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Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.

Publication ,  Journal Article
Brown, AL; Sok, P; Taylor, O; Woodhouse, JP; Bernhardt, MB; Raghubar, KP; Kahalley, LS; Lupo, PJ; Hockenberry, MJ; Scheurer, ME
Published in: Journal of pain and symptom management
March 2021

Cancer-related fatigue (CRF) is one of the most distressing and persistent symptoms reported during pediatric acute lymphoblastic leukemia (ALL) therapy; however, information on the pathways underlying CRF severity is limited.We conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF.Fatigue in pediatric ALL patients (2012-2017) was assessed during postinduction therapy approximately six months after diagnosis. Postinduction CSF was collected from 171 participants, comprising discovery (n = 86) and replication (n = 85) cohorts. We also conducted secondary validation using diagnostic CSF from 48 replication cohort participants. CSF metabolomic profiling was performed using gas chromatography-mass spectrometry (MS) and liquid chromatography-MS/MS. Kendall's rank correlation was used to evaluate associations between metabolite abundance and CRF. False discovery rate was used to account for multiple comparisons.Participants were 56% males and 59% Hispanic with a mean age at diagnosis of 8.5 years. A total of 274 CSF-derived metabolites were common to the discovery and replication cohorts. Eight metabolites were significantly associated with fatigue in the discovery cohort (P < 0.05), of which three were significant in the replication cohort, including false discovery rate-corrected associations with gamma-glutamylglutamine (Pcombined = 6.2E-6) and asparagine (Pcombined = 3.5E-4). Notably, the abundance of gamma-glutamylglutamine in diagnostic CSF samples was also significantly associated with fatigue (P = 0.0062).The metabolites identified in our assessment have been implicated in neurotransmitter transportation and glutathione recycling, suggesting that glutamatergic pathways or oxidative stress may contribute to ALL-associated CRF. This information could inform targeted therapies for reducing CRF in at-risk individuals.

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Published In

Journal of pain and symptom management

DOI

EISSN

1873-6513

ISSN

0885-3924

Publication Date

March 2021

Volume

61

Issue

3

Start / End Page

464 / 473

Related Subject Headings

  • Tandem Mass Spectrometry
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Metabolomics
  • Male
  • Humans
  • Female
  • Fatigue
  • Cohort Studies
  • Child
  • Biomarkers
 

Citation

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Brown, A. L., Sok, P., Taylor, O., Woodhouse, J. P., Bernhardt, M. B., Raghubar, K. P., … Scheurer, M. E. (2021). Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia. Journal of Pain and Symptom Management, 61(3), 464–473. https://doi.org/10.1016/j.jpainsymman.2020.08.030
Brown, Austin L., Pagna Sok, Olga Taylor, John P. Woodhouse, M Brooke Bernhardt, Kimberly P. Raghubar, Lisa S. Kahalley, Philip J. Lupo, Marilyn J. Hockenberry, and Michael E. Scheurer. “Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.Journal of Pain and Symptom Management 61, no. 3 (March 2021): 464–73. https://doi.org/10.1016/j.jpainsymman.2020.08.030.
Brown AL, Sok P, Taylor O, Woodhouse JP, Bernhardt MB, Raghubar KP, et al. Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia. Journal of pain and symptom management. 2021 Mar;61(3):464–73.
Brown, Austin L., et al. “Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia.Journal of Pain and Symptom Management, vol. 61, no. 3, Mar. 2021, pp. 464–73. Epmc, doi:10.1016/j.jpainsymman.2020.08.030.
Brown AL, Sok P, Taylor O, Woodhouse JP, Bernhardt MB, Raghubar KP, Kahalley LS, Lupo PJ, Hockenberry MJ, Scheurer ME. Cerebrospinal Fluid Metabolomic Profiles Associated With Fatigue During Treatment for Pediatric Acute Lymphoblastic Leukemia. Journal of pain and symptom management. 2021 Mar;61(3):464–473.
Journal cover image

Published In

Journal of pain and symptom management

DOI

EISSN

1873-6513

ISSN

0885-3924

Publication Date

March 2021

Volume

61

Issue

3

Start / End Page

464 / 473

Related Subject Headings

  • Tandem Mass Spectrometry
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Metabolomics
  • Male
  • Humans
  • Female
  • Fatigue
  • Cohort Studies
  • Child
  • Biomarkers