Predictors, incidence, and clinical implications of arrhythmia following CAR-T therapy: a competing-risk analysis

Background

Arrhythmias are the most common cardiovascular complication following chimeric antigen receptor T-cell (CAR-T) therapy, contributing to acute morbidity in the post transfusion period. Baseline patient characteristics and echocardiographic (ECHO) parameters have been previously evaluated as predictors of major adverse cardiovascular events at large, but their utility in predicting arrhythmia remains poorly characterized.

Purpose

Identify baseline patient characteristics and ECHO parameters that are associated with development of arrhythmia following CAR-T infusion, and characterize the timing, subtype distribution, and clinical implications of arrhythmic events.

Methods

We conducted a retrospective cohort study of 321 patients treated with CAR-T therapy for B cell malignancy. The primary endpoint was new or worsening arrhythmia, the secondary endpoint was de novo arrhythmia, and tertiary endpoints were length of stay, ICU admission and 30-day mortality. Statistical analyses included cause specific cox regression and cumulative incidence (Aelen-Johansen) accounting for competing risk of death.

Results

New or worsening arrhythmia occurred in 29 patients over a median follow up of 11 months. Median age at event was 67 (50,70), 25 (86%) were male, and atrial fibrillation was the predominant subtype (n=23). 15- and 30-day cumulative incidence was 5.9% (95% CI 3.7%-8.9%) and 6.5% (95% CI 4.2-9.6). On univariable analysis, prior arrhythmia (HR 6.5; 95% CI 3.1-13.4, p<0.001), diabetes (HR 2.6; 95% CI 1.2-5.8, p=0.015), BMI > 30 (HR 2.4; 95% CI 1.2-4.93, p=0.02), and high grade CRS (>2) (HR 2.5; 95% CI 1.2-5.4, p=0.01) were associated with increased risk while female sex was protective (HR 0.32; 95% CI 0.1-0.9, p=0.03) (Table 1). Obesity and diabetes together demonstrated even higher risk (HR 4.5; 95% CI 1.5-13.2, p=0.006). No baseline ECHO parameters were found to be predictive, when adjusted for prior arrhythmia.

In patients with de novo arrhythmia (n=15), RVSP (HR 1.37 per 5 mmHg; CI 1.04-1.8, p=0.02) and E/e' lateral (HR 1.5; 95% CI 1.01-2.2, p=0.04) were predictive when adjusted for age and sex (Table 1, Figure 1). BMI remained predictive within this cohort.

Clinical implications of arrhythmic events included increased length of stay (16 vs 11 days, p=0.003), ICU admission (48% vs 18%, p<0.001), and 30-day mortality (10.3 vs 2.1%, p=0.03). All-cause mortality occurred in 48% of the full cohort.

Conclusion

In patients treated with CAR-T therapy, obesity, diabetes, and prior arrhythmia were predictive of new or worsening arrhythmia, while RVSP and diastolic function appear predictive of de novo arrhythmia. These findings suggest metabolic dysfunction, and cardiac filling pressures may play a mechanistic role in arrhythmogenesis. The significant morbidity associated with these events demonstrates a need for risk stratification, and prospective studies aimed at mitigating their development should be explored.Table 1:Cause Specific Cox RegressionFigure 1:Cubic Spline ECHO Parameters