Superior Survival of Myeloablative over Reduced-Intensity Conditioning in MDS Patients below 65 Years Using a Combination of Antithymocyte Globulin and Post-Transplantation Cyclophosphamide As Gvhd Prophylaxis
Authors: Alnughmush Ahmed , Alyamany Ruah , Remberger Mats , Pasic Ivan , Novitzky-Basso Igor , Law Arjun , Lam Wilson , Kim Dennis Dong Hwan , Michelis Fotios , Gerbitz Armin , Kumar Rajat , Mattsson Jonas , Viswabandya Auro 
Published: December 2024

Background:
Allogeneic hematopoietic cell transplantation (Allo-HCT) is a potentially curative treatment for patients with myelodysplastic syndrome (MDS), particularly those classified as high-risk. The choice of conditioning regimen remains contentious, with previous studies indicating that overall survival (OS) is similar between myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), although RIC is associated with lower transplant-related mortality (TRM) and higher relapse rates. This study aims to evaluate the outcomes of MAC versus RIC in patients undergoing Allo-HCT for MDS, with a unified graft-versus-host disease (GVHD) prophylaxis regimen comprising a combination of anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy).
Methods:
We performed a retrospective analysis of 80 MDS patients who underwent Allo-HCT at Princess Margaret Cancer Centre between October 2015 and October 2023. Patients were under the age of 65 years and received the same GVHD prophylaxis with a combination of ATG, PTCy, and cyclosporine. Outcomes assessed included overall survival (OS), relapse-free survival (RFS), GVHD-free/RFS (GRFS), acute and chronic GVHD, and graft failure.
Results:
Among our cohort, 59 patients received RIC (Fludarabine 35 mg/m²/day for 4 days + Busulfan 3.2 mg/kg/day for 2 days + TBI 200, Fludarabine 35 mg/m²/day for 4 days + Treosulfan 10 or 14 g/m² for 3 days) and 21 patients received MAC (Fludarabine 35 mg/m²/day for 4 days + Busulfan 3.2 mg/kg/day for 4 days). The median age was significantly lower in the MAC group than in the RIC group (52 years vs. 60 years) (p&lt;0.001). Matched unrelated donors (MUD) constituted the majority of the donor pool (52.5%), with no significant difference between the RIC and MAC groups (p=0.25). The RIC group had a higher proportion of patients with a hematopoietic cell transplant comorbidity index (HCT-CI) ≥3 (44.1% vs. 14.3%, p=0.02).
The 1-year OS was significantly higher in the MAC group than in the RIC group (85.7% vs. 52.0%, p=0.03). The 1-year non-relapse mortality (NRM) did not significantly differ between the RIC and MAC groups (20.4% vs. 14.3%, p=0.47). The 1-year relapse rate was higher in the RIC group than in the MAC group (28.9% vs. 9.5%, p=0.05).
The incidence of acute GVHD grade I-IV at day 100 was higher in the MAC group but did not reach statistical significance (52.4% vs. 39.0%, p=0.19). There were no significant differences observed between MAC and RIC in the incidence of acute GVHD grade II-IV (23.8% vs. 27.1%, p=0.85) or grade III-IV (9.5% vs. 6.8%, p=0.61), respectively. However, the incidence of chronic GVHD at 1 year was significantly higher in the MAC group compared to the RIC group (36.8% vs. 5.7%, p&lt;0.001). Our analysis also indicated a trend of superiority in the 1-year GRFS in the MAC group compared to the RIC group (61.9% vs. 43.9%, p=0.17). Regarding the risk of graft failure, there was no significant difference in the incidence of graft failure between the comparative groups (p=0.22). Looking at infectious complications post-HCT, there was no significant difference in the incidence of bloodstream infection (BSI) between the MAC group and the RIC group (61.9% vs. 50.8%, p=0.52). Additionally, the risk of CMV reactivation did not statistically differ between the groups (p=0.12).
Conclusion:
Our findings suggest that MAC may offer better overall survival and relapse-free survival in patients under 65 years undergoing stem cell transplantation with ATG-PTCy-CSA, despite a higher incidence of chronic GVHD. The lack of significant differences in non-relapse mortality between conditioning regimens highlights the need for individualized patient assessment when selecting the appropriate conditioning regimen.