Atrial Fibrillation in CLL/SLL Patients on Ibrutinib
Authors: Farooqui Mohammed , Valdez Janet , Soto Susan , Bray Amanda , Tian Xin , Wiestner Adrian 
Published: October 2019

Abstract
INTRODUCTION: Ibrutinib is approved for treatment (tx) of CLL in patients (pts) with previously treated disease and CLL with deletion (del) 17p. It has shown substantial improvements in progression free survival (PFS) and overall survival (OS) with a tolerable safety profile. Atrial fibrillation (Afib) has been observed in pts treated with ibrutinib, particularly in pts with cardiac risk factors, acute infections, and history of Afib. In the RESONATE study 3% of pts on ibrutinib developed Afib (median follow-up (f/u) 8.6 months (mo)) while 1% of pts on ofatumumab (median f/u 5.3 mo) developed Afib. Here we assessed the incidence of Afib in an independent cohort of pts with long f/u enrolled in our investigator-initiated trial of single agent ibrutinib.
PATIENTS AND METHODS: This phase II trial (NCT01500733) enrolled 86 pts (Cohort 1: ≥ 65 years old (yo) without del 17p (n=35); Cohort 2: ≥ 18 yo with presence of del 17p (n=51)) who were treated with ibrutinib 420 mg daily continuously. Treatment-naive and previously treated pts in need of treatment (tx) were eligible. Safety data for Afib was compiled on all pts who received tx. All pts who developed Afib (per patient report or incidental finding) stopped ibrutinib therapy and underwent a cardiology evaluation which may have included an echocardiogram, stress test, and/or holter monitor at the discretion of the evaluating cardiologist. The annualized exposure adjusted incidence rate of Afib was estimated and compared between subgroups.
RESULTS: At a median follow-up of 28 mo, 14 (16%) of 86 patients were found to have Afib while on study, 11 pts were ≥65 yo; 3 pts < 65 yo. In 9 (10%) pts this was the first recorded event, while 5 (6%) had a prior history of Afib. One patient developed Afib during pneumonia and in all other pts no contributing factors were identified. The median time to the first event on study was 18.24 (IQR: 10.8-26.0) mo. The annualized incidence was 0.052 (95% CI, 0.024- 0.099) events per person-year of treatment exposure among pts (n=81) without a prior history of Afib, 0.061 (95% CI: 0.025-0.126) in pts ≥65 yo (n=52), and 0.035 (95% CI: 0.004-0.125) in pts <65 yo (n=29, P =0.43 for difference in incidence based on age).
In 11 (79%) of 14 pts Afib was grade 2, and in 3 (21%) grade 3. The grade 3 events required hospitalization and control of Afib through intravenous medications. All 3 pts had resolution of Afib and completed cardiology evaluation prior to restarting ibrutinib at a lower dose (280 mg), one received only aspirin (ASA) 81 mg, one received ASA 81 mg and an antiarrhythmic (sotalol), and one patient was anticoagulated with apixaban. Of 11 pts with grade 2 events, 6 (55%) pts currently do not have any symptoms or EKG findings of Afib, 3 (27%) pts intermittently have symptoms or EKG findings of Afib, and 2 (18%) pts have ongoing Afib. All of these 11 pts restarted ibrutinib at the same dose (420 mg); 5 received ASA 81 mg, 2 were on dabigatran transiently and then continued ASA 81 mg, and the other 4 pts started apixiban. F/u on apixiban ranges from 7-17 mo with no bleeding-related adverse events grade >1.
CONCLUSION: The rate of Afib in this study at 16% is higher than previously reported, likely due to longer f/u. Indeed, the estimated Afib rate at 17 mo in RESONATE was 5.1%, similar to 5.6% at the same timepoint in our study. The annualized incidence rate of Afib in our study at 0.052 (95% CI, 0.024- 0.099) is higher than the estimated rate of 0.0124 per person-year in the general population (Schnabel et al, Lancet 2015). Given that the rate of Afib is higher in illness, longer follow-up in randomized studies will be needed to distinguish disease from drug-related factors. Notably, none of our pts had to discontinue ibrutinib because of Afib. Furthermore, there is currently no evidence that the severity of Afib in pts on ibrutinib differs from the general population. Given that the majority of our patients have del 17p and/or previously treated disease we feel that the risk-benefit profile favors continued ibrutinib treatment. In a small number of pts and with limited duration of observation we have not noted any serious bleeding complications in pts on ibrutinib and concurrent apixaban or 81 mg ASA.
Research supported by the Intramural Research Program of NHLBI. We thank our patients for participation. We acknowledge Pharmacyclics for providing study drug.

Disclosures
Wiestner: Pharmacyclics: Research Funding.