Ibrutinib is a Bruton tyrosine kinase inhibitor approved by the US Food and Drug Administration for the treatment of refractory mantle cell lymphoma (MCL). It has shown promising results in MCL,[1] chronic lymphocytic leukemia,[2–5] and Waldenstrom macroglobulinemia.[6] However, the observed high incidence of atrial fibrillation (AF) creates a challenging dilemma in balancing the intended oncologic on-target effects and the unintended cardiac off-tissue effects. AF was recognized as an off-tissue complication in up to 11% of patients receiving ibrutinib.[1, 2, 4–8] Its management is complicated by the fact that ibrutinib is associated with increased bleeding risks. Most trials excluded patients on anticoagulation at initial enrollment. Our aim was to report the incidence, management, and cardiovascular outcomes of new-onset AF related to ibrutinib therapy. In this study, we reviewed the records of patients with relapsed MCL treated with ibrutinib. Patients included in this study were enrolled in a clinical trial of ibrutinib alone or ibrutinib plus rituximab for relapsed MCL at MD Anderson Cancer Center from 2011 to 2013. Patient eligibility criteria has been previously published.[9] Of the 105 consecutive patients identified, 55 received ibrutinib alone and 50 received ibrutinib plus rituximab. Patients who had a history of AF prior to ibrutinib treatment were excluded. A total of 91 patients were included in the final analysis and all patients gave written informed consent. The development of AF was confirmed by a cardiologist and documented in the patients’ medical records. Oncologic and cardiovascular baseline characteristics were compared between patients who developed AF and those who did not. Oncologic outcomes included ibrutinib suspension, discontinuation or dose reduction. Cardiovascular outcomes included bleeding of grade III or higher, transient ischemic attacks (TIA)/cerebrovascular events, and changes made in cardiac management, including electrical/chemical cardioversion, initiation of rate control and antiarrhythmic medication, and anticoagulation treatment. The time to development of AF was calculated from the start date of the ibrutinib protocol treatment. The cumulative incidence of AF was calculated by competing-risks regression,[10] with death without the development of AF considered a competing event. Patient characteristics and the association with AF was evaluated using competing-risk regression analysis. All analyses were performed using STATA version 13.1 software (StataCorp LP, College Station, TX), with the significance level set at p¼0. 05.

The clinical characteristics and univariate analysis of the risk factors for AF are listed in Table 1. Over a median follow-up time of 16.8 months, nine patients developed AF. All were men> 60 years (median age, 72 years; range, 67–82 years). The median time to developing AF was 4.8 months (range 1.6–21.5 months). The 6-month, 1-year, and 2-year cumulative incidences of AF were 5.6%(95% confidence interval [CI]: 2.1–11.7%), 7.2%(95% CI: 2.9–14.1%), and 14.2%(95% CI: 6.4–25.1%), respectively [Figure 1]. A history of diabetes was significantly associated with a higher risk of developing AF (hazard ratio [HR]: 4.96, 95% CI: 1.38–17.8). No difference was seen in the incidence of AF between those patients treated with or without rituximab (p¼0. 78). The cardiovascular and oncologic treatment of the patients who developed AF is summarized in Figure 1. Ibrutinib was discontinued in two patients. Temporary suspension or dose reduction of ibrutinib was observed in four patients. Of those, two received low-molecular weight heparin while three received aspirin. One patient who had …