Chemotherapy Pharmacodynamics and Neuroimaging and Neurocognitive Outcomes in Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia
Open accessAbstract
Purpose: To examine associations among methotrexate pharmacodynamics, neuroimaging, and neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on a contemporary chemotherapy-only protocol. Patients and Methods: This longitudinal study linked pharmacokinetic assays collected during therapy to neurocognitive and brain imaging outcomes during long-term follow-up. A total of 218 (72.2%) of 302 eligible long-term survivors were recruited for outcome studies when they were more than 5 years post-diagnosis and older than 8 years of age. At long-term follow-up, survivors were an average of 13.8 years old and 7.7 years from diagnosis, and 51% were male. Neurocognitive testing, functional magnetic resonance imaging (MRI) during an executive function task, and structural MRI with diffusion tensor imaging were conducted. Generalized linear models were developed to identify predictors, and models were adjusted for age at diagnosis, sex, and parent education. Results: Intelligence was within normal limits (mean, 98; standard deviation, 14) compared with population expectations (mean, 100; standard deviation, 15), though measures of executive function, processing speed, and memory were less than population means (all P < .02 after correction for false discovery rates). Higher plasma concentration of methotrexate was associated with a poorer executive function score (P < .02). Higher plasma methotrexate was also associated with higher functional MRI activity, with thicker cortices in dorsolateral prefrontal brain regions, and with white matter microstructure in the frontostriatal tact. Neurocognitive impairment was associated with these imaging findings as well. Associations did not change after adjustment for age or dose of leucovorin rescue. Conclusion: Survivors of childhood acute lymphoblastic leukemia treated on contemporary chemotherapy-only protocols demonstrate executive dysfunction. A higher plasma concentration of methotrexate was associated with executive dysfunction as well as with a thicker cortex and higher activity in frontal brain regions, regions often associated with executive function.
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Since MTX is delivered through all phases of ALL treatment, folate metabolism may be altered for an extended period, possibly resulting in build-up of homocysteine and/or secondary metabolic alterations.
“Since MTX is delivered through all phases of ALL treatment, folate metabolism may be altered for an extended period, possibly resulting in build‐up of homocysteine (Fox & Stover, 2008; Krull et al., 2016; Li et al., 2010; Steinfeld et al., 2009), and/or secondary metabolic alterations (van der Plas et al., 2015; Steinfeld et al., 2009; Strain et al., 2013).”
From Brain structure, working memory and response inhibition in childhood leukemia survivors (2017) · cites this paper as Krull et al., 2016
The Appendix treatment schema lists methotrexate in multiple phases of ALL treatment, and the Discussion reports elevated homocysteine during therapy in association with high-dose methotrexate exposure. But the paper does not establish that folate metabolism remains altered for an extended period; the Discussion says treatment-related hyperhomocysteinemia is transient in most cases. The secondary-metabolic-alterations clause is cited to other sources, not Krull et al. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA recent study reported correlations between plasma MTX, cortical thickness in the dorsolateral prefrontal cortex and microstructure of the frontostriatal tract, suggesting that exposure to MTX is related to neuroanatomical changes.
“A recent study reported correlations between plasma MTX, cortical thickness in the dorsolateral prefrontal cortex and microstructure of the frontostriatal tract (Krull et al., 2016), suggesting that exposure to MTX is related to neuroanatomical changes.”
From Brain structure, working memory and response inhibition in childhood leukemia survivors (2017) · cites this paper as Krull et al., 2016
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Dynamic mapping of human cortical development during childhood through early adulthood
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Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia
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Brain structure, working memory and response inhibition in childhood leukemia survivors
van der Plas, E., Schachar, R. J., Hitzler, J., Crosbie, J., Guger, S. L., Spiegler, B. J., Ito, S., & Nieman, B. J. (2017) · Brain and Behavior · doi:10.1002/brb3.621 · Cited by 59 · see citing works
“…of ALL treatment, folate metabolism may be altered for an extended period, possibly resulting in build- up of homocysteine (Fox & Stover, 2008; Krull et al., 2016; Li et al., 2010; Steinfeld et al., 2009), and/or secondary metabolic alterations (van der Plas et al., 2015; Steinfeld et al.,…”
BackgroundInfluentialNeurocognitive and behavioral outcomes of Chinese survivors of childhood lymphoblastic leukemia
Peng, L., Yang, L. S., Yam, P., Lam, C. S., Chan, A. S.-Y., Li, C. K., & Cheung, Y. T. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.655669 · Cited by 29 · see citing works
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- Authors
- Krull, K. R., Cheung, Y. T., Liu, W., Fellah, S., Reddick, W. E., Brinkman, T. M., Kimberg, C., Ogg, R., Srivastava, D., Pui, C.-H., Robison, L. L., & Hudson, M. M.
- Affiliations
- St. Jude Children's Research Hospital (US)
- All authors: St Jude Children’s Research Hospital, Memphis, TN
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2016-08-01
- Volume
- 34
- Issue
- 22
- Pages
- 2644-2653
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC5321052
- OpenAlex
- W2415263224
- Cited by
- 136
- References
- 4
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 14 · 2023: 12 · 2022: 12 · 2021: 14 · 2020: 16 · 2019: 14 · 2018: 20 · 2017: 10 · 2016: 5
- FWCI
- 16.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Oncology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- St. Jude Children's Research Hospital
- American Lebanese Syrian Associated Charities (CA195547, MH085849)
- National Institute of Mental Health (CA195547, R01MH085849, MH085849)
- National Cancer Institute (CA195547, U01CA195547, MH085849)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Childhood Cancer Survivors' Quality of Life
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
- Keywords
- childhood acute lymphoblastic leukemia, long-term survivors, neurocognitive impairment, executive dysfunction, executive function, leucovorin rescue, neuroimaging, functional MRI, diffusion tensor imaging, white matter microstructure, dorsolateral prefrontal cortex, cortical thickness, chemotherapy-induced neurotoxicity
- MeSH terms
- Adolescent, Child, Female, Frontal Lobe, Humans, Intelligence, Longitudinal Studies, Magnetic Resonance Imaging, Male, Methotrexate, Linear Models, Treatment Outcome, Prefrontal Cortex, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Executive Function, Neuroimaging
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