THE IMPORTANCE OF BIOTRANSFORMATION GENE POLYMORPHISM IN THE SELECTION OF ANTITHYROSINE KI- NASE THERAPY FOR CHRONIC MYELOID LEUKEMIA

One of the urgent problems in helping patients with chronic myeloid leukemia BCR / ABL1 + (CML) is the development of various types of toxicity of tyrosine kinase inhibitors (TKI), which may be based on impaired drug metabolism. The paper presents preliminary results of a study of the polymorphism of genes of the enzyme system involved in the biotransformation of drugs (genes CYP2C9, CYP3A4, CYP3A5, CYP4E2 and VKORC1) in patients with CML with or without symptoms of dasatinib intolerance. It was found that in patients with non-hematologic toxicity-specific effects of dasatinib therapy (recurrent pleural effusions), the frequency of occurrence of various single-nucleotide polymorphisms was 100% compared with the control group. Polymorphism rs2740574 (AG) of the CYP3A4 cytochrome isoenzyme gene, the main enzyme involved in dasatinib metabolism, was detected in 20% of subjects, based on which it was concluded that the functional activity of this enzyme is not a reliable predictive indicator of the toxic effect, but there can be one from the causes of its occurrence, which requires further study. It was also found that rs99232231 (GA) polymorphism of the VKORC1 vitamin K-reductase gene was detected in 60% of subjects; a decrease in the functional activity of this enzyme may be one of the causes of adverse events. The results obtained indicate the prospect of further development of the topic in order to search for new approaches to the choice of treatment for TKI and the prediction of complications in CML.

myeloproliferative neoplasms, MPN, chronic myeloid leukemia, CML, tyrosine kinase inhibitors, TKI, dasatinib, biotransformation, P450 cytochromes, gene polymorphism, toxicity