Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL

Area of Science:

• Hematology
• Oncology
• Genomics

Background:

• Genomic classification has improved risk stratification in pediatric B-lineage acute lymphoblastic leukemia (B-ALL), but its utility in adult B-ALL remains less defined.
• The UKALLXII/ECOG-ACRIN E2993 trial enrolled a large cohort of adolescent and adult patients with BCR-ABL1- B-ALL, providing an opportunity to investigate genomic subgroups.

Purpose of the Study:

• To perform comprehensive genomic subtyping of adult B-ALL patients treated on the UKALLXII/ECOG-ACRIN E2993 trial.
• To correlate genomic subtypes with clinical outcomes, including remission rates, relapse frequencies, and overall survival.
• To identify potential discrepancies between traditional risk stratification and genomic classification.

Main Methods:

• Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction were employed for genomic subtyping.
• 264 patient samples, representing 64.5% of the trial cohort, were eligible for genomic analysis.
• Genomic subtypes were categorized into favorable, intermediate, and high-risk groups based on 5-year overall survival (OS) data.

Main Results:

• Genomic subtyping identified distinct prognostic groups with varying 5-year OS rates: favorable (65%–80%), intermediate (33%–45%), and high-risk (0%–27%).
• Specific genetic alterations defined these risk groups, including DUX4-rearranged, ETV6-RUNX1/-like, TCF3-PBX1, PAX5 P80R, high-hyperdiploid (favorable); PAX5alt, ZNF384/-like, MEF2D-rearranged (intermediate); and Ph-like, KMT2A-AFF1, low-hypodiploid/near-haploid, BCL2/MYC-rearranged (high-risk).
• A significant proportion (40%) of patients considered high risk by traditional criteria harbored genetic alterations associated with standard or intermediate risk, highlighting the prognostic value of genomic analysis.

Conclusions:

• Genomic subtyping provides crucial prognostic information in adult B-ALL, refining risk stratification beyond traditional clinical parameters.
• Distinct immunophenotypic features were associated with specific genotypes (DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like).
• These findings underscore the importance of genomic analyses for potential future therapeutic targeting and improved outcomes in adult B-ALL.