The dissertation focuced on the role of genetic alterations on both the gene and chromosome levels in molecular mechanisms of resistance to therapy with tyrosine kinase inhibitors (TKI) among patients with chronic myeloid leukemia (CML).
Pre-treatment with non-TKI medications of more than 8 months prior to the initiation of TKI therapy was identified as an independent prognostic risk factor for the development of resistance to therapy, disease progression and overall survival of CML patients. An association between the duration of treatment prior to tyrosine kinase inhibitor therapy and the presence of additional chromosomal aberrations was established (p <0.001).
Additional chromosomal aberrations in Ph + cells detected both at the stage of diagnostic and follow-up testing were associated with the development of secondary resistance. The most prognostically unfavorable additional chromosomal aberrations were monosomy chromosome 7, rearrangements in segment 3q26, isochromosome long arm of chromosome 17 and the presence of several additional chromosomal aberrations in one patient.
It was shown that the type of BCR/ABL1 gene transcript determined the extent of tumor clone reduction. A high frequency of mutations in the kinase domain of the BCR/ABL1 gene was detected in CML patients with primary resistance (45/108, 41.7%) and secondary resistance to imatinib therapy (8/14, 57.1%). For the first time, a high frequency of p.F359V/I missense mutations (15/53, 28.3%) was determined in the studied cohort of CML patients compared with patients of other European research groups. Kinase domain mutations of the BCR/ABL1 gene in CML patients corresponded to a faster development of secondary resistance compared with patients with wild-type BCR/ABL1. The p.T315I mutation and the presence of two mutations simultaneously we found to be the most prognostically unfavorable. The combination of point mutations and additional chromosomal aberrations in patients with CML were associated with a higher risk of disease progression and reduction of overall survavil (p = 0.016).
Independent initial factors for predicting a major molecular response within 24 months of imatinib therapy initiation were determined as follows: e14a2 transcript of the BCR/ABL1 gene, administration of imatinib shortly after diagnosis, normal hemoglobin level and the absence of blast cells in the peripheral blood. Expression levels of the fusion BCR/ABL1 ≤ 3.7 % after 3 months and BCR/ABL1 ≤ 0,4 % after 6 months of imatinib therapy were established as discriminatory for the prediction of the likelihood of the major molecular response.
A higher frequency of mutations in the following genes GATA2, STAG2, ASXL1, KDM6A, BCOR, CUX1, GNAS, KMT2A, SMC3, TET2, PHF6, DNMT3A, BCORL1, JAK2, TP53, HRAS, IKZF1, CARL in addition to the fusion gene BCR/ABL1 was found among the patients who have been exposed to ionizing radiation as a result of the Chernobyl Nuclear Power Plan Accident compared to the patient without any history of ionizing radiation exposure (68.2 % vs 20.0 %, respectively, p = 0.004), which was accompanied by diminished response to therapy and a more aggressive course of the disease.
Based on the obtained data, the author elaborated a new concept of TKI therapy resistance development outlining the role of gene- and chromosome-level aberrations in the genetic mechanisms of resistance to therapy with tyrosine kinase inhibitors in patients with chronic myeloid leukemia. The algorithm for molecular monitoring of TKI therapy response was proposed to individualize targeted therapy.
