Retrospective analysis of own long-term experience in studying the BCR::ABL kinase domain mutational status in patients with chronic myeloid leukemia

Background . Most patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitors achieve durable optimal responses. Loss of the achieved molecular response is observed in 15–30 % of patients. Mutations in the BCR::ABL kinase domain are one of the most common mechanisms for the development of resistance to tyrosine kinase inhibitors. Aim . To conduct a retrospective analysis of the BCR::ABL kinase domain mutational profile in patients with CML observed at the Russian Research Institute of Hematology and Transfusiology from 2012 to 2023. To assess the impact of mutations type and number on the rate of achieving a major molecular response (MMR). To study the risk of MMR loss depending on the therapy line and existing mutational status. Materials and methods . 1831 patients with CML were examined at different times. The mutational status of the BCR::ABL kinase domain was analyzed by direct Sanger sequencing. A standard cytogenetic study was carried out using GTG banding technology with the analysis of at least 20 metaphase plates. Results . Mutations in the BCR::ABL kinase domain were identified in 27.6 % of the total studied patients. The most common mutation, 6.3 % in the overall group or 22.7 % among patients with mutations, was the T315I mutation. Additional chromosomal aberrations (ACAs) were detected in Ph-positive cells in 20.5 % of patients, in Ph-negative clones in 3.9 % of cases (p = 0.0001). The frequency of ACAs detection did not statistically significantly differ (p = 0.25) between patients with BCR::ABL mutations (23.5 %) and with a negative mutation status (17.7 %), and the presence of mutations in the kinase domain did not correlate with ACAs in Ph-positive clones (p = 0.73). However, the frequency of T315I mutation detection in Ph-positive cells had significant differences: 40.9 % in combination with ACAs and 21 % without ACAs (p = 0.032). Patients with the T315I mutation had significantly worse MMR than patients with mutations in other BCR::ABL regions (p = 0.04) and patients without mutations (p = 0.02). The probability of MMR achieving did not differ significantly between patients with different numbers of BCR::ABL mutations (p = 0.14). Loss of MMR occurred more often in patients with mutations (p = 0.04) and not depend on the line of therapy (p = 0.03). Conclusion . For complete monitoring and optimal choice of therapy, CML patients require not only monitoring of BCR::ABL relative expression level, but also standard cytogenetic and analysis of the mutational status.