Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials

Jennifer R Brown, Javid Moslehi, Susan O'Brien, Paolo Ghia, Peter Hillmen, Florence Cymbalista, Tait D Shanafelt, Graeme Fraser, Simon Rule, Thomas J Kipps, Steven Coutre, Marie-Sarah Dilhuydy, Paula Cramer, Alessandra Tedeschi, Ulrich Jaeger, Martin Dreyling, John C Byrd, Angela Howes, Michael Todd, Jessica Vermeulen, Danelle F James, Fong Clow, Lori Styles, Rudy Valentino, Mark Wildgust, Michelle Mahler, Jan A Burger, Jennifer R Brown, Javid Moslehi, Susan O'Brien, Paolo Ghia, Peter Hillmen, Florence Cymbalista, Tait D Shanafelt, Graeme Fraser, Simon Rule, Thomas J Kipps, Steven Coutre, Marie-Sarah Dilhuydy, Paula Cramer, Alessandra Tedeschi, Ulrich Jaeger, Martin Dreyling, John C Byrd, Angela Howes, Michael Todd, Jessica Vermeulen, Danelle F James, Fong Clow, Lori Styles, Rudy Valentino, Mark Wildgust, Michelle Mahler, Jan A Burger

Abstract

The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation (AF) has been reported in 6-16% of ibrutinib patients. We pooled data from 1505 chronic lymphocytic leukemia and mantle cell lymphoma patients enrolled in four large, randomized, controlled studies to characterize AF with ibrutinib and its management. AF incidence was 6.5% [95% Confidence Interval (CI): 4.8, 8.5] for ibrutinib at 16.6-months versus 1.6% (95%CI: 0.8, 2.8) for comparator and 10.4% (95%CI: 8.4, 12.9) at the 36-month follow up; estimated cumulative incidence: 13.8% (95%CI: 11.2, 16.8). Ibrutinib treatment, prior history of AF and age 65 years or over were independent risk factors for AF. Multiple AF events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with AF did not discontinue ibrutinib, and more than half received common anticoagulant/antiplatelet medications on study. Low-grade bleeds were more frequent with ibrutinib, but serious bleeds were uncommon (ibrutinib, 2.9%; comparator, 2.0%). Although the AF rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that AF among clinical trial patients is generally manageable without ibrutinib discontinuation (clinicaltrials.gov identifier: 01578707, 01722487, 01611090, 01646021).

Trial registration: ClinicalTrials.gov NCT01578707 NCT01722487 NCT01611090 NCT01646021.

Copyright© 2017 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Onset of first atrial fibrillation event by treatment.
Figure 2.
Figure 2.
Cumulative incidence (95% CI) of atrial fibrillation with ibrutinib. (A) unadjusted for competing risks (death and progressive disease) and (B) adjusted. With extended follow up: unadjusted (C) and adjusted (D).
Figure 3.
Figure 3.
Significant factors for development of atrial fibrillation using univariate and multivariate Cox regression. HR: Hazards Ratio; CI: Confidence Interval.
Figure 4.
Figure 4.
Progression-free survival in patients with and without atrial fibrillation (AF).

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