大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的安全性观察

Safety of high-dose methotrexate for treatment of children with acute lymphoblastic leukemia

目的探讨大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病（ALL）的安全性。方法62例ALL患儿参照诊疗建议行大剂量甲氨蝶呤治疗，观察治疗的不良反应。结果62例ALL患儿行大剂量甲氨蝶吟治疗257次，Ⅱ～Ⅳ级中性粒细胞减少、血红蛋白降低和血小板减少的发生率分别为54．1％（139／257）、48．2％（124／257）和14．8％（38／257），Ⅱ～Ⅳ级肝功能损害、口腔炎和胃肠道反应发生率分别为38．1％（98／257），42．0％（108／257）和26．8％（69／257），治疗中未发现Ⅱ～Ⅳ级肾功能损害、严重感染及死亡病例。检测甲氨蝶呤血药浓度202次，发生延迟排泄共61次（30．2％），其中治疗44h后甲氨蝶呤浓度〉1．0μmol／L者占42．4％（56／132），治疗68h后甲氨蝶呤血药浓度〉0．3μmol／L者占7．1％（5／70）。治疗后44h，排泄延迟组患儿口腔炎、骨髓抑制、胃肠道反应、肝功能损害等方面不良反应发生率明显高于排泄正常组（P〈0．05）。36h、42h首次亚叶酸钙解救的患儿不良反应发生率比较，差异无统计学意义（P〉0．05）。结论甲氨蝶呤排泄具有个体差异，临床依照血药浓度进行亚叶酸钙解救是安全有效的，可以减少大剂量甲氨蝶呤治疗ALL的不良反应。

Objective To explore the safety of high-dose methotrexate（HD-MTX） for the treatment of children with acute lymphoblastic leukemia（ALL）. Methods A total of 62 children with ALL were treated with HD-MTX according to the corresponding protocol,and the side effects of treatment were observed. Results Among 257 case-times HD-MTX therapy in 62 children with ALL, the occurrence rates of neutropenia of grade Ⅱ～Ⅳ, hypohemoglobinemia and thrombocytopenia were 54.1% （139/257） ,48.2% （124/257） and 14.8% （ 38/257 ）, respectively,and the occurrence rates of liver function damage of gradeⅡ～Ⅳ, stomatitis and gastrointestinal reaction were 38. 1% （98/257） ,42.0% （108/257） and 26. 8% （69/257）, respectively. No intraoperative renal function damage of grade Ⅱ～Ⅳ, severe infection or death occurred. Of 202 tests of plasma methotrexate（MTX） concentration ,the incidence of excretion delay was 30.2% （61/202）. The proportion of patients with plasma MTX concentration 〉 1.0 μmol/L 44 hours after treatment was 42.4% （56/132） ,and plasma MTX concentration 〉 0.3 μmol/L 68 hours after treatment was 7.1% （5/70）. The incidences of stomatitis, myelosuppression, gastrointestinal reaction and 1 iver function damage in the delayed excretion group were significantly higher than those in the normal excretion group 44 hours after treatment（P 〈 0. 05 ）. There was no significant difference in the incidences of side effects between children receiving the first-time rescue with calcium folinate in the 36th and 42nd hour after treatment （P 〉 0.05 ）. Conclusion Individual difference exists in ethotrexate excretion. Rescue with calcium folinate according to the plasma MTX concentration is safe and effective, which can reduce the side effects of HD-MTX for ALL.