Relationship of SLCO1B1 and ABCB1 gene polymorphisms with clinical variants of methotrexate toxicity in pediatric acute lymphoblastic leukemia therapy

Background. Despite the significant clinical efficacy of current treatment protocols for acute lymphoblastic leukemia (ALL) in children, high-dose methotrexate demonstrates significant interindividual variability in drug toxicity and disease outcomes due to polymorphisms of drug transporter genes and genes responsible for cytostatic metabolism, which makes pharmacogenetic studies increasingly relevant.

Aim. To evaluate the association of ABCB1 (C3435T rs1045642, rs1128503, rs2032582, rs4148738), SLCO1B1 T521C rs4149056 gene polymorphisms with the main types of methotrexate toxicity and the onset of clinical events (death, recurrence, progression) during the treatment of childhood ALL.

Materials and methods. The study enrolled 103 patients diagnosed with ALL who received therapy according to BFM group protocols (2002/2009), using high-dose (2000 and 5000 mg/m²) methotrexate. Laboratory methods using NCI toxicity scales (CTCAE v5.0 2018) were used to assess adverse reactions. Real-time polymerase chain reaction method was used to study ABCB1 and SLCO1B1 gene polymorphisms. The study material was peripheral blood. Material was sampled once, regardless of the duration of methotrexate therapy. SPSS Statistics 21.0 software was used for statistical processing of the results. Analysis of associations was performed using the χ2 criterion and Fisher’s exact test.

Results. Development of infectious complications, oropharyngeal mucositis, delayed MTX elimination, events were significantly associated with polymorphisms of the studied genes: SLCO1B1 T521C rs4149056, ABCB1 rs4148738, ABCB1 rs1128503, which correlates with the data of world scientific literature.

Conclusion. Determination of polymorphisms of genes responsible for the transport and metabolism of methotrexate is a promising and dynamically developing area of clinical oncology.