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. 2017 Oct;102(10):1796-1805.
doi: 10.3324/haematol.2017.171041. Epub 2017 Jul 27.

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

Jennifer R Brown  1 , Javid Moslehi  2 , Susan O'Brien  3 , Paolo Ghia  4 , Peter Hillmen  5 , Florence Cymbalista  6 , Tait D Shanafelt  7 , Graeme Fraser  8 , Simon Rule  9 , Thomas J Kipps  10 , Steven Coutre  11 , Marie-Sarah Dilhuydy  12 , Paula Cramer  13 , Alessandra Tedeschi  14 , Ulrich Jaeger  15 , Martin Dreyling  16 , John C Byrd  17 , Angela Howes  18 , Michael Todd  19 , Jessica Vermeulen  20 , Danelle F James  21 , Fong Clow  21 , Lori Styles  21 , Rudy Valentino  21 , Mark Wildgust  19 , Michelle Mahler  19 , Jan A Burger  22
Affiliations

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

Jennifer R Brown et al. Haematologica. 2017 Oct.

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.

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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).
See this image and copyright information in PMC

References

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MeSH terms

Associated data