KEY TAKEAWAYS
- The phase 3 trial aimed to investigate the safety and efficacy of combining sitagliptin with a regimen for preventing aGVHD in alternative donor TX.
- The primary endpoint was to measure the occurrence of aGvHD, graded II to IV by day +100.
- The study observed that combining Sitagliptin and conventional prophylaxis (CsA+MTX+MMF+ATG), significantly reduces grade II-IV aGVHD in ADT.
Acute graft versus host disease (aGVHD) poses a significant threat after allogeneic hematopoietic stem cell transplantation (allo-HSCT), often leading to high mortality rates. Notably, alternative donor transplantation (ADT) using unrelated or haploidentical family donors has been linked to an increased incidence of aGVHD and severe graft-versus-host disease (GvHD).
The study focused on the assessment of sitagliptin, a selective dipeptidyl peptidase 4 (DPP-4; also known as CD26) inhibitor targeting T cells. Man Qiao, and his dedicated team, spearheaded the trial that aimed to determine the safety and efficacy of integrating sitagliptin with a prophylactic regimen comprising a calcineurin inhibitor, methotrexate (MTX), mycophenolate mofetil (MMF), and antithymocyte globulin (ATG) in preventing aGVHD in the context of ADT.
This prospective, multicenter, open-label, randomized controlled trial (NCT05149365) involves five hematopoietic stem cell transplant (HSCT) centers from China. The study focussed on patients (pts) aged 18-60 who underwent their initial allogeneic-HSCT while in the first or second complete remission state for hematologic malignancies. These patients received a busulfan and cyclophosphamide (Bu/Cy) myeloablative conditioning regimen, followed by ADT.
A total of 190 eligible patients were randomly assigned in a 1:1 ratio to either the sitagliptin group or the conventional prophylaxis control group. In the sitagliptin group, patients receive 600mg of sitagliptin orally every 12 hours from day -1 to +14, along with conventional prophylaxis including Cyclosporin A(CsA)/ tacrolimus (FK506), MTX, MMF and ATG). The conventional prophylaxis control group was administered by CsA/FK506, MTX, MMF, and ATG.
Randomization was based on a computer-generated priori list of 190 binary numbers, utilizing block-balanced random variable block sizes of two or four patients, without stratification. The primary endpoint is the occurrence of grade II to IV acute graft-versus-host disease (aGvHD) by day +100. Key secondary endpoints encompass severe (grade III or IV) aGvHD by day +100, transplant-related mortality (TRM), relapse-free survival (RFS), and GVHD-free, relapse-free survival (GRFS) from HSCT.
The trial has completed patient enrollment, and the current focus is on the ongoing follow-up to monitor and assess the study endpoints.
About 191 patients were enrolled, with a male-to-female ratio of 113 to 78 and a median age of 38 years (range, 18-60 years). The participants were randomly assigned to the sitagliptin group (95 patients) and the control group (96 patients). Baseline clinical and transplantation characteristics of the intention-to-treat (ITT) population were well-balanced between the two groups (Table 1). The last follow-up, conducted on May 30, 2023, revealed a median follow-up time of 164 (20–512) days.
Comparison of the sitagliptin group and the control group by day +100 showed a significant difference in the cumulative incidence rate of grade II-IV aGVHD (15.1% vs. 28.6%, P=0.019). The cumulative incidence rate of grade III or IV aGVHD was 7.6% in the sitagliptin group and 15.9% in the control group (P=0.068). The median days of neutrophil engraftment were +11.48 and +11.65 days in the sitagliptin and control groups, respectively (P=0.545). Transplant-related mortality (TRM) was 3.7% in the sitagliptin group and 7.1% in the control group (P=0.454). RFS was 98.7% in the sitagliptin group and 95.9% in the control group (P=0.889), with overall survival (OS) being 96.7% and 93.6%, respectively (P=0.341). No significant differences were observed between the sitagliptin and control groups regarding cytomegalovirus reactivation, Epstein-Barr virus reactivation, and transplant-related complications.
The regimen, including sitagliptin, was well-tolerated. Only 5 out of 95 patients discontinued sitagliptin treatment due to adverse events (AEs). Among them, 4 patients experienced abdominal pain (CTCAE Grade 1-2) during sitagliptin therapy for 3-7 days, with one of them also exhibiting hypoglycemia (CTCAE Grade 1), deemed as probably associated with sitagliptin according to clinicians (WHO-UMC). Symptoms resolved spontaneously within 2 days of cessation. Another patient discontinued treatment due to mild hematemesis, initiating sitagliptin therapy only 2 days, determined by the clinician as unlikely to be associated with sitagliptin (WHO-UMC).
The reported outcome suggested that the incorporation of sitagliptin into the conventional prophylaxis regimen (CsA+MTX+MMF+ATG) yielded a notable reduction in the incidence of grade II-IV aGVHD in alternative donor transplantation (ADT).
This finding underscores the potential of sitagliptin as an adjunct therapy to enhance the overall success of ADT. Beyond its effectiveness, sitagliptin’s ready availability, ease of administration, safety, and cost-effectiveness underscore its potential as a valuable addition to prophylactic regimens. However, ongoing investigation is essential to determine its impact on infection rates, relapse, and overall prognosis in patients undergoing allo-HSCT. The study is sponsored by The First Affiliated Hospital of Soochow University
Source: https://ash.confex.com/ash/2023/webprogram/Paper189348.html
Clinical Trial: https://clinicaltrials.gov/study/NCT05149365
