巯嘌呤治疗儿童急性淋巴细胞白血病相关毒副作用及其与TPMT基因多态性关系的研究

Mercaptopurine related toxicity in the child patients with acute lymphoblastic leukemia and its relationship with the thiopuine S-methyltransferase genetic polymorphisms

目的:观察CCLG-08方案中含有巯嘌呤的巩固和维持阶段急性淋巴细胞白血病(Acute lymphoblastic leukemia,ALL)简称急淋。患儿毒副作用的发生情况,检测急淋患儿巯嘌呤甲基转移酶(Thiopurine S-methyltransferase,TPMT)基因多态性,研究其与巯嘌呤相关药物毒副作用的关系。方法:观察急淋患儿巩固和维持阶段发生的以外周血白细胞显著减少、肝脏损害为主的毒副作用;采用等位基因特异性聚合酶链反应、限制性片断长度多态性和时间飞行质谱技术检测TPMT基因G238C、G460A、A719G多态性。结果:急淋患儿巩固化疗阶段外周血白细胞显著减少的血液系统毒副作用发生率是19.35%(n=24);维持治疗1个月以上,外周血白细胞显著减少的血液系统毒副作用发生率是13.82%(n=13),肝脏损害的发生率是10.64%(n=10);维持治疗Ⅰ和Ⅱ组急淋患儿的血液系统毒副作用和肝损害发生率没有显著的统计学差异。没有发现急淋患儿TPMT基因型与其巯嘌呤相关毒副作用间的相关性。结论:研究显示急淋患儿可以良好耐受CCLG-08方案中的巩固和维持治疗;汉族急淋患儿TPMT基因G238C、G460A、A719G位点总突变率为0.67%;研究没有发现急淋患儿巯嘌呤相关的白细胞减少和肝脏损害与TPMT基因型的相关性;CCLG-08方案维持治疗Ⅰ组(连续服用巯嘌呤)较之维持治疗Ⅱ组(连续服用3周间断1周)不会导致更多和更严重的外周血白细胞减少以及肝损害的发生。

Objective：To observe the mercaptopurine related toxicity in the child patients with acute lymphoblastic leukemia（ALL）treated with CCLG-08 protocol,and to investigate the thiopurine S-methyltransferase（TPMT）gene polymorphisms in the patients and discuss its relationship with the mercaptopurine related toxicity.Methods：The occurances of leukocytopenia,hepatotoxicity and pancreatitis in the consolidation therapy stage and the maintenane therapy stage were observed.The polymorphisms of TPMT G238C,G460A,and A719G were determined by allele-specific PCR（ASPCR）,PCR-restriction fragment length polymorphism（PCR-RFLP）,and MALDI-TOF MS technique.Results：19.35%（n=24）of the ALL patients in the consolidation therapy stage and 13.83%（n=13）in the maintenane therapy stage experienced serious leukocytopenia.10.64%（n=10）of the patients experienced hepatotoxicity in the maintenane therapy stage.No different occurance rate of mercaptopurine related toxicity was found in the two groups of the maintenance therapy.The study didn＇t find the relationship between the TPMT polymorphisms and the mercaptopurine related toxicity.Conclusion：Although considerable ratio of the mercaptopurine related toxicity occured,the consolidation therapy and the maintenance therapy of CCLG-08 protocol were safely experienced by the ALL patients in this study.The mutation rate of TPMT gene G238C,G460A,and A719G is 0.67% in Han ethnic patients with ALL in Chongqing area.No relationship between TPMT G238C,G460A,and A719G genetic polymorphisms and the mercaptopurine related leukocytopenia and hepatotoxicity were found in the study.GroupⅠof maintenance therapy（take mercaptopurine 4 weeks continuously）was not lead to more or severe leukocytopenia and hepatotoxicity compared with groupⅡ of maintenance therapy（take mercaptopurine 3 weeks continuously and withdrawal 1 week）.