Impact of pre-existing central nervous system conditions and cognitive impairments on toxicity and outcomes after BCMA-directed CAR-T cell therapy

Abstract

Abstract Background: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are BCMA-directed CAR-T therapies approved for treating relapsed/refractory multiple myeloma (RR-MM). Despite their efficacy, adverse events such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) remain a concern, especially for patients with pre-existing neurologic conditions and neurocognitive impairments who may have a greater risk of toxicity. We evaluated the effects of pre-existing central nervous system (CNS) conditions (PCCs) and neurocognitive impairments (NCI) on efficacy and toxicity. Methods: A retrospective cohort study of RR-MM patients treated with ide-cel or cilta-cel at Moffitt Cancer Center from 2021 to 2024 assessed clinically significant PCCs, which were defined as requiring long-term medication management. Peripheral nervous system conditions, such as neuropathies, were not included. PCCs included neurocognitive disorders, migraines, seizures, cerebrovascular disease, CNS neoplasms, tremors, radiculopathies, trauma, and neurodevelopmental conditions. NCI was evaluated pre-CAR-T using the Color Trails Test (Parts 1 & 2), Repeatable Battery for the Assessment of Neuropsychological Status, Conners CPT-3, and Stroop Test, assessing attention (A), executive function (EF), verbal ability (VA), immediate verbal memory (IVM), visuospatial ability (VSA), delayed memory (DM), and total neuropsychological performance (TNP). Clinically significant NCI was pre-defined as ≥2 SDs below the mean in a domain. Cumulative incidence of CRS and ICANS was compared between patients. Cox proportional hazards modeling assessed the impact of PCCs and NCI on outcomes. Results: Among 176 patients who received ide-cel, the median age at time of CART therapy was 68 (43-88) years, 56% were male, and 31 (18%) had PCCs. Among 17 (10%) patients with NCI in ≥ 1 category, 3 were for A, 6 for EF, 6 for VA, 4 for IVM, 5 for VSA, and 3 for TNP (no patient had an impairment in DM). Five (29%) patients had NCI in ≥2 categories. For patients with vs without PCCs, the incidence of CRS (84% vs 86%, p = 0.77), severe CRS (6% vs 1%, 2/31 vs 2/145, p = 0.23), ICANS (35% vs 21%, p = 0.107), severe ICANS (13% vs 8%, p = 0.26), and mean ICANS duration (3.45 vs 3 days, p = 0.85) were not statistically different. For patients with vs without preexisting NCI, the incidence of CRS (100% vs 84%, p = 0.136), severe CRS (0% vs 2.5%, p = 1.0), ICANS (35% vs 22%, p = 0.24), and severe ICANS (18% vs 8%, 3/17 vs 12/159, p = 0.164) were not statistically different. Patients with PCCs vs patients without, had similar OS and PFS, regardless of whether they had ICANS. Regarding NCI, OS and PFS were also similar between the groups, whether or not they had ICANS. Among 78 patients who received cilta-cel, the median age was 61 (38-79) years, 56% were male, and 7 (9%) had PCCs. Among the 9 (11%) patients with NCI in ≥ 1 category, 2 were for A, 3 for EF, 2 for VA, 5 for IVM, 2 for VSA, 2 for DM, and 2 for TNP. Five patients (56%) had NCI in ≥ 2 categories. The incidence of CRS (71% vs 87%, p = 0.25), severe CRS (0% vs 6%, p = 0.99), ICANS (0% vs 17%, p = 0.587), and severe ICANS (0% vs 8%, p = 0.99) were not statistically different between patients with vs without PCCs. Between patients with vs without NCI, the incidence of CRS (89% vs 86%, p = 1.00), severe CRS (0% vs 6%, p = 1.00), ICANS (22% vs 16%, 2/9 vs 10/69, p = 0.622), severe ICANS (11% vs 7%, 1/9 vs 5/69, p = 0.533), and mean ICANS duration (2.5 (2 patients) vs 5.7 (10 patients) days, p = 0.583) were not statistically different. Patients with PCCs, vs without, had similar OS and PFS, whether or not they had ICANS. Patients with NCI vs without NCI, had similar OS and PFS, regardless of whether they had ICANS. Conclusion: Pre-existing CNS conditions and NCI did not increase the incidence of CRS, severe CRS, ICANS, severe ICANS, or ICANS duration in patients receiving ide-cel or cilta-cel. Neither PCCs nor NCI impacted survival or relapse following BCMA-CAR-T cell therapy. Clinically significant CNS comorbidity and neurocognitive impairment should not preclude a patient from receiving BCMA-CAR-T cell therapy. Future research on pre-CAR-T neurologic prognostic testing is warranted.