Clinical Relevance and Applicability of the 2022 World Health Organization Classification of Childhood B Lymphoblastic Leukemia in the Context of MRD-Directed Therapy

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 MRD-directed therapy is unclear. We analyzed 533 pediatric B-ALL uniformly treated with ICiCLe-ALL-14 protocol as defined by WHO2016 and reclassified them as per WHO5-2022 using targeted sequencing, FISH, and cytogenetics. Subtype-defining genetic abnormalities were identified in 81.2% of the cohort as per the WHO5 classification. Among the new subtypes, PAX5alt, MEF2D-r, and BCR::ABL1-like(ABL-class) were associated with an inferior 2-year event-free survival (EFS) of 39.1% (p<0.0001), 53.8% (p=0.024) and 60.6% (p=0.043), respectively. We developed a 3-tier genetic risk stratification model incorporating 15 genetic subtypes and the IKZF1 deletion. Children with standard, intermediate, and high genetic risk demonstrated 2-year EFS of 92.6%, 71.0%, and 50.7% (p<0.0001), and 2-year overall survival of 94.3%, 81.9%, and 71.6% (p<0.0001), respectively. Genetic risk further identified heterogeneous outcomes among ICiCLe risk groups (p<0.0001). Standard genetic risk was associated with superior OS and EFS irrespective of MRD status. We demonstrate the applicability of the WHO5 classification in routine practice and create a general framework for incorporating the WHO5 classification in risk-adapted therapy for childhood B-ALL.