Precision Therapy of 6-mercaptopurine in Chinese Children with Acute Lymphoblastic Leukaemia

Overview

Journal Br J Clin Pharmacol

Specialty Pharmacology

Date 2020 Feb 21

PMID 32077136

Citations 10

Authors

Yue Zhou

Li Wang

Xiao-Ying Zhai

Li Wen

Fang Tang

Fan Yang

Xi-Ting Liu

Lei Dong

Li-Juan Zhi

Hai-Yan Shi

Guo-Xiang Hao

Yi Zheng

Evelyne Jacqz-Aigrain

Tian-You Wang

Wei Zhao

Affiliations

Soon will be listed here.

Abstract

Aims: Chinese children are more susceptible to the development of thiopurine-induced leukopenia compared with Caucasian populations. The aim of our study was to establish a 6-mercaptopurine (6-MP) dose-concentration-response relationship through exploration of pharmacogenetic factors involved in the thiopurine-induced toxicities in Chinese paediatric patients afflicted by acute lymphoblastic leukaemia (ALL).

Methods: Blood samples were obtained from ALL children treated with 6-MP. We determined the metabolite steady-state concentrations of 6-MP in red blood cells (RBCs) by using high-performance liquid chromatography. Pharmacogenetic analysis was carried out on patients' genomic DNA using the MassArray genotyping platform.

Results: Sixty children afflicted by ALL who received 6-MP treatment were enrolled in this study. The median concentration of 6-thioguanine in patients afflicted by leukopenia was 235.83 pmol/8 × 10 RBCs, which was significantly higher than for patients unafflicted by leukopenia (178.90 pmol/8 × 10 RBCs; P = 0.029). We determined the population special target 6-thioguanine threshold to have equalled 197.50 pmol/8 × 10 RBCs to predict leukopenia risk in Chinese paediatric patients afflicted by ALL. Among 36 candidate single nucleotide polymorphisms, our results indicated that NUDT15 (rs116855232) and IMPDH1 (rs2278293) were correlated with a 5.50-fold and 5.80-fold higher risk of leukopenia, respectively. MTHFR rs1801133 variants were found to have had a 4.46-fold significantly higher risk of hepatotoxicity vs wild-type genotype.

Conclusion: Our findings support the idea that predetermination of genotypes and monitoring of thiopurine metabolism for Chinese paediatric patients afflicted by ALL is necessary to effectively predict the efficacy of treatments and to minimize the adverse effects of 6-MP maintenance therapy.

Citing Articles

Polymorphism and Its Association With Mercaptopurine Hematotoxicity in Acute Lymphoblastic Leukemia in Indonesian Children.

Rosdiana D, Saputri D, Louisa M, Setiabudy R In Vivo. 2024; 38(4):2041-2048.

PMID: 38936894 PMC: 11215610. DOI: 10.21873/invivo.13662.

Association of gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis.

Du S, Huang X, He X, Mao M, Chen M, Zhang R Haematologica. 2023; 109(4):1053-1068.

PMID: 37794799 PMC: 10985454. DOI: 10.3324/haematol.2023.282761.

Pharmacogenetics of 6-mercaptopurine in a black Zimbabwean cohort treated for acute lymphoblastic leukaemia.

Chikondowa P, Munkombwe D, Chikwambi Z, Kuona P, Masimirembwa C Pharmacogenomics. 2023; 24(8):449-457.

PMID: 37248698 PMC: 10463210. DOI: 10.2217/pgs-2023-0026.

Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising "MINT" sequencing strategy and therapeutic "DNA-TG" monitoring.

Guo H, Zhao Y, Wang W, Dong N, Hu Y, Zhang Y Front Pharmacol. 2022; 13:941182.

PMID: 36238550 PMC: 9552076. DOI: 10.3389/fphar.2022.941182.

A Retrospective Cohort Study of the Efficacy, Safety, and Clinical Value of 6-TG versus 6-MP Maintenance Therapy in Children with Acute Lymphoblastic Leukemia.

Tu M, Zhang A, Hu L, Wang F Biomed Res Int. 2022; 2022:7580642.

PMID: 36046443 PMC: 9420618. DOI: 10.1155/2022/7580642.

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