Chimeric Antigen Receptor T-Cell Therapy–Associated Cardiomyopathy in Patients With Refractory or Relapsed Non-Hodgkin Lymphoma
Authors: Sarju Ganatra, Robert Redd, Salim S. Hayek, Rohan Parikh, Tariq Azam, Gregory A. Yanik, Lauren Spendley, Sarah Nikiforow, Caron Jacobson, Anju Nohria
Journal: Circulation (2020)

◼ cardiotoxicity ◼ cytokine release syndrome ◼ heart failure ◼ lymphoma, non-Hodgkin ◼ receptors, chimeric antigen ◼ tisagenlecleucel A doptive cell therapy using chimeric antigen receptor (CAR) T cells augments the ability of the patient's immune system to recognize and destroy cancer cells.Genetically modified autologous T-cell agents that target CD-19, tisagenlecleucel and axicabtagene ciloleucel, are currently approved for the treatment of children with B-cell acute lymphocytic leukemia and adults with aggressive B-cell lymphoma.Cytokine release syndrome (CRS) is a frequent adverse effect of CAR T-cell therapy and has been associated with cardiotoxicity. 1 The pathophysiology of CAR T cell-associated cardiac dysfunction is unclear, but potential mechanisms include interleukin-6-mediated myocardial depression during CRS 2 and direct cardiotoxicity attributed to off-target cross-reactivity of T cells against titin. 3In this study, we examined the incidence and impact of CAR T-cell therapy-associated cardiomyopathy.This retrospective cohort study included all patients who received CAR T-cell therapy for refractory or relapsed, aggressive non-Hodgkin lymphoma at the Dana Farber Cancer Institute, in Boston, Massachusetts, and at the University of Michigan, Ann Arbor, Michigan, between February 2016 and April 2019.The respective institutional review boards approved this study and waived the requirement for informed consent.All patients underwent baseline echocardiography to assess left ventricular ejection fraction (LVEF).Institutional protocols recommended follow-up echocardiograms in patients with high-grade CRS (grade ≥2 at Dana Farber Cancer Institute and grade ≥3 at University of Michigan). 4Other patients had follow-up echocardiograms at the discretion of the treating physicians.LVEF was assessed with 2-dimensional echocardiography using the Simpson biplane method.New or worsening cardiomyopathy was defined as a reduction in LVEF >10% from baseline to <50% during the index hospitalization. 5In patients with new or worsening cardiomyopathy, postdischarge LVEF was obtained from echocardiograms performed within 3 to 6 months at Dana Farber Cancer Institute or University of Michigan, or through communication with referring physicians.Baseline characteristics and inhospital complications were obtained from review of the electronic medical record and were compared in patients with and without serial echocardiograms and in those with and without CAR T-cell-associated cardiomyopathy.Characteristics and outcomes of the study cohort are shown in the Table .The study included 187 patients: median age, 63 (range, 19-80) years, 39% female, and 91% White.The majority had diffuse large B-cell lymphoma (73%), and 97% were treated with axicabtagene ciloleucel.A total of 155 patients (83%) experienced CRS, with almost half sustaining grade ≥2 CRS.Patients with diabetes (odds ratio, 3.7 [95% CI, 1.22-11.28],P=0.02) and grade ≥2 CRS (odds ratio, 3.03 [95% CI, 1.62-5.69],P<0.001) were more likely to get serial echocardiograms.Other baseline cardiovascular risk factors and LVEF did not differ between patients with and without serial echocardiograms.