Incorporating ALL Biology into Treatment Decisions: Next Steps toward Targeted Therapy in Adult ALL

Acute lymphoblastic leukemia (ALL) management is evolving from a generalized approach toward a precision medicine paradigm driven by molecular heterogeneity. This review highlights how genomic profiling identifies high-risk subtypes, including KMT2A-rearranged, IKZF1-plus BCR::ABL1-positive, BCR::ABL1-like, and TP53-mutant B-cell ALL, which necessitate tailored therapies. We explore novel strategies such as BH3 mimetics, menin inhibitors, pre-T-cell receptor signaling blockade, and targeted immunotherapy, which show promise in relapsed/refractory and high-risk groups. We also address emerging challenges, including therapy-induced phenotypic escape mechanisms such as lineage switch and antigen loss. The future of ALL therapy lies in integrating these biology-driven approaches to improve outcomes across all age groups. SIGNIFICANCE: This review provides a roadmap for the targeted therapy era in ALL, defining high-risk molecular subtypes and their targeted vulnerabilities. It synthesizes advances in BH3 mimetics, menin inhibition, and immunotherapy, while addressing the critical challenges of treatment resistance and phenotypic escape that define the next frontier of research.