Parkinsonism and other non-immune effector cell-associated neurotoxicities related to BCMA-directed chimeric antigen receptor T-cell therapy

Abstract Background: In the setting of relapsed/refractory (R/R) multiple myeloma (MM), B-cell maturation antigen (BCMA) directed chimeric antigen receptor T-cell (CAR-T) therapies have been observed to cause non-ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome) neurotoxicities (NINTs). Despite the well-known association of CAR-T and ICANS, the occurrence of NINTs and in particular new-onset and worsening Parkinsonism is less understood. The incidence, treatment, and potential resolution of these symptoms has not been well described. This study seeks to quantify CAR-T therapy related NINTs as well as provide prognostic data for the clinical course and resolution of symptoms. Methods: This study included all (n=128) patients who had been treated with either ciltacabtagene autoleucel (cilta-cel) or idecabtagene vicleucel (ide-cel) at the University of Kansas Medical Center from December 12, 2019 until December 28, 2024. This study was conducted with local IRB approval and in accordance with the declaration of Helsinki. From this initial patient population, a retrospective cohort analysis was done to describe neuromotor symptoms. Data collection included neurotoxicity symptoms that developed within six months after CAR-T infusion. Of these 128 patients, 18 developed at least one new or worsened neuromotor symptom after treatment. Symptoms studied include palsy, tremor, rigidity, bradykinesia, Parkinsonism, and neuropathy. Descriptive analysis was performed on these 18 patients; Kaplan-Meier models for overall survival rate and relapse-free survival were calculated. Results: The incidence of NINTs was 14% of patients (18) and include 14 (78%) cilta-cel patients, and 4 (22%) ide-cel patients with a combined median age of 63 (range of 58-72) years old. Most of the patients were males (n=12, 67%) and Caucasian (n=16, 89%). Most patients did not have extramedullary disease (n=15, 83%). Disease history prior to treatment included deep vein thrombosis or pulmonary embolism (n=4, 22%), coronary artery disease (n=2, 11%), cerebral vascular accidents (n=2, 11%), chronic kidney disease (n=7, 39%), HFrEF < 50% or HFpEF (n=2, 11%). Most patients (n=13, 72%) had a previous history of an autologous hemopoietic stem cell transplant. The cytokine release syndrome (CRS) maximum grade for most patients was 1 (n=14, 78%). There were no cases of high grade CRS. The most common maximum ICANS was 0 (n=10, 56%). High grade ICANS occurred in 2 patients, grade 3 (n=1, 5.6%), and 4 (n=1, 5.6%). As previously mentioned, post CAR-T Parkinsonism can occur without the presence of ICANS. Post-treatment, 18 patients were found to have at least one of the following new or worsening symptoms: nerve palsy (n=9, 50%), tremor (n=7, 39%), rigidity (n=3, 17%), bradykinesia (n=2, 11%), Parkinsonism (n=3, 17%), and neuropathy (n=4, 22%). Of note, no cases of new or worsening palsy, rigidity, bradykinesia, or Parkinsonism were seen in patients who received ide-cel. The only neurotoxicity observed in the ide-cel group was tremors, one patient additionally had neuropathy. Symptom resolution occurred in most patients (n=11, 61%). Treatment of NINTs consisted of corticosteroids (n=16, 89%), tocilizumab (n=13, 72%), IVIG (n=2, 11%), and anakinra (n=3, 17%) during their treatment course. The median hospital stay was 13 days (range of 10-19 days). Relapse-free survival was determined to be 11 months, 95% CI [11 months, not reached], with 5 patients relapsing since treatment. Overall survival for patients who developed at least one neurotoxicity was 19 months, 95% CI [13 months, not reached], with 6 patients dying since treatment. Conclusions: Since the initial registrational trials for BCMA targeted CAR-T therapy in R/R MM NINTs and in particular Parkinsonism has been noted. While the mechanism of ICANS is well understood, an understanding of the incidence and treatment of NINTs remains far less well known. In our single institution review, 14% of patients that have received ide-cel or cilta-cel developed at least one NINTs after treatment. The incidence and type of NINTs manifestation differed between ide-cel and cilta-cel. Ide-cel was limited to tremors, while cilta-cel had more manifestations of palsy, tremors, rigidity, bradykinesia, and Parkinsonism. Fortunately, for the majority of patients (61%), these side effects were reversible with corticosteroids, tocilizumab, IVIG, and time.