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Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia
Open accessAbstract
Purpose: Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods: Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results: Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion: MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.
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“Transient lesions in the white matter (leukoencephalopathy) due to chemotherapy are well‐documented in ALL survivors (Bhojwani et al., 2014; Reddick, Glass, Johnson, Laningham, & Pui, 2009; Reddick et al., 2005);”
From Brain structure, working memory and response inhibition in childhood leukemia survivors (2017) · cites this paper as Bhojwani et al., 2014
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“however, these lesions do not show a clear relationship with functional abilities (Bhojwani et al., 2014; Pääkkö et al., 2000) and are therefore unlikely to account for the full range of deficits in ALL survivors.”
From Brain structure, working memory and response inhibition in childhood leukemia survivors (2017) · cites this paper as Bhojwani et al., 2014
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Metadata
- Authors
- Bhojwani, D., Sabin, N. D., Pei, D., Yang, J. J., Khan, R. B., Panetta, J. C., Krull, K. R., Inaba, H., Rubnitz, J. E., Metzger, M. L., Howard, S. C., Ribeiro, R. C., Cheng, C., Reddick, W. E., Jeha, S., Sandlund, J. T., Evans, W. E., Pui, C.-H., & Relling, M. V.
- Affiliations
- St. Jude Children's Research Hospital (US)
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2014-03-20
- Volume
- 32
- Issue
- 9
- Pages
- 949-959
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC3948096
- OpenAlex
- W2098676147
- Cited by
- 400
- References
- 48
- Citations by year
- 2026: 38 · 2025: 36 · 2024: 40 · 2023: 27 · 2022: 47 · 2021: 40 · 2020: 33 · 2019: 30 · 2018: 27 · 2017: 34 · 2016: 28 · 2015: 16 · 2014: 3
- FWCI
- 26.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 36401, R01CA036401, R01 CA90246, R01CA090246, R37CA036401, P30CA021765)
- National Institute of General Medical Sciences (U01GM092666, GM 92666)
- Topics
- Health Sciences › Medicine › Hematology › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
- Keywords
- methotrexate neurotoxicity, leukoencephalopathy, childhood acute lymphoblastic leukemia, intrathecal methotrexate, methotrexate pharmacokinetics, germline polymorphisms, neurodevelopmental genes, brain MRI
- MeSH terms
- Adolescent, Antimetabolites, Antineoplastic, Antineoplastic Combined Chemotherapy Protocols, Brain, Child, Child, Preschool, Leucovorin, Female, Humans, Magnetic Resonance Imaging, Male, Methotrexate, Polymorphism, Genetic, Prospective Studies, Risk Factors, Logistic Models, Germ-Line Mutation, Genetic Predisposition to Disease, Neurotoxicity Syndromes, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Genome-Wide Association Study, Leukoencephalopathies
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