Superior long-term outcomes with fludarabine and melphalan reduced intensity regimen in older AML/MDS patients undergoing allogeneic stem cell transplantation: An analysis of CIBMTR data

Abstract Introduction: Reduced intensity and non-myeloablative (RIC/NMA) conditioning regimens are routinely utilized in allogeneic hematopoietic cell transplantation (alloHCT) for older patients with AML/MDS. However, the efficacy of different conditioning regimens remains unclear. Previous work has suggested that the FM100 regimen is associated with improved long-term outcomes vs. more intense conditioning regimens (Ciurea S, et al. Blood 2020). Using a national registry, we compared outcomes across five commonly used fludarabine-based RIC/NMA regimens in a large cohort of older AML/MDS patients undergoing alloHCT. Methods: We included patients aged ≥50 years who were transplanted between 2013 and 2022 and reported to the CIBMTR registry. All included patients underwent their first alloHCT for AML or MDS using one of five fludarabine-based RIC/NMA regimens: fludarabine/melphalan 100 mg/m² (FM100) or 140 mg/m² (FM140), fludarabine with 2 days of busulfan (FB2), fludarabine/cyclophosphamide/2 gy TBI (FCT), or fludarabine/2 gy TBI (FT) with any graft-versus-host disease (GVHD) prophylaxis regimen. Patients who received haploidentical transplants or ex vivo T cell-depleted grafts were excluded from the analysis. To account for multiple comparisons, the false discovery rate was controlled using the Benjamini-Hochberg method. To reduce treatment allocation bias, outcomes were compared using propensity score inverse probability weighting (PS-IPW). Results: A total of 11,731 patients from 183 centers were analyzed, including FB2 (n=4,571), FM100 (n=1,666), FM140 (n=4,242), FCT (n=786), and FT (n=466). The median age was 66 years (range 50-83). Overall, 55% had HCT-CI > 2, and 51% had KPS < 90%. For the entire cohort, 9% had AML in ≥ 3rd CR or with active disease at transplant, while 9% had MDS with high/very high IPSS-R scores. Donor types included MSD (27%), MUD (60%), MMUD (7%), other related donors (2%), unrelated with unknow matching status (4%). Post-transplant cyclophosphamide for GVHD prophylaxis was administered in 15% of cases. With a median follow-up of 60 months, the adjusted 3-year OS was 53% for FM100, 53% for FM140, 48% for FB2, 47% for FCT, and 38% for FT (p < 0.0001). The 3-year GVHD-free, relapse-free survival (GRFS) was 15%, 19%, 16%, 14%, and 8%, respectively (p < 0.0001). Multivariable analysis showed that the FCT regimen was significantly associated with worse early (≤ 6 months) OS (HR 1.58, p = 0.014) and late (> 6 months) OS (HR 1.24, p = 0.011) compared to FB2. Conversely, both FM100 (HR 0.77, p < 0.0001) and FM140 (HR 0.77, p < 0.0001) were associated with better late OS than FB2. Additionally, FM100 and FM140 demonstrated higher OS in pairwise comparisons with FCT and FT regimens (p < 0.0001). Due to a significant interaction between conditioning regimens and transplant year, the disease-free survival (DFS) analysis was stratified into three transplant periods. For patients transplanted between 2019-2022, FM100 (HR 0.70, p < 0.0001), FM140 (HR 0.70, p < 0.0001), and FCT (HR 0.86, p = 0.004) showed improved DFS compared to FB2. Both FM100 and FM140 also exhibited significantly better DFS than FCT and FT, with no notable difference between FM100 and FM140. Similar trends were observed for GRFS, with FM100 and FM140 associated with improved late GRFS compared to other regimens. The survival benefit of FM regimens was primarily driven by significantly lower relapse rates compared to the other regimens, with no significant difference in relapse rates between FM100 and FM140. However, higher early transplant-related mortality (TRM) was noted in FM regimens, though they did not significantly affect TRM beyond 6 months post-transplant. No significant differences were observed in the risk of chronic or grade 2–4 acute GVHD among these groups. PS-IPW analyses demonstrated similar results, with better survival and lower relapse rates for FM regimens compared to all other RIC regimens. Conclusion: This large-scale analysis demonstrates that FM regimens, particularly FM100 and FM140, provide superior long-term survival and significantly lower relapse rates in older AML/MDS patients undergoing alloHCT. PS-IPW analyses confirmed these benefits despite early TRM risks. These results strongly support the adoption of FM regimens as the preferred conditioning approach to optimize outcomes in this population.