Prospective, Comprehensive Cardiac Assessment in Patients Receiving BTK Inhibitor Therapy
Authors: Tang Chloe Pek Sang , La Gerche Andre , McMullen Julie , Howden Erin , Handunnetti Sasanka M. , Goncalves Isaac , Ooi Jenny , Tam Constantine S. 
Published: November 2019

The development of Bruton Kinase Inhibitors (BTKi) has been a major advance in the treatment of chronic lymphocytic leukaemia and related B cell malignancies, but atrial fibrillation (AF) and sudden cardiac deaths are emerging as unique side effects of BTKi. The pathophysiology of cardiac side effects in BTKi treated patients is not known, and an excess of cardiac diseases is not exhibited in the congenital BTK deficiency population. Our group has previously shown in cell models that ibrutinib inhibits the phosphoinositide 3-kinase (PI3K)-AKT pathway in the heart, providing a potential explanation for cardiotoxicity. The PI3K pathway is the major cardioprotective mechanism in the heart under stress conditions, and mice with cardiomyopathy and reduced PI3K can display AF, ventricular arrhythmias and develop severe cardiomyopathy. Concerningly, given the above information, cardiac surveillance has not been routinely incorporated in BTKi trials. We therefore sought to prospectively and systemically assess cardiac function and rhythm in patients commencing BTKi therapy.
Method: This is a prospective, multicentre study with the aim of conducting comprehensive cardiac assessment of patients commencing BTKi. This assessment involved 2 domains: 1) detection of subclinical arrhythmias by performing baseline and 3 month follow-up Holter Monitor testing, 2) quantification of subclinical structural changes including dynamic atrial and ventricular contractile function using transthoracic echocardiogram (TTE) and exercise cardiac magnetic resonance imaging (MRI) at baseline and 3 months. The primary outcome assessed was significant reduction in left atrial(LA) volume as a measure of ibrutinib-induced myocardial dysfunction. A 12.5% difference in LA volume is clinically meaningful given that it has been associated with greater AF risk in predisposed individuals. A sample size of 40 provides adequate power of 0.8, α = 0.05 for detecting a 12.5% increase in LA volume from an expected baseline of -18±3. Secondary outcomes measured were: 1) Reduction in ventricular ejection fraction during exercise cardiac MRI, 2) reduction in VO2 max on cardiopulmonary exercise testing.
Results: A total number of 40 patients with median age of 68 years were recruited over median follow-up of 12 months (Table 1). 6/40 patients demonstrated significant reduction in left atrial volume at 3 month follow-up. They were not clinically symptomatic and did not have co-existing history of AF. Functional testing with VO2 max on cardiopulmonary exercise testing showed significant reduction in VO2 max in 8/40 patients. There were no significant reduction in ventricular ejection fraction during exercise cardiac MRI. 1/40 patients developed symptomatic AF 257 days after commencing ibrutinib and symptoms were controlled with a beta blocker. He had normal baseline TTE but was found to have enlargement of LA volume during follow-up. One patient with Waldenstrom Macroglobulinameia with normal baseline cardiac testing died from presumed ventricular tachycardia 3 months after commencing trial drug, before reassessment could be conducted. Overall, our data indicated that despite thorough cardiac surveillance, no significant cardiac abnormalities were detected at 3 month follow-up.
Conclusion: This prospective and comprehensive cardiac study demonstrated no significant evidence of functional, structural or rhythm abnormalities at 3 month follow-up of patients commencing BTKiinhibitor, as assessed by Holter monitor, exercise cardiac MRI, cardiopulmonary testing and transthoracic echocardiography. Longer follow-up and additional electrophysiological studies may be required to further delineate the cause of BTKi induced cardiotoxicity.

Disclosures
McMullen: CLL Global Research Funding: Research Funding. Handunnetti:Gilead: Honoraria; Abbvie: Other: Travel Grant. Tam:Abbvie, Janssen: Research Funding; Abbvie, Janssen, Beigene, Roche, Novartis: Honoraria.