BCR/ABL1 KINASE DOMAIN MUTATIONS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA WITH SECONDARY RESISTANCE TO THE IMATINIB THERAPY

Dmytrenko I. V., Minchenko Zh. M., Dyagil I. S.

MEDICAL GENETICS

Scentific article

Study of the chronic myeloid leukemia (CML) pathogenesis have provided the basis for the development of targeted therapy of this disease using specific inhibitors of tyrosine kinases (TKI). The use of imatinib has shown the high effectiveness of this drug. However, 20-30% of CML patients are initially resistant, i.e. they practically do not respond to therapy, and 17% of patients lose the respond. The presence of BCR/ABL1 mutations in patients with CML may be responsible for the failure of the TKI treatment. The aim of the study was to determine the frequency and range of mutations in the BCR/ABL1 kinase domain of the in patients with CML who lost their response to therapy and to investigate role of these mutations in the development of secondary resistance to imatinib therapy. BCR/ABL1 kinase domain mutations were retrospectively studied in 32 peripheral blood samples of BCR/ABL1-positive CML patients (9 patients with the optimal response and 23 patients with sub-optimal response to imatinib therapy) by Senger’s direct sequencing. The median time from the start of imatinib therapy to the development of secondary resistance was 28.6 months. (17.1 – 72.0) months. Patients with primary imatinib resistance were excluded from the analysis. All patients in the observation group received imatinib 400 mg/day, with dose escalation to 800 mg/day. The duration of imatinib therapy was Me = 33.9 months (11.3 – 104.9) months. The median age of patients was 41.5 years (22 – 65) years. There were 18 women and 14 men. A chronic phase of the disease was recorded in 30 patients at the time of diagnosis, and acceleration phase – in 2 patients. The median time between diagnosis and imatinib therapy initiation was 4.0 months. (0.3 – 95.0) months. The rate of BCR/ABL1 kinase domain mutations in patients with chronic myeloid leukemia with secondary resistance to imatinib therapy was determined. In 8 of 15 patients (60%) identified 8 mutations in the BCR/ABL1 kinase domain: F317L, T315I, M244V, F359I, F359V in 2 patients, E255K, E355G and H396R. Most of the detected mutations (7 out of 9) were intermediate resistant to imatinib. In 2 patients mutations caused complete resistance to imatinib (E255K and T315I). All detected mutations were registered only in patients with sub-optimal response to imatinib and amounted to 39.1% (9 out of 23 patients) in this group of patients. The presence of kinase domain mutations increases the likelihood of secondary resistance compared to patients with the wild type of the BCR/ABL1 gene (p = 0.004).

chronic myeloid leukemia, resistance, BCR/ABL1 mutations

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«Bulletin of problems biology and medicine» Issue 1 Part 2 (143), 2018 year, 249-254 pages, index UDK 616.155.392-002.2:616-085:575.113.224:577.21

10.29254/2077-4214-2018-1-2-143-249-254