Association of cerebrospinal fluid biomarkers of central nervous system injury with neurocognitive and brain imaging outcomes in children receiving chemotherapy for acute lymphoblastic leukemia

Yin Ting Cheung, Raja B. Khan, Wei Liu, Tara M. Brinkman, Michelle N. Edelmann, Wilburn E. Reddick, Deqing Pei, Angela Panoskaltsis-Mortari, Deokumar Srivastava, Cheng Cheng, Leslie L. Robison, Melissa M. Hudson, Ching Hon Pui, Kevin R. Krull

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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 sampleswere assayed at 5 points from diagnosis to reinduction for biomarkers ofmyelin 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 injurymay 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.

Original languageEnglish (US)
Article numbere180089
JournalJAMA Oncology
Volume4
Issue number7
DOIs
StatePublished - Jul 2018

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    Cheung, Y. T., Khan, R. B., Liu, W., Brinkman, T. M., Edelmann, M. N., Reddick, W. E., Pei, D., Panoskaltsis-Mortari, A., Srivastava, D., Cheng, C., Robison, L. L., Hudson, M. M., Pui, C. H., & Krull, K. R. (2018). Association of cerebrospinal fluid biomarkers of central nervous system injury with neurocognitive and brain imaging outcomes in children receiving chemotherapy for acute lymphoblastic leukemia. JAMA Oncology, 4(7), [e180089]. https://doi.org/10.1001/jamaoncol.2018.0089