Abstract
BACKGROUND
Chimeric Antigen Receptor (CAR) T-cells targeting the B-cell maturation antigen (BCMA) represent an emerging immunotherapy for refractory multiple myeloma. While acute neurologic toxicities frequently occur and are well-described, hypokinetic movement disorders are rare and ill-defined. Clinical experience and therapeutic management therefore remain to be elucidated.
MATERIAL AND METHODS
We retrospectively searched the institutional databases from the Sections for Neuro-Oncology at the Yale School of Medicine (New Haven, Connecticut) and the Massachusetts General Hospital (Boston, Massachusetts) to identify patients that presented for evaluation of movement disorders following transfusion of BCMA-directed CAR T-cells.
RESULTS
We identified four patients (females: n = 3, males: n = 1) with complex movement symptoms following transfusion of BCMA-targeting CAR T-cells. At presentation, median age was 74.5 ± 4.3 years (range, 67-77 years). All patients received a single transfusion of a commercially available CAR T-cell product (ciltacabtagene-autoleucel: n = 3; idecabtagene-vicleucel: n = 1). Parkinsonism-like symptoms were generally preceded by mild (maximal ICANS: grade 3) and transient (median duration: 4 days) neurotoxicity.Following resolution of acute neurotoxicity, all patients developed parkinsonism-like symptoms after a median of 23 ± 7 days (range, 19-35 days). Predominant motor symptoms were bradykinesia, oppositional paratonia, postural instability, and hypomimia. Psychiatric involvement was noted in three patients. Consistent with the potential on-target/off-tumor toxicity of the CAR T-cells against BCMA-positive basal ganglia, MRI revealed bilateral hyperintensities in the head of the caudate nucleus on FLAIR/T2-weighted or diffusion-weighted sequences in two patients. [18F]-FDG-PET scans revealed basal ganglia hypometabolism in one patient, diffuse frontal hypometabolism in another, and diffuse hypometabolism in a third patient.As symptoms progressed, treatment for movement symptoms was administered in all patients and included systemic immunosuppression (corticosteroids), interleukin-antagonists, aimed to reduce the number of circulating CAR T-cells (cyclophosphamide, intrathecal methotrexate, cytarabine) or symptomatic treatment (levodopa/carbidopa). At a median follow-up of 115 days (range, 69-198 days), one patient died of sepsis despite aggressive therapy while symptoms stabilized in three patients.
CONCLUSION
Given that parkinsonism-like movement disorders may develop weeks after transfusion of BCMA-directed CAR T cells, a high degree of suspicion is crucial to establish diagnosis. Since symptom stabilization may be achieved, early diagnosis may form the basis for more favorable outcomes. Thus, a multidisciplinary care team appears crucial to provide optimal care of affected patients.