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Neurotoxicity after CTL019 in a pediatric and young adult cohort
Author(s) -
Gofshteyn Jacqueline S.,
Shaw Pamela A.,
Teachey David T.,
Grupp Stephan A.,
Maude Shan,
Banwell Brenda,
Chen Fang,
Lacey Simon F.,
Melenhorst Jan J.,
Edmonson MacKenzie J.,
Panzer Jessica,
Barrett David M.,
McGuire Jennifer L.
Publication year - 2018
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25315
Subject(s) - neurotoxicity , cytokine release syndrome , medicine , cytokine , oncology , toxicity , chimeric antigen receptor , cancer , immunotherapy
Objective To characterize the incidence and clinical characteristics of neurotoxicity in the month following CTL019 infusion in children and young adults, to define the relationship between neurotoxicity and cytokine release syndrome (CRS), and to identify predictive biomarkers for development of neurotoxicity following CTL019 infusion. Methods We analyzed data on 51 subjects, 4 to 22 years old, who received CTL019, a chimeric antigen receptor–modified T‐cell therapy against CD19, between January 1, 2010 and December 1, 2015 through a safety/feasibility clinical trial (NCT01626495) at our institution. We recorded incidence of significant neurotoxicity (encephalopathy, seizures, and focal deficits) and CRS, and compared serum cytokine levels in the first month postinfusion between subjects who did and did not develop neurotoxicity. Results Neurotoxicity occurred in 23 of 51 subjects (45%, 95% confidence interval = 31–60%) and was positively associated with higher CRS grade ( p < 0.0001) but was not associated with demographic characteristics or prior oncologic treatment history. Serum interleukin (IL)‐2, IL‐15, soluble IL‐4, and hepatocyte growth factor concentrations were higher in subjects with neurotoxicity than those with isolated CRS. Differences in peak levels of select cytokines including IL‐12 and soluble tumor necrosis factor receptor‐1 within the first 3 days were seen in subjects with neurotoxicity. Interpretation Neurotoxicity is common after CTL019 infusion in children and young adults, and is associated with higher CRS grade. Differences in serum cytokine profiles between subjects with neurotoxicity and those with isolated CRS suggest unique pathophysiological mechanisms. Serum cytokine profiles in the first 3 days postinfusion may help identify children and young adults at risk for neurotoxicity, and may provide a foundation for investigation into potential mitigation strategies. Ann Neurol 2018;84:537–546