Novel Fusion Gene Transcripts and Targetable Mutations in High-Risk B-ALL With Exceptional Response to Venetoclax-Based Therapy.

Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous malignancy characterized by a broad spectrum of chromosomal and gene abnormalities that define distinct genetic subtypes driving disease development. Although numerous driver fusion genes have been documented, a considerable proportion of ALL cases remain inadequately defined, classified, and consequently lack access to precisely targeted therapies. Herein, we report a case of high-risk B-ALL harboring four novel fusion gene transcripts-MAN1A1::GRIK2, ZCCHC7::CASC11, OSTM1-AS1::ZBTB24, and IGL::BCL6-along with concurrent mutations in CREBBP, BCL2, and ARID1B. These four novel fusion genes, particularly the BCL6 rearrangement, may represent a genetic feature that warrants further investigation in B-ALL. The patient received induction therapy with a modified COP regimen (cyclophosphamide, vindesine, dexamethasone) combined with the BCL2 inhibitor venetoclax, achieving a rapid and sustained complete remission. This case suggests that integrating deep genomic analysis can help identify potentially actionable therapeutic targets and provides preliminary clinical evidence supporting the efficacy of modified COP plus venetoclax in high-risk B-ALL with similar molecular features, highlighting a promising precision medicine strategy.