Rate of Atrial Fibrillation in Patients With B-Cell Malignancies Who Undergo Treatment With Zanubrutinib

Introduction:
Treatment of B-cell malignancies has been improved by effective inhibitors of B-cell receptor signaling, such as the first-generation Bruton tyrosine kinase inhibitor (BTKi), ibrutinib. Although ibrutinib has demonstrated efficacy, it has been associated with an increased risk for cardiovascular toxicities, such as atrial fibrillation (Afib). Zanubrutinib is an irreversible, potent, next-generation BTKi designed to maximize BTK occupancy and minimize off-target inhibition. Zanubrutinib has been generally well tolerated in clinical trials. This abstract reports the occurrence of Afib/flutter in ALPINE (NCT03734016), ASPEN (NCT03053440), and a larger pooled analysis of zanubrutinib trials.
Methods:
This pooled analysis included patients with B-cell malignancies who were enrolled in 10 clinical studies of zanubrutinib, including ALPINE and ASPEN. The ALPINE study and ASPEN Cohort 1 comparing zanubrutinib with ibrutinib in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or Waldenström macroglobulinemia, respectively, were also analyzed separately. Patients were evaluated through a blinded study for exposure-adjusted incidence rate (EAIR) of Afib, which was the pre-specified primary endpoint. To compare EAIR of Afib between zanubrutinib and ibrutinib, the difference of EAIR and the value of the difference based on asymptotic normal distribution were also calculated.
Results:
In the pooled analyses of 10 trials, 1550 patients received zanubrutinib as monotherapy, 938 had CLL/SLL (525 R/R CLL/SLL), and the median age was 67 years, with 61% of patients aged ≥65 years. Most patients were men (66%) and white (67%), with European Cooperative Oncology Group performance status of 0 or 1 (44.5% and 49.4%, respectively). Specifically, among patients enrolled in ALPINE, 5.8% (19/327; zanubrutinib) vs 5.8% (19/325; ibrutinib) had a history of Afib/flutter, whereas 1.9% vs 8.0% experienced a new Afib/flutter event. Among patients in ASPEN (Cohort 1), 10.8% (11/102; zanubrutinib) vs 8.1% (8/99; ibrutinib) had a history of Afib/flutter and 5.9% vs 22.4% experienced a new Afib/flutter event, respectively. The EAIR of Afib/flutter per 100 person-month was lower in both studies for zanubrutinib vs ibrutinib: 1) in ALPINE the EAIR was 0.16 for zanubrutinib and 0.79 for ibrutinib (  = 0.0003); 2) in ASPEN the EAIR was 0.19 for zanubrutinib and 0.86 for ibrutinib (  = 0.001). Afib rates in the pooled analyses were comparable to those observed with zanubrutinib in ALPINE and ASPEN.
Discussion:
Data from this analysis support the use of zanubrutinib as a treatment option for patients with B-cell malignancies, demonstrating reduced risk of Afib/flutter compared with ibrutinib.