Optimal Time Points for BCR-ABL1 Tyrosine Kinase Domain Mutation Analysis on the Basis of European LeukemiaNet Recommendations in Chronic Myeloid Leukemia

Background: In this study we aimed to evaluate appropriate time points for mutation analysis of chronic myeloid leukemia. Patients and Methods: In total, 961 blood samples obtained from 605 chronic-phase chronic myeloid leukemia patients treated with imatinib were subjected to Sanger sequencing to detect BCR-ABL1 mutations. Mutation frequencies at landmark time points (3, 6, and 12 months) were assessed with 16 landmark responses defined by European LeukemiaNet and 2 additional responses, including a complete hematologic response (CHR) at 3 months and a complete cytogenetic response (CCyR) at 12 months. Results: After 12 months of imatinib treatment of 605 patients, 28 (4.6%) patients harbored 33 mutations, including 23 (69.7%) highly resistant T315I and P-loop mutations. Sequencing data from 650 samples were compared with cytogenetic responses. The mutation frequencies in optimal, warning, and failure groups were 0.5% (2/430), 1.8% (2/110), and 19.1% (21/110), respectively. The molecular response was assessed using 956 samples, and the mutation frequencies were 0.7% (3/425), 3.4% (12/358), and 7.6% (14/173) for the optimal, warning, and failure groups, respectively. For the 2 additional responses, the mutation frequencies in patients with CHR at 3 months and with CCyR at 12 months were 0% (0/160) and 1.7% (4/242), respectively. Overall, mutations were frequently detected at 3-month cytogenetic failure (25.0%), 12-month cytogenetic failure (23.2%), and 6-month cytogenetic failure (10.5%) using response–mutation association analysis. Conclusion: Irrespective of mutation frequency, failure of achievement of a cytogenetic response should be conducted with appropriate mutation analysis.