of patients (78%) had acute myeloid leukemia or acute lymphoblastic leukemia, 11% had myelodysplastic syndrome and 11% had chronic myeloid leukemia.

Forty-four percent of patients had Hematopoietic Cell Transplantation-specific Comorbidity Index scores of 3 or higher, 67% had intermediate-risk disease, and 28% had high- or very high-risk disease.

Patients received thiotepa dosed at 15 mg/kg and cyclophosphamide dosed at 120 mg/kg, followed by granulocyte-colony stimulating factor-mobilized peripheral blood stem cells from matched related (6/6 HLA match, 36%) or unrelated (10/10 HLA match, 64%) donors.

Patients received sitagliptin dosed at 600 mg every 12 hours beginning 1 day prior to transplant through day 14 after transplant, for a total of 32 doses. Tacrolimus and sirolimus were started 3 days prior to transplant until day 100 after transplant, and then were tapered with a plan to stop at approximately 180 days after transplant.

Patients also routinely received antibiotic prophylaxis with ciprofloxacin, fluconazole and trimethoprim/ sulfamethoxazole.

A reduction in grade 2 to grade 4 acute GVHD by day 100 from the historical rate of 30% to 15% or less served as the study’s primary endpoint.

Median follow-up was 700 days (range, 118-1,313).

Median time to neutrophil engraftment was 13 days (range, 10-20) and median time to platelet engraftment was 15 days (range, 13-114).

Two patients developed acute GVHD by day 100. One case was grade 2 and one case was grade 4, equating to a 5.6% (95% CI, 0-13.2) cumulative incidence of grade 2 to grade 4 GVHD and a 2.8% (95% CI, 0-8.2) cumulative incidence of grade 3 to grade 4 acute GVHD.

Most patients (78%) received 80% or more of the planned total sitagliptin dose, and none of them developed acute GVHD (P = .04). The two patients who developed acute GVHD received less — 75% of the total dose for one and 65% of the total dose for the other — due to mucositis.

Researchers reported a 37% (95% CI, 21-54) cumulative incidence of chronic GVHD at 1 year.

Cumulative incidence of relapse at 1 year was 23%, and 2-year OS was 88% (95% CI, 76-99).

No patients died due to nonrelapse mortality by 12 months.

Clinically significant nonhematological toxicities included grade 3 to grade 4 mucositis (n = 15), acute hemolysis (n = 2), and one case each of lower gastrointestinal bleeding, thrombotic microangiopathy and transient respiratory failure due to fluid overload.

Infectious complications included cytomegalovirus viremia without invasive infection (n = 4), BK virus cystitis (n = 3) and sepsis (n = 2). One patient developed human herpesvirus 6 viremia and Epstein-Barr virus reactivation.

“High-dose sitagliptin was well-tolerated, confirming what we had seen previously in the myeloablative setting in cord blood,” Farag said. “Sitagliptin represents a simple and inexpensive approach to GVHD prevention, and we feel that sitagliptin with tacrolimus and sirolimus should be compared with other standard prophylaxis strategies for the prevention of acute GVHD.” – by Mark Leiser

Reference: Farag SS, et al. Abstract 32. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.

Disclosures: Farag reports research funding from Bristol-Myers Squibb, as well as an advisory board role with and honoraria from Jazz Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.

Sherif S. Farag, MD, PhD, FRACP, FRCPA
Sherif S. Farag

ORLANDO — The anti-diabetic medication sitagliptin significantly reduced incidence of acute graft-versus-host disease after myeloablative allogeneic peripheral blood stem cell transplantation, according to results of a prospective phase 2 study presented at TCT | Transplantation & Cellular Therapy Meetings.

“Reduction in acute GVHD is extremely important for patients because it is one of the major complications after allogeneic transplants,” Sherif S. Farag, MD, PhD, FRACP, FRCPA, Lawrence H. Einhorn professor of oncology at Indiana University School of Medicine, told Healio. “This trial, which really was repurposing a drug used for diabetes, shows very promising results. Hopefully we can take this investigation further, perhaps into a randomized trial.”

Approximately 34% to 51% of patients who undergo allogeneic stem cell transplant develop acute GVHD.

Dipeptidyl peptidase (DPP)-4 is a homodimeric type II transmembrane glycoprotein receptor that is identical to the leucocyte surface antigen CD26. It is expressed on a variety of cells and circulates in an enzymatically active form in plasma. It is involved in a multiple biological processes, including insulin release and metabolism, homing and engraftment, and T-cell activation and migration, according to study background.

Results from a mouse xenograft model of GVHD showed an anti-CD26 monoclonal antibody downregulated CD26 expression and protected against acute GVHD while preserving graft-versus-leukemia effects, Farag said.

Preclinical studies showed sitagliptin — a small-molecule specific DPP-4 inhibitor approved in the United States for treatment of type 2 diabetes — inhibits mixed-lymphocyte reactions in a dose-dependent manner. The agent typically is dosed at 50 mg/day to 100 mg/day.

Farag and colleagues previously conducted a pilot trial to evaluate sitagliptin for enhancement of cord blood engraftment, and results showed only one of 16 patients developed grade 2 acute GVHD, suggesting the agent may have a role in GVHD prevention.

They conducted the prospective phase 2 trial to evaluate whether CD26/DPP-4 inhibition with sitagliptin in combination with tacrolimus and sirolimus could reduce the rate of grade 2 to grade 4 acute GVHD after myeloablative allogeneic peripheral blood stem cell transplant.

The study included 36 patients (median age, 46 years; range, 25-59; 19 women). The majority of patients (78%) had acute myeloid leukemia or acute lymphoblastic leukemia, 11% had myelodysplastic syndrome and 11% had chronic myeloid leukemia.

Forty-four percent of patients had Hematopoietic Cell Transplantation-specific Comorbidity Index scores of 3 or higher, 67% had intermediate-risk disease, and 28% had high- or very high-risk disease.

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Patients received thiotepa dosed at 15 mg/kg and cyclophosphamide dosed at 120 mg/kg, followed by granulocyte-colony stimulating factor-mobilized peripheral blood stem cells from matched related (6/6 HLA match, 36%) or unrelated (10/10 HLA match, 64%) donors.

Patients received sitagliptin dosed at 600 mg every 12 hours beginning 1 day prior to transplant through day 14 after transplant, for a total of 32 doses. Tacrolimus and sirolimus were started 3 days prior to transplant until day 100 after transplant, and then were tapered with a plan to stop at approximately 180 days after transplant.

Patients also routinely received antibiotic prophylaxis with ciprofloxacin, fluconazole and trimethoprim/ sulfamethoxazole.

A reduction in grade 2 to grade 4 acute GVHD by day 100 from the historical rate of 30% to 15% or less served as the study’s primary endpoint.

Median follow-up was 700 days (range, 118-1,313).

Median time to neutrophil engraftment was 13 days (range, 10-20) and median time to platelet engraftment was 15 days (range, 13-114).

Two patients developed acute GVHD by day 100. One case was grade 2 and one case was grade 4, equating to a 5.6% (95% CI, 0-13.2) cumulative incidence of grade 2 to grade 4 GVHD and a 2.8% (95% CI, 0-8.2) cumulative incidence of grade 3 to grade 4 acute GVHD.

Most patients (78%) received 80% or more of the planned total sitagliptin dose, and none of them developed acute GVHD (P = .04). The two patients who developed acute GVHD received less — 75% of the total dose for one and 65% of the total dose for the other — due to mucositis.

Researchers reported a 37% (95% CI, 21-54) cumulative incidence of chronic GVHD at 1 year.

Cumulative incidence of relapse at 1 year was 23%, and 2-year OS was 88% (95% CI, 76-99).

No patients died due to nonrelapse mortality by 12 months.

Clinically significant nonhematological toxicities included grade 3 to grade 4 mucositis (n = 15), acute hemolysis (n = 2), and one case each of lower gastrointestinal bleeding, thrombotic microangiopathy and transient respiratory failure due to fluid overload.

Infectious complications included cytomegalovirus viremia without invasive infection (n = 4), BK virus cystitis (n = 3) and sepsis (n = 2). One patient developed human herpesvirus 6 viremia and Epstein-Barr virus reactivation.

“High-dose sitagliptin was well-tolerated, confirming what we had seen previously in the myeloablative setting in cord blood,” Farag said. “Sitagliptin represents a simple and inexpensive approach to GVHD prevention, and we feel that sitagliptin with tacrolimus and sirolimus should be compared with other standard prophylaxis strategies for the prevention of acute GVHD.” – by Mark Leiser

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Reference: Farag SS, et al. Abstract 32. Presented at: TCT | Transplantation & Cellular Therapy Meetings; Feb. 19-23, 2020; Orlando.

Disclosures: Farag reports research funding from Bristol-Myers Squibb, as well as an advisory board role with and honoraria from Jazz Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective

    The idea that an anti-diabetic drug can prevent GVHD really is pretty remarkable. The CD26 marker plays an important role in GVHD, so it was a rational hypothesis. There’s also a monoclonal antibody against CD26 that has been used. This probably has greater applicability and we probably can expect a very good safety profile. I think it’s an interesting study, but it obviously needs to be extended to a phase 3 study before this is ready for widespread use. I’m sure the investigators will do a phase 3 study, and everyone will await those results with great interest.

    • Ronjon Chakraverty, MD, PhD
    • University College London

    Disclosures: Chakraverty reports no relevant financial disclosures.

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