Cardiotoxicity of BTK inhibitors: ibrutinib and beyond

ABSTRACT

Introduction

The development of Bruton<apos;>s Tyrosine Kinase (BTK) inhibitors has transformed the treatment of B-cell malignancies and other non-malignant conditions. Management of the unique cardiotoxic profile of these agents requires prompt recognition and a multi-disciplinary approach.

Areas Covered

The increasing indications and addition of newer agents to clinical practice and emergence of BTK inhibitor-related cardiac adverse events have complicated the management decisions for utilization of this class of therapy. We review the incidence, mechanisms, and management approaches for BTK inhibitor-related atrial fibrillation, hypertension, and ventricular arrhythmias.

Expert Opinion

The newer BTK inhibitor acalabrutinib represents a new standard of care in front-line chronic lymphocytic leukemia (CLL) given the results of the ELEVATE-RR trial demonstrating comparable efficacy and a more favorable toxicity profile especially with regard to cardiac adverse events as compared to ibrutinib. Often not recognized by clinicians, BTK inhibitor-induced hypertension is common and can be severe, requiring prompt recognition and initiation or adjustment of anti-hypertensive medications to prevent major adverse cardiac outcomes. Novel BTK inhibitors in development are being designed to overcome the patterns of resistance from first-generation agents and to minimize off-target kinase activity, with promising toxicity profiles in early trials.

KEYWORDS:

• Acalabrutinib
• atrial fibrillation
• cardio-oncology
• chronic lymphocytic leukemia
• hypertension
• ibrutinib
• non-Hodgkin lymphoma
• ventricular tachycardia
• zanubrutinib

Article highlights

• Ibrutinib, a first-in-class irreversible BTK inhibitor, also acts on multiple off-target kinases that underlie its unique toxicity profile.

• The reported cardiac adverse effects of BTK inhibitors are atrial fibrillation, hypertension, and ventricular arrhythmias.

• Atrial fibrillation is the most common reason for toxicity-related drug discontinuation in patients on ibrutinib. It occurs in 5–16% of patients, most frequently in those older than 65 years of age and/or with cardiovascular risk factors.

• Hypertension is the most common cardiac adverse event with ibrutinib, reported in up to 30% of patients in clinical trials and up to 80% of patients in real-world studies.

• Newer BTK inhibitors acalabrutinib and zanubrutinib act on fewer off-target kinases and have demonstrated a superior cardiotoxicity profiles compared to ibrutinib in clinical trials to date.

• Acalabrutinib is an effective alternative agent in patients who develop atrial fibrillation while on ibrutinib.

• Novel BTK inhibitors in development are being designed to overcome the resistance to earlier BTK inhibitors while minimizing off-target kinase effects.

Declaration of Interest

Farrukh T Awan has provided consultancy to Genentech, Astrazeneca, Abbvie, Janssen, Pharmacyclics, Gilead sciences, Kite pharma, Celgene, Karyopharm, MEI Pharma, Verastem, Incyte, Beigene, Johnson and Johnson, Dava Oncology, BMS, Merck, Cardinal Health, ADCT therapeutics, and Epizyme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.