Analysis on adverse reactions of high-dose methotrexate in treatment of childhood acute lymphoblastic leukemia and influencing factors of delayed methotrexate excretion

LI Qin; DAI Yan; LI Xinye; TANG Huihe; MA Hongyan; HUANG Jinxian; CHEN Zhaohui; LI Junjun

doi:10.3969/j.issn.1674-3806.2026.01.10

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≥gradeⅡwere 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 in31cases(9.66%).The immunophenotyping results revealed Blineage in304cases(94.70%)and Tlineage 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 in13 cases(4.05%),and fusion gene was negative in232 cases(72.27%).Myelosuppression(62.62%)was the most common in adverse reactions of gradesⅡ-Ⅳin 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.