Cardiovascular complications of chimeric antigen receptor (CAR)-T cell therapy

Abstract

Abstract Background Mechanisms of cardiotoxicity during chimeric antigen receptor (CAR)-T cell therapy remain unclear to this day, with the main hypotheses revolving around IL-6 mediated myocardial depression during cytokine release syndrome (CRS), stress-induced or takotsubo cardiomyopathy, and direct toxicity from CAR-T cells. Hereby we present the experience of a regional referral centre for CAR-T therapy and the program developed with a dedicated cardio-oncology centre. Purpose To provide preliminary data on cardiovascular-related toxicity of CAR-T therapy in terms of incidence and management. Methods All consecutive candidates for CAR-T therapy were prospectively enrolled since the inception of the CAR-T program in our institution (2021). All patients were refractory to at least two lines of immune chemotherapy and had already undergone anthracycline treatment. After conditioning, all patients were treated with autologous CAR-T cells (tisagenlecleucel, Kymriah). Prior to CAR-T cell therapy, all patients underwent baseline cardiac evaluation at our cardio-oncology facility, including a 12-lead ECG, a complete echocardiogram and cardiac biomarkers. The same routine was performed before discharge, after one month. Supplementary evaluations were performed by an on-call cardio-oncology team according to the attending physicians. Results Eleven patients (6 males, mean age 60±11 years) underwent CAR-T cell infusion. Over the course of follow-up, six patients (54%) experienced CRS after a median follow-up of 12 days (7-40). Two patients with mild symptoms (Grade I) were managed with non-cardiac-related therapy while three Grade 2 patients had to start cardioprotective drugs (ACE-Is and beta-blockers) for transient left ventricular systolic dysfunction (mean lowest LVEF 44.8±3.7%). One patient experienced a Grade IV CRS due to takotsubo syndrome complicated by cardiogenic shock on day 4 and required high-dose vasopressors and mechanical ventilation. Patients experiencing a CRS had similar demographical characteristics and medical history but standard echocardiogram before CAR-T showed a lower baseline LVEF (54.5±5.6% vs 64.6±6.7%; p=.02) and lower baseline right longitudinal systolic function markers (TAPSE: 19±3 vs. 24±4 mm; p=.02 S': .09±.01 vs .13±.02 m/s; p=.03). Cardiac biomarkers (high-sensitivity Troponin I and NT-proBNP) did not show any significant predictive power at baseline. All CRS patients showed a progressive recovery of ventricular function and survived up to one-year of follow-up. Conclusions CAR-T therapy is associated with an increased risk of cardiotoxicity, with up to 36% of all patients requiring unscheduled cardio-oncology evaluation and management both during admission and after discharge. Cardiac adverse events range in degree of severity and should be promptly managed by a dedicated team.