Cerebrospinal fluid metabolomic profiles associated with fatigue during treatment for pediatric acute lymphoblastic leukemia

Introduction: 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. Therefore, 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 post-induction therapy approximately 6-months post-diagnosis. Post-induction CSF was collected on 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 (FDR) was used to account for multiple comparisons.

Results: Participants were 56% male 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 FDR-corrected associations with gamma-glutamylglutamine (p_combined = 6.2E-6) and asparagine (p_combined = 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 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: Biomarkers; Cancer-related Fatigue; Cerebrospinal fluid; Metabolomics; Patient-reported Symptoms; Pediatric Acute Lymphoblastic Leukemia.