Ibrutinib and Bruton’s Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: Focus on Atrial Fibrillation and Ventricular Tachyarrhythmias/Sudden Cardiac Death

Abstract

Background: The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton’s kinase (BTK) inhibitor. In this review we aimed to summarize and critically evaluate the association between first and second generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA). Summary: Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient’s predisposing risk factors and concomitant cardiac morbidities. More recently both ibrutinib dose reduction and arrhythmia management allowed long-term treatment, with positive effects on progression-free survival and reduced all-cause mortality as well. Second-generation BTK inhibitors, acalabrutinib and zanubrutinib have been tested and validated in CLL. A lower occurrence of AF as compared with ibrutinib has been found, although AF has always been a secondary endpoint of all studies that probed these agents. Key Messages: For this reason, caution should be exercised before concluding that second-generation BTK inhibitors are safer than ibrutinib. Recent data on the effectiveness of ibrutinib over a follow-up of 8 years show a remarkable benefit on all-cause mortality, which is of great value also for interpreting the clinical impact of the few cases of VA and sudden cardiac death (SCD) reported for ibrutinib, independently of QT lengthening. Since a risk of VA and SCD has been recently reported also during treatment with second-generation BTK inhibitors, it appears that this risk, usually reaching its maximum size effect at long-term follow-up, likely denotes a class effect of BTK-inhibitors.

Challenges associated with the use of Bruton's tyrosine kinase inhibitors: A life‑saving therapy for chronic lymphocytic leukemia (Review)

“…Following an 8-year follow-up, it was found that ibrutinib reduced all-cause mortality, and produced few cases of ventricular arrhythmias and sudden cardiac death, independently of QT lengthening (28). In the case that AEs occur, both the reduction of the dose of ibrutinib and the careful management of arrhythmia can allow for long-term treatment and reduce all-cause mortality with a prolonged PFS and a reduced all-cause mortality (30).…”

Zanubrutinib for the treatment of lymphoid malignancies: Current status and future directions

“…Treatment with BTK inhibitors in continuous monotherapy may not be optimal, as most responses are PRs and only the minority of patients achieve CR ( 64 ). There are long-term safety concerns including cardiac events and the risk of rapid progression following BTKi cessation ( 65 , 66 ). Some patients might find the ongoing need for therapy unacceptable and difficult to comply in real-life scenarios.…”

Arrhythmogenic Ventricular Remodeling by Next-Generation Bruton’s Tyrosine Kinase Inhibitor Acalabrutinib

“…Despite the small number of investigations that have drawn attention to VAs associated with ABR [ 13 , 14 ], its impact on VA remains inadequately assessed and the underlying mechanisms of ABR-induced VAs remain unclear. Our group has demonstrated that acute as well as chronic IBR treatments are associated with the aberration of membrane voltage and intracellular calcium (Ca 2+ ) dynamics in the heart, with a subsequent increase in VA vulnerability [ 15 , 16 ].…”