Core Binding Factor AML Beyond Favorable Risk: Molecular Heterogeneity, MRD Dynamics, and Implications for Clinical Decision-Making

Core-binding factor acute myeloid leukemia (CBF-AML), defined by the chromosomal rearrangements t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16), has traditionally been classified as a favorable-risk subtype of AML. Nevertheless, relapse occurs in approximately 30–40% of patients, highlighting substantial biological and clinical heterogeneity within this entity. In this review, we synthesize emerging evidence delineating the distinct molecular architecture and prognostic divergence between RUNX1::RUNX1T1 and CBFB::MYH11 AML. We focus on the clinical implications of measurable residual disease (MRD) dynamics and recurrent cooperating lesions, including KIT, FLT3, RAS pathway genes, cohesin-complex alterations, and ZBTB7A, and critically evaluate their impact on relapse risk and therapeutic decision-making. Current treatment paradigms, centered on intensive chemotherapy and high-dose cytarabine consolidation, are reviewed alongside evolving targeted, epigenetic, and immunotherapeutic strategies, with emphasis on distinguishing practice-changing interventions from investigational approaches. Collectively, the available data challenge a uniform “favorable-risk” designation for CBF-AML and support a shift toward fusion-specific, MRD-guided, and molecularly integrated management strategies. We propose a contemporary framework in which dynamic MRD assessment and biological risk modifiers inform treatment intensification, including selective use of targeted agents and allogeneic transplantation, with the goal of achieving durable remissions and reducing relapse in this heterogeneous leukemia subtype.