Intra‐subtype heterogeneity shapes treatment response in KMT2A ‐rearranged ALL across all age groups
Year: 2026
Type: article
Study design: Observational Study
Abstract: Background KMT2A -rearranged B-cell acute lymphoblastic leukemia ( KMT2A 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. We aimed to comprehensively assess how leukemic developmental state, fusion partner, and patient age jointly influence early treatment response and drug sensitivity. Methods To identify determinants of early treatment response to induction chemotherapy, we analysed 465 KMT2A 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. Transcriptomic profiling was used to derive a developmental maturity score based on proximity to physiological B-cell differentiation from a normal B-lymphopoiesis reference. Using an ordinal regression model we identify gene expression programs associated with early MRD response. Results 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 AFF1 as fusion partner (p=7.0E-04). A combined model confirmed the predominate impact of both maturity and KMT2A fusion 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 by ex-vivo induction drug sensitivity. Notably, good responders to ex-vivo induction drugs were characterized by a higher maturity score (p=1.8E-03), whereas for less mature KMT2A r B-ALL cases response profiles suggested higher Venetoclax sensitivity. Conclusions Our study provides an integrative framework linking developmental phenotype, fusion partner, and MRD kinetics across the full age spectrum of KMT2A r B-ALL. The maturity score, derived from bulk transcriptome data, offers a biologically relevant predictor of early treatment response and drug sensitivity. These insights may support future risk-adapted strategies and therapeutic targeting, particularly in immature KMT2A r B-ALL.
Source: HemaSphere
DOI: 10.1002/hem3.70324
Authors: Alina M. Hartmann, Lorenz Bastian, Malwine J. Barz, Johannes Haas, Eric Amelunxen, Patrick Ehm, Lennart Lenk, Michaela Kotrova, Thomas Beder, Fabio D. Steffen, Kerstin Rauwolf, Nadine Wolgast, Sonja Bendig, Cecilia Bozzetti, Julia Alten, Mayukh Mondal, Annika Rademacher, Julia Heymann, Wencke Walter, Claudia Haferlach, Aeint‐Steffen Ströh, Anke K. Bergmann, Thomas Burmeister, Nicola Gökbuget, Beat Bornhauser, Jean‐Pierre Bourquin, Monika Brüggemann, Martin Schrappe, Gunnar Cario, Claudia D. Baldus
Institutions: University Hospital Schleswig-Holstein, University of Zurich, University Children's Hospital Zurich, Munich Leukemia Laboratory (Germany), Universitätsklinikum Würzburg, Humboldt-Universität zu Berlin, Freie Universität Berlin, Charité - Universitätsmedizin Berlin, Goethe University Frankfurt, University Hospital Frankfurt
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,480
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W7130517599