Sitagliptin for Prophylaxis of aGVHD in Alternative Donor Transplantations: Updated Results of 2 Years Follow-up of a Superiority, Randomized Controlled Phase III Trial

Abstract Background: Sitagliptin, an approved medication for type 2 diabetes, has been reported to possess the potential to reduce the occurrence of acute graft versus host disease(aGVHD) via various mechanisms. We previously reported that adding sitagliptin (600mg taken orally every 12 hours on day -1 to +14) to the standard prophylaxis therapy(CNI+MMF+MTX) resulted in a significant reduction of aGVHD in haploidentical or unrelated donor hematopoietic stem cell transplantation (HSCT) and demonstrated promising efficacy and safety at median follow-up of 164 days in a randomized controlled trial (RCT)(Qiao et al, ASH 2023). Here we present an updated analysis of 2 years of follow-up results in this trial. Methods: We conducted a prospective, open-label, superiority, RCT(NCT05149365) in 5 transplantation centers in China from December 2021 to June 2024. The study design was previously reported. Patients were randomly allocated by a computer-generated priori list of binary numbers, with block-balanced with random variable block sizes in a 1:1 ratio. The primary endpoint was the cumulative incidence of grade II-IV aGVHD at day 100 post-transplantation. Key secondary endpoints included cumulative incidence of severe (grade III or IV) aGVHD, non-relapse mortality(NRM), the cumulative incidence of chronic GVHD and relapse, overall survival(OS), relapse free survival(RFS), and GVHD-free, relapse-free survival (GRFS) from HSCT. Efficacy was assessed both in the intention to treat (ITT) population and in the per-protocol set (PPS). Safety was assessed in the safety set(SS), which included the randomized pts who received any amount of study drug. Results: Participants were recruited between December 2021 and June 2023. A total of 251pts underwent screening and 190 pts were enrolled (95 pts in each group). The ratio of male to female was 113 to 77 with a median age of 38.5 years (range, 18-60 years). 181 received the complete study intervention and were included in PPS: 89 in the sitagliptin group and 92 pts in the control group.The clinical and transplantation characteristics at baseline of the two groups were well balanced. At the time of analysis, median follow-up was 662 days (IQR 521-788). In the ITT population, the cumulative incidence of grade II-IV acute GVHD at day 100 was lower in the sitagliptin group compared with the control group (14.8% [95% CI 11.2-18.4] in the sitagliptin group vs 32.0% [27.2-36.8] in the control group; P=0.004), and the cumulative incidence of grade III or IV aGVHD was 6.3%(95% CI 3.8-8.8) and 17.0%(13.1-20.9) (P=0.019). We observed no difference in the cumulative incidence of cGVHD ( 22.3% [17.8-26.8] in the sitagliptin group vs 25.8% [ 21.1-30.5] in the control group; P=0.514) and relapse (6.7% [4.0-9.4] in sitagliptin group vs 11.6% [7.8-15.4] in the control group; P=0.463). After 100 days and 2 years, NRM increased to 3.2% (95% CI 1.4-5.0)and 12% (8.6-15.4) in the sitagliptin group and 6.4% (3.9-8.9) and 8.6% ( 5.7-11.5) in the control group (P=0.499). OS at 100 days was 96.8% (95% CI 95.0-98.6 ) in the sitagliptin group and 93.7%(91.2-96.2) in the control group and at 2 years, it was 86.3% (82.8-89.8) in the sitagliptin group and 89.5% in the control group ( 86.4-92.6; P=0.689). RFS at 2 years was 82.1% (95% CI 78.2-86.0) in the sitagliptin group and 80.8% (76.5-85.1;P=0.987) in the control group, and GRFS at 2 years was 62.1% in the sitagliptin group (57.1-67.1) and 52.8% in the standard group (46.9-58.7%; P=0.201). In the SS, the common non-hematological adverse events between two groups have no difference and the combination regimen was well tolerated (Qiao et al, ASH 2023). Conclusions: Adding sitagliptin to the standard prophylaxis therapy in ADT was safe and reduced aGVHD without affecting the CIR or NRM. Though there is currently no demonstrated advantage in long-term survival, the combination of sitagliptin and CNI+MMF+MTX represents a promising and cost-effective prophylaxis , particularly for pts with low income/affordability.