Strength to Endure: Superiority of MAC over RIC in Patients <65 Years Undergoing Stem Cell Transplantation Using ATG-Ptcy-CSA for Gvhd Prophylaxis

Background: Allogeneic Hematopoietic Cell Transplantation (Allo-HCT) is a curative treatment for many hematological diseases. Reduced-intensity conditioning (RIC) regimens were developed to decrease the toxicities associated with myeloablative conditioning (MAC) regimens, especially in older or less fit patients. RIC and MAC have been compared previously; RIC is known to have a higher risk of relapse, but this is usually counterbalanced by the higher rate of non-relapse mortality (NRM) with MAC, making overall survival (OS) between the two options comparable. However, it remains unclear how younger patients perform with RIC in terms of toxicity and overall survival compared to MAC. This study aims to compare the outcomes of RIC and MAC in patients younger than 65 years, all receiving a unified graft-versus-host disease (GVHD) prophylaxis regimen. Methods: A retrospective analysis was conducted for 640 patients who underwent Allo-HCT for different hematological diseases at Princess Margaret Cancer Centre between October 2015 and October 2023. All patients were under the age of 65 years and received a unified GVHD prophylaxis with a combination of ATG, PTCy, and cyclosporine. Outcomes compared included overall survival (OS), relapse-free survival (RFS), GVHD-free/RFS (GRFS), acute and chronic GVHD, post-transplant bloodstream infections, and graft failure. Results: A total of 640 patients were reviewed, with 434 receiving RIC and 206 receiving MAC. AML was the most common diagnosis (50.3%), with similar distributions in both RIC (47.7%) and MAC (55.8%) groups (p=0.07). Significant differences were noted in ALL (RIC 6.9% vs. MAC 17.0%, p<0.001) and MF (RIC 11.1% vs. MAC 2.9%, p<0.001). Lymphoma was more prevalent in the RIC group (5.8% vs. 1.9%, p<0.05). The RIC group was older on average (57 vs. 45 years, p<0.001). More RIC patients had KPS <90 (20.3% vs. 8.7%, p<0.001) and HCT-CI ≥3 (41.7% vs. 20.9%, p<0.001). Significant differences were seen in the use of matched related donors (16.6% RIC vs. 2.9% MAC, p=0.004) and frozen grafts (29.5% RIC vs. 20.4% MAC, p=0.02). The MAC group showed significantly higher 2-year OS (70.8% vs. 61.1%, p=0.02), RFS (66.4% vs. 54.7%, p=0.014), and GRFS (55.2% vs. 43.2%, p=0.012) compared to the RIC group. The 2-year cumulative incidence of relapse was higher in the RIC group (26.7% vs. 17.5%, p=0.018), while NRM rates were similar (13.9% vs. 16.8%, p=0.54). Although the overall incidence of acute GVHD was higher in the MAC group (44.2% vs. 32.7%, p=0.013), there was no significant difference in acute GVHD grades II-IV or chronic GVHD between the groups. The overall rate of BSI by day 30 was similar between the MAC and RIC groups (49.5% vs. 46.8%, p=0.90). Graft failure at one year was significantly higher in the RIC group compared to the MAC group (7.4% vs. 2.9%, p=0.02). Conclusion: In patients younger than 65 years undergoing Allo-HCT with ATG and PTCy for GVHD prophylaxis, MAC is associated with superior OS, RFS, and GRFS compared to RIC. The RIC group had higher relapse rates, with NRM rates being comparable, suggesting that MAC should be considered for patients who can tolerate it, especially those at higher risk of relapse. The study's limitations include its retrospective nature and unbalanced cohorts. Future prospective trials are warranted to validate these findings in the context of combining ATG and PTCy for GVHD prophylaxis.