Atrial Fibrillation in a CLL Patient Treated with Ibrutinib Yishay Wasserstrum Sackler Faculty of Medicine Tel-Aviv University, Israel Department of Cardiology Rabin Medical Center Petach-Tikva, Israel

Clinical presentation 65 y/o male patient. Chief complaints: Dizziness, lightheadedness, shortness of breath, dry cough. 1 month after initiation of ibrutinib, 420 mg daily. 6 days after initiation of amiodarone loading dose, 1200 mg daily, d/t recurrent paroxysmal atrial fibrillation.

Medical history Regular medications: Aggressive resistant CLL. Paroxysmal Atrial fibrillation (CHADS-VASC = 2). Ischemic heart disease. Underwent coronary artery bypass surgery (2007). Good LV function with infero-basal wall akinesis. Regular medications: Atorvastatin, losartan, carvedilol, apixaban

Timeline 11/8 – Echo: Preserved LV function and no diastolic dysfunction, Mild mitral regurgitation 19/8 – Initiation of amiodarone loading dose. 14/7 – Initiation of ibrutinib therapy. 19/8 – Presentation at ED with Rapid AF. 26/8 – Current presentation.

Physical examination Blood pressure 126/78 mm Hg, Heart rate - 78/min, regular, SpO2 92 % (room air). Jugular vein distension. Bibasilar pulmonary rales, Orthopnea. S4, holosystolic systolic murmur 3/6 – at apex with radiation into the axilla. New-onset edema (3+) of lower extremities.

Laboratory data Negative cardiac biomarkers (Hs-cTnT <0.013). CRP – 0.5 (normal) Stable anemia (Hb ~10) Normal renal, hepatic and thyroid functions. No electrolyte imbalance.

Borderline QTc prolongation 446 ms

Echocardiography New onset diastolic dysfunction, grade 3 (restrictive LV filling pattern). New onset mild to moderate mitral regurgitation. Mild to moderate tricuspid regurgitation, progression compared with previous exam. IVC – distended without respiratory collapse (RA pressure > 20 mm Hg) Pulmonary artery systolic pressure elevated to 50 mm Hg (previously documented 21 mm Hg).

Treatment Amiodarone wash-out for 2 days, then continued 200 mg/day. Additional furosemide 40 mg/daily. No dose adjustment for ibrutinib or other daily meds.

Outcome Day 9 after presentation, near complete clinical resolution. After one month echocardiography was repeated: diastolic dysfunction and pulmonary hypertension resolved completely. Mild mitral regurgitation, mild tricuspid regurgitation. ECG showed normal sinus rhythm, without QT rolongation.

Suggested Etiology of New-Onset Heart Failure Ibrutinib is metabolized by CYP3A. Amiodarone is a strong inhibitor of CYP3A4. Concomitant treatment may lead to rise of serum levels of ibrutinib.

Suggested Etiology of New-Onset Heart Failure Ibrutinib is metabolized by CYP3A. Amiodarone is a strong inhibitor of CYP3A4. Concomitant treatment may lead to rise of serum levels of ibrutinib.

Key points Possible cardiotoxic effect of ibrutinib in the supra-therapeutic range. The combination of amiodarone with ibrutinib is expected to occur frequently (atrial fibrillation was more frequent in ibrutinib group vs placebo and amiodarone is the most utilized drug for long-term rhythm control in the patients with coronary artery disease and left ventricular dysfunction). Dose adjusments may allow safe concomitant treatment with ibrutinib and CYP-3A4 inhibitors such as amiodarone.

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