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| Home > Publications database > Non‐ICANS neurotoxicity after BCMA‐directed CAR‐T therapy: Clinical spectrum, outcomes, and a framework for neurology–oncology co‐management |
| Home > Publications database > Non‐ICANS neurotoxicity after BCMA‐directed CAR‐T therapy: Clinical spectrum, outcomes, and a framework for neurology–oncology co‐management |
| Journal Article | FZJ-2026-04883 |
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2026
John Wiley & Sons Ltd.
Hoboken
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Please use a persistent id in citations: doi:10.1002/hem3.70404 doi:10.34734/FZJ-2026-04883
Abstract: Ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapy, has demonstrated deep and durable responses in patients with relapsed or refractory multiple myeloma and is rapidly moving into routine clinical practice worldwide.1, 2 While cytokine release syndrome (CRS) and immune-effector cell-associated neurotoxicity syndrome (ICANS) are well described, increasing attention is directed toward rarer but potentially severe neurotoxicity outside the ICANS spectrum.3, 4 Non-ICANS immune-effector cell-associated (IEC) toxicities reported after BCMA-directed CAR-T therapies include movement/neurocognitive treatment-emergent events with Parkinsonism-like features (IEC-PKS), cranial nerve palsies (IEC-NP), Guillain–Barré-syndrome-like presentations (IEC-GBS), and myelopathy.5 Phenotypes can overlap and evolve over weeks, complicating recognition and therapeutic decision-making.The biological basis of delayed non-ICANS neurotoxicity after BCMA-directed CAR-T therapy is an active area of investigation. Early reports have detected CAR-T in the cerebrospinal fluid (CSF) during neurotoxicity and, in individual cases, have described neuropathologic evidence of lymphocytic infiltration in affected brain regions, findings compatible with central nervous system (CNS) trafficking and the persistence of CAR-T, together with local inflammatory tissue injury.4 These observations have raised the possibility of an on-target/off-tumor mechanism in susceptible neural tissues, although causality has not been established.4, 6 At the cohort level, delayed non-ICANS neurotoxicity has been linked to pronounced CAR-T expansion and persistence and to heightened immune activation, often in patients with clinically relevant CRS and/or ICANS, suggesting that both cellular kinetics and inflammatory activation may contribute.3, 5-8 Despite these signals in clinical trials and real-world settings, non-ICANS neurotoxicity remains insufficiently characterized, and data from large in-label cohorts are limited. Against this background, this report pursues two aims: (1) to characterize the clinical spectrum, management, and outcomes of severe non-ICANS IEC neurotoxicity in a real-world in-label cilta-cel cohort, and (2) to propose a structured framework for triage, diagnostic evaluation, and initial neurology–oncology co-management applicable beyond specialized CAR-T centers.We conducted a retrospective single-center analysis within a predefined hematology–neurology collaboration. Consecutive patients receiving in-label cilta-cel for relapsed or refractory multiple myeloma between May 2023 and December 2025 were included (n = 117; median age, 69 years [range, 59–79]; median follow-up, 11.3 months [range, 1–31.5]). Severe non-ICANS neurotoxicity was distinguished from ICANS per EBMT recommendations6 and adjudicated by joint hematology–neurology review. Cases of severe non-ICANS neurotoxicity were identified after exclusion of alternative causes (infection, metabolic/toxic disturbances, medication effects, and CNS myeloma/relapse).Ten patients (8.5%) met the criteria, with the majority primarily treated on oncology wards with structured inpatient neurology consultation and outpatient follow-up. Patient characteristics are summarized in Table 1; timing, overlap, management, and outcomes are shown in Figure 1. Non-ICANS IEC neurotoxicity began a median of 45 days post CAR-T infusion (range, 11–160 days). IEC-GBS occurred in three patients (all CTCAE Grade 5; Days 24–97) and followed fulminant courses despite escalation from IVIG and corticosteroids to intensified immunosuppression and extracorporeal antibody/cytokine depletion. All three patients deceased 3–7 weeks after the diagnosis of IEC-GBS. Median time from symptom onset to high-dose corticosteroids was 3.5 days (range, 2–13); the start of corticosteroid treatment for each patient is depicted in Figure 1A. Notably, immune-directed escalation coincided with marked declines in circulating CAR-T copies, yet without neurologic recovery. IEC-PKS developed in three patients (CTCAE Grades 2–4; Days 45–160) and was persistently dopamine-nonresponsive. Two patients underwent intensified immunosuppression (including chemotherapy) and deceased from infectious complications in the context of cytopenia; one remains alive with ongoing symptoms. Five patients had severe IEC-NP, predominantly peripheral facial palsies. One case included oculomotor palsy as part of multisyndromic toxicity. Treatment was generally corticosteroid-based, with escalation in multisyndromic neurotoxicity. Improvement occurred in some cases after intensification of immunosuppression, whereas deficits persisted in a patient with facial palsy and concomitant IEC-encephalitis despite high-dose corticosteroids plus etoposide and intrathecal chemotherapy. Two IEC-NP cases occurred within broader syndromes of IEC-PKS or IEC-GBS. IEC-encephalitis was observed in two patients (CTCAE Grade 4; Days 11 and 39). Both received high-dose corticosteroids (with additional etoposide and intrathecal chemotherapy in one); encephalitis resolved in one patient (while concomitant IEC-PKS persisted), whereas encephalitis persisted in the other at the last follow-up.
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