Neurological Complications in CAR T-Cell Therapy: A Case of Parkinsonism

A recent case study published in JAMA Neurology describes a rare but serious complication of chimeric antigen receptor (CAR) T-cell therapy, where a patient developed parkinsonism following treatment for multiple myeloma (MM). The case involves a 67-year-old woman who, after receiving CAR T-cell therapy, began showing signs of neurocognitive slowing and movement difficulties just weeks after treatment.¹

CAR T-cell therapy has revolutionized cancer treatment | image credit: Serhii - stock.adobe.com

While immune effector cell-associated neurotoxicity affects up to 40% of patients with MM treated with B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, parkinsonism has an estimated frequency of 3%.² “The underlying pathophysiology presumably involves on-target/of-tumor toxicity of CAR T cells against BCMA-positive basal ganglia,” the current study further explains.¹

The patient was treated with ciltacabtagene autoleucel as fifth-line therapy, with no immediate neurological issues identified. However, 24 days after receiving treatment, she began to exhibit parkinsonism-like symptoms, including hypomimia, oppositional paratonia, right-predominant rigidity, a small-stepped gait, and decreased arm swing. Symptoms continued progressing over the next few days, including dysgraphic features in the patient’s handwriting. Subsequent MRI on day 27 revealed new bilateral hyperintensities in the caudate head, putamen, and globus pallidus. This was accompanied by cerebrospinal fluid (CSF) analysis indicating lymphocytic pleocytosis with 28 nucleated cells/μL and 94% lymphocytes but no evidence of an infectious process.

On day 37, a fluorodeoxyglucose PET scan revealed diffuse hypometabolism throughout the cerebral cortex. CAR T cell-induced parkinsonism-like movement disorder was suspected at this time. The authors note that previous cases described in the literature have shown substantial bilateral hypometabolism in the basal ganglia on PET-CT scans, which was not present in the patient in this study.³ “MRI findings and lymphocytic pleocytosis in CSF support the hypothesis of an underlying process within the striatum. These MRI findings have not been previously reported in the literature and may reflect early manifestation of an inflammatory process,” the authors noted.¹

Treatment of CAR T-cell-mediated movement and neurocognitive adverse effects often includes a combination of steroids and immunosuppressive therapies. Management of these effects has proven difficult due to the long duration of symptoms and weak responses to steroids.³ Despite initial treatments with methylprednisolone, the patient’s symptoms continued to worsen.¹ The patient was then treated with Anakinra and intrathecal methotrexate, cytarabine, and hydrocortisone, which stabilized her symptoms. A repeated CSF analysis showed resolution of nucleated cells. Follow-up MRI scans on day 57 showed resolution of the hyperintensities previously observed in the basal ganglia, however, the patient’s movement symptoms persisted.

The increased use of CAR T-cell therapy may result in a rise in similar cases. The study’s findings suggest that early intervention is crucial in managing such adverse effects to avoid the need for more intensive immunosuppression, which could compromise the effectiveness of the cancer treatment. “Early intervention appears to be crucial, a high level of suspicion for basal ganglia–directed toxicity is warranted when patients present with movement disorders following BCMA-directed CAR T cell therapy,” the authors added.

References:

1. Gudera JA, Baehring JM, Karschnia P. Parkinsonism following chimeric antigen receptor T-cell therapy. JAMA Neurol. Published online August 12, 2024. doi:10.1001/jamaneurol.2024.2506
2. Karschnia P, Miller KC, Yee AJ, et al. Neurologic toxicities following adoptive immunotherapy with BCMA-directed CAR T cells. Blood. 2023;142(14):1243-1248. doi:10.1182/blood.2023020571
3. Rendo MJ, Joseph JJ, Phan LM, DeStefano CB. CAR T-cell therapy for patients with multiple myeloma: current evidence and challenges. Blood Lymphat Cancer. 2022;12:119-136. doi:10.2147/BLCTT.S327016