CAR T Cell Therapy-Related Cardiovascular Outcomes and Management: Systemic Disease or Direct Cardiotoxicity?

Abstract

CD19-specific chimeric antigen receptor (CAR) T cell therapies have shown remarkable early success in highly refractory and relapsing hematological malignancies. However, this potent therapy is accompanied by significant toxicity. Cytokine release syndrome and neurotoxicity are the most widely reported, but the true extent and characteristics of cardiovascular toxicity remain poorly understood. Thus far, adverse cardiovascular effects observed include sinus tachycardia and other arrhythmias, left ventricular systolic dysfunction, profound hypotension, and shock requiring inotropic support. The literature regarding cardiovascular toxicities remains sparse; prospective studies are needed to define the cardiac safety of CAR T cell therapies to optimally harness their potential. This review summarizes the current understanding of the potential cardiovascular toxicities of CD19-specific CAR T cell therapies, outlines a proposed cardiac surveillance protocol for patients receiving this new treatment, and provides a roadmap of the future direction of cardio-oncology research in this area.

Keywords: ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CI, confidence interval; CMR, cardiac magnetic resonance imaging; CR, complete response; CRS, cytokine release syndrome; IL, interleukin; LVSD, left ventricular systolic dysfunction; TTE, transthoracic echocardiography; cardiomyopathy; cytokine release syndrome; immunotherapy; leukemia; lymphoma.

© 2020 The Authors.

Figures

Graphical abstract

Figure 1

Manufacturing CAR T Cell Therapy Autologous T cells are collected from the patient. A chimeric receptor antibody (CAR) that recognizes CD19 is inserted into the cell surface using lentiviral or retroviral vectors. The CAR T cells undergo ex vivo rapid multiplication to generate therapeutic quantities. The patient undergoes lymphodepleting chemotherapy (usually a combination of fludarabine and cyclophosphamide) before receiving an infusion of the CAR T cells to reduce the native population of T cells, which in turn promotes CAR T-cell expansion.

Figure 2

CAR T Cell Toxicities Significant multiorgan toxicities can be associated with chimeric receptor antibody (CAR) T-cell therapy.

Figure 3

Management of CRS Low-grade cytokine release syndrome (CRS) can be managed with supportive care alone. Tocilizumab, an interleukin (IL)-6 receptor blocker, is considered as a first line of treatment in patients with grade 2 or higher CRS. When this approach is ineffective, a dose of corticosteroids is the second-line treatment. ASTCT = American Society for Transplantation and Cellular Therapy.

Central Illustration

A Single Institution Proposed Cardiac Screening and Monitoring in Patients Undergoing Chimeric Antigen Receptor T Cell Therapy Patient journey through cardio-oncology screening and monitoring as part of the chimeric receptor antibody (CAR) T cell therapy program at the University College of London Hospital. CMR = cardiac magnetic resonance; ECG = electrocardiography; NT-proBNP = N-terminal pro–B-type natriuretic peptide; TnT = troponin T; TTE = transthoracic echocardiography.