Influence of pharmacogenetic parameters on clinical variants of methotrexate toxicity in acute lymphoblastic leukemia in children

Background. Despite significant evidence of the clinical efficacy of modern protocols for the treatment of acute lymphoblastic leukemia (ALL) in children, high doses of methotrexate as the main therapeutic agent demonstrate significant inter-individual variability in drug toxicity and disease outcomes due to polymorphisms of drug transporter genes and genes responsible for the metabolism of cytostatics, which makes pharmacogenetic studies highly relevant. Objective. Evaluation of the relationship of pharmacogenetic parameters with the main types of methotrexate toxicity in the treatment of ALL in children. Methods. The study included 67 children diagnosed with ALL treated according to the ALL IC-BFM 2002/2009 protocols using high-dose methotrexate. To assess adverse reactions, laboratory methods with NCI toxicity scales (CTCAE v5.0, 2018) were used. Real-time PCR was used to study the polymorphisms of the ABCB1 and SLCO1B1 genes. Peripheral blood samples were used as a research material. The samples was taken once, regardless of the duration of methotrexate therapy. SPSS Statistics 21.0 was used for statistical analysis of the results. Association analysis was performed using the x2 test and Fisher’s exact test. The selection criteria for SNPs were as follows: a frequency of minor alleles >5%, genes that matched the Hardy-Weinberg equilibrium (HWE), and finally the level of evidence from previously published studies. Results. The development of infectious complications in the postcytostatic period against the background of myelotoxic agranulocytosis was significantly associated with polymorphisms of the ABCB1 rs1128503 and SLCO1B1 T521C rs4149056 genes, which correlates with the data of world scientific literature. Conclusion. Determination of polymorphisms of genes that provide transport and metabolism of cytostatics, i.e., pharmacogenetic aspects of toxicity, is a promising and dynamically developing area of clinical oncology.

pharmacogenetics, drug toxicity, chemotherapy, methotrexate, acute lymphoblastic leukemia, children