甲氨蝶呤（MTX）是治疗高危儿童急性淋巴细胞白血病（ALL）的关键组成部分，但由于清除延迟可能导致急性肾损伤和长时间住院治疗。本研究旨在确定临床和遗传因素，以预测哪些儿童有患肌酐升高和长时间清除MTX的风险。我们进行了一项单中心、回顾性队列研究，纳入接受4000-5000 mg/m2 MTX治疗的儿童ALL患者。我们进行了谷嗪基因分型以确定基因祖先和49个单核苷酸多态性位点（SNP）的等位基因状态，这些位点与MTX代谢相关。开发了贝叶斯层次有序回归模型，用于肌酐升高和延迟MTX清除。结果发现，Hispanic种族、身体质量指数（BMI）＜3%及BMI在85％-95％之间和美洲原住民基因祖先与患者患肌酐升高的风险增加有关，而年龄较大、黑人种族以及采用密集监测方案与患肌酐升高的风险降低有关。年龄较大、比起T-ALL，B-型ALL以及rs2838958/SLC19A1和rs7317112/ABCC4的小等位基因与患MTX代谢清除延迟有关，而黑人种族、MTX剂量减少以及rs2306283/SLCO1B1的小等位基因与患MTX代谢清除延迟风险降低有关。这些MTX毒性的预测因素可允许更精确的个体化毒性风险预测。© 2023 Pharmacotherapy Publications, Inc.

Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. The purpose of this study is to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance.We conducted a single-center, retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m2 of MTX. Measurements We performed germline genotyping to determine genetic ancestry and allele status for 49 single nucleotide polymorphisms (SNPs) identified from the literature as related to MTX disposition. Bayesian hierarchical ordinal regression models for creatinine increase and for prolonged MTX clearance were developed.Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85%-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958/SLC19A1 and rs7317112/ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283/SLCO1B1 were found to be associated with a decreased risk for delayed clearance.These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.© 2023 Pharmacotherapy Publications, Inc.