Neuroimaging Findings in Children and Young Adults With Neurotoxicity After CAR T-Cell Therapy for B-Cell Malignancies.
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BACKGROUND AND OBJECTIVES: Neuroimaging findings in immune effector cell-associated neurotoxicity syndrome (ICANS) have not been systematically described. We created the chimeric antigen receptor (CAR) T-cell Neurotoxicity Imaging Virtual Archive Library (CARNIVAL), a centralized imaging database for children and young adults receiving CAR T-cell therapy. Objectives of this study were to (1) characterize neuroimaging findings associated with ICANS and (2) determine whether specific ICANS-related neuroimaging findings are associated with individual neurologic symptoms. METHODS: We performed a multicenter retrospective cohort study of patients ≤30 years who experienced ICANS following CAR T-cell therapy for B-cell malignancies between January 1, 12, and January 31, 23, and had a brain MRI in the first 30 days after CAR T-cell infusion. Deidentified MRIs were reviewed by a central study team of pediatric neuroradiologists with experience in ICANS neuroimaging. Imaging features were categorized and correlated with CAR product and clinical characteristics including preinfusion neurologic history, and postinfusion neurologic symptoms alongside CAR T-cell toxicities using logistic regression. RESULTS: Of 864 patients treated with CD19 and/or CD22-directed CAR T-cells, 343 developed ICANS. 96 of the patients with ICANS (median age 12, 43% female) had an acute brain MRI. Of these, 36% (95% CI 27%-47%) had ICANS-related MRI abnormalities, most commonly affecting the white matter (24/35, 69%), brainstem (14/35, 40%), leptomeninges (10/35, 29%), and thalami (9/35, 26%). ICANS-related white matter abnormalities were generally bilateral, symmetric, and involved the supratentorial deep white structures, including the external and extreme capsules, corticospinal tracts, centrum semiovale, and periatrial white matter. There were no significant associations between ICANS-related MRI abnormalities and baseline clinical/demographic characteristic or specific ICANS symptoms, but higher ICANS grade was positively associated with MRI abnormalities (adjusted odds ratio 3.7, p < 0.001). Among 12 patients with ICANS-related MRI abnormalities who had follow-up imaging, 10 of 12 (83%) improved and 3 of 12 fully resolved. DISCUSSION: ICANS-related brain MRI abnormalities demonstrate unique patterns in the cerebral white matter, brainstem and thalami; their prevalence increases with ICANS clinical grade. Because our cohort is enriched for patients with severe ICANS, it likely overestimates the incidence of ICANS-related imaging abnormalities. A better understanding of neuroimaging findings is valuable for parsing pathophysiologic mechanisms of ICANS and optimizing patient outcomes.