Search academic texts

Information × Registration Number 0215U003219, 0113U002315 , R & D reports Title Study of the molecular-genetic mechanisms of resistance to the tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia and reasoning of resistance overcoming ways popup.stage_title Head Dyagil I.S., Minchenko J.M., Registration Date 21-01-2015 Organization State institution "National research centеr for radiation medicine of the National academy of medical sciences of Ukraine " popup.description2 The object of study - patients with chronic myeloid leukemia with secondary resistance to the tyrosine kinase inhibitors therapy. Aim - to determine the clinical course of the disease and cytogenetic, molecular genetic, morphological, immunogenetic characteristics of the tumor clone in patients with chronic myeloid leukemia who lost their response to therapy at the different stages of tyrosine kinase inhibitors treatment. Methods - hematologic, cytogenetic, molecular genetic, immunogenetic, cultural and statistics. Results. The study involved 52 CML patients with secondary resistant to imatinib therapy. 20 CML patients who were exposed to radiation due to the CPP accident also were examined. It was found that the development of secondary resistance to imatinib therapy in CML patients is characterized by the presence of intermediate and high prognostic Sokal index. In patients from study group at the time of diagnosis werw not revealed additional specific karyotype abnormalities, but b2a2 BCR/ABL transcript expression occurred significantly more often. The majority of patients from study group had suboptimal response to imatinib therapy. It was found that patients the risk of secondary resistance for these increased after 24 months imatinib therapy. Secondary resistance developed later in patients who have achieved major molecular response, as compared with patients who had only complete cytogenetic response. It was shown that the level of BCR/ABL?0,1% determined high probability of stable molecular remission for at least the next year. Exceeding of 0.1% increased probability of complete cytogenetic response loss. It was found that mutation were dominated in CML patients with secondary resistance to imatinib therapy.It was shown that secondary resistance to imatinib therapy developed more frequently in CML patients who had a history of radiation exposure, than in the non-irradiated group of CML patients and was 25%. Development of secondary resistance to TKI therapy in CML patients significantly associated with the presence abnormal transcript b2a2 and immunogenetic markers HLA-DRB1 * 12 and DRB1 * 11 in genotype. At the same time allele HLA-A * 03, HLA -B * 15 and DQB1 * 0604 frequency was reduced. Significant increasing of anti-inflammatory interleukins IL-4 and IL-10 concentration ( 2.2 and 2.5 times respectively) during the loss of cytogenetic response to imatinib therapy was shown. Increased colony forming ability of progenitor cells and increased number of large clusters were found in CML patients with secondary resistance to imatinib therapy. The range of clinical, morphological, cytogenetic, molecular genetic, immunogenetic characteristics of the tumor clone in CML patients, causing the formation of secondary resistance to tyrosine kinase inhibitor treatment was defined: intermediate and high Sokal prognostic index, b2a2 BCR/ABL transcript expression, lack of complete cytogenetic response at 6 months of imatinib therapy and major molecular response at 12 months of therapy, mutations, and increased interleukin IL-4 and IL-10 concentration, maintaining high proliferative activity of hematopoietic cells, the absence of HLA-A*03, HLA-B*15 and DQB1*0604 allele and the presence of HLA-DRB1*12 and DRB1*11 allele in genotype. Product Description popup.authors Балан Валентина Володимирівна Дмитренко Ірина Віталіївна Дмитренко Олена Олександрівна Любарець Тетяна Федорівна Малінкіна Тетяна Володимирівна Федоренко Віра Григорівна Шляхтиченко Тетяна Юрівна Шолойко Валентина Василівна popup.nrat_date 2020-04-02 Close