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Clinical Predictors of Neurotoxicity After Chimeric Antigen Receptor T-Cell Therapy

Educational Objective
To determine risk factors for development of delayed neurotoxicity after treatment with chimeric antigen receptor T cells.
1 Credit CME
Key Points

Question  Which patients are at risk for delayed neurotoxicity after treatment with chimeric antigen receptor T cells?

Findings  In this diagnostic/prognostic study of 204 adults receiving axicabtagene ciloleucel for relapsed or refractory lymphoma, clinical and laboratory markers identified as risk factors for the subsequent development of neurotoxicity were used to create a prognostic model that had a sensitivity of 82% and a specificity of 70% when tested on an internal validation cohort for predicting which patients develop neurologic toxicity.

Meaning  Early identification of risk of neurotoxicity may allow for more appropriate triage and anticipatory care of patients receiving chimeric antigen receptor T-cell therapy.


Importance  Chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory hematologic malignant neoplasm causes severe neurologic adverse events ranging from encephalopathy and aphasia to cerebral edema and death. The cause of neurotoxicity is incompletely understood, and its unpredictability is a reason for prolonged hospitalization after CAR T-cell infusion.

Objective  To identify clinical and laboratory parameters predictive of neurotoxicity and to develop a prognostic score associated with its risk.

Design, Setting, and Participants  This single-center diagnostic/prognostic accuracy study was conducted at Brigham and Women’s Hospital/Dana Farber Cancer Institute from April 2015 to February 2020. A consecutive sample of all patients undergoing CAR T-cell therapy with axicabtagene ciloleucel for relapsed or refractory lymphoma were assessed for inclusion (n = 213). Patients who had previously received CAR T cells or who were treated for mantle cell lymphoma were excluded (n = 9). Patients were followed up for a minimum of 30 days from the date of CAR T-cell infusion.

Main Outcomes and Measures  The primary outcomes were measures of performance (accuracy, sensitivity, specificity, area under the curve) of a diagnostic tool to predict the occurrence of CAR-associated neurotoxicity, as graded by the Common Terminology Criteria for Adverse Events criteria.

Results  Two hundred four patients (127 men [62.2%]; mean [SD] age, 60.0 [12.1] years) were included in the analysis, of which 126 (61.8%) comprised a derivation cohort and 78 (38.2%), an internal validation cohort. Seventy-three patients (57.9%) in the derivation cohort and 45 patients (57.7%) in the validation cohort experienced neurotoxicity. Clinical and laboratory values obtained early in admission were used to develop a multivariable score that can predict the subsequent development of neurotoxicity; when tested on an internal validation cohort, this score had an area under the curve of 74%, an accuracy of 77%, a sensitivity of 82%, and a specificity of 70% (positive:negative likelihood ratio, 2.71:0.26).

Conclusions and Relevance  The score developed in this study may help predict which patients are likely to experience CAR T-cell–associated neurotoxicity. The score can be used for triaging and resource allocation and may allow a large proportion of patients to be discharged from the hospital early.

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Article Information

Corresponding Author: Daniel B. Rubin, MD, PhD, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 175 Cambridge St, Ste 300, Boston, MA 02114 (drubin4@partners.org).

Accepted for Publication: April 27, 2020.

Published Online: August 10, 2020. doi:10.1001/jamaneurol.2020.2703

Author Contributions: Drs Rubin and Vaitkevicius had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rubin, Basil Ali, Spendley, Vaitkevicius.

Acquisition, analysis, or interpretation of data: Rubin, Al Jarrah, Li, LaRose, Monk, Basil Ali, Nikiforow, Jacobson, Vaitkevicius.

Drafting of the manuscript: Rubin, Li, Vaitkevicius.

Critical revision of the manuscript for important intellectual content: Rubin, Al Jarrah, LaRose, Monk, Basil Ali, Spendley, Nikiforow, Jacobson, Vaitkevicius.

Statistical analysis: Rubin, Li.

Administrative, technical, or material support: LaRose, Monk, Basil Ali, Nikiforow, Jacobson, Vaitkevicius.

Supervision: Rubin, Nikiforow, Jacobson, Vaitkevicius.

Conflict of Interest Disclosures: Dr Rubin reports personal fees from Celgene/Bristol-Myers Squibb outside the submitted work. Ms Spendley reports other support for serving on an advisory board for Celgene outside the submitted work. Dr Nikiforow reports personal fees from Kite Pharma/Gilead Sciences and Novartis outside the submitted work. Jacobson reports personal fees from Kite Pharma, Novartis, Celgene, Bristol-Myers Squibb, Humanigen, Precision BioSciences, and Nkarta outside the submitted work. No other disclosures were reported.

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