What is the clinical evidence from this study?

Study design: Observational. Population: B-cell lymphoma (n=90). Intervention: CAR-T therapy vs. Patients without adverse cardiac events. Primary outcome: Day 5 B-type natriuretic peptide (BNP) levels (pg/mL) (p=0.019).

April 1, 2023Open Access

Cardiac and inflammatory biomarker differences in adverse cardiac events after chimeric antigen receptor T-Cell therapy: an exploratory study

Key Result

CAR-T therapy resulted in adverse cardiac events in 12.2% of patients, which were associated with significantly higher day 5 BNP levels and peak inflammatory cytokines including IL-6, IFN-γ, and IL-15.

Study Design

Type

Observational (n=90)

Multicenter

Structured PICO

Are adverse cardiac events after CAR-T therapy associated with differences in cardiac and inflammatory biomarkers in patients with hematological malignancies?

Population

90 consecutive patients with B-cell lymphoma (diffuse large B cell lymphoma, mantle cell lymphoma, follicular lymphoma, and B-Cell acute lymphoblastic leukemia) treated with CAR-T therapy, median age 68 years, 61.1% male, at a single US center.

Intervention

Chimeric antigen receptor T-Cell (CAR-T) therapy (axicabtagene ciloleucel, tisagenlecleucel, brexucabtagene autoleucel, or lisocabtagene maraleucel)

Comparator

Patients who did not develop adverse cardiac events after CAR-T therapy (observational comparison)

Outcome

Adverse cardiac events (composite of new-onset cardiomyopathy/heart failure, acute coronary syndrome, arrhythmia, and cardiovascular death) monitored during index hospitalization and up to 12 monthscomposite

Adverse cardiac events, primarily atrial fibrillation, occur in approximately 12% of patients receiving CAR-T therapy and are associated with elevated pro-inflammatory cytokines and BNP, though these biomarkers did not independently predict events.

Main Result

Absolute Event Rate: 125% vs 63%

p-value: p=0.019

Limitations

Retrospective review of cardiac events and method of detecting arrhythmia via abnormal heart rate or symptoms may underestimate the incidence of atrial fibrillation.
Lack of daily measurements of cardiac biomarkers could have missed pre-clinical cardiac injury.
Small sample size and lower incidence of adverse cardiac events did not allow for multivariate analysis.

Abstract

BACKGROUND: Chimeric antigen receptor T- Cell (CAR-T) immunotherapy has been a breakthrough treatment for various hematological malignancies. However, cardiotoxicities such as new-onset heart failure, arrhythmia, acute coronary syndrome and cardiovascular death occur in 10-15% of patients treated with CAR-T. This study aims to investigate the changes in cardiac and inflammatory biomarkers in CAR-T therapy to determine the role of pro-inflammatory cytokines. METHODS: In this observational study, ninety consecutive patients treated with CAR-T underwent baseline cardiac investigation with electrocardiogram (ECG), transthoracic echocardiogram (TTE), troponin-I, and B-type natriuretic peptide (BNP). Follow-up ECG, troponin-I and BNP were obtained five days post- CAR-T. In a subset of patients (N = 53), serum inflammatory cytokines interleukin (IL)-2, IL-6, IL-15, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and angiopoietin 1 p = 0.042). Day 5 BNP levels (125 vs. 63pg/mL; p = 0.019), but not troponin-I, were higher in patients with adverse cardiac events, compared to those without. The maximum levels of IL-6 (3855.0 vs. 254.0 pg/mL; p = 0.021), IFN-γ (474.0 vs. 48.8pg/mL; p = 0.006) and IL-15 (70.2 vs. 39.2pg/mL; p = 0.026) were also higher in the adverse cardiac events group. However, cardiac and inflammatory biomarker levels were not associated with cardiac events. Patients who developed cardiac events did not exhibit worse survival compared to patients without cardiac events (Log-rank p = 0.200). CONCLUSION: Adverse cardiac events, predominantly atrial fibrillation, occur commonly after CAR-T (12%). The changes in serial inflammatory cytokine after CAR-T in the setting of adverse cardiac events suggests pro-inflammation as a pathophysiology and require further investigation for their role in adverse cardiac events. TWEET BRIEF HANDLE: CAR-T related Cardiotoxicity has elevated cardiac and inflammatory biomarkers. #CARTCell #CardioOnc #CardioImmunology.

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