NGS-based retrospective profiling of BCR::ABL1 kinase domain mutations in chronic myeloid leukemia: Findings from the largest South Asian cohort.

The retrospective study screened 1193 patients with haematological malignancies, of whom 416 (34.9%) were diagnosed with chronic myeloid leukemia (CML). Among the ABL1 mutation-positive CML patients, longitudinal follow-up data with serial BCR::ABL1 transcript levels were available for 26 patients, enabling assessment of molecular response following TKI therapy. Next-generation sequencing (NGS) was used to identify BCR::ABL1 kinase domain (KD) mutations and correlate mutation status with CML disease progression and treatment outcomes. Peripheral blood or bone marrow samples were collected; RNA was extracted, reverse-transcribed, and the ABL1 KD region PCR-amplified to detect point mutations. Overall, 352 patients (29.5%) harboured KD mutations, and their frequency increased with disease progression from 22.9% in the chronic phase to 44.8% in the accelerated phase and 42.1% in blast crisis. The T315I mutation was most frequently identified in advanced phases and it was significantly associated with disease progression (p = 0.0008 in Blast Crisis, p = 0.011 in Accelerated Phase). ABL1 mutation rates were slightly higher in males (31.5%) than in females (26.3%) and reached their highest level in the 41-60-year age group (32.2%). Tailored TKI shifts improved molecular response with 30.7% of mutation-positive CML patients achieved major molecular response after TKI therapy adjustment. The study represents the largest reported retrospective amplicon-based-NGS analysis of BCR::ABL1 kinase domain mutations in CML patients from South Asia. These findings provide comprehensive real-world molecular epidemiological data and underscore the value of routine NGS-based BCR::ABL1 mutation profiling for mutation-guided TKI selection, timely therapeutic adaptation, and improved clinical management of patients with CML.