Beyond the Typical ICANS: Characterizing Non-ICANS Neurological Complications in CAR-T Therapy – A Retrospective Analysis
Melissa A Nicholas, Abdulaziz Abu-Haimed, Faisal Abushullaih, Emily N Davidson, Graeme A Fenton, Justin W Kehm, Hakan Kocoglu, Jean A Yared, Ariel Fromowitz, Nancy M Hardy, Aaron P Rapoport, Djordje Atanackovic, Lily Pham, Ashraf Badros, Haroon AhmadAbstract
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. 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.