Concurrent ETV6::ABL1 and BCR::ABL1 in a rare case of Chronic Myeloid Leukemia: A paradox of imatinib resistance and indolent clinical course

Chronic myeloid leukaemia (CML) is characterized by the presence of BCR::ABL1 showing favorable response to imatinib therapy. Complex rearrangements in CML are indicative of clonal evolution and often associated with disease progression and poor response to therapy. Cytogenetically, these cases present with atypical Fluorescence in-situ hybridization signal patterns and additional cytogenetic abnormalities on conventional karyotyping. Current research in CML is primarily focused on discovery of new tyrosine kinase inhibitors (TKIs) and uncovering the underlying causes of resistance to imatinib. In this report, we describe a rare case of Ph-positive CML on imatinib therapy showing atypical FISH signal pattern, harboring concurrent BCR::ABL1 and ETV6::ABL1 fusions characterized by conventional cytogenetics and Fluorescence in-situ hybridization. This is the first report of dual oncogenic fusions in a case CML, showing complex ABL1 rearrangements along with Philadelphia chromosome, demonstrating long term survival on imatinib therapy despite the failure to achieve major molecular response throughout the course of the disease. The key highlight of the study was the pivotal role of cytogenetic analysis in elucidating the underlying cause of imatinib resistance. The systematic documentation of such rare cases is essential for efficient management and evolving our understanding of dual oncogenic drivers in myeloid neoplasms.