| 摘要: |
| ［摘要］ 目的 观察大剂量甲氨蝶呤（HD-MTX）治疗儿童急性淋巴细胞白血病（ALL）不良反应的发生情况，并分析影响甲氨蝶呤（MTX）排泄延迟发生的因素。方法 回顾性分析2017年1月至2020年12月广西壮族自治区人民医院儿科收治的74例ALL患儿的临床资料，参照中国儿童肿瘤协作组急性淋巴细胞白血病2015（CCCG-ALL-2015）方案进行321例次HD-MTX化疗。以HD-MTX治疗44 h后血液MTX浓度>1.0 μmol/L，或HD-MTX治疗68 h后血液MTX浓度>0.3 μmol/L定义为MTX排泄延迟。根据美国卫生及公共服务部的常见不良事件评价标准5.0（NCI-CTCAE v5.0）对不良事件进行分级，以≥Ⅱ级的不良反应界定为HD-MTX化疗相关的、具有临床意义的不良反应。分析不良反应发生情况与危险度分层、免疫分型的关联性。分析影响HD-MTX治疗后44 h、68 h MTX排泄延迟发生的因素。结果 74例ALL患儿中男40例（54.05%），女34例（45.95%）；年龄1～14岁，中位年龄4岁。危险度为低危73例次（22.74%），中危217例次（67.60%），高危31例次（9.66%）。免疫分型为B系304例次（94.70%），T系17例次（5.30%）。融合基因类型为BCR/ABL1型34例次（10.59%），ETV6/RUNX1型42例次（13.08%），其他类型13例次（4.05%）；融合基因阴性232例次（72.28%）。ALL患儿接受HD-MTX化疗后Ⅱ～Ⅳ级不良反应以骨髓抑制最为常见（62.62%），随后为胃肠道反应（包括腹泻和便秘，31.78%）和口腔黏膜炎（30.53%）。B系和T系ALL患儿HD-MTX治疗后不良反应发生情况比较差异无统计学意义（P>0.05）。不同危险度分层ALL患儿行HD-MTX治疗后骨髓抑制、感染、口腔黏膜炎和胃肠道反应发生情况比较差异无统计学意义（P>0.05）。低危ALL患儿肝损害发生率显著低于中危ALL患儿（P<0.05），中危ALL患儿和高危ALL患儿的肝损害发生率比较差异无统计学意义（P>0.05）。多因素logistic回归分析结果显示，年龄>7～14岁［OR（95%CI）=13.022（1.396～121.436），P=0.024］和融合基因类型为ETV6/RUNX1型［OR（95%CI）=5.863（1.641～20.948），P=0.006］是促进44 h MTX排泄延迟发生的独立危险因素。 结论 HD-MTX治疗儿童ALL的不良反应以骨髓抑制、胃肠道反应和口腔黏膜炎为主，年龄>7～14岁、融合基因类型为ETV6/RUNX1型是促进44 h MTX排泄延迟发生的危险因素。 |
| 关键词: 大剂量甲氨蝶呤 儿童 急性淋巴细胞白血病 不良反应 排泄延迟 |
| DOI：10.3969/j.issn.1674-3806.2026.01.10 |
| 分类号:R 725.5 |
| 基金项目:广西重点研发计划项目（编号：桂科AA23073014）；广西医疗卫生适宜技术开发与推广应用项目（编号：S2021054）；广西研究生教育创新计划项目（编号：YCSW2024442） |
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| Analysis on adverse reactions of high-dose methotrexate in treatment of childhood acute lymphoblastic leukemia and influencing factors of delayed methotrexate excretion |
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LI Qin1,2, DAI Yan2, LI Xinye2, TANG Huihe2, MA Hongyan2, HUANG Jinxian2, CHEN Zhaohui2, LI Junjun1,2
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1.Graduate School, Guilin Medical University, Guilin 541000, China; 2.Department of Pediatrics, the People′s Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
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| Abstract: |
| ［Abstract］ Objective To observe the adverse reactions of high-dose methotrexate(HD-MTX) in treatment of childhood acute lymphoblastic leukemia(ALL), and to analyze the influencing factors of delayed methotrexate(MTX) excretion. Methods A retrospective analysis was conducted on the clinical data of 74 pediatric patients with ALL who were admitted to Department of Pediatrics, the People′s Hospital of Guangxi Zhuang Autonomous Region from January 2017 to December 2020. HD-MTX-based chemotherapy was performed on 321 cases according to Chinese Children′s Cancer Group ALL-2015(CCCG-ALL-2015) protocol. The blood drug concentration of MTX greater than 1.0 μmol/L after 44 hours of HD-MTX treatment, or that of MTX greater than 0.3 μmol/L after 68 hours of HD-MTX treatment was defined as delayed MTX excretion. The adverse events were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0(NCI-CTCAE v5.0). The grades of adverse events ≥grade Ⅱ were defined as HD-MTX chemotherapy-related and clinically significant adverse reactions. The correlation between the occurrence of adverse reactions and risk stratification as well as immunophenotypes was analyzed. The factors influencing the occurrence of delayed excretion of MTX at 44 hours and 68 hours after HD-MTX treatment were analyzed. Results Among the 74 pediatric patients with ALL, 40 patients were male(54.05%) and 34 patients were female(45.95%), aged from 1 to 14 years old, with a median age of 4 years old. Risk stratification was low-risk in 73 cases(22.74%), intermediate-risk in 217 cases(67.60%), and high-risk in 31 cases(9.66%). The immunophenotyping results revealed B lineage in 304 cases(94.70%) and T lineage in 17 cases(5.30%). Fusion gene types were BCR/ABL1 in 34 cases(10.59%), ETV6/RUNX1 in 42 cases(13.08%), other types in 13 cases(4.05%), and fusion gene was negative in 232 cases(72.28%). Myelosuppression(62.62%) was the most common in adverse reactions of grades Ⅱ-Ⅳ in the ALL pediatric patients after HD-MTX chemotherapy, followed by gastrointestinal reactions(including diarrhea and constipation, 31.78%) and oral mucositis(30.53%). There was no statistically significant difference in the occurrence of adverse reactions after HD-MTX treatment between the pediatric patients with B lineage ALL and those with T lineage ALL(P>0.05). There were no statistically significant differences in the incidence rates of myelosuppression, infection, oral mucositis and gastrointestinal reaction among the ALL pediatric patients with different risk stratifications after HD-MTX treatment(P>0.05). The incidence of liver damage in the pediatric patients with low-risk ALL was significantly lower than that in the pediatric patients with intermediate-risk ALL(P<0.05), while there was no statistically significant difference in the incidence of liver damage between the pediatric patients with intermediate-risk ALL and those with high-risk ALL(P>0.05). The results of multivariate logistic regression analysis indicated that age >7-14 years［OR(95%CI)= 13.022(1.396-121.436), P=0.024］ and fusion gene type of ETV6/RUNX1［OR(95%CI)=5.863(1.641-20.948), P=0.006］ were independent risk factors for promoting delayed MTX excretion at 44 hours after HD-MTX treatment. Conclusion The main adverse reactions of HD-MTX in treatment of childhood ALL are myelosuppression, gastrointestinal reaction and oral mucositis. Age >7-14 years and fusion gene type of ETV6/RUNX1 are independent risk factors for promoting delayed MTX excretion at 44 hours after HD-MTX treatment. |
| Key words: High-dose methotrexate(HD-MTX) Children Acute lymphoblastic leukemia(ALL) Adverse reaction Delayed excretion |
