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Precision therapy of 6-mercaptopurine in Chinese children with acute lymphoblastic leukaemia
Yue Zhou1, Li Wang2, Xiao-Ying Zhai2
1Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Insights
Chinese children with ALL are at higher risk for 6-mercaptopurine (6-MP) toxicity. Genetic factors like NUDT15 and IMPDH1 influence leukopenia risk, necessitating genotype-guided 6-MP therapy for better outcomes.
Area of Science:
- Pharmacogenomics
- Paediatric Oncology
- Clinical Pharmacology
Background:
- Chinese children exhibit increased susceptibility to thiopurine-induced leukopenia compared to Caucasian populations.
- Acute lymphoblastic leukemia (ALL) treatment often involves 6-mercaptopurine (6-MP), a thiopurine drug.
- Understanding genetic factors influencing 6-MP toxicity is crucial for optimizing treatment in paediatric ALL.
Purpose of the Study:
- To establish a 6-mercaptopurine (6-MP) dose-concentration-response relationship in Chinese children with ALL.
- To explore pharmacogenetic factors contributing to thiopurine-induced toxicities.
- To identify genetic markers for predicting leukopenia and hepatotoxicity.
Main Methods:
- Collected blood samples from paediatric ALL patients undergoing 6-MP treatment.
- Quantified 6-MP metabolite concentrations in red blood cells (RBCs) using high-performance liquid chromatography.
- Performed pharmacogenetic analysis on genomic DNA using MassArray genotyping.
Main Results:
- Identified a 6-thioguanine concentration threshold of 197.50 pmol/8 × 10^8 RBCs for predicting leukopenia risk.
- NUDT15 (rs116855232) and IMPDH1 (rs2278293) polymorphisms were associated with significantly higher leukopenia risk (5.50-fold and 5.80-fold, respectively).
- MTHFR rs1801133 variants increased hepatotoxicity risk by 4.46-fold.
Conclusions:
- Predetermining genotypes and monitoring thiopurine metabolism are essential for Chinese paediatric ALL patients.
- This approach can effectively predict treatment efficacy and minimize adverse effects of 6-MP maintenance therapy.
- Personalized medicine strategies are vital for safe and effective ALL treatment in this population.
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 × 108 RBCs, which was significantly higher than for patients unafflicted by leukopenia (178.90 pmol/8 × 108 RBCs; P = 0.029). We determined the population special target 6-thioguanine threshold to have equalled 197.50 pmol/8 × 108 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.
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