CLL-354: Pooled Analysis of Cardiovascular Events from Clinical Trials Evaluating Acalabrutinib Monotherapy in Patients with Chronic Lymphocytic Leukemia (CLL)

Abstract

Context: Bruton tyrosine kinase (BTK) inhibitors are effective treatments for B-cell malignancies, but an increased incidence of cardiovascular (CV) toxicities has been observed with ibrutinib. Acalabrutinib is a next-generation, highly selective BTK inhibitor approved for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma and mantle cell lymphoma. Objective: To characterize CV adverse events (AEs). Patients: Patients with CLL who received acalabrutinib monotherapy. Design: Pooled data from patients with CLL in 4 studies (NCT02029443; NCT02475681; NCT02970318; NCT02337829). Interventions: Acalabrutinib was given orally at total daily doses of 100 mg to 400 mg, later switched to 100 mg twice daily, and continued until disease progression (PD) or toxicity. Main Outcome Measures: Cardiac AEs and hypertension were examined. Results: Seven hundred sixty-two patients were included (median age: 67 years [range: 32–89]; median follow-up: 25.9 months [range: 0–58.5]). A total of 199 cardiac AEs of any grade (irrespective of treatment relationship) were reported in 129 patients (17%). Cardiac AEs led to treatment discontinuation in 7 patients (0.9%). The most frequent cardiac AEs reported in ≥2% of patients were atrial fibrillation (afib: n=34; 4%; afib/flutter: n=38; 5%), palpitations (n=23; 3%), and tachycardia (n=17; 2%). Overall, 91% (117/129) of patients with cardiac AEs had ≥1 CV risk factor before acalabrutinib initiation. Hypertension AEs were reported in 9% (67/762) of patients, among whom 46 (69%) had pre-existing hypertension and 18 (27%) had hypertension risk factors. Thirty-seven patients (5%) had 51 grade ≥3 cardiac AEs (grade 3: n=37; grade 4: n=12; grade 5: n=2). Grade ≥3 cardiac AEs of interest included afib (n=10; 1.3%), complete atrioventricular block (n=2; 0.3%), acute coronary syndrome (n=1; 0.1%), atrial flutter (n=1; 0.1%), second degree atrioventricular block (n=1; 0.1%), and ventricular fibrillation (n=1; 0.1%). Two patients experienced grade 5 AEs (cardiac failure congestive [n=1], acute myocardial infarction [n=1]). Most grade ≥3 events (43/51 [84%]) resolved (dose delay: n=15; drug withdrawal: n=4; no dose change: n=24). Conclusions: These data suggest a low risk of cardiac AEs with acalabrutinib treatment in patients with CLL. The safety of acalabrutinib versus ibrutinib in patients with high-risk CLL is being investigated in the phase 3, randomized ACE-CL-006 trial (NCT02477696). Bruton tyrosine kinase (BTK) inhibitors are effective treatments for B-cell malignancies, but an increased incidence of cardiovascular (CV) toxicities has been observed with ibrutinib. Acalabrutinib is a next-generation, highly selective BTK inhibitor approved for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma and mantle cell lymphoma. To characterize CV adverse events (AEs). Patients with CLL who received acalabrutinib monotherapy. Pooled data from patients with CLL in 4 studies (NCT02029443; NCT02475681; NCT02970318; NCT02337829). Acalabrutinib was given orally at total daily doses of 100 mg to 400 mg, later switched to 100 mg twice daily, and continued until disease progression (PD) or toxicity. Cardiac AEs and hypertension were examined. Seven hundred sixty-two patients were included (median age: 67 years [range: 32–89]; median follow-up: 25.9 months [range: 0–58.5]). A total of 199 cardiac AEs of any grade (irrespective of treatment relationship) were reported in 129 patients (17%). Cardiac AEs led to treatment discontinuation in 7 patients (0.9%). The most frequent cardiac AEs reported in ≥2% of patients were atrial fibrillation (afib: n=34; 4%; afib/flutter: n=38; 5%), palpitations (n=23; 3%), and tachycardia (n=17; 2%). Overall, 91% (117/129) of patients with cardiac AEs had ≥1 CV risk factor before acalabrutinib initiation. Hypertension AEs were reported in 9% (67/762) of patients, among whom 46 (69%) had pre-existing hypertension and 18 (27%) had hypertension risk factors. Thirty-seven patients (5%) had 51 grade ≥3 cardiac AEs (grade 3: n=37; grade 4: n=12; grade 5: n=2). Grade ≥3 cardiac AEs of interest included afib (n=10; 1.3%), complete atrioventricular block (n=2; 0.3%), acute coronary syndrome (n=1; 0.1%), atrial flutter (n=1; 0.1%), second degree atrioventricular block (n=1; 0.1%), and ventricular fibrillation (n=1; 0.1%). Two patients experienced grade 5 AEs (cardiac failure congestive [n=1], acute myocardial infarction [n=1]). Most grade ≥3 events (43/51 [84%]) resolved (dose delay: n=15; drug withdrawal: n=4; no dose change: n=24). These data suggest a low risk of cardiac AEs with acalabrutinib treatment in patients with CLL. The safety of acalabrutinib versus ibrutinib in patients with high-risk CLL is being investigated in the phase 3, randomized ACE-CL-006 trial (NCT02477696).