Intra‐subtype heterogeneity shapes treatment response in <i>KMT2A</i> ‐rearranged ALL across all age groups

<i>KMT2A</i>-rearranged B-cell acute lymphoblastic leukemia (<i>KMT2A</i>r 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 analyzed 465 <i>KMT2A</i>r 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), and <i>AFF1</i> as fusion partner (P = 7.0E-04). A multivariable analysis confirmed the strong impact of maturity (P = 0.02) and <i>KMT2A</i> fusion partner (P = 0.03) on MRD clearance, supporting the concept that the cell's developmental state defines therapy response. Gene expression analysis identified cellular traits that relate to MRD clearance (e.g., chromatin organization, immune modulation, and proliferation). This gene expression classifier grouped cases not only by MRD clearance but also by ex vivo sensitivity to induction therapy drugs. Notably, good responders to ex vivo induction drugs were characterized by a higher maturity score (P = 1.8E-03), whereas for less mature <i>KMT2A</i>r B-ALL cases, response profiles suggested higher Venetoclax sensitivity. Our study provides an integrative framework linking developmental phenotype, fusion partner, and MRD kinetics across the full age spectrum of <i>KMT2A</i>r B-ALL. These insights may support future risk-adapted strategies and therapeutic targeting, particularly in immature <i>KMT2A</i>r B-ALL.