Prior Comorbidities Predict Risk of Treatment-Emergent Atrial Fibrillation in CLL

Roughly 4% of patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib (Imbruvica) may experience atrial fibrillation (AF), but their comorbidities, rather than their CLL-related factors, predict risk of treatment-emergent AF, according to a retrospective review published in Annals of Hematology.

Treatment-emergent AF was associated with shorter event-free survival (EFS) and overall survival (OS) in patients treated with ibrutinib at Mayo Clinic between October 2012 and November 2018, but a majority of patients were able to continue on therapy.

“In this large, retrospective analysis of [patients with] CLL treated with ibrutinib, the risk of treatment-emergent AF at 2 years was ~16%, which is significantly higher than that reported in ibrutinib registration trials,” the authors wrote in their discussion of the review. “As would be expected, comorbidities of patients (particularly past history of AF and heart failure) and not CLL characteristics (such as Rai stage, CLL [fluorescence in situ hybridization] profile or IGHV mutation status) predicted the development of treatment-emergent AF.”

Of the 298 patients with CLL identified in the Mayo Clinic CLL Database, 51 developed treatment-emergent AF after receiving ibrutinib. There were 39 incidents of AF and 12 incidents of recurrent AF. Persistent AF was present in 8 (2.7%) patients when they started ibrutinib therapy. Twenty-one of the other 290 had prior history of AF but 9 did not relapse when receiving ibrutinib.

The risk of treatment-emergent AF was 9% at 6 months (95% CI, 6%-13%), 12% at 1 year (95% CI, 9%-17%), and 16% at 2 years (95% CI, 12%-21%). Patients with recurrent AF had a higher estimated cumulative incidence of treatment-emergent AF: 43% (95% CI, 25%-71%) at 1 year, 48% (95% CI, 30%-76%) at 2 years, and 56% (95% CI, 36%-86%) at 3 years.

History of AF (HR, 3.5; P = .0072) and heart failure (HR, 3.4; P = .0028) were both associated with increased risk of treatment-emergent AF in multivariate analyses. After adjusting for age, prior treatment status, TP53 disruption, past history of AF, valvular disease, and heart failure, the data showed patients who experienced treatment-emergent AF tended to have shorter OS (HR, 3.2; P = .001) and shorter EFS (HR, 2.0; P = .02).

In a univariable analysis, patients who experienced treatment-emergent AF also had shorter EFS (HR, 2.7; 95% CI, 1.6-4.5; P < .001) and OS (HR, 4.1; 95% CI, 2.3-7.3; P < .001). The univariable analysis also showed statistically significant risk factors for developing AF were a history of AF (HR, 4.8; 95% CI, 2.5-9.4; P < .0001), heart failure (HR, 4.8; 95% CI, 2.6-8.9; P < .0001), valvular heart disease (HR, 3.4; 95% CI, 2.0-5.9; P < .0001), age of 65 years or older (HR, 2.5; 95% CI, 1.3-5.1; P < .008), sleep apnea (HR, 2.1; 95% CI, 1.02-4.4; P < .04), and hypertension (HR, 1.8; 95% CI, 1.003-3.1; P < .049).

There were 13 (25%) patients with grade 3 or more treatment-emergent AF. Rate control measures such as beta blockers were used to manage treatment-emergent AF in 27 (53%) patients, 2 (4%) patients received digoxin for rhythm control, and 1 (2%) patient received both. Additional interventions were used in 16 (31%) patients; this included cardioversion in 11 patients, atrioventricular nodal ablation in 3 patients, and placement of a permanent pacemaker in 2 patients. There were 5 (10%) patients who did not receive therapy for their treatment-emergent AF.

Dose reduction of ibrutinib was used in 22 (43%) patients so they could continue on therapy. Twelve (24%) patients had ibrutinib held temporarily at the onset of treatment-emergent AF and then resumed their original dose later. There were 11 patients who continued their ibrutinib dose without interruption or reduction. Lastly, 6 (12%) patients permanently discontinued due to treatment-emergent AF.

For the entire cohort, there was a median EFS of 3.9 years in, and a median OS of 5.3 years. The median age for ibrutinib initiation was 68 years (range, 35-93) and 70.5% were men. Almost 70% were being treated for relapsed/refractory disease, with a median of 1 prior therapy (range, 0-15). There was a median time on ibrutinib of 19 months (range, 0.23-69.7 months).

“The results of our study, obtained from careful follow-up of patients treated at our center, provide important information to practicing clinicians about the prediction, incidence, and management of AF in patients with CLL treated with ibrutinib. Patient comorbidities including history of AF and heart failure predicted risk of treatment-emergent AF in patients treated with ibrutinib. Most patients who develop AF are able to continue ibrutinib therapy, but the occurrence of AF appears to be associated with adverse clinical outcomes,” the authors concluded.


Archibald WJ, Rabe KG, Kabat BF, et al. Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib: risk prediction, management, and clinical outcomes. Ann Hematol. 2021;100(1):143-155. doi:10.1007/s00277-020-04094-3