Abstract
Objectives
To evaluate the role of ABCB1 (C3435T rs1045642, rs1128503, rs2032582, rs4148738), SLCO1B1 T521C rs4149056 genetic polymorphisms in the development of major types of methotrexate (MTX) toxicities and the occurrence of a terminal event (death, relapse) in pediatric АLL.
Methods
The study included 124 patients diagnosed with pediatric ALL. All patients treated according to the protocols of the German BFM group (2002/2009) with high-dose (1,000, 2,000 and 5,000 mg/m2) methotrexate. MTX-related toxicities, including hematologic, hepatic and renal, were evaluated according to the common terminology criteria for adverse events version 5.0 (CTCAE v.5.0). Real-time PCR method was used to investigate polymorphisms of ABCB1 and SLCO1B1 genes. The study material was peripheral blood.
Results
A competitive analysis demonstrated significant relationships between MTX ADRs. The results of the study support the existence of relationships between some ADRs and MTX kinetics. An associative analysis showed association with the development of AEs to methotrexate indicating their clinical significance from different genetic polymorphisms protein-transporters. The available results confirm the associations of the studied genes with the increased risk of high doses MTX toxic ADRs and terminal events.
Conclusions
Complementing the existing criteria for pediatric ALL risk groups with pharmacogenetic indicators will allow further individualization of therapy.
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Research ethics: Clinical studies of the research were conducted in accordance with all the relevant Russian national regulations, institutional policies, and in accordance with the principles of the Declaration of the World Medical Association (Edinburgh, 2000), and in accordance with the tenets of the Helsinki Declaration. The study was approved by the Research Ethics Committee of the Pediatric Oncology and Hematology Research Institute, Blokhin’ National Medical Research Cancer Center of the Ministry of Health of Russia, Protocol No. 4 dated October 17, 2021, in accordance with the approved regulations for conducting clinical and experimental research at the Institute.
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Informed consent: Written informed consent was obtained from all participants in the study before the beginning of any procedures especially pharmacogenetic testing.
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Author contributions: Oxana D. Gurieva as a PhD student of the Department of Pediatric Oncology and Hematology has substantial contributions to the conception and design of data for the work; and statistical analysis of research results; and final approval of the version to be published; and integrity of any part of the work are appropriately investigated and resolved. Marina I. Savelyevа as a Professor of Clinical Pharmacology has substantial contributions to the interpretation of data for the work and drafting the work (writing an article in English); and revising it critically for important intellectual content; and final approval of the version to be published; and agreement to be accountable for all aspects of the work because she is a main scientific leader of this research study. Timur T. Valiev as Head of Chemotherapy Hemoblastoses Department of Pediatric Oncology and Hematology has substantial contributions to the conception and design of data for the work; and revising it critically for important intellectual content especially in the pharmacogenetic data field; and final approval of the version to be published; and integrity of any part of the work are appropriately investigated and resolved. Zhannet A. Sozaeva as a junior researcher of the Research Institute of Molecular and Personalized Medicine has substantial contributions to the pharmacogenetic testing, and interpretation of data for the work; and final approval of the version to be published; and agreement to be accountable for all aspects of the work. Svetlana N. Kondratenko as a Professor of Clinical Pharmacology has substantial contributions to the interpretation of MTX kinetic data for the work, and drafting the article; and final approval of the version to be published; and agreement to be accountable for all aspects of the work. Mikhail V. Ilyin as Head of Therapy Department has substantial contributions to the revising of all statistic data and to the building of preventing models of data for the work; and final approval of the version to be published. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Competing interests: The authors state no conflict of interest.
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Research funding: None declared.
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Data availability: The raw data can be obtained on request from the corresponding author.
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