Cardiovascular Toxicity and Clinical Outcomes Following Chimeric Antigen Receptor T-Cell Infusion (CART) for Lymphoid Malignancies

Introduction: CART-cell therapy is associated with dramatic efficacy in patients with relapsed/refractory diffuse large B-cell lymphoma and B-acute lymphoblastic leukemia. However, the efficacy of CART therapy is limited by potentially fatal toxicities including cytokine release syndrome (CRS) and neurotoxicity. Increasingly, emerging reports have suggested the potential for significant hemodynamic collapse following CART therapy. Yet, whether the occurrence of these hemodynamic shifts or any other cardiovascular disease (CVD) events have bearing on clinical outcomes after CART initiation is unknown. Methods: We evaluated all patients treated with CART therapy for lymphoid malignancies at The Ohio State University James Comprehensive Cancer Center between 2016-2019 and assessed the incidence of CVD events and severe hemodynamic collapse [systolic blood pressure (SBP) cutoff of less than 80 mmHg]. We also evaluated the relationship of CVD events, hemodynamic collapse, and the presence of preceding CVD on overall survival (OS) and progression-free-survival (PFS) following infusion of CART cells utilizing univariate log-rank comparison. Results: We evaluated 66 patients with 62% male and 38% female with an average age of 60 years (range 23-80). 49 (74%) patients received Yescarta and 17 (26%) patients received Kymriah. With a median follow-up time of 21 months, OS and PFS at 1 year were 72% and 43%, respectively, in concordance with previously reported ZUMA1 and JULIET survival rates. Overall, from 66 CART-treated patients, 14 (21.2%) developed incident CVD events, including 11 patients with arrhythmias and 2 with CHF. The median decrease in peak systolic blood pressure after infusion was 32 mmHg (IQR 22-47 mmHg), noted at a median of 4 days post-CART. Furthermore, after infusion, 17 (25.8%) saw falls in systolic pressure to < 80 mmHg, with 10 (15.2%) developing hypotension requiring vasopressor support. Three of these patients did not have any recovery of their hypotension and died. For patients who developed a SBP < 80 mmHg, there was a significantly impaired PFS at 30 days, 90 days, and 1 year (85%, 54%, and 0%, respectively) versus those who did not develop SBP < 80 mmHg PFS (100%, 83%, and 49%, respectively), p = 0.014 (figure). OS demonstrated similar results at 30 days, 90 days, and 1 year (85%, 54%, and 14%, respectively), compared to 100%, 83%, and 49.1%, respectively, p = 0.03. There was no difference in PFS or OS, based on the presence of neurotoxicity, steroid use, vasopressor use, preceding cardiovascular risk factors, or the development of other non-hypotension CVD events. Conclusion: The development of significant early hypotension is associated with a marked decrease in survival among patients receiving CART therapy. Further understanding of this finding, and its relation to CRS is urgently needed in order to maximize the effectiveness of this novel anticancer therapy.