Impact of pre-existing psychiatric conditions on toxicity and outcomes of patients after BCMA-directed CAR-T cell therapy

Abstract Background: Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) are BCMA-directed CAR-T cell 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 in patients with pre-existing psychiatric conditions given psychotropic medications may confound the Immune Effector Cell-Associated Encephalopathy (ICE) score. This study evaluates the impact of pre-existing psychiatric conditions (PPCs) on the efficacy and incidence of CRS and ICANS. Methods: A retrospective cohort study of RR-MM patients treated with ide-cel and cilta-cel at Moffitt Cancer Center between 2021 and 2024 was conducted to identify patients with clinically significant PPCs that required long-term medication management. PPCs included major depression disorder, generalized anxiety disorders, bipolar disorder, insomnia, ADHD, and PTSD. In addition, Generalized Anxiety Disorder 7-item scale (GAD-7) and Patient Health Questionnaire-9 (PHQ9) scores were calculated as part of a routine pre-CAR-T psychiatric evaluation and were considered clinically significant if scores were ≥10. The cumulative incidence of CRS and ICANS were calculated for patients with and without PPCs and clinically significant GAD7 and PHQ9 scores. Cox proportional hazards modeling was used to study the effects of PPCs, GAD7 and PHQ9 scores on overall survival (OS) and progression free survival (PFS). Results: Among the 176 patients who received ide-cel, the median age was 68 (43-88) years, 56% were male, and 40 (23%) had PPCs. Six (3%) patients had GAD scores ≥10 and 15 (9%) patients had PHQ scores ≥10. For patients with PPCs vs without, the incidence of CRS (88% vs 85%, p = 1), severe CRS (5% vs 1.5%, p = 0.223), ICANS (30% vs 22%, p = 0.229), severe ICANS (8% vs 9%, p = 1), and mean duration of ICANS (3.4 vs 3 days, p = 0.795) were not statistically different. The incidence of CRS (67% vs 87%, p = 0.20), severe CRS (0% vs 2%, p = 1), ICANS (33% vs 24%, p = 0.63), severe ICANS (0% vs 9%, p = 1), and mean duration of ICANS (2 vs 3.2 days, p = 0.43) were similar between patients with GAD ≥10 vs GAD ≤9. The incidence of CRS (87% vs 86%, p = 1), severe ICANS (20% vs 7.5%, p = 0.142), and mean duration of ICANS (3.2 vs 3.1 days, p = 0.137) were similar but severe CRS (13% vs 1%, p = 0.0369), and any ICANS (53% vs 21%, p = 0.0096) were higher in patients with PHQ9 ≥10 vs PHQ9 ≤9. Patients with PPCs vs without, had similar OS and PFS, regardless of whether or not they had ICANS. Patients with GAD ≥10 vs without, had similar OS and PFS. Patients with PHQ ≥10 vs without, had similar OS and PFS. Among the 78 patients who received cilta-cel, the median age was 61 (38-79) years, 56% were male, and 13 (17%) had PPCs. Eight (10%) patients were considered to have major depression according to their PHQ9 scores ≥10 and no patients had major anxiety per GAD. For patients with vs without PPCs, the incidence of CRS (85% vs 86%, p = 1), severe CRS (0% vs 6%, p = 1), ICANS (23% vs 14%, p = 0.41), and severe ICANS (15% vs 6%, 2/13 vs 4/65, p = 0.26) were not statistically different. Between patients with PHQ9 ≥10 vs PHQ9 ≤9, the incidence of CRS (88% vs 86%, p = 1), severe CRS (0% vs 6%, p = 1), ICANS (25% vs 14%, 2/8 vs 10/70, p = 0.608), and severe ICANS (13 vs 7%, 1/8 vs 5/70, p = 0.49), were not statistically different, although mean duration of ICANS (8.5 (2 patients) vs 2.9 (9 patients) days, p = 0.070) was numerically higher. Patients with PPCs vs without, had similar OS and PFS, regardless of whether or not they had ICANS. Patients with PHQ9 ≥10 vs without, had similar OS and PFS. Conclusion: PPCs and clinically significant GAD scores do not seem to impact CRS, severe CRS, ICANS, severe ICANS, mean duration of ICANS, OS or PFS. For ide-cel, clinically significant PHQ scores may increase the risk of severe CRS and ICANS. Future research on the development of toxicity among patients with clinically significant depression is warranted.