急性淋巴细胞白血病患儿维持治疗期间6-巯基嘌呤 使用剂量与TPMT和NUDT15基因多态性的关系

doi:10.3969/j.issn.1673-5501.2024.01.010

摘要/Abstract

摘要： 背景：6-巯基嘌呤（6-MP）是急性淋巴细胞白血病（ALL）维持治疗最主要的药物之一，代谢酶基因多态性与药物的骨髓抑制程度有关。目的：探讨ALL患儿维持治疗期间6-MP使用剂量与TPMT和NUDT15基因多态性的关系。设计：回顾性队列研究。方法：纳入2020年1月至2021年12月于郑州大学第一附属医院明确诊断为ALL、经前期化疗骨髓达完全缓解、进入维持治疗阶段且口服6-MP治疗的患儿。口服6-MP前患儿行TPMT和NUDT15基因型检测，分析TPMT、NUDT15不同基因型患儿应用6-MP治疗的使用剂量和骨髓抑制情况。主要结局指标：6-MP使用剂量。结果：61例维持治疗的ALL患儿纳入本文分析。纳入TPMT基因多态性统计分析的ALL患儿48例（除外NUDT15基因突变13例），野生型45例，突变型3例；纳入NUDT15基因多态性统计分析的ALL患儿58例（除外TPMT基因突变3例），CC型45例，CT型9例，TT型4例。在6-MP维持治疗阶段，TPMT和NUDT15不同基因型患儿的WBC、Hb、PLT计数差异均有统计学意义（均P<0.05）。患儿用药后出现不同程度的中性粒细胞减少，包括TPMT野生型15例，突变型3例；NUDT15基因CC型15例，CT型5例，TT型4例；TPMT和NUDT15不同基因型患儿骨髓抑制情况差异均有统计学意义（均P<0.05）。TPMT和NUDT15不同基因型患儿6-MP使用剂量差异有统计学意义（均P<0.05），TPMT野生型和突变型ALL患儿维持治疗期6-MP使用剂量分别为（40.81±6.02）和（16.25±4.42）mg·m-2·d-1；NUDT15基因CC型、CT型和TT型6-MP使用剂量分别为（40.81±6.02）、（34.28±4.53）和（10.00±1.28）mg·m-2·d-1。结论：TPMT和NUDT15突变型患儿的骨髓抑制程度均较野生型严重。ALL患儿维持治疗期间6-MP使用剂量与TPMT和NUDT15基因多态性相关。

关键词: 急性淋巴细胞白血病, 6-巯基嘌呤, TPMT, NUDT15, 基因多态性, 药物使用剂量

Abstract: Background：6-mercaptopurine (6-MP) is one of the main drugs used in the maintenance therapy of acute lymphoblastic leukemia (ALL), and its metabolism enzyme gene polymorphism is associated with the degree of bone marrow suppression caused by the drug. Objective：To investigate the relationship between the dose of 6-MP use and TPMT and NUDT15 gene polymorphisms during maintenance therapy in children with ALL. Design：Retrospective cohort study. Methods：Children with a clear diagnosis of ALL at the First Affiliated Hospital of Zhengzhou University from January 2020 to December 2021 were included, who achieved complete remission after prior chemotherapy and entered the maintenance therapy stage with oral 6-mercaptopurine (6-MP) treatment. Before starting oral 6-MP, genetic testing for TPMT and NUDT15 genotypes was conducted to analyze the dosage and bone marrow suppression of 6-MP treatment in children with different TPMT and NUDT15 genotypes. Main outcome measures：6-MP dosage. Results：This study analyzed 61 pediatric ALL patients undergoing maintenance therapy. Among them, 48 patients were included in the statistical analysis of TPMT gene polymorphism (excluding 13 cases with NUDT15 gene mutations), with 45 wild-type cases and 3 mutant cases. Additionally, 58 patients were included in the statistical analysis of NUDT15 gene polymorphism (excluding 3 cases with TPMT gene mutations), with 45 CC genotype cases, 9 CT genotype cases, and 4 TT genotype cases. During the maintenance therapy with 6-MP, significant differences in WBC, Hb, and PLT counts were observed among patients with different TPMT and NUDT15 genotypes (all P< 0.05). Patients experienced varying degrees of neutropenia after medication, including 15 cases with wild-type TPMT and 3 mutant TPMT cases, as well as 15 CC genotype cases, 5 CT genotype cases, and 4 TT genotype cases of NUDT15 gene. The differences in bone marrow suppression among patients with different TPMT and NUDT15 genotypes were statistically significant (all P< 0.05). Furthermore, there were significant differences in the dosage of 6-MP among patients with different TPMT and NUDT15 genotypes (all P< 0.05). Specifically, the maintenance therapy dosage of 6-MP for patients with wild-type TPMT and mutant TPMT was (40.81 ± 6.02) and (16.25 ± 4.42) mg·m-2·d-1, respectively. For patients with CC genotype, CT genotype, and TT genotype of the NUDT15 gene, the 6-MP dosage was (40.81 ± 6.02), (34.28 ± 4.53), and (10.00 ± 1.28) mg·m-2·d-1, respectively. Conclusion：Patients with mutations in the TPMT and NUDT15 genes experience more severe bone marrow suppression compared to those with the wild-type genotype. The dosage of 6-MP used during maintenance therapy in pediatric ALL patients is associated with TPMT and NUDT15 gene polymorphisms.

Key words: Acute lymphoblastic leukemia, 6-mercaptopurine, TPMT, NUDT15, Genetic polymorphism, Dosage of drugs

吴新蕊刘玉峰李白刘莹刘姗姗. 急性淋巴细胞白血病患儿维持治疗期间6-巯基嘌呤使用剂量与TPMT和NUDT15基因多态性的关系[J]. 中国循证儿科杂志, 2024, 19(1): 52-56.

WU Xinrui, LIU Yufeng, LI Bai, LIU Ying, LIU Shanshan. Relationship between 6-mercaptopurine dosage and polymorphisms of TPMT and NUDT15 genes during maintenance therapy for children with acute lymphoblastic leukemia[J]. Chinese Journal of Evidence-Based Pediatrics, 2024, 19(1): 52-56.

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