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

J Pain Symptom Manage. 2021 Mar;61(3):464-473. doi: 10.1016/j.jpainsymman.2020.08.030. Epub 2020 Sep 1.

Abstract

Context: 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.

Objectives: We conducted global metabolomics profiling of cerebrospinal fluid (CSF) samples to provide insight into the underlying mechanisms of CRF.

Methods: 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.

Results: 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).

Conclusion: 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.

Keywords: Patient-reported symptoms; biomarkers; cancer-related fatigue; cerebrospinal fluid; metabolomics; pediatric acute lymphoblastic leukemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Child
  • Cohort Studies
  • Fatigue
  • Female
  • Humans
  • Male
  • Metabolomics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / complications
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Tandem Mass Spectrometry*

Substances

  • Biomarkers