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Fludarabine\/melphalan (Flu\/Mel) conditioning is associated with effective disease control but results in significant toxicity and non-relapse mortality (NRM) when combined with calcineurin-inhibitors plus methotrexate or mycophenolate mofetil. Flu\/Mel with alternative graft-versus-host disease (GVHD) prophylaxis may be better tolerated and result in superior outcomes in patients with AML. In this single-center retrospective analysis, we analyzed long-term outcomes of patients with AML (n\u2009=\u2009342) who underwent allo-HCT with Flu\/Mel conditioning and tacrolimus\/sirolimus (Tac\/Sir)-based GVHD prophylaxis from 2008-2019 at City of Hope. Patient median age was 63 years (range: 23\u201378), with 37% having high-very high Disease Risk Index (DRI) and 42% with HCT-Comorbidity Index (CI)\u2009\u2265\u20093. Five-year overall survival (OS: primary objective) was 55% (95% CI: 49\u201361%) among all patients and 70% (95% CI: 55\u201381%) in patients \u226570 years old. Only presence of active disease correlated with lower 5-year OS on multivariate analysis (HR\u2009=\u20091.95; p\u2009&lt;\u2009.001). Five-year NRM was 24% (95% CI: 19\u201329%) among all patients and 21% (95% CI: 11\u201334%) in those \u226570 years old. In conclusion, Flu\/Mel conditioning with Tac\/Sir GVHD prophylaxis is associated with favorable OS and acceptable NRM, even in older\/infirm patients with AML.<\/jats:p>","DOI":"10.1038\/s41409-025-02738-4","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T04:51:22Z","timestamp":1763441482000},"page":"82-91","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Long-term survival outcomes of allo-HCT in AML with fludarabine\/melphalan conditioning and tacrolimus\/sirolimus GVHD 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