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Original Investigation
July 12, 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

Author Affiliations
  • 1Department of Epidemiology and Cancer Control, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 2Department of Neurology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 3Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 4Department of Psychology, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 5Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Denver
  • 6Department of Diagnosis Imaging, St Jude Children’s Research Hospital, Memphis, Tennessee
  • 7Pediatric Blood and Bone Marrow Transplant Program, University of Minnesota, Minneapolis
  • 8Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Minnesota, Minneapolis
  • 9Department of Oncology, St Jude Children’s Research Hospital, Memphis, Tennessee
JAMA Oncol. 2018;4(7):e180089. doi:10.1001/jamaoncol.2018.0089
Key Points

Question  Are cerebrospinal fluid biomarkers of brain injury associated with treatment-related neurotoxic effects in children who receive chemotherapy for acute lymphoblastic leukemia?

Findings  In this cohort study of 235 children with acute lymphoblastic leukemia, methotrexate exposure was positively correlated with markers of neuronal damage, and markers of demyelination and axonal damage were associated with as much as a 70% higher risk of developing leukoencephalopathy during therapy, worse long-term frontal lobe white matter integrity, and poorer neurocognitive function. Carriers of the Val allele in the COMT gene demonstrated greater biomarker level elevations after methotrexate exposure than did carriers of the Met allele.

Meaning  Monitoring cerebrospinal fluid biomarkers and screening for genetic mediators of brain injury may help in identifying survivors at risk for abnormal neurodevelopment.

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.

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