大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病血药浓度安全性的实证研究

Empirical Study on the Blood Concentration Safety of High-dose Methotrexate in the Treatment of Acute Lymphoblastic Leukemia Children

目的:探索大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病(ALL)血药浓度的安全性。方法:回顾性收集河北燕达陆道培医院儿童ALL病例109例,依据ALL患儿甲氨蝶呤静滴结束后不同时间点血药浓度结果,分为甲氨蝶呤用药结束后0 h血药浓度(A组)、24 h血药浓度(B组)、48 h血药浓度(C组)及72 h血药浓度(D组),分析大剂量甲氨蝶呤治疗后4周内不同血药浓度与骨髓抑制、肝肾损伤及其他不良反应,采用受试者工作特征曲线(ROC)分析甲氨蝶呤用药后不同时间血药浓度在预测其不良反应是否发生中的价值。结果:ROC分析显示,停药后48 h血药浓度对于肾脏损伤的发生具有预警作用,最佳警戒值为0.13μmol·L^(-1),曲线下面积为0.735(95%CI:0.601,0.869,P<0.05);停药后72 h血药浓度对于肝损伤具有预警作用,最佳警戒值为0.02μmol·L^(-1),曲线下面积为0.717(95%CI:0.389,1.000,P>0.05);停药后72 h血药浓度对于患者是否发生骨髓抑制毒性具有提示作用,辅助参考浓度为0.02μmol·L^(-1),曲线下面积为0.635(95%CI:0.346,0.924,P>0.05)。甲氨蝶呤血药浓度检测对患者是否发生毒性反应具有预测价值,曲线下面积为0.886(95%CI:0.813,0.958,P<0.05)。结论:采用大剂量甲氨蝶呤治疗儿童ALL,甲氨蝶呤血药浓度对是否发生毒性反应具有预测价值,及时准确进行甲氨蝶呤血药浓度监测可较好地指导ALL患儿的临床治疗。

Objective: To explore the safety of high-dose methotrexate in the treatment of children with acute lymphoblastic leukemia(ALL) by an empirical study.Methods: The medical records of 109 ALL children in Hebei Yanda Lu Dopei Hospital were retrospectively collected. The ALL children were grouped according to the results of methotrexate concentration at different time points after intravenous infusion of methotrexate, and divided into 4 groups: 0 h methotrexate concentration(group A), 24 h methotrexate concentration(group B), 48 h methotrexate concentration(group C) and 72 h methotrexate concentration(group D). Bone marrow suppression, liver and kidney function and other adverse reactions of the patients in 4 weeks after treatment with high-dose methotrexate were analyzed. Receiver operating characteristic curve(ROC) was used to analyze the value of methotrexate concentration at different time points after treatment with methotrexate in predicting the occurrence of adverse reactions. Results: ROC analysis showed that 48 h methotrexate concentration had an early warning effect on the occurrence of renal injury, with the best warning value of 0.13 μmol·L^(-1)and the area under the curve of 0.735(95%CI 0.601 to 0.869,P<0.05);72 h methotrexate concentration had an early warning effect on liver injury, with the best warning value of 0.02 μmol·L^(-1)and the area under the curve of 0.717(95%CI 0.389 to 1.000, P>0.05);72 h methotrexate concentration had a predictive effect on the occurrence of myelsuppressive toxicity in the patients, with the auxiliary reference concentration of 0.02 μmol·L^(-1)and the area under the curve of 0.635(95%CI 0.346 to 0.924, P>0.05). Methotrexate concentration detection had predictive value in the occurrence of toxic reactions in the patients, and the area under the curve was 0.886(95%CI 0.813 to 0.958, P<0.05).Conclusion: During the treatment of ALL children with high-dose methotrexate, methotrexate concentration detection has predictive value in the occurrence of toxic reactions in patients. Timely and accurate monitoring of methotrexate concentration can better guide the clinical treatment of ALL children.