Cardiotoxic profiles of CAR-T therapy and bispecific T-cell engagers in hematological cancers

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy and bispecific T-cell engagers, which redirect T-cells to tumor antigens, have immensely benefitted patients with relapsed/refractory B-cell cancers. How these therapies differ in cardiotoxicity is underexplored. We used the World Health Organization pharmacovigilance database, VigiBase, to compare cardiotoxicity profiles between CD19-targeted CAR-T therapy and blinatumomab (a CD19/CD3-targeted bispecific T-cell engager).

Methods: Safety reports in VigiBase were filtered for diffuse large B-cell lymphoma (DLBCL, n = 17,479) and acute lymphocytic leukemia (ALL, n = 28,803) for all adverse reactions. Data were further filtered for patients taking CAR-T therapy or blinatumomab. Reporting odds ratios (ROR) and fatality rates were compared between CAR-T cell products (e.g. tisagenlecleucel and axicabtagene ciloleucel), and between CAR-T therapy and blinatumomab.

Results: Tisagenlecleucel is associated with cardiac failure (IC₀₂₅ = 0.366) with fatality rates of 85.7% and 80.0% in DLBCL and pediatric ALL patients respectively. For DLBCL patients, axicabtagene ciloleucel has greater reporting for hypotension than tisagenlecleucel (ROR: 2.54; 95% CI: 1.28-5.03; p = 0.012), but tisagenlecleucel has higher fatality rates for hypotension than axicabtagene ciloleucel [50.0% (tisagenlecleucel) vs 5.6% (axicabtagene ciloleucel); p < 0.001]. Blinatumomab and tisagenlecleucel have similar fatality rates for hypotension in pediatric ALL patients [34.7% (tisagenlecleucel) vs 20.0% (blinatumomab); p = 0.66].

Conclusions: Tisagenlecleucel is associated with severe and fatal adverse cardiac events, with higher fatality rates for hypotension compared to axicabtagene ciloleucel in DLBCL patients, but similar hypotension fatality rates compared to blinatumomab in pediatric ALL patients. Effective management necessitates experienced physicians, including cardio-oncologists, skilled in interdisciplinary approaches to manage these toxicities.

Fig. 1. Flowchart illustrating the filtering of Individual Case Safety Reports (ICSRs).

After obtaining all CAR-T therapy ICSRs from VigiBase, the reports were filtered for tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel for all cardiac, vascular, and investigational adverse reactions. These ICSRs were subsequently filtered by cancer indications consisting of diffuse large B-cell lymphoma (DLBCL), acute lymphocytic leukemia (ALL), and mantle cell lymphoma (MCL).

Fig. 2. Distribution of Individual Case Safety Reports (ICSRs) by report type.

ICSRs for CAR-T therapy were categorized by report type documented in VigiBase for (a) cardiac, (b) investigational, and (c) vascular adverse reactions from 2018 to 2022.

Fig. 3. Comparison of CAR-T Cardiotoxicities for Diffuse Large B-Cell Lymphoma (DLBCL).

Reporting odds ratios were compared for significant adverse reactions between tisagenlecleucel (N = 237 reports) and axicabtagene ciloleucel (N = 42 reports) for DLBCL patients. Significant adverse reactions include atrial fibrillation (n = 8 reports [tisagenlecleucel] and n = 3 reports [axicabtagene ciloleucel]), tachycardia (n = 12 reports [tisagenlecleucel] and n = 3 reports [axicabtagene ciloleucel]), cardiac arrest (n = 1 reports [tisagenlecleucel] and n = 1 reports [axicabtagene ciloleucel]), and hypotension (n = 54 reports [tisagenlecleucel] and n = 18 reports [axicabtagene ciloleucel]). Error bars denote 95% confidence intervals.

Fig. 4. Cardiovascular toxicity comparisons for immunotherapies targeting Acute Lymphocytic Leukemia (ALL).

Reporting odds ratios were compared for significant adverse reactions between tisagenlecleucel (N = 219 reports) and blinatumomab (N = 28 reports) for pediatric ALL patients (aged 17 or younger). Significant adverse reactions include tachycardia (n = 17 reports [tisagenlecleucel] and n = 2 reports [blinatumomab]), sinus tachycardia (n = 5 reports [tisagenlecleucel] and n = 2 reports [blinatumomab]), pericardial effusion (n = 3 reports [tisagenlecleucel] and n = 3 reports [blinatumomab]), and hypotension (n = 72 reports [tisagenlecleucel] and n = 5 reports [blinatumomab]). Error bars denote 95% confidence intervals.