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Treatment-Emergent Atrial Fibrillation in Ibrutinib-Treated CLL Patients

Simoneaux, Richard

doi: 10.1097/01.COT.0000577168.29298.27
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Atrial fibrillation, chronic lymphocytic leukemia

Atrial fibrillation, chronic lymphocytic leukemia

CHICAGO—The use of the Bruton's tyrosine kinase inhibitor ibrutinib has had a tremendous impact on the therapy of chronic lymphocytic leukemia (CLL) patients. Despite the successes which have been noted for this targeted therapy, a small percentage of patients taking ibrutinib do develop treatment-emergent atrial fibrillation (AF).

The ability to predict which patients might have a higher chance of developing AF if treated with ibrutinib has the potential to be a valuable tool when evaluating candidates for ibrutinib therapy. To see if any trends were discernible in their patients, a single institution retrospective study was undertaken at the Mayo Clinic by William Archibald, MD, and colleagues.

“Given the levels of AF which we noted in our retrospective study, it may not be necessary to discontinue ibrutinib therapy in most instances, as it is generally a very well-tolerated drug,” Archibald noted.

Findings from this study were reported at the 2019 ASCO Annual Meeting (Abstract 7522, Board 276).

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Research Study Details

The retrospective study included 299 CLL patients treated with ibrutinib at the Mayo Clinic between October 2012 and November 2018 for a total of 565 patient-years of exposure to ibrutinib.

“In our study, we utilized three different risk models for assessing risk for AF in ibrutinib-treated CLL patients,” Archibald explained. They included the Framingham (Lancet 2009;373:739-745), Italian (Blood 2018;132:3118), and Shanafelt (Blood 2015;126:2950) risk models.

Among these patients, 51 developed treatment-emergent AF, of which 25 percent (13) were Common Terminology Criteria for Adverse Events (CTCAE) grade 3 level or higher toxicities. A total of 30 patients that developed AF received medical treatment for that condition: rate control–27, rhythm control–2, and rate plus rhythm control–1. In addition, 16 patients received interventional treatment consisting of cardioversion–11, atrioventricular node ablation–3, and pacemaker–2.

Ibrutinib dosing was affected in the following manner in the 51 patients that experienced AF: maintained original dosing level–11, temporary dosing hold followed by original dosing–12, dose reduction–22, and permanent dosing discontinuation–6.

The CHA2DS2-VASc scores (Chest 2010;137:263-272) of the 51 patients who developed treatment-emergent AF were as follows: 41 had a score of 2 or greater and 10 had a score of 1 or less. For those with a score of 2 or higher, 41 percent received only anticoagulation therapy, 12 percent received only antiplatelet therapy, and 10 percent received dual anticoagulant/antiplatelet therapy. In addition, for those with CHA2DS2-VASc scores of 1 or less, 40 percent received only anticoagulation therapy and 20 percent received only antiplatelet therapy.

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Discussion

When asked if there were any discernible trends among those patients that did eventually develop AF, Archibald replied, “The development of AF had a tendency to be associated with shorter event-free survival, with a hazard ratio (HR) of 2.5 (95% CI: 1.5-4.2; p< .001). There was also an association with shorter overall survival, with an HR of 3.5 (95% CI: 2.0-6.3, p< .001).”

When discussing the individual risk models for AF development, Archibald noted, “The model which best captures the risk of treatment-emergent AF for CLL patients associated with ibrutinib therapy is the Italian model proposed by Visentin, et al. In this model, a patient is given the following points for each criterion met: age greater than 65 years–1 point, male gender–1 point, valvular disease–2 points, cardiopathy–1 point, hyperthyroidism–1 point, chronic lung diseases–1 point, diabetes mellitus–1 point, severe infections–1 point.” At 2 years, the risks for developing AF are as follows for the respective scores: 0 – 6 percent, 1-2 – 8 percent, 3-4 – 26 percent, and 5+ – 47 percent.

When asked about the more interesting findings in this retrospective study, Archibald noted, “We were pleased to find that only two patients developed major bleeding; one of these patients was on concomitant antiplatelet and anticoagulant therapy, while the other had neither of those therapies. Given these findings, it appears that the dosing of ibrutinib with anticoagulation/antiplatelet therapy is generally well-tolerated.”

Regarding their outcomes, he stated, “We found that, [in] using the Shanafelt and Italian models, we were able to identify those patients that were at the highest risk for AF. Ultimately, these findings will need to be validated in a prospective study. In future efforts, we will see if we can develop a better model for predicting risks for AF in our patients.”

Richard Simoneaux is a contributing writer.

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