Drug Sensitivity and Treatment Response Are Modulated By the Cell of Origin, the Underlying Gene Fusion, and Patient Age in KMT2A-Rearranged BCP-ALL

• Published in: Blood 2024-11, Vol.144, p.318-318
• Main Authors: Hartmann, Alina M., Bastian, Lorenz, Barz, Malwine J, Amelunxen, Eric, Haas, Johannes, Lenk, Lennart, Kotrova, Michaela, Beder, Thomas, Steffen, Fabio D., Rauwolf, Kerstin K., Wolgast, Nadine, Ehm, Patrick, Bendig, Sonja, Alten, Julia, Mondal, Mayukh, Ströh, Aeint-Steffen, Burmeister, Thomas, Goekbuget, Nicola, Bornhauser, Beat, Bourquin, Jean-Pierre, Brüggemann, Monika, Schrappe, Martin, Cario, Gunnar, Baldus, Claudia D
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-199017

Minimal residual disease (MRD) is the most important outcome predictor in B precursor acute lymphoblastic leukemia (B-ALL), but additional contributing factors are poorly understood. To address the molecular and functional underpinnings of MRD kinetics in KMT2A-rearranged (KMT2A-r) as high-risk disease across all age groups, we analyzed a cohort of 325 KMT2A-r BCP-ALL patients (0-89 years, median: 32 years; n = 59 infants, n = 67 pediatric, n = 179 adults, n = 20 NA). Diagnostic samples were studied by integrating gene expression and gene fusion profiling (RNA-Seq; discovery cohort: n=148, validation cohort: n=177) with karyotyping (SNP-Arrays; n=113), ex-vivo drug-response profiling (n=62) and MRD measurements at follow-up (n=97). To unravel the cell of origin of KMT2A-r ALL, we used the machine learning classifier ALLCatchR to define developmental trajectories and fitted linear slopes on the enrichment across B-cell-developmental stages as a measure for cell stemness. Stemness scores were validated using IG-rearrangement patterns and surface marker expression (FACS). Patients were treated according to the AIEOP-BFM ALL/INTERFANT and GMALL study group protocols, with IG/TR MRD measurements performed in the central reference laboratories. Pediatric-inspired induction therapy protocols in adult patients with comparable MRD sampling time points in pediatric regimens allowed for kinetic definitions of MRD clearance (fast / intermediate / slow) across age groups. Age did not affect the initial MRD clearance (p = 0.96), but the patient age was significantly correlated with the underlying driver gene fusion (p = 9.2e-7) and stemness (p = 1.9e-15); gene fusion and stemness were also interdependent (p= 2.2e-16). Thus, the dissection of these co-factors on MRD clearances is needed to allow a comprehensive understanding of this molecular interplay. Considering the most frequent fusion partners of KMT2A, AFF1 (n=63; 65%), MLLT1 (n=16; 16.5 %), and MLLT3 (n=13; 13.5%), we observed a skewed distribution in the three MRD categories fast / intermediate / slow. KMT2A::AFF1-r cases predominantly showed an intermediate or slow MRD clearance compared to KMT2A::MLLT1 and KMT2A::MLLT3 cases (83%, 38% and 30% slow/intermediate clearance respectively, p = 0.001). Compared to slow/intermediate MRD clearance, ALLs with fast MRD clearance were significantly more mature (p = 0.0018), with closer proximity towards more mature B-precursor stages (Pre-B-II-Large p = 0.037; Pre-B-II-Sma