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Registration Number

0216U003545, 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

Head

Dyagil I.S., Minchenko J.M.,

Registration Date

01-02-2016

Organization

State institution "National research centеr for radiation medicine of the National academy of medical sciences of Ukraine "

Description

The object of study - patients with chronic myeloid leukemia, primary and secondary resistant to tyrosine kinase inhibitor therapy. The aim - to determine the main molecular genetic mechanisms of primary and secondary resistance to tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia, to justify the ways of resistance overcoming and increasing of treatment efficiency. Research Methods - hematologic, cytogenetic, molecular genetic, immunogenetic, cultural and statistics. The results of research. The study involved 154 patients with CML. Among them, 102 - with primary and 52 - with secondary resistance to imatinib treatment. It was found that primary resistance was defined mainly in CML patients pretreated during more than 6 months. The vast majority of patients with primary and secondary resistance had intermediate and high risk prognostic Sokal index. These patients did not achieve a complete cytogenetic and major molecular response in the expected time frame. Additional clonal chromosomal abnormalities (mostly extra Ph-chromosome) was present in 10% of primary resistant patients at diagnosis. It was found that patients with e14a2 transcript respond better to treatment with imatinib. The best event-free survival, and a lower incidence of secondary resistance were shown for these patients. CML patients, primary and secondary resistant to imatinib, with the marker mutations (G250E, Y253F / H, T315I, F359I) need to be switched on the 2nd generation of tyrosine kinase inhibitors or use of allogenic hematopoietic stem cell transplantation. The connection of pretreatment time with the appearance of BCR/ABL1 mutations. Patients achieved major molecular response, developed the secondary resistance later in comparison with patients who achieved only a complete cytogenetic response. It is shown that the level of BCR/ABL1 ? 0,1% causes a high probability of stable molecular remission for at least the next year. Exceeding of BCR/ABL1 level in 0.1 % increases the probability of loss of complete cytogenetic response. It was revealed that the secondary resistance to imatinib therapy was more frequent in CML patients with radiation exposure in anamnesis compared to the group of non-irradiated patients. It was found that the allele HLA-DRB1*12 is an optional marker of the risk of the secondary resistance to TKI therapy in CML patients. The carriage of the allele HLA-A*68, HLA-B*15, HLA-B*40, DQB1*0304 and DQB1*0604 reduces the risk of secondary resistance. High levels of pro-inflammatory IL-8, anti-inflammatory IL-4 and IL-10 and low concentrations of IL-2 and IFN-gamma in peripheral blood serum during CML diagnosis increased the risk of resistance development. Increasing concentration of proinflammatory interleukins IL-4 and IL-10 was determined in patients with secondary resistance. High proliferative capacity of hematopoietic and bone marrow stromal cells was revealed in patients with CML with resistance to imatinib treatment. A set of prognostic factors of primary and secondary resistance in CML patients was designed. Ways to overcome the primary and secondary resistance were offered. Recommendations to improve the effeciency of TKI therapy were made. The algorithm of molecular monitoring of CML patients with primary and secondary resistance was developed.

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Балан Валентина Володимирівна
Дмитренко Ірина Віталіївна
Дмитренко Олена Олександрівна
Любарець Тетяна Федорівна
Малінкіна Тетяна Володимирівна
Парамонов Віктор Володимирович
Товстоган Анжела Олександрівна
Федоренко Віра Григорівна
Шляхтиченко Тетяна Юрівна
Шолойко Валентина Василівна