Pre-Existing Cardiovascular Disease Increases the Risk of Cardiovascular Adverse Events during Bruton Tyrosine Kinase Inhibitor Therapy
Authors: Fernandez Turizo Maria J. , Kim Eunice , Asnani Aarti , Yankama Tuyen , Von Keudell Gottfried , Mejías-De Jesús Caroline 
Published: December 2023

Background
Bruton tyrosine kinase inhibitors (BTKis) have revolutionized the treatment of B-cell neoplasms. BTKi treatment has been associated with a higher incidence of cardiovascular adverse events (CVAE), which contribute significantly to morbidity and mortality in this population. Ibrutinib has been more strongly associated with CVAE compared to more selective 2 nd-generation BTKis. Although predisposing factors are not clear, pre-existing cardiovascular disease (CVD) appears to increase the risk of atrial arrhythmias and mortality during BTKi treatment. Our primary objective was to evaluate and compare the rate of CVAE during BTKi therapy, in individuals with and without pre-existing CVD. In addition, we aimed to compare the outcomes of patients treated with 1 st vs. 2 nd generation BTKis and characterize management decisions.
Methods
A retrospective review was conducted on patients treated with BTKis for hematologic malignancies from 2013 to 2022 at Beth Israel Deaconess Medical Center. Exclusion criteria included prior treatment with anthracyclines and BTKis, prescription of BTKi therapy without administration, prior BTKi treatment for graft-vs-host disease, and loss to follow-up. CVAE were defined as new-onset or worsening atrial fibrillation (AF), new-onset or worsening hypertension (HTN), supraventricular or ventricular arrhythmias, and sudden cardiac death. Pre-existing CVD included coronary artery disease, congestive heart failure, cerebrovascular disease, and pulmonary HTN. Student's t-test and Fisher's exact test were performed to compare the differences in continuous and categorical variables between patients with and without pre-existing CVD, respectively. Logistic regression analyses were performed to evaluate the association between pre-existing CVD and CVAE. All statistics were performed using R version 4.3.
Results
We identified 274 patients and 180 met inclusion criteria. Primary indications were Chronic Lymphocytic Leukemia (CLL) in 106 patients (60%), Mantle Cell Lymphoma (MCL) in 31 (17.2%), Diffuse Large B-Cell Lymphoma (DLBCL) in 17 (9.4%), and Waldenström Macroglobulinemia (WM) in 16 (8.9%). In terms of BTKi selection, 141 patients (78.3%) received ibrutinib, 35 (19.4%) acalabrutinib, and 4 (2.2%) zanubrutinib. Prevalent comorbidities were HTN in 103 patients (57%), dyslipidemia in 80 (44%), and diabetes in 26 (14%).
Overall, 49 patients (27.2%) had preexisting CVD, and 21 (11.6%) experienced CVAE during BTKi therapy. In our cohort, (11/49) patients with pre-existing CVD developed CVAE, compared to (10/131) patients without pre-existing CVD, (22% vs 8% respectively), OR 3.38 (95%CI = [1.3, 8.5], p-value= 0.01). The OR remained robust ranging from 3.4 to 4.1 (p &lt; 0.05) in multiple adjusted logistic regression models, accounting for imbalances in gender, comorbidities, type of BTKi, and baseline medications.
Patients with pre-existing CVD had significantly higher odds of developing new or worsening AF, (16% vs. 5% respectively), OR = 3.94, (95%CI = [1.3, 12.0], p-value= 0.02) (Table 1). In subgroup analysis, patients treated with 1 st generation BTKis had a numerically higher rate of CVAE than those treated with 2 nd generation BTKis, OR = 6.28 (95%CI = [0.8, 48.3], p-value= 0.08) (Table 2).
Regarding management, BTKi treatment was discontinued in 13 patients (62%) and continued in 8 (38%). Medical interventions were required in 17 patients (80%). In contrast, the event resolved in 4 patients (19%) with only BTKi discontinuation. Following CVAE, 3 patients (14%) were transitioned to a 2 nd generation BTKi with complete resolution.
Conclusions
CVAE remain significant contributors to treatment discontinuation. Patients treated with 1st-generation BTKis and pre-existing CVD had significantly higher odds of developing CVAE. Our study is the first to evaluate the impact of pre-existing CVD on CVAE during treatment with 2nd-generation BTKis. Patients on Ibrutinib developed more CVAE compared to patients on 2nd-generation BTKis, though differences were not statistically significant. This study was limited due to its retrospective and single-centered nature. Results highlight the need for structured approaches to prevent and promptly detect CVAE, particularly in patients with pre-existing CVD.