iwCLL 2017 | Baseline left atrial abnormality independently predicts atrial fibrillation in CLL patients treated with ibrutinib

On 14^th May 2017, during iwCLL, the fifth session took place titled “Additional Considerations for the Initial Treatment of CLL.” This session was chaired by Richard Furman (Weill Cornell) and Jae Park (Memorial Sloan Kettering Cancer Center).

During this session, a talk titled “Left Atrial Abnormality as a Predictor of Ibrutinib-Associated Atrial Fibrillation in Patients With Chronic Lymphocytic Leukemia: a Predictive Model” was given by Anthony Mato from the Hospital of the University of Pennsylvania, Philadelphia, PA, USA.

Results from long-term follow-up data indicate an approximate incidence of Atrial Fibrillation (AF) of 9–11% in CLL patients treated with ibrutinib. AF is the most frequent cause of ibrutinib interruption or discontinuation. Patients with AF are also more likely to experience Congestive Heart Failure (CHF), embolic Cerebrovascular Accident (CVA), and bleeding events. A higher risk of AF is associated with Hypertension (HTN), older age, mitral valve disease, and CHF. Left Atrial Abnormality (LAA) detected by ECG indicates remodeling of the left atrium (fibrosis, microscopic myocyte hypertrophy), which has been associated with AF development.

Anthony Mato presented results from a case-controlled, retrospective study of patients with CLL treated at two centers. Patients with pre-ibrutinib AF, no pre-treatment ECG, and receiving less than 420mg ibrutinib daily were excluded. The primary outcome was AF during ibrutinib therapy and secondary outcomes included time from ibrutinib exposure to AF, incidence of ibrutinib-associated HTN, and the association between baseline cardiovascular characteristics and AF.

Overall, 153 consecutive patients with CLL were treated at a dose of 420mg ibrutinib:

Characteristic	Result (range)
Median age at diagnosis	61
Median age at ibrutinib initiation	70
Media prior therapies	2 (0–10)
R/R CLL	87%
Del(17p)	28%
Del(11q)	32%
Complex karyotype (≥3)	35%
Median follow-up	17 months
Median time from diagnosis to ibrutinib	73 months

In total, 44 patients with pre-ibrutinib ECG were selected for LAA analysis: 20 cases and 24 controls. On univariate and multivariate analysis, baseline LAA independently predicted ibrutinib-associated AF:

• Univariate: OR = 9.1 (95% CI, 2.2–37.3; P = 0.002)
• Multivariate: OR = 6.6 (95% CI, 1.5–29.2; P = 0.01)

The test characteristics of the association between LAA and AF were also presented:

Characteristic	Value	95% CI
Sensitivity	79%	54–94%
Specificity	71%	49–87%
Positive likelihood ratio	2.7	1.4–5.3
Negative likelihood ratio	0.30	0.1–0.74
Positive predictive value	68%	45–86%
Negative predictive value	81%	58–95%

No patient required electrophysiological intervention including cardioversion, ablation, or left atrial appendage occlusion device. The methods of AF management carried out during the study were presented:

Pharmacologic intervention	Percentage
ASA or anti-platelet	40%
Systemic anti-coagulation	45%
Anti-arrhythmic agent	45%
Rate control	90%
ACE/ARB	40%
Diuretic	25%

Anthony Mato then discussed limitations of the study which included the retrospective nature of the study, the fact that the cases and controls were not balanced for baseline cardiovascular characteristics, the small number of AF cases included, and the variable timing of pre-ibrutinib ECG. In addition, the results require validation in prospective studies.