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Identifying risk factors for high-dose methotrexate-induced toxicities in children with acute lymphoblastic leukemia

Authors Li X, Sui Z, Jing F, Xu W, Li X, Guo Q, Sun S, Bi X

Received 7 March 2019

Accepted for publication 6 June 2019

Published 5 July 2019 Volume 2019:11 Pages 6265—6274

DOI https://doi.org/10.2147/CMAR.S207959

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Melinda Thomas

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Xiao Li,1 Zhongguo Sui,1 Fanbo Jing,1 Wen Xu,1 Xiangpeng Li,1 Qie Guo,1 Shuhong Sun,1 Xiaolin Bi2

1Department of Clinical Pharmacy, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, People’s Republic of China; 2Department of Nutrition, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266003, People’s Republic of China

Background: Whether monitoring of the methotrexate (MTX) concentrations after high-dose MTX (HD-MTX) infusion can predict toxicities is still controversial, especially when HD-MTX therapy is used in the treatment of children with acute lymphoblastic leukemia (ALL), which is different than the previous schedules. The relationship between patient characteristics and severe adverse events (AEs) has yet to be determined.
Objective: To analyze the relationship between the MTX concentration and toxicities and to identify the risk predictors from patient characteristics for severe AEs during HD-MTX therapy in children with ALL.
Methods: We conducted a retrospective study on children with ALL who were treated with 388 HD-MTX infusions. The chi-square test and univariate and logistic regression analyses were used to analyze the relationship between the MTX concentrations and toxicities and to identify predictors for severe AEs.
Results: Febrile neutropenia (P=0.000) and vomiting (P=0.034) were more likely to occur if the infusion had an MTX level ≥1 μmol/L at 44 h, but other toxicities had no correlations with MTX concentration. Predictive factors for toxicities were as follows: higher risk stratification and higher values of albumin (ALB) for leucopenia, higher values of white blood cell count (WBC) for anemia, higher values of ALB and creatinine (Cr) for neutropenia, higher risk stratification and higher 44-h MTX concentration for febrile neutropenia, higher values of alanine transferase (ALT) for elevated ALT, higher values of ALT for elevated aspartate transferase (AST), and higher values of total bilirubin (TBil) for vomiting.
Conclusion: Routine monitoring of 44-h MTX concentrations is essential to identify patients at high risk of developing febrile neutropenia and vomiting. This study may provide a reference for clinicians to distinguish patients with a relatively high risk of severe AEs based on certain characteristics before HD-MTX infusion.

Keywords: high-dose methotrexate, methotrexate concentration, toxicities, patient characteristics, risk predictors, acute lymphoblastic leukemia


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