The effect of the plasma methotrexate concentration during high-dose methotrexate therapy in childhood acute lymphoblastic leukemia

Abstract

Two hundred and thirty-one acute lymphoblastic leukemia (ALL) children with 1376 high-dose methotrexate (HD-MTX) courses (3–5 g/m²) were enrolled to analyze the influence of the plasma MTX concentration (C_MTX) in ALL. The 24-h target peak C_MTX (C_24h) was set at 33 μmol/l for low-risk (LR) and 65 μmol/l for intermediate/high-risk (IR/HR) groups. The median C_24h was 42.0 μmol/l and 69.7 μmol/l for LR and IR/HR groups, respectively. MTX excretion delay was observed in 14.6% of courses, which was more frequent in IR/HR groups (56.9% vs. LR group 40.2%, p = .014) and T-ALL patients (82.6% vs. B-ALL 47.1%, p = .001). MTX-related toxicities were more common in courses with MTX excretion delay. However, survival between the patients who failed to reach the target C_24h or not, with or without MTX excretion delay, was comparable. These findings suggest that, owing to the effectiveness of risk stratification chemotherapy, C_MTX does not exert an independent influence on the prognosis of childhood ALL.

Keywords:

• Methotrexate
• childhood
• acute lymphoblastic leukemia

Acknowledgements

We thank Ju-fei Yang (pharmacist, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China) for the pharmacokinetics work and Jian-feng Liang (statistician, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou, China) for the statistical analysis assistance.

Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The protocol was approved by the Medical Ethics Committee of Children’s Hospital, Zhejiang University School of Medicine.

Consent form

Informed consent was obtained from the parents or legal guardians.

Author contributions

Yong-Min Tang and Chan Liao contributed to the conception of the study and the manuscript preparation and amendment; Chan Liao designed the study and manuscript drafting; Jing Nie contributed significantly to analyze the data and part of the manuscript drafting; Xiao-Jun Xu contributed to the data analyses and part of the manuscript preparation; Jing-Ying Zhang, Wei-Qun Xu, Hua Song, He-Ping Shen, Di-Ying Shen, Fen-Ying Zhao, and Juan Liang contributed to the study performed, data collection, and helped the constructive discussions; Jing Nie and Jing Miao are the pharmacists and contributed to the pharmacokinetics work of the study.

Disclosure statement

The authors declare no conflict of interest in this work.

Data availability statement

The datasets created and analyzed during this study are included in this manuscript and supplemental material. Additional information is available from the corresponding author at [email protected] upon reasonable request.

Additional information

Funding

This work was partially supported by the National Natural Science Foundation of China (Nos. 81770202 and 81470304), the Natural Science Foundation of Zhejiang Province (No. LY21H080002), the Health Science and Technology Program of Health Department of Zhejiang Province (2022KY191), Key Grant from Science and Technology Department of Zhejiang Province (2019C03032), and the Pediatric Leukemia Diagnostic and Therapeutic Technology Research Center of Zhejiang Province (No. JBZX-201904).