Beyond the typical immune effector cell-associated neurotoxicity syndrome: Characterizing non-immune effector cell-associated neurotoxicity syndrome neurological complications in chimeric antigen receptor T-cell therapy-A retrospective analysis.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory hematologic malignancies. While immune effector cell-associated neurotoxicity syndrome (ICANS) is a well-recognized complication, expanding clinical use has revealed distinct non-ICANS neurological complications that challenge standard diagnostic and management approaches. We characterize the clinical features and outcomes of these non-classic presentations. METHODS: A retrospective analysis was conducted on 357 patients receiving commercial CAR-T therapy for non-Hodgkin lymphoma or multiple myeloma at a single academic center (2015-2025). Non-ICANS neurological complications were defined by neurologic deficits, movement disorders, or neurocognitive syndromes occurring in the absence of global encephalopathy (ICE scores 9-10). Institutional protocol included baseline neurology evaluation and brain MRI. RESULTS: Non-ICANS complications occurred in 17 patients (4.76%). Manifestations included focal neuropathies or myelopathy (n = 5), progressive leukoencephalopathy (n = 4), neuropsychiatric symptoms (n = 3), Parkinsonism (n = 2), and cranial nerve palsies (n = 4). Compared to the institutional median for classic ICANS (7 days), non-ICANS demonstrated a prolonged median duration of 14 days (range, 4-365+ days). Abnormal brain MRI findings were present in 5 of 15 (33.3%) cases with post-treatment brain MRI, manifesting commonly as T2/FLAIR hyperintensities in the white matter. Cerebrospinal fluid (CSF) immunomonitoring in a subset of cases (n = 2) revealed an enrichment of CAR T-cells compared to peripheral blood. CONCLUSIONS: Non-ICANS neurological complications represent a distinct clinical subset characterized by atypical findings, neuroimaging abnormalities, and/or protracted recovery. Increased clinical vigilance and tailored diagnostic approaches are essential to mitigate long-term morbidity, as standard screening tools fail to capture these focal neurotoxicities.