An Observational Study of the Occurrence of Atrial Fibrillation and Hypertension in Patients Treated with Ibrutinib
Authors: Binsah George , Philip Thompson A , Ferrajoli Alessandra , Jan Burger , Jain Nitin , Wierda William G , O'Brien Susan , Durand Jean Bernard , Keating Michael J 
Published: October 2019

Abstract
Background: Ibrutinib (Ib) is active in relapsed/refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Patients receive indefinite therapy until progression. Published reports describe the occurrence of hypertension (HTN) and Atrial Fibrillation (AF) to be 8% and 6-9% respectively in patients treated with Ib.
Methods: We evaluated 176 CLL patients treated on investigational protocols with Ib-based regimens from 2010-14 to determine the incidence of AF and HTN while receiving Ib. All pts gave informed consent and studies were conducted according to the Declaration of Helsinki. Blood pressure (BP) was evaluated at baseline and 6 months (mo). New onset HTN was defined as systolic BP (SBP) >140mmHg or diastolic BP (DBP) >90mmHg at 6mo in a pt with normal baseline BP. An increase in baseline SBP by ≥20mmHg and/or increase in DBP by ≥10mmHg was considered separately to be significant regardless of the absolute BP. AF was defined by an R-R interval following no repetitive pattern with no distinct P wave and an atrial rate of more than 300 beats/min. Electrocardiography (EKG) was reviewed to confirm AF. Baseline EKGs were required, but subsequent EKGs were performed only for symptom evaluation. Echocardiography (echo) was not performed at baseline, but was available in 6 of 9 pts at onset of AF.
Results: Baseline characteristics are given below: TableCharacteristicAge (median, range)65 (35-87)Male129 (73)Treatment group:Ib monotherapy, n(%)83 (47)Ib + Rituximab, n(%)78 (44)Ib + Bendamustine + Rituximab, n(%)15 (8)Unmutated IGHV gene, n(%)112 (64)FISH hierarchydel(17p), n(%)59 (34)del(11q), n(%)32 (18)Other, n(%)25 (14)
The median follow up of the entire patient cohort is 13 months (mo), range, 1-47mo. 9 patients (5%) developed new onset AF after starting Ibrutinib therapy, 7/9 were not on prior Beta blocker. 5 on Ib monotherapy, 3 patients on Ib + R, 1 on Ib+BR. The median time to AF after starting Ibrutinib was 20 weeks (range, 2-101). Six pts had a Hx of paroxysmal AF pre-dating Ib therapy (3.4%) and were already on treatment with Beta blocker of which none had recurrence of AF after or during Ib therapy, after a median follow up of 24 months (range=2-46).
Six of 9 pts with new AF had an echo. Echo was normal in 2 pts, while 4 showed mild-severe left atrial (LA) dilatation; severe LA dilatation had developed during Ib treatment in the 1 pt who had had a normal baseline echo. One pt also had moderate left ventricular (LV) failure in addition to LA dilatation, but LV function was normal in the remaining pts. No pt had thyrotoxicosis as a contributing factor.
Serial BP results were available in 111 pts. Median BP was 129/73 at baseline and 137/73 after 6mo of Ib therapy (p<0.001). New onset HTN occurred in 26 pts (23%); this was isolated systolic HTN in 23 pts and both systolic and diastolic in 3. Median change in SBP in pts with new-onset HTN was 27mmHg, range 4-55mmHg. Increase in SBP of >20mmHg occurred in 26 pts (23%); 21 of these pts had new onset HTN, while 5 had exacerbation of pre-existing HTN. Of the 9 pts with new AF, 5 had serial BP measurements. One developed new-onset HTN and 2 had a >20mmHg rise in SBP.
Conclusions: In our experience, 5% of pts undergoing treatment with Ib develop new-onset AF. This incidence is comparable to prior reported data. Given that AF may be paroxysmal and asymptomatic, routine surveillance was not performed, the true incidence may be higher. The causative mechanism is unclear. 2/3 of pts with new AF, echo results showed significant structural LA abnormalities which have been associated with AF in the general cardiology literature.
Twenty-three % of the pts developed new onset HTN, which was usually isolated systolic HTN. Most of these pts had increases in SBP >20mmHg. New onset HTN is likely therapy-related, although the mechanism is unclear. Development of AF did not appear to be dependent on the development of HT, as only 1 of 5 pts with new AF had new-onset HT. AF and HTN were generally manageable with medical intervention and did not require permanent cessation of Ib. Close monitoring of heart rhythm and blood pressure is recommended during treatment with Ib.

Disclosures
Jan: pharmacyclics: Research Funding. Wierda:Pharmacyclics: Consultancy. O'Brien:Pharmacyclics: Research Funding.