Assessment of Major Adverse Cardiac Events (MACE) and Arrhythmias in Patients with Large B-Cell Lymphoma Undergoing Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Impact of Baseline Cardiac Biomarkers

Introduction: Chimeric antigen receptor - T Cell (CAR-T) therapy is widely used for relapsed or refractory (r/r) large B-cell lymphoma (LBL), now with approval for second-line use. Cytokine release syndrome (CRS) is commonly seen after CAR-T therapy and can lead to increased cardiovascular circulatory demand. Additionally, the pro-inflammatory milieu from CAR-T cells can lead to coagulopathy, endothelial damage, and myocardial stunning which may lead to major adverse cardiac events (MACE) and/or cardiac arrhythmias. Recent single center and pharmacovigilance studies have reported increased risk of MACE as well as cardiac arrhythmias after CAR-T cell therapy (Steiner, et al and Goldman, et al), but there are no data describing the predictive value of high sensitivity troponin and NT-proBNP as biomarkers of adverse cardiovascular outcomes after CAR-T therapy.

Methods: Data were collected through retrospective chart analysis from a patient registry of 71 r/r LBL patients who received commercial anti-CD19 CAR-T therapy at Cleveland Clinic from May 2018 to October 2020. Baseline serum high sensitivity-troponin and NT-proBNP were collected on the day of but prior to treatment (i.e. day 0). Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction by 10% or occurrence of arrhythmia. MACE was defined as cardiovascular death, myocardial infarction, coronary revascularization, stroke, or hospitalization because of heart failure. Univariate and multivariate logistic analyses were performed to determine the impact of baseline clinical and laboratory parameters on the risk for developing MACE as well as cardiac arrhythmia.

Results: Median age was 63 years [interquartile range (IQR): 54 to 69 years]. 68% were male. Full details of baseline characteristics are shown in the attached table. Baseline troponin was elevated above laboratory reference range in 82% of patients and baseline NT-proBNP was elevated in 58% of patients. Median follow up was 326 days from cellular infusion. Three of 71 patients (4%) developed MACE and 11 (15%) developed atrial/ventricular arrhythmias. Baseline troponin was elevated in two of the patients who developed MACE and baseline NT-proBNP was elevated in all three patients who developed MACE. All three occurrences of MACE were within 45 days of CAR-T infusion. In univariate analysis, baseline troponin was associated with a statistically significant increased risk of developing atrial arrhythmia after treatment but other known risk factors such as hypertension, obesity, and congestive heart failure were not. In multivariable analysis, baseline troponin was associated with an increased risk of developing atrial arrhythmia [OR 1.07, 95% CI (1.004-1.145), p=0.039].

Conclusions: In contrast to previous reports, we found a low rate of MACE in our patient population, possibly due to patient selection. However, 15.4% of patients developed atrial fibrillation, consistent with prior reports of elevated risk of arrhythmias. Baseline elevation in troponin was associated with an increased risk of subsequent atrial arrhythmia. Further data are needed to explore the predictive value of baseline NT-proBNP in predicting MACE. As CAR-T cell therapy is likely to increasingly take place in the outpatient setting, future prospective and validation studies may explore the use of baseline troponin to risk stratify patients.

References: Lefebvre, B. et al (2020). Cardiovascular effects of CAR T cell therapy: a retrospective study. Cardio Oncology, 2(2), 193-203.

Patel, N. P. et al (2021). Cardiovascular Toxicities of CAR T-cell Therapy. Current oncology reports, 23(7), 1-10.

Steiner, R. E. et al (2022). Cardiovascular events in patients treated with chimeric antigen receptor T-cell therapy for aggressive B-cell lymphoma. Haematologica, 107(7), 1555-1566. https://doi.org/10.3324/haematol.2021.280009

Goldman, A. et al (2021). Adverse Cardiovascular and Pulmonary Events Associated With Chimeric Antigen Receptor T-Cell Therapy. Journal of the American College of Cardiology, 78(18), 1800-1813. https://doi.org/10.1016/j.jacc.2021.08.044

Shalabi, H. et al (2020). Impact of cytokine release syndrome on cardiac function following CD19 CAR-T cell therapy in children and young adults with hematological malignancies. Journal for immunotherapy of cancer, 8(2).

Winter:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seagen, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; OncLive: Honoraria. Jagadeesh:Regeneron Pharmaceuticals, Inc.: Research Funding; LOXO Pharmaceuticals: Research Funding; Debio pharma: Research Funding; Affimed: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; ATARA Biotherapeutics: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Seagen: Research Funding; Trillium Pharmaceuticals: Research Funding. Anwer:Janssen: Consultancy; Allogene Therapeutics: Research Funding; BMS: Consultancy, Research Funding, Speakers Bureau. Hamilton:Incyte: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees. Caimi:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sauter:Genzyme/Sanofi: Other: PI; CSL Behring: Consultancy; Ono Pharmaceuticals: Consultancy; Karyopharm Therapeutics Inc.: Consultancy; Kite Pharma Inc.: Consultancy; Gamida Cell: Consultancy; BMS: Other: PI; Precision Biosciences: Other: PI. Hill:Novartis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Research Funding.