目的 氨甲蝶呤（methotrexate, MTX）血清浓度和MTHFR基因多态性与儿童急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）大剂量MTX延迟代谢及不良反应的关联性。 方法 纳入2021年8月—2023年12月中国医学科学院血液病医院收治的ALL患儿214例，均检测第1次大剂量MTX用药后的血清浓度和MTHFR C677T和A1298C多态性，回顾性分析患儿数据。 结果 214例ALL患儿中，C677T的TT基因型发生延迟代谢的比率高于CT基因型，CC基因型高于CT基因型。携带A1298C的AC基因型发生Ⅰ级及以上中性粒细胞减少的比率高于AA基因型。MTX的较高浓度和发生Ⅱ级及以上的肾损伤、胃肠道反应和高胆红素血症密切关联。疾病分层为中/高危、年龄>14岁、体重指数≥17 kg/m²是延迟代谢的危险因素；相对于MTHFR C677T CC基因型，C677T CT发生延迟代谢的风险降低；TT与CC相比，对延迟代谢的影响没有显著性差异。 结论 MTX浓度可作为MTX相关毒性的客观标志物，而在充分解救治疗与浓度监测下，单一MTHFR多态性可能不足以指导剂量调整，因此应以浓度监测为主、基因为辅的联合治疗策略。

Objective To evaluate the associations of serum methotrexate (MTX) concentrations and MTHFR gene polymorphisms with delayed metabolism of high-dose MTX and adverse reactions in children with acute lymphoblastic leukemia (ALL). Methods Children with ALL treated at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, between August 2021 and December 2023 were included (n=214). Serum MTX concentrations after the first HD-MTX administration and MTHFR C677T and A1298C polymorphisms were determined. Clinical data were retrospectively analyzed. Results Among 214 children with ALL, the C677T TT genotype had a higher rate of delayed metabolism than the CT genotype, and the CC genotype had a higher rate than the CT genotype. For A1298C, the AC genotype was associated with a higher incidence of grade I or higher neutropenia than the AA genotype. Higher MTX concentrations were closely associated with grade Ⅱ or higher renal injury, gastrointestinal reactions, and hyperbilirubinemia. Intermediate/high-risk disease category, age >14 years, and body mass index ≥17 kg/m² were risk factors for delayed metabolism. Compared with the C677T CC genotype, the CT genotype had a reduced risk of delayed metabolism, whereas no significant difference was observed between TT and CC. Conclusions Serum MTX concentration serves as an objective marker of MTX-related toxicity. Under adequate rescue therapy and concentration monitoring, a single MTHFR polymorphism appears insufficient to guide dose adjustment. A combined strategy is recommended, with concentration monitoring as the primary approach and genetic factors as an adjunct.