Cardiovascular Risk Associated With Ibrutinib Use in Chronic Lymphocytic Leukemia: A Population-Based Cohort Study

Abstract

PURPOSE Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous system ischemic events. The magnitude of these risks remains poorly quantified. METHODS Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate. RESULTS We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI. CONCLUSION Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke.

Chronic lymphocytic leukemia: 2022 update on diagnostic and therapeutic procedures

“…The occurrence of AF, which occurs typically in elderly patients with CLL regularly necessitates therapeutic anticoagulation, which potentially increases the risk of bleeding events. This cardiac toxicity does not seem to be associated with AF‐associated thromboembolism or acute myocardial infarction 123 …”

“…This cardiac toxicity does not seem to be associated with AF-associated thromboembolism or acute myocardial infarction. 123 Acalabrutinib. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor when compared to ibrutinib.…”

BTK Inhibitors and CAR T-Cell Therapy in Treating Mantle Cell Lymphoma—Finding a Dancing Partner

“…Bleeding events are associated with ibrutinib, with up to 5% being cases of major hemorrhage [ 30 ], and may be attributed to dysfunctional glycoprotein VI signaling and repressed collagen-mediated platelet aggregation, likely stemming from inhibition of BTK and other TEC family kinases [ 5 , 34 ]. Patients receiving ibrutinib have an increased risk for atrial fibrillation, heart failure, ventricular arrhythmias, and supraventricular arrhythmias [ 35 , 36 ]. In patients receiving ibrutinib, inhibition of off-target kinases and PI3K/AKT signaling pathways essential for the maintenance of cardiomyocytes may contribute to the development of heart failure [ 36 ].…”

“…In patients receiving ibrutinib, inhibition of off-target kinases and PI3K/AKT signaling pathways essential for the maintenance of cardiomyocytes may contribute to the development of heart failure [ 36 ]. Evidence suggests that atrial fibrillation may be due to ibrutinib-induced cardiac fibrosis, atrial enlargement, and dysregulation of calcium flux and repolarization [ 35 ]. Diarrhea and dermatologic AEs are observed with ibrutinib and acalabrutinib [ 37 , 38 ] and may stem from an inhibitory effect on EGFR [ 5 , 38 ].…”

Zanubrutinib for the Treatment of B-cell Malignancies

“…20,24 The BTK-TEC pathway mediates platelet function, and ibrutinib use was shown to be associated with an increased risk of bleeding, especially in older patients and in those receiving antithrombotic treatment. 22,[25][26][27] Gastrointestinal and skin toxicities associated with ibrutinib therapy may be the result of the offtarget inhibition of EGFR signalling. [28][29][30][31] Ibrutinib intolerance and disease progression are the main factors dictating treatment discontinuation.…”