57. Developing oncogenicity guidelines for BCR::ABL1-like B-lymphoblastic leukemia/lymphoma through expert consensus

B-lymphoblastic leukemia/lymphoma (B-ALL) includes multiple distinct genetic subtypes. BCR::ABL1-like B-ALL is associated with high-risk disease with alterations impacting cytokine receptors and kinases that drive a gene expression profile which mimics BCR::ABL1-positive B-ALL. Given the significant genetic heterogeneity and various methodologies used to identify gene fusions, clinical diagnosis and decision-making for patients with this B-ALL subtype remain challenging.

Existing professional guidelines for BCR::ABL1-like B-ALL are not sufficiently detailed for consistent variant interpretation and routine practice between labs, which may impact both treatment decisions and clinical trial enrollment. To promote consensus, ClinGen has assembled a BCR::ABL1-like B-ALL Somatic Cancer Variant Curation Expert Panel (SC-VCEP) for variant interpretation related to this high-risk disease based on guidelines from the Somatic Cancer Clinical Domain Working Group.

Initially using ABL1 fusions not involving BCR, we have drafted oncogenicity guidelines for fusions in this subtype of B-ALL. Adapting the NTRK SC-VCEP fusion guidelines we are evaluating fusion structure, cancer association, and functional evidence to support variant classification. To establish the scope of our pilot fusions for oncogenicity guidelines and AMP/ASCO/CAP categorization, we have expanded our evaluation to include other ABL-class genes (e.g., ABL2, CSF1R). These guidelines will be publicly available with finalized interpretations relevant to B-ALL. Ultimately, these efforts aim to provide community consensus related to the diagnostic, prognostic, and therapeutic implications of genetic changes in B-ALL.