Intra-subtype heterogeneity shapes treatment response inKMT2A-rearranged ALL across all age groups

KMT2A-rearranged B-cell acute lymphoblastic leukemia (KMT2Ar B-ALL) exhibits significant heterogeneity in age of onset, developmental origins, and clinical outcomes. The interplay of individual factors influencing early treatment response within this high-risk molecular subtype remains poorly elucidated. To identify determinants of early treatment response to induction chemotherapy, we analysed 465KMT2Ar B-ALL cases spanning a wide age range (1 month to 89 years) by integrating transcriptomic and genomic profiling with functional drug response and measurable residual disease (MRD) kinetics. We observed a strong inverse correlation between MRD clearance with advancing age (p=2.1E-04), proximity to early B-cell-precursor developmental state (low maturity score, p=1.3E-03) andAFF1as fusion partner (p=7.0E-04). A combined model confirmed the predominate impact of both maturity andKMT2Afusion partner on MRD response, supporting the concept that the cell’s developmental state defines therapy response. Gene expression analysis identified cellular traits that relate to MRD response (e.g. chromatin organization, immune modulation and proliferation). This gene expression classifier grouped cases by MRD response but also byex-vivoinduction drug sensitivity. Notably, good responders toex-vivoinduction drugs were characterized by a higher maturity score (p=1.8E-03), whereas for less matureKMT2Ar B-ALL cases response profiles suggested higher Venetoclax sensitivity. This study provides an integrative framework of the biological determinants of treatment response and possible therapeutic implications inKMT2ArB-ALL.