Clinical Relevance of Genomics Defined WHO5 Subtypes of Pediatric B-ALL in the Context of Measurable Residual Disease-Directed Risk-Based Therapy.

Authors

Sweta Rajpal, Gaurav Chatterjee, Prasanna Bhanshe, Vishram Terse, Swapnali Joshi, Shruti Chaudhary, Dhanalaxmi Shetty, Purvi Mohanty, Chetan Dhamne, Prashant Ramesh Tembhare, Shyam Srinivasan, Akanksha Chichra, Nirmalya Roy Moulik, Shripad Banavali, Sumeet Gujral, Gaurav Narula, Papagudi G Subramanian, Nikhil Patkar

Published in

JCO global oncology. Volume 12. Issue 9. Pages e2500665. Epub Sep 03, 2026.

Abstract

WHO5 (2022) classification of B-lymphoblastic leukemia (B-ALL) incorporates several novel entities requiring high-throughput sequencing for their accurate characterization. The clinical relevance of this classification in the context of contemporary measurable residual disease (MRD)-directed therapy is unclear.
We analyzed 533 pediatric B-ALL uniformly treated with Indian Collaborative Childhood Leukaemia group (ICiCLe)-ALL-14 protocol as defined by WHO-2016 and reclassified them as per WHO5 using targeted sequencing, FISH, and cytogenetics.
Subtype-defining genomic abnormalities were identified in 81.2% of the cohort as per the WHO5 classification. Among the new subtypes, PAX5^alt and MEF2D-r were associated with a trend toward an inferior 3-year event-free survival (EFS) of 32.8% (P = .003) and 33.7% (P = .091), respectively. We developed a three-tier genomic risk stratification model incorporating 15 genomic subtypes and the IKZF1 deletion. Children with standard (SGR), intermediate (IGR), and high genomic risk (HGR) demonstrated 3-year EFS of 80.4%, 59.3%, and 45.8% (P < .0001), and 3-year overall survival of 89.6%, 75.3%, and 62.3% (P < .0001), respectively. Genomic risk further identified heterogeneous outcomes among ICiCLe risk groups (P < .0001). SGR was associated with superior EFS irrespective of MRD status (3-year EFS 80.5% in postinduction [PI] MRD-negative v 80.8% PI-MRD-positive patients, P = .530). On multivariable analysis, genomic risk (hazard ratio [HR], 1.7 [95% CI, 1.41 to 2.01]; P < .0001), initial ICiCLe risk (HR, 1.3 [95% CI, 1.06 to 1.49]; P = .009), and PI-MRD (HR, 2.2 [95% CI, 1.66 to 2.90]; P < .0001) independently predicted EFS.
The study demonstrates the potential role of genomic risk stratification, in conjunction with MRD, in stratifying patients into clinically relevant risk categories.

PMID:
42691457
Bibliographic data and abstract were imported from PubMed on 04 Sep 2026.

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