Outcomes with a combination of treosulfan and fludarabine in acute myeloid leukemia and myelodysplastic syndrome: A systematic review and meta-analysis

Abstract Introduction: Conventionally, myeloablation with high-dose chemotherapy, with or without total body irradiation (TBI), has been used as the conditioning regimen before allogenic hematopoietic stem-cell transplantation (allo-HSCT). Still, not all patients are good candidates for it. The combination of Treosulfan and Fludarabine has emerged as an alternative conditioning regimen, and we aim to investigate the safety and efficacy outcomes of the patients treated with this combination. Methods: A comprehensive literature search was conducted in PubMed, Cochrane, Embase, Scopus, Google Scholar, and , by PRISMA guidelines. The search included articles from inception to May 2025, using keywords “Treosulfan”, “Fludarabine”, “Acute myeloid leukemia”, and “Myelodysplastic syndrome.” Of 763 articles identified, 12 studies reporting the outcome of Treosulfan and Fludarabine in AML and MDS were included. Proportional meta-analysis was performed using the ‘meta’ package in R (version 4.4.1), applying a random-effects model due to high heterogeneity. Between-study variance was calculated using restricted maximum likelihood (REML). Some characteristics were described systematically. Results: A total of 1,140 patients from six prospective, three randomized, two Phase II, and one retrospective study were included for analysis and review. The median age was 47 years (range, 1 to 70), with the majority being male (53%, n = 433/818). Underlying conditions included AML (50%, n=418/829) and MDS (50%, n=419/829). For AML, 35% (n=107/307) had high-risk disease by ELN classification, and 35% had high to very high-risk disease among MDS patients (n=56/164). Treosulfan doses ranged from 30–126 g/m² (most commonly 42 g/m²); fludarabine doses ranged from 150–750 mg/m² (most commonly 150 mg/m²). The pooled relapse rate was 24% [95% CI: 18–31%, I² = 86%]. Overall survival (OS) at 24 months was 67% [95% CI: 63–72%, I² = 57%]; disease-free survival (DFS) was 59% [95% CI: 54–64%, I² = 69%]; The pooled rate fort non-relapsed mortality (NRM) was 13% [95% CI: 10–16%, I² = 45%]. Platelet and neutrophil engraftment rates were 95% and 97%, respectively. Chronic GVHD occurred in 46% [95% CI: 37–55%, I² = 76%]; grade 1–2 GVHD in 32% [95% CI: 22–41%, I² = 93%], and grade 3–4 GVHD in 9% [95% CI: 6–13%, I² = 57%]. GI toxicities and infection rates were 29% and 46%, respectively. Overall adverse event rate was 67% [95% CI: 44–90%, I² = 97%]. Conclusion: The Treosulfan and Fludarabine conditioning regimen demonstrates favorable efficacy in AML/MDS patients undergoing allo-HSCT, with high engraftment and survival rates and low NRM. Safety outcomes remain a concern and necessitate further trials with larger patient populations and standardized dosing regimens.