Characterization of atrial fibrillation adverse events reported in ibrutinib randomized controlled registration trials.
Brown JR, Moslehi J, O' Brien S, Ghia P, Hillmen P, Cymbalista F, Shanafelt TD, Fraser G, Rule S, Kipps TJ, Coutre S, Dilhuydy MS, Cramer P, Tedeschi A, Jaeger U, Dreyling M, Byrd JC, Howes A, Todd M, Vermeulen J, James DF, Clow F, Styles L, Valentino R, Wildgust M, Mahler M, Burger JA
Haematologica in press 07/27/2017
The first-in-class Bruton's tyrosine kinase inhibitor ibrutinib has proven clinical benefit in B-cell malignancies; however, atrial fibrillation 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 atrial fibrillation with ibrutinib and its management. Atrial fibrillation incidence was 6.5% (95% CI: 4.8, 8.5) for ibrutinib at 16.6-months (vs. 1.6% [95% CI: 0.8, 2.8] for comparator) and 10.4% (95% CI: 8.4, 12.9) at 36-month follow-up (estimated cumulative incidence: 13.8% [95% CI:11.2,16.8]). Ibrutinib treatment, prior history of atrial fibrillation and age =65 years were independent risk factors for atrial fibrillation. Multiple atrial fibrillation events were more common with ibrutinib (44.9%; comparator, 16.7%) among patients with AF. Most (85.7%) patients with atrial fibrillation 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 atrial fibrillation rate among older non-trial patients with comorbidities is likely underestimated by this dataset, these results suggest that atrial fibrillation among clinical trial patients is generally manageable without ibrutinib discontinuation. (ClinicalTrials.gov number, NCT01578707, NCT01722487, NCT01611090,NCT01646021).Full Text