High Incidence of Chronic Graft-Versus-Host Disease (cGVHD) with Post-Transplant Cyclophosphamide/Sirolimus/Mycophenolate (PTCy/Siro/MMF) Compared to Ptcy/Tacrolimus(Tac)/MMF Prophylaxis in Patients Undergoing Myeloablative Allogeneic Stem Cell Transplant (alloHCT)

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Background PTCy/Tac/MMF has demonstrated low rates of grade III-IV acute GVHD (aGVHD) and cGVHD necessitating systemic immunosuppressive therapy in myeloablative (MA) alloHCT. Sirolimus (Siro) has theoretical benefits in immune reconstitution compared to Tac through preservation of regulatory T cells . We studied PTCy/Siro/MMF in adults undergoing MA alloHCT from matched or mismatched donors and compared its outcomes with PTCy/Tac/MMF in a before-and-after Phase II trial design (NCT03314974). Methods Patients received MA conditioning with either TBI or Bu/Flu from 7/8 or 8/8 donors. Patients receiving Tac were enrolled from 2018-2022 and those receiving Siro from 2022-2023. Primary endpoint was cumulative incidence of cGVHD requiring immunosuppression (IST) at 1 year. Secondary endpoints were incidences of aGVHD, overall survival (OS), relapse rate (RR), non-relapse mortality (NRM), and GVHD free relapse free survival (GRFS). Cumulative incidence was used to estimate aGVHD, cGVHD , and relapse, with competing risks considered. Fine and Gray regression analysis compared cumulative incidence curves, while OS and GRFS were estimated via Kaplan-Meier curves and compared using the log-rank test. Results 196 patients were enrolled; 34 received Siro (median follow up 1.97 years) and 162 received Tac-based prophylaxis (median follow up 4.05 years). At 1 year, the incidence of cGVHD requiring IST and cGVHD of any grade was higher in the Siro group at 26% vs 5%, p<0.01 (Table). There was numerically a higher incidence of Grade II-IV and Grade III-IV aGVHD, although this was not statistically significant. The 1-year OS, GRFS, RR and NRM was similar between groups. On multivariate analysis , Siro was associated with a higher risk of cGVHD (hazard ratio [HR] 5.19 for 7/8 (95% CI 1.20-22.34), 4.8 for 8/8 (95% CI 1.67-13.74, p<0.01). Conclusion Although this is a before-and-after, not a randomized trial design, our analysis suggests that PTCy/Siro/MMF results in inferior GVHD outcomes compared to PTCy/Tac/MMF.

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