Background: Chimeric Antigen Receptor T-cell (CAR-T) therapy is a transformative treatment for relapsed/refractory Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) yet is frequently complicated by cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Typical ICANS presents within days of infusion and is well-characterized by encephalopathy, delirium, tremors, and seizures. However, as CAR-T indications broaden, atypical ICANS presentations are increasingly encountered. These manifestations remain poorly described, often leading to diagnostic uncertainty and delayed management. This study characterizes the clinical features, diagnostic patterns, management, and outcomes of atypical ICANS in a large CAR-T–treated cohort.

Methods: A retrospective review was conducted of adult patients with NHL or MM who received commercial CAR-T cell therapy at a single academic center between 2015 and 2023. Patients with atypical ICANS were identified based on chart review and adjudicated by neurologists and oncologists. Atypical ICANS refers to neurotoxic manifestations that deviate from the characteristic presentations of standard ICANS. Data collected included timing, symptomatology, diagnostics, treatment strategies, and outcomes. This study was approved by the institutional review board and conducted as a retrospective chart review.

Results: Among 357 patients (NHL: 63%, MM: 37%), the incidence of typical ICANS was 40%. Atypical ICANS occurred in 16 patients (4.5%) with a median age of 64.3 years (SD ±11) and a male predominance (56%). The majority had NHL (75%) and received Axi-cel (69%) or Cilta-cel (25%). Pre-existing neurologic comorbidities were present in three patients (19%). Atypical symptoms manifested later than typical ICANS, with a mean onset on day 9 post-cell infusion (SD ±8) compared to day 4 (SD ±3) for typical ICANS. Presentations were heterogeneous and included cranial neuropathies (n=3), expressive aphasia (n=2), parkinsonism (n=2), psychiatric symptoms (n=2), acute neurovascular events (n=2), radiographic leukoencephalopathy (n=4), and one case of transverse myelitis. Notably, 50% of these patients also experienced concurrent cytokine release syndrome (CRS).

Diagnostic evaluations included brain MRI (n=14), of which 57% revealed abnormalities; EEG (n=5), all demonstrating diffuse slowing; and cerebrospinal fluid (CSF) analysis (n=3), with CAR-T cells detected in all samples. One CSF specimen was positive for human herpesvirus 6 (HHV-6). All patients received immunosuppressive therapy, predominantly systemic corticosteroids. Additional agents used included tocilizumab, siltuximab, anakinra, intravenous immunoglobulin (IVIG), and anti-thymocyte globulin. Seven patients (44%) required intensive care unit (ICU)-level support. The average duration of neurologic symptoms was 19 days (SD ±17). At discharge, only 31% achieved full neurologic recovery, while 69% had persistent deficits. Three patients (19%) died as a direct result of neurotoxicity.

Outcomes varied by symptom type: among patients with leukoencephalopathy, two were transitioned to hospice care, and one died within two months. Both patients who experienced ischemic strokes achieved full recovery. Of the two cases of parkinsonism, one attained complete recovery following prolonged rehabilitation, while the other remained wheelchair-bound until death. Psychiatric symptoms resolved in both patients; however, one required long-term treatment with selective serotonin reuptake inhibitors (SSRIs). The patient with transverse myelitis also achieved full recovery after extended rehabilitation. Detailed analyses of cytokine profiles and their radiologic correlations from this cohort will be presented, emphasizing the role of chemokine dysregulation contribution to pathogenesis.

Conclusion: Atypical ICANS occurred in 4.5% of CAR-T–treated patients with NHL or MM and was associated with delayed diagnosis, diverse neurologic symptoms, diagnostic challenges, and significant morbidity (69% with persistent deficits) and mortality (19%). Early recognition and immunosuppressive treatment may improve outcomes. Despite study limitations such as retrospective design and small sample size, these findings emphasize the need for improved diagnostic framework and heightened clinical awareness. Our results warrant further investigation in prospective multicenter studies with standardized reporting of atypical neurotoxicity.

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2025
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