Treatment-Related Changes in Cerebrospinal Fluid Markers of Oxidative Stress and Neurodegeneration during Therapy for Childhood Acute Lymphoblastic Leukemia

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) frequently exhibit treatment-related neurocognitive impairment, although there is substantial interpatient variability in this outcome. Analysis of biomarkers that reflect the impact of chemotherapy during the two years of treatment for ALL offers the potential to identify children who have subclinical treatment-related neurotoxicity at a time when a protective intervention could prevent the development of persistent impairment. METHODS: We prospectively measured markers indicative of oxidative stress (8-hydroxydeoxyguanosine) and neurodegeneration (total tau) in cerebrospinal fluid (CSF) collected at five timepoints before and during the first year of chemotherapy for ALL among 529 patients enrolled on Dana-Farber Cancer Institute ALL Consortium protocol 16-001 (NCT03020030). RESULTS: CSF 8-hydroxydeoxyguanosine and total tau change significantly over time, with parallel increases emerging during intensive phases of therapy, especially following repeated doses of intrathecal chemotherapy. A concordant increase in both markers was observed in 50% of patients; a concordant decrease was seen in a smaller subset (15%). In multivariable analysis, higher CSF tau was significantly associated with White race and non-Hispanic ethnicity. CONCLUSIONS: Analysis of CSF collected prospectively in a large cohort of children treated for ALL demonstrated significant changes in markers of oxidative stress and neurodegeneration within three months of treatment initiation. IMPACT: The clinical relevance of the putative biomarkers reported here will be validated by testing whether they are predictive of treatment-related cognitive decline. These biomarkers may then serve as surrogate markers for testing the efficacy of protective interventions designed to protect against treatment-induced neurotoxicity and cognitive decline.