Neurotoxicity was common among adult patients who underwent chimeric antigen receptor (CAR) T-cell (CAR-T) therapy for relapsed lymphomas, and was associated with cytokine release syndrome (CRS), according to data from a longitudinal study published in Scientific Reports.

Although CAR-T therapy results in high response rates and durable remissions among patients with B-cell hematologic malignancies, it has also been associated with substantial toxicities, including CRS and neurotoxicity. The aim of this study was to characterize the incidence and pattern of neurotoxicity in this population.

The study included 84 consecutive patients from 4 French centers who underwent anti-CD19 CAR-T therapy to treat relapsed B-cell lymphomas. All patients received commercially-available products and not through a clinical trial. Patients were identified prospectively and followed longitudinally for neurotoxicity between 2018 and 2019. Neurotoxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

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At baseline, the median age of the patients was 59 years (range, 19-77 years), and 31% were female. A neurologic exam was normal among 70% of patients, with 24% having peripheral sensitive neuropathy from prior chemotherapy. Several patients had Horner syndrome due to localization of their disease, Wallenberg syndrome with sequelae, mild executive problems, or mild mnesic impairment.

CRS developed in 80% of patients; of which, 94% was grade 1 to 2, and 6% was grade 3 to 4. The median time to CRS was 3 days and the median duration was 5 days.

Neurotoxicity occurred in 43% of patients; of which, 64% was grade 1 to 2 and 36% was grade 3 to 4. The median time to neurotoxicity was 7 days and the median duration was 6 days. In all cases, neurotoxicity was associated with CRS.

Among the patients who developed neurotoxicity, the most common symptoms included cognitive signs and nonpyramidal motor disorders. Cognitive signs included aphasia and agraphia signs, executive disorders, cognitive slowness, apraxia, disorientation, restlessness, attentional disorders, hallucinations, and confusional states. Other less common neurotoxicity symptoms included consciousness disorders, seizures, and miscellaneous symptoms, such as headaches, dysesthesias, meningismus, and transitory focal weakness.

The majority of patients recovered from their neurotoxicity (87%), regardless of grade. There were 11 patients who died within 2 months after reinfusions due to disease progression; however, 5 of these patients also had neurotoxicity. It was unknown whether neurotoxicity played a role in these patients’ deaths.

Brain imaging by MRI or CT of 27 of the 36 patients with neurotoxicity were normal. Cerebrospinal fluid examination was abnormal in 9 of the 11 patients evaluated, including isolated high protein levels, isolated pleocytosis, or hyperproteinorachia with pleocytosis.

There were 20 patients with neurotoxicity who were treated with steroids, including 12 of the 13 patients with grade 3 to 4 neurotoxicity.

Neurotoxicity was associated with posttreatment C-reactive protein levels in a multivariate analysis (P =.047).

The authors concluded that “the pattern of neurotoxicity in this homogeneous group of patients treated for B-cell lymphomas identified cognitive disorders and, to a minor degree, nonpyramidal motor disorders, as the hallmark of neurotoxicity linked to CAR T-cell therapy.” The authors added that “these symptoms are insufficiently captured with available scales, which should be updated accordingly.”


Belin C, Devic P, Ayrignac X, et al. Description of neurotoxicity in a series of patients treated with CAR T-cell therapy. Sci Rep. 2020;10:18997. doi:10.1038/s41598-020-76055-9