Are cerebrospinal fluid biomarkers of brain injury associated with treatment-related neurotoxic effects in children who receive chemotherapy for acute lymphoblastic leukemia?
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.
Monitoring cerebrospinal fluid biomarkers and screening for genetic mediators of brain injury may help in identifying survivors at risk for abnormal neurodevelopment.
Little is known about treatment-related neurotoxic mechanisms in children with acute lymphoblastic leukemia (ALL) treated with chemotherapy only.
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.
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.
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.
Cheung YT, Khan RB, Liu W, et al. 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 Oncol. Published online July 01, 20184(7):e180089. doi:10.1001/jamaoncol.2018.0089
Customize your JAMA Network experience by selecting one or more topics from the list below.
Create a personal account or sign in to: