巯嘌呤甲基转移酶基因检测用于指导6-巯基嘌呤在中国儿童急性淋巴细胞白血病中个体化治疗的循证评价

Evidence-based Evaluation of Thiopurine Methyltransferase Genetic Testing in Guiding the Individualized Treatment of Childhood Acute Lymphoblastic Leukemia with 6-Mercaptopurine in China

目的系统评价6-巯基嘌呤(6-mercaptopurine,6-MP)治疗亚洲儿童急性淋巴细胞白血病(acute lymphoblastic leukemia,ALL)出现骨髓抑制与巯嘌呤甲基转移酶(thiopurine methyltransferase,TPMT)基因多态性的相关性,并分析中国ALL患儿TPMT基因检测的经济性。方法采用循证医学方法搜集6-MP治疗亚洲儿童ALL相关骨髓抑制与TPMT基因多态性相关的随机对照试验或观察性研究进行meta分析。针对中国ALL患儿,借助决策树模型对2种6-MP初始给药剂量方案进行成本效果分析。结果最终纳入6个观察性研究,共577例亚洲患儿。Meta分析结果显示,TPMT基因多态性与骨髓毒性[OR=5.61,95%CI(2.05,15.34),P=0.000 8]发生有关。在基础数据分析中,针对中国ALL患儿,以上2个方案以严重骨髓抑制发生率为效果指标,增量成本-效果比为10 403.83,敏感性分析显示结果稳定。结论亚洲ALL患儿的TPMT基因多态性与6-MP的骨髓毒性显著相关。中国ALL患儿通过TPMT基因检测调整6-MP初始剂量并不优于标准剂量给药。

OBJECTIVE To systematically review the association between 6-mercaptopurine(6-MP) treatment of acute lymphoblastic leukemia(ALL) related bone marrow suppression and thiopurine methyltransferase(TPMT) gene polymorphism in Asian children and evaluate the economy of TPMT genetic testing in Chinese ALL children. METHODS Evidence-based medicine method was used to collect the randomized control trials or observational studies about the relationship between 6-MP treatment of ALL related bone marrow suppression and TPMT gene polymorphism in Asian children by meta analysis, and cost-effectiveness analysis of 2 kinds of initial dose regimen of 6-MP for ALL children in China were performed with decision tree model. RESULTS Finally a total of 6 literatures involving 577 Asian children with ALL were included. The results of meta-analysis showed the following: the TPMT polymorphisms were relevant to myelotoxicity[OR=5.61, 95%CI(2.05, 15.34), P=0.000 8]. In the fundamental data analysis, aimed to the above 2 kinds of treatment, the incremental cost-effectiveness ratio was 10 403.83 when the incidence of severe myelosuppression was taken as the effective index. Sensitivity analysis showed that the results were stable. CONCLUSION This meta-analysis suggest that the TPMT polymorphisms of Asian children with ALL are significantly associated with myelosuppression. In China, the initial dose of 6-MP adjusted by TPMT gene detection in ALL children is not superior to the standard dose.