儿童急性白血病应用大剂量甲氨蝶呤严重并发症3例临床分析及文献复习

A retrospective clinic analysis on high-dose methotrexate related severe complications in three cases of pediatric acute lymphoblastic leukemia-cases report and literature review

目的探讨儿童白血病（ALL）应用大剂量甲氨蝶呤（HD-MTX）严重并发症的临床特点、发生机制及预防处理措施。方法总结3例在本院确诊并按ALL治疗方案规范化疗的儿童急性淋巴细胞白血病应用HD．MTX后出现严重并发症病例的临床特点并复习文献。结果3例患儿均为学龄期儿童、急性淋巴细胞白血病应用HD．MTx（5g／m2）期间发生严重高甲氨蝶呤血症，治疗期间严密监测血药浓度，持续水化、碱化以及多种方式四氢叶酸钙解救但甲氨蝶呤排泄延迟，2～3周后血清甲氨蝶呤浓度仍明显高于中毒浓度，化疗后2周均合并严重骨髓抑制，2例出现表皮松解、1例消化道溃疡，均因继发感染及多脏器损害并发症死亡。结论甲氨蝶呤体内的代谢受到多种因素影响，持续高血药浓度可造成严重并发症，对儿童ALL应用HD．MTX应根据细胞免疫学表型、细胞遗传学及甲氨蝶呤静脉滴注后不同时段的血药浓度及药物代谢酶相关基因情况采用个体化治疗。

Objective To investigate the clinical features and mechanism of high-dose methotrexate （HD-MTX） related severe complications in pediatric acute lymphoblastic leukemia （ALL）. Methods Severe complications and clinical features of 3 ALL cases treated with HD-MTX were summarized. The related literatures were reviewed. Results Three school-age patients were received HD-MTX （5 g/m2） for the first time, and showed a extremely high levels of serum MTX 45 hours after MTX therapy. Several methods including continuous hydration/alkalization, calcium folinate （CF） rescue with different doses and dialysis were used. Nevertheless, the high MTX levels still lasted for more than two weeks. Severe bone marrow suppression happened after two weeks; two cases suffered from epidermolysis; one case was complicated with peptic ulcer. They died from severe complications. Conclusions Many factors are involved in the metabolism of MTX. Persistent high MTX levels can induce severe complications. In the HD-MTX treatment of pediatric ALL, individualized therapy should be considered based on the characteristics of immunophenotype, cytogenetics and MTX metabolism enzyme related genes.