Parkinsonism Associated with Anti‐B‐Cell Maturation Antigen Chimeric Antigen Receptor T‐Cell Therapy

Abstract

As chimeric antigen receptor T-cell (CAR-T) therapy becomes more common, so will rare and unforeseen treatment complications. Among the complications of CAR-T therapy targeting B-cell maturation antigen (BCMA) in multiple myeloma is the emergence of movement and neurocognitive treatment-emergent adverse events (MNT).1 This term refers to a hypokinetic movement disorder characterized by dopamine-unresponsive bradykinesia, postural instability, hypomimia, hypophonia, micrographia, and impaired short-term memory. Eight cases of ciltacabtagene autoleucel–associated MNTs were reported in the CARTITUDE-1 trial for multiple myeloma,1-5 representing 6% of patients enrolled. Two cases of grade 3 parkinsonism were also reported after treatment with idecabtagene vicleucel in the KarMMa-2 trial.5, 6 In these cases, the median onset of parkinsonism occurred 17 days after CAR-T infusion1, 4; all cases affected men, and three patients died (one from parkinsonism-related complications4). Symptomatic improvement was reported for two patients; however, information on symptom severity and treatment approaches is limited.1, 3, 4 We report the case of a female patient who was diagnosed with stage III multiple myeloma at age 51. Her disease proved resistant to multiple chemotherapy agents and autologous stem cell transplant. She required local radiation to vertebral and skull base plasmacytomas and ultimately received CAR-T therapy (ciltacabtagene autoleucel) at age 54 (Fig. 1). Six days after infusion, she developed grade 2 cytokine release syndrome (CRS), which resolved with tocilizumab. On day seven, she became encephalopathic with disorientation, inattention, and expressive aphasia. Peak immune effector cell-associated neurotoxicity syndrome (ICANS) score was 2. Her cognitive symptoms resolved after four days of dexamethasone treatment, and she was discharged home. Three weeks after CAR-T infusion, she reported cognitive dysfunction, reduced verbal output, flat affect, and a shuffling gait. Central nervous system imaging was unremarkable with stable calvarial and skull base lesions (Fig. 2A–D). Neurological examination showed inattention, slowed responses, hypomimia, bradykinesia, cogwheeling, and a shuffling gait with reduced arm swing. Due to concern for CAR-T-associated MNT,1 she received high-dose steroids and six months of monthly IVIg (0.5 mg/kg) followed by bimonthly infusions. Parkinsonism did not improve, and neurologic assessments at 9 and 12 months post-infusion showed persistent inattention, hypomimia, asymmetric bradykinesia, mild-to-moderate rigidity, and a slow shuffling gait with reduced arm swing (Video 1). Unified Parkinson's Disease Rating Scale, Part III (UPDRS-III), score at 9 months was 49 (Fig. 2E). She relied on family caregivers for basic and instrumental activities of daily living (ADL) due to slowed cognition and difficulties with word finding and fine motor activities. Dopamine transporter single-photon emission computed tomography (DAT-SPECT) with 123I-ioflupane was negative (Fig. 2F), and a trial of carbidopa/levodopa (maximum: 900 mg daily) was unsuccessful. Trihexyphenidyl did not affect motor symptoms, but amantadine 100 mg three times a day improved arousal and attention, allowing her to become more independent in ADLs. She received regular speech and physical therapy, and UPDRS-III score at 17 months showed a mild improvement in speech, facial expression, rigidity, and bradykinesia (Fig. 2E). Repeat magnetic resonance imaging after one year was unchanged. Similar to prior cases, a normal DAT-SPECT and the emergence of parkinsonism soon after anti-BCMA CAR-T therapy suggest causality. ICANS, a steroid-responsive syndrome characterized by confusion, dysphagia, impaired fine motor skills, cerebral edema, and seizures, is a well-known CAR-T complication and occurs in up to 50% of patients within days of infusion.7 ICANS is attributed to systemic cytokine release that disrupts the blood–brain barrier and causes glial and neuronal dysfunction.8 In contrast, anti-BCMA MNTs are delayed in onset and harder to treat with unclear pathophysiology. Although BCMA is thought to be exclusively expressed in B-cell lineage cells,9 BCMA protein expression within the basal ganglia was reported in one patient with MNT,2 and low levels of striatal BCMA RNA are present in healthy adults aged <30,10 suggesting that aberrant BCMA protein expression within the basal ganglia may predispose to MNTs. In patients with MNT, CAR-T cells and CD3+ T-cell infiltrates have also been reported in the cerebrospinal fluid and basal ganglia, respectively. Although these findings suggest that CAR-T therapy may cause neuronal loss, no direct cytotoxic damage has been confirmed in persons with CAR-T-associated parkinsonism.1, 2 Cytokine-mediated dysfunction has also been postulated because all patients with MNTs had prior grade ≥2 CRS, and 80% developed ICANS. Furthermore, high interferon-γ and interleukin-6 levels, elevated CD4+ counts, and CAR-T-cell expansion and persistence are statistically associated with increased MNT risk.1 Prior cases of MNT have been treated with corticosteroids, anakinra, dasatinib, siltuximab, carbidopa/levodopa, intrathecal methotrexate and cytarabine, and levetiracetam without symptomatic improvement.1, 2 A single case report recently described complete remission of parkinsonism after treatment with cyclophosphamide.3 This option was considered high risk for our patient, but we now report that amantadine may improve cognitive symptoms. Amantadine's mechanism of action is incompletely understood, but its unique antiglutaminergic activity may contribute to observed effects.11 It is important for movement disorders specialists to recognize this dopamine-unresponsive parkinsonism to avoid unnecessary diagnostic testing and potentially harmful treatments, particularly as more data are collected. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique. S.S.: 1A, 1B, 1C, 3A, 3B W.W.A.: 1B, 1C, 3B A.A.P.: 3B J.R.B.: 1A, 3B We would like to thank the patient and her family for their incredible generosity and patience without which this manuscript would not have been possible. Ethical Compliance Statement: The authors confirm that they have read the journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. This medical case report is exempt from institutional review board review per the University of Pennsylvania Human Research Protections Program. Explicit informed consent for publication of this case report and all supplementary files was obtained. Funding Sources and Conflicts of Interest: No specific funding was received for this work. The authors have no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: The authors have no financial disclosures relevant to this work. The data that supports the findings of this study are available in the supplementary material of this article.

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