Cardiotoxicity in Malignant Hematology: A Focus on CAR T-cell Therapy
Treatment-related cardiotoxicity has been increasingly recognized as a challenge in the clinical management of cancer. Frequently used cancer drugs associated with a high risk of cardiotoxicity include anthracyclines, BCR-ABL kinase inhibitors, proteasome inhibitors, and Bruton tyrosine kinase inhibitors (BTKIs).1 Less is known about the potential acute and long-term cardiotoxic effects of chimeric antigen receptor T-cell (CAR-T) therapy, which has emerged as an efficacious treatment for hematologic malignancies. To date, six CAR-T cell therapies have been granted approval by the Food and Drug Administration (FDA) for indications including B-cell acute lymphoblastic leukemia, large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma.
Cytokine release syndrome (CRS), an acute systemic inflammatory syndrome characterized by fever and multiorgan dysfunction, is a major form of toxicity associated with CAR-T, with the reported incidence ranging from 37 to 93%.2 Development of high-grade (grade 3-4) CRS has been associated with major adverse cardiovascular events (MACE).3 The frequency of such events is variably defined, as original trial data often do not include rates of cardiotoxicity independent of CRS. However, retrospective studies have reported MACE in 10 to 20% of cases,4 with a relatively short time to onset of 11 to 21 days.5 Risk factors for MACE include high risk for CRS (high disease burden, high-intensity lymphodepletion, high T-cell dose), underlying cardiac disease, and renal insufficiency.4 Reported MACEs in the setting of CAR-T include arrhythmias, stress cardiomyopathy, pericardial effusion, hypotension, pulmonary edema, ventricular failure, and cardiac arrest.4,6
Several mechanisms have been proposed to underlie the cardiotoxicity associated with CAR-T. The most frequently defined are MACE in the setting of inflammatory cytokine release, including interleukin 6 (IL-6), tumor necrosis factor alpha, and interferon gamma.7 Cytokine surge and activation of a systemic inflammatory response can lead to subsequent capillary leak syndrome and refractory shock. Events related to T-cell receptor (TCR) recognition of epitopes on myocardial cells or TCR activity against a different target (e.g., titin, a cardiac myofilament polypeptide) may also emerge.5 Concomitant effects from the use of lymphodepleting agents prior to CAR-T administration may represent another influential factor.5
Management strategies for cytokine release syndrome and the resultant acute cardiac effects vary depending on the CAR-T product, and the US FDA Risk Evaluation and Mitigation Strategy (REMS) program should be consulted for specific aspects of CRS management for each agent.8 Mild CRS is often managed symptomatically using antihistamines, antipyretics, volume resuscitation, and frequent monitoring. Severe CRS is frequently treated with intravenous tocilizumab, an IL-6 receptor antagonist, with or without glucocorticoid therapy depending on the clinical scenario. Siltuximab, an IL-6-directed monoclonal antibody, and anakinra, an anti-IL-1 receptor antagonist, are two agents under investigation as possible treatments for severe CRS.9
Prior to receiving CAR-T, patients may already be at risk of cardiac complications, as they have often already been exposed to potentially cardiotoxic cancer-directed treatments and are generally of older age with cardiovascular comorbidities. Cardiovascular screening may aid in the management of cardiotoxicity; however, there are currently no evidence-based guidelines available. Expert panels suggest that screening prior to CAR-T infusion include a comprehensive cardiovascular assessment including detailed cardiovascular history, physical examination, screening for cardiovascular risk factors, a baseline 12-lead ECG, and a baseline echocardiogram in patients at higher risk.4
As the approved indications for CAR-T expand, it will be increasingly important for treating physicians to identify and manage toxicities related to CAR-T therapy. Currently, data on the long-term cardiotoxicity of CAR-T are limited, necessitating further investigation. Management will require a multidisciplinary approach, with involvement from cardiologists, critical care specialists, and other subspecialty colleagues to navigate cardiotoxic effects of CAR-T agents.
COI Disclosure: Drs. Snider and Jain indicated no relevant conflicts of interest.
This article was edited by Drs. Emily Liang and Leidy Isenalumhe. Faculty review was performed by Dr. Divya Koura at the University of California San Diego.
References
1. Alexandre J, Cautela J, Ederhy S, et al. Cardiovascular toxicity related to cancer treatment: A pragmatic approach to the American and European Cardio‐Oncology Guidelines. J Am Heart Assoc. 2020;9(18):e018403.
2. Messmer AS, Que YA, Schankin C, et al. CAR T-cell therapy and critical care: A survival guide for medical emergency teams. Wien Klin Wochenschr. 2021;133(23-24):1318–1825.
3. Lefebvre B, Kang Y, Smith AM, et al. Cardiovascular effects of CAR T cell therapy: A retrospective study. JACC CardioOncology. 2020;2(2):193-203.
4. Ganatra S, Carver JR, Hayek SS, et al. Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives. J Am Coll Cardiol. 2019;74(25):3153-3163.
5. Marar RI, Abbasi MA, Prathivadhi-Bhayankaram S, et al. Cardiotoxicities of novel therapies in hematologic malignancies: Chimeric antigen receptor T-cell therapy and bispecific T-cell engager therapy. JCO Oncol Pract. 2023;19(6):331-342.
6. Burns EA, Gentille C, Trachtenberg B, et al. Cardiotoxicity associated with anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy: Recognition, risk factors, and management. Diseases. 2021;9(1):20.
7. Baik AH, Oluwole OO, Johnson DB, et al. Mechanisms of cardiovascular toxicities associated with immunotherapies. Circ Res. 2021;128(11):1780-1801.
8. Food and Drug Administration. Approved Risk Evaluation and Mitigation Strategies (REMS). Accessed January 21, 2024. https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm
9. Yáñez L, Alarcón A, Sánchez-Escamilla M, et al. How I treat adverse effects of CAR-T cell therapy. ESMO Open. 2020;4(suppl4):e000746.
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