Allogeneic transplantation in adverse-risk acute myeloid leukemia: Challenges, strategies, and future directions

Adverse-risk acute myeloid leukemia (AML) is a therapeutic challenge despite advances in risk stratification. Unmet needs persist in high-risk molecular subgroups, such as AML with myelodysplasia-related changes, TP53 mutations, or rearrangements involving NUP98, NUP214, or FUS::ERG. These subtypes are associated with poor responses to conventional induction therapies and high relapse rates. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the cornerstone of consolidation for eligible patients; however, due to high relapse rates, regimen-related toxicity, and variable responses across genetic subtypes, optimal transplant timing, conditioning regimens (e.g., busulfan- or melphalan-based protocols), and bridging strategies require further refinement. Meanwhile, post-transplant maintenance therapies, such as hypomethylating agents or targeted drugs, are one emerging area under investigation for relapse prevention. In this perspective, we review the latest advances in allo-HSCT strategies for adverse-risk AML and highlight the importance of molecularly-guided approaches to improve outcomes in these aggressive subtypes.