Spectrum of BCR-ABL Mutations and Treatment Outcomes in Imatinib-Resistant CML Patients: A Retrospective Analysis from a Tertiary Centre in South India
DOI:
https://doi.org/10.64149/J.Carcinog.24.4.261-270Keywords:
Chronic myeloid leukemia, BCR-ABL mutations, Imatinib resistance, T315I, Tyrosine kinase inhibitors.Abstract
Background: Despite revolutionary advances with tyrosine kinase inhibitors (TKIs), imatinib resistance remains a significant challenge in chronic myeloid leukemia (CML) management. BCR-ABL kinase domain mutations represent the predominant resistance mechanism. This study aimed to characterize the mutation spectrum and evaluate treatment outcomes in imatinib-resistant CML patients from South India.
Methods: This retrospective analysis included 101 consecutive CML patients with confirmed imatinib resistance mutation analysis (IRMA) positivity treated at Kidwai Memorial Institute of Oncology, Bangalore, between 2010-2025. BCR-ABL mutation detection was performed using direct Sanger sequencing. Response assessment followed European Leukemia Net 2020 guidelines. Survival analysis employed Kaplan-Meier methodology with log-rank testing for comparisons.
Results: Median age was 41 years (range 19-72) with male predominance (72.3%). Median time to IRMA positivity was 41.5 months (range 4-254). T315I was the most frequent mutation (33.7%), followed by P-loop mutations (37.6%). Compound mutations occurred in 7.9% and sequential mutations in 5.9% of patients. Complete hematologic response at 3 months was achieved in 78.2%. Patients with T315I showed significantly inferior outcomes compared to non-T315I mutations: CHR at 3 months (58.6% vs 86.1%, p=0.002), MMR achievement (10.3% vs 26.4%, p=0.048), and progression to blast phase (34.5% vs 16.7%, p=0.045). Overall survival was 90.1%, with median overall survival not reached at 5 years.
Conclusions: P-loop mutations predominated in this South Indian cohort, with T315I conferring the worst prognosis. The high frequency of rare mutations and prolonged time to mutation detection underscore the need for comprehensive mutation profiling and long-term molecular monitoring. Economic constraints limiting access to second-generation TKIs likely contributed to delayed mutation detection and inferior outcomes.
