Cardiovascular Toxicities of BTK Inhibitors in Chronic Lymphocytic Leukemia: JACC: CardioOncology State-of-the-Art Review

Abstract

Over the past decade, the treatment landscape of chronic lymphocytic leukemia (CLL) has dramatically changed, shifting from cytotoxic chemotherapy to targeted therapies. Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of CLL and are increasingly applied in many other malignancies. However, ibrutinib, the first BTK inhibitor approved, is associated with serious toxicities, including atrial fibrillation in up to 38% of patients, ventricular arrhythmias, and other cardiovascular toxicities. Emerging data suggest several newer BTK inhibitors (eg, acalabrutinib, zanubrutinib) are still associated with cardiotoxic risks. This review examines the current state of evidence, including incidence rates, risk factors, mechanisms, and management strategies of cardiovascular toxicities with BTK inhibitors and other CLL therapies. We specifically focus on atrial fibrillation, ventricular arrhythmias/sudden death, hypertension, heart failure, bleeding, and stroke. We also touch on other emerging BTK therapies (eg, pirtobrutinib). Finally, we highlight key unanswered questions and future directions of research.

Keywords: Bruton’s tyrosine kinase inhibitors; acalabrutinib; atrial fibrillation; cardio-oncology; ibrutinib; sudden death; zanubrutinib.

Graphical abstract

Figure 1

Representative Electrocardiograms From Patient(s) With BTK Inhibitor-Associated Arrhythmias (A) A patient with the development of atrial fibrillation shortly after Bruton’s tyrosine kinase inhibitor (here ibrutinib) initiation. (B) A patient with ventricular arrhythmia development after Bruton’s tyrosine kinase inhibitor therapy.

Figure 2

Cardiac Magnetic Resonance Images From a Patient With Ibrutinib-Associated Cardiotoxicity Representative late gadolinium enhancement (white arrows) cardiac magnetic resonance images from hematologic malignancy patients with suspected cardiotoxicity (paroxysms of atrial fibrillation and nonsustained ventricular tachycardia) after ibrutinib initiation.

Figure 3

Change in Blood Pressure From a Patient Initiated on BTKi Therapy Increase in systolic blood pressure in a patient treated with ibrutinib over a period of several years (A). The left green vertical line represents the initiation of antihypertensive therapy, and the right red vertical line represents the time of ibrutinib discontinuation because of subsequent symptomatic atrial fibrillation development. (B) The rapid onset of hypertension in the same patient in the months after starting ibrutinib. BTKi = Bruton’s tyrosine kinase inhibitor.

Figure 4

Proposed Algorithm for Risk Stratifying and Managing Ibrutinib-Associated Arrhythmias Among patients with suspected ibrutinib-associated cardiotoxicity, the presence of late gadolinium enhancement (LGE) or elevated native T₁ is associated with a higher risk of future or recurrent cardiotoxic events. ∗Additional cardiac data on the safety of newer Bruton’s tyrosine kinase (BTK) inhibitors is still needed. CMR = cardiac magnetic resonance; ECG = electrocardiogram.

Central Illustration

Common Cardiovascular Effects of BTK Inhibitor Treatment in the Patient With Hematologic Malignancy ∗Symptom (eg, palpitations, shortness of breath, chest pain) triggered Holter monitoring strategy is suggested for patients treated with BTK inhibitor therapies. ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; ARNI = angiotensin receptor neprilysin inhibitor; BP = blood pressure; BTK = Bruton’s tyrosine kinase; DOAC = direct oral anticoagulant; HF = heart failure; SGLT2i = sodium/glucose cotransporter-2 inhibitor.

Figure 5

Proposed Algorithm for Routine Cardiac Monitoring for Patients Initiating BTK Inhibitor Therapy We suggest a screening ECG as part of each office visit (or at least every quarter during the first year of treatment) when initiating any BTK inhibitor therapy, and further assessment with longer-term Holter monitoring in those with symptoms (eg, palpitations). If arrhythmia is detected on screening ECG, an echocardiogram and potential referral to cardiology (or cardio-oncology referral, if available) is suggested, with potential modification of BTK inhibitor therapy. ∗ECG every 3-6 months after the first year of BTK inhibitor treatment; cardio-oncology referral, if available, otherwise general cardiology. AF = atrial fibrillation; CV = cardiovascular disease; SVT = supraventricular tachycardia; VA = ventricular arrhythmia; other abbreviations as in Figure 4.