TCF3::HLF-positive B-ALL: integrated clinical and molecular characterization of 34 cases from a single-center cohort.

[BACKGROUND] TCF3::HLF-positive B-cell acute lymphoblastic leukemia (B-ALL) is a rare, highly aggressive subtype with historically poor outcomes. Despite its classification as a distinct entity, its clinical and molecular landscape remains poorly understood.

[METHODS] This study presents a single-center cohort of 34 TCF3::HLF-positive B-ALL patients, providing comprehensive clinical and molecular characterization by integrating clinical data, treatment responses, survival outcomes, whole-transcriptome sequencing (WTS), targeted sequencing, and flow cytometry.

[RESULTS] TCF3::HLF accounted for 1.59% of B-ALL cases. Three fusion isoforms were identified, with Isoform III likely arising from alternative splicing. No significant clinical or transcriptomic differences were observed between Isoform I and II. The 5-year overall survival (OS) was 35.2%. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) significantly improved OS and event-free survival (p < 0.0001), while chimeric antigen receptor T-cell (CAR-T) therapy facilitated allo-HSCT but lacked durable efficacy. RAS pathway mutations were prevalent (85.7%), and CD33 expression was frequent (79.4%), suggesting potential therapeutic targets. WTS analysis revealed dysregulation of epithelial-mesenchymal transition, coagulation, and immune pathways.

[CONCLUSIONS] TCF3::HLF-positive B-ALL represents an ultra-high-risk leukemia requiring allo-HSCT for long-term remission. CAR-T serves as a bridge to transplantation, while RAS and CD33-directed therapies warrant further investigation. These findings provide critical insights into disease biology and potential treatment.