Results of therapy of acute lymphoblastic leukemia in children depending on the mutational status of the ABCB1 gene

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Abstract

Background. Despite significant evidence of clinical efficacy of modern protocols for the treatment of acute lymphoblastic leukemia (ALL) in children, methotrexate (MTX) in high doses (HD-MTX>1000 mg/m2) is still one of the main components of therapy; significant interindividual variability of disease outcomes have been noted, which determines the possible role of pharmacogenetics (PG) in the identification of polymorphisms in candidate genes.

Objective. To evaluate the efficacy of MTX therapy for pediatric ALL by identifying possible associations of ABCB1 (ATP-binding cassette subfamily B member 1) gene polymorphisms with treatment outcomes.

Methods. A prospective analysis of a database of pediatric patients with ALL in an observational (cohort) single-center study. The study included 124 children diagnosed with ALL who received therapy according to ALL BFM 2002/2009 protocols using HD-MTX. Real-time PCR (polymerase chain reaction) method was used to study ABCB1 gene polymorphisms. The study material was peripheral blood. The material was sampled once regardless of the duration of MTX therapy. SNPs (single nucleotide polymorphisms) selection criteria: minor allele frequency >5%, genes that corresponded to Hardy–Weinberg equilibrium (HWE, Hardy–Weinberg equilibrium) and finally the level of evidence of previously published studies. SPSS Statistics 26.0 (USA). program was used for statistical processing of the results. Survival analysis was performed by the Kaplan-Meier method. In all statistical analysis procedures, the critical level of significance was taken as p<0.05.

Results. Significant associations of increased risk of delayed-onset events were found in carriers of the GG allele of the ABCB1 gene rs2032582 (OR=2.5, 95% CI 1.12–5.5; p=0.023) and the TT polymorphism of the ABCB1 gene rs4148738 (OR=2.4, 95% СI 1.07–5.3; p=0.031). Event-free and relapse-free survival rates were significantly higher in the TT, TC carrier group than in the group of carriers of the CC «wild type» allele of the ABCB1 C3435T rs1045642 gene (p=0.018 and p=0.026 respectively). All three types of estimated survival (EFS, RFS, OS) were higher in the group of patients receiving MTX at a dose of more than 1000 mg/m2 (p<0.001, p<0.001, p=0.047 respectively).

Conclusion. The need for innovative approaches, including the determination of polymorphisms of genes providing transport and metabolism of cytostatics, to further increase patient survival while reducing adverse effects of antitumor treatment is undoubted.

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About the authors

Oksana D. Gurieva

N.N. Blokhin National Medical Research Centre of Oncology

Author for correspondence.
Email: swimmer96ok@gmail.com
ORCID iD: 0000-0002-0050-0721

Pediatric Oncologist Department of Pediatric Oncology and Hematology (Chemotherapy of Hemoblastosis) No. 1 of the Research Institute of Pediatric Oncology and Hematology

Russian Federation, Moscow

T. T. Valiev

N.N. Blokhin National Medical Research Centre of Oncology; Russian Medical Academy of Continuing Professional Education

Email: swimmer96ok@gmail.com
ORCID iD: 0000-0002-1469-2365

Department of Pediatric Oncology n.a. Academician L.A. Durnov, Russian Medical Academy of Continuing Professional Education

Russian Federation, Moscow; Moscow

M. I. Savelyeva

Yaroslavl State Medical University

Email: swimmer96ok@gmail.com
ORCID iD: 0000-0002-2373-2250
Russian Federation, Yaroslavl

S. R. Varfolomeeva

N.N. Blokhin National Medical Research Centre of Oncology

Email: swimmer96ok@gmail.com
ORCID iD: 0000-0001-6131-1783
Russian Federation, Moscow

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2. Fig. Graphic representation of the frequency of occurrence of treatment outcomes in children with ALL in the study sample (n=124)

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