Background: Chimeric antigen receptor T-cell (CAR-T) therapies target cell surface proteins, most notably CD19 and B-cell maturation antigen (BCMA), as treatment of hematologic malignancy. These therapies have been associated with significant neurotoxicity. BCMA CAR-T has recently been uniquely associated with a parkinsonism-like syndrome that is unresponsive to dopamine replacement. Autopsy data revealed low level BCMA expression in the basal ganglia, suggesting an on-target, off tumor effect of BCMA CAR-T. No cases of parkinsonism have been reported after treatment with CD19 CAR-T. Here we present the first reported case of parkinsonism after receiving CD19 CAR-T which we further investigated through review of our institutional CAR-T database and analysis of the FDA Adverse Event Reporting System (FAERS) database.

Methods & Results: A 61-year-old woman with follicular lymphoma developed a movement disorder with parkinsonian features 4 days after CD19 CAR-T therapy infusion with persistent symptoms after 497 days despite early treatment with dexamethasone and anakinra. Neurologic consultation noted tremor, gait imbalance, mixed rest and action tremor, slight limb and gait bradykinesia, and dream enactment behavior, all concerning for parkinsonism. She further underwent DAT-SPECT which was qualitatively normal.

We subsequently reviewed 31 patients who received CD19 CAR-T at the University of Vermont Cancer Center. 12 patients reported new or worsening tremor or gait disturbance after receiving CD19 CAR-T, often independent of immune effector cell associated neurotoxicity syndrome (ICANS). Baseline characteristics along with neurologic symptoms, workup, and treatment were collected. 7 patients were female and 5 were male. Median age at time of CAR-T therapy was 71 years (range: 60-85yr). Patients were treated for DLBCL (n=6), B-cell lymphoma (n=2), follicular lymphoma (n=2), splenic marginal zone lymphoma (n=1), and mantle cell lymphoma (1). Patients received Yescarta (n=8), Breyanzi (n=3), and Tectarus (n=1). Peak CRS grade was 2 (7 pts), 1 (4 pts), and 0 (1 pt). Peak ICANS grade was 3 (1 pt), 2 (3 pts), 1 (6 pts), and 0 (2 pts).

Median onset of neurologic symptoms was 10 days after infusion (range: 4-36d). Parkinsonism symptoms included tremor (n=8), ataxia (n=5), visual hallucinations (n=4), and speech changes (n=4). Median duration of symptoms was 9.5 days (range: 1-497d and ongoing). 3 patients had existing baseline tremor which worsened after CAR-T infusion. Treatment included dexamethasone (n=10) and anakinra (n=6). Symptoms resolved in the majority (83%).

We furthermore investigated nervous system adverse events (NSAE) associated with FDA-approved CD19 CAR-T reported in the FAERS database between January 2017 and March 2025.Analysis was performed in R using the Bioconductor package “faers”. Data was standardized using preferred term (PT) according to the Medical Dictionary for Regulatory Activities (MedDRA). NSAE were extracted according to MedDRA classification. Data was deduplicated based on concordance across drugs administered and adverse reactions, and discrepancies in gender, age, reporting country, event date, start date, and drug indications. Disproportionality Analysis was performed using reporting odds ratio (ROR).

We extracted 11,595,294 total reports from FAERS. 13,983 reports were related to CD19 CAR-T and 5751 CAR-T reports contained NSAE. Significantly overreported NSAE related to parkinsonism included aphasia (n=344, ROR=20.07), tremor (n=340, ROR=3.59), memory impairment (n=145, ROR=1.56), cognitive disorder (n=68, ROR=2.27), dysarthria (n=49, ROR=2.43), Speech disorder (n=45, ROR=1.47), motor dysfunction (n=20, ROR=3.2), ataxia (n=12, ROR =1.81), slow speech (n=8, ROR=4.54), cogwheel rigidity (n=3, ROR=5.31), and micrographia (n=2, ROR=97.59). Notably there were also 4 reports of parkinsonism, however this was not statistically significant.

Conclusion: Our report of parkinsonism after CD19 CAR-T suggests that CAR-T induced parkinsonism may not be unique to BCMA CAR-T and may be caused by an additional or separate mechanism of which further study is warranted. Review of our institutional database and FAERS suggests these symptoms may be common but underreported in the literature. Our findings support the need for further close neurological monitoring in patients after treatment with CD19 CAR-T.

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2025
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