Association of Cerebrospinal Fluid Biomarkers of Central Nervous System Injury With Neurocognitive and Brain Imaging Outcomes in Children Receiving Chemotherapy for Acute Lymphoblastic Leukemia

Abstract

Importance: Little is known about treatment-related neurotoxic mechanisms in children with acute lymphoblastic leukemia (ALL) treated with chemotherapy only.

Objective: To examine concentration of cerebrospinal fluid (CSF) biomarkers of brain injury at ALL diagnosis and during cancer therapy and to evaluate associations with long-term neurocognitive and neuroimaging outcomes and relevant genetic polymorphisms.

Design, setting, and participants: This prospective cohort study included 235 patients with ALL who received a chemotherapy-only protocol. Patients provided CSF samples after diagnosis and throughout treatment. At 5 or more years after the diagnosis, 138 (69.7%) of 198 eligible survivors participated in long-term follow-up assessments. Children were treated from June 1, 2000, through October 31, 2010. Follow-up was completed on October 21, 2014, and data were analyzed from August 1, 2015, through September 30, 2016.

Exposures: Plasma concentration of high-dose intravenous methotrexate sodium and number of triple intrathecal chemotherapy injections.

Main outcomes and measures: The CSF samples were assayed at 5 points from diagnosis to reinduction for biomarkers of myelin degradation (myelin basic protein [MBP]), neuronal damage (nerve growth factor [NGF] and total and phosphorylated tau protein), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuroinflammation (chitotriosidase). DNA was genotyped for polymorphisms in drug metabolism, oxidative stress, and neurodevelopment. Leukoencephalopathy was evaluated by brain imaging. At 5 or more years after the diagnosis, survivors completed neurocognitive testing and brain imaging of white matter integrity.

Results: Among the 235 patients with CSF samples (120 boys [51.1%] and 115 girls [48.9%]; mean [SD] age at diagnosis, 6.8 [4.7] years), MBP and GFAP levels were elevated at baseline and through consolidation. The number of intrathecal injections was positively correlated with NGF level increase at consolidation (r = 0.19; P = .005). Increases in GFAP (risk ratio [RR], 1.23; 95% CI, 1.09-1.40), MBP (RR, 1.06; 95% CI, 1.01-1.11), and total tau (RR, 1.76; 95% CI, 1.11-2.78) levels were associated with a higher risk for leukoencephalopathy and higher apparent diffusion coefficient in frontal lobe white matter 5 years after diagnosis (standardized estimate, 0.05; P < .001). Increase in total tau at consolidation was associated with worse attention (omissions z score estimate, -0.20; P = .04).

Conclusions and relevance: Glial injury may be present at diagnosis of ALL. Neuronal injury was associated with intrathecal chemotherapy. The CSF biomarkers may be useful in identifying individuals at risk for worse neurologic outcomes, particularly those with genetic susceptibility to poor brain function.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Variation in Biomarker Levels From Baseline to Reinduction II

Details of timing of cerebrospinal fluid sample collection relative to the treatment phases are found in eFigure 2 and eTable 3 in the Supplement. Data are expressed as means; errors bar represent 95% CIs. GFAP indicates glial fibrillary acidic protein; MBP, myelin basic protein; and NGF, nerve growth factor.

Figure 2.. Association Between Intrathecal Methotrexate and Change in Nerve Growth Factor (NGF) From Baseline to Consolidation

Analyses were adjusted for age at diagnosis and baseline level of each biomarker. Intrathecal methotrexate dose is qualified in milliliters in which 1 mL contains 1 mg of methotrexate. Data points indicate unique measurements for each patient: Solid line indicates the regression line showing the association between change in NGF and intrathecal methotrexate.

Figure 3.. Association of Total Tau Level During Active Treatment Phase and Neurocognitive/Neuroimaging Outcomes at Long-term Follow-up

The change in level of total tau was measured from baseline to consolidation; long-term neurocognitive function and neuroimaging outcomes at 5 or more years after diagnosis. A, Higher age-adjusted z scores for these measures were indicative of better functioning. All models were adjusted for age at diagnosis and corrected for multiple comparisons. Details of associations between change in biomarkers from baseline to consolidation and other neurocognitive measures are described in eTable 11 in the Supplement. B, All models are adjusted for age at diagnosis and age at evaluation and corrected for multiple comparisons. Details of associations between change in biomarkers from baseline to consolidation and neuroimaging indices on the frontal and parietal lobes are described in eTable 13 in the Supplement.