Journal
ANNALS OF NEUROLOGY
Volume 86, Issue 1, Pages 42-54Publisher
WILEY
DOI: 10.1002/ana.25502
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Funding
- Child Neurology Career Development Program K-12 award [1K12NS098482-02]
- Stand Up to Cancer
- St. Baldrick's Pediatric Dream Team Translational Research Grant [SU2C-AACR-DT1113, RO1 CA136551-05]
- Alex's Lemonade Stand Phase I/II Infrastructure Grant
- Conquer Cancer Foundation Career Development Award
- Washington State Life Sciences Discovery Fund
- Ben Towne Foundation
- William Lawrence & Blanche Hughes Foundation
- Juno Therapeutics
- Institute of Translational Health Science (ITHS) from NCRR/NIH [UL1TR000423]
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Objective To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. Methods We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). Results Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores >= 9 had 94% sensitivity and 33% specificity for grade >= 3 neurotoxicity, and 91% sensitivity and 72% specificity for grade >= 2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium-binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-gamma (IFN gamma), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFN gamma IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. Interpretation Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury. ANN NEUROL 2019
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