BETHESDA, MD—Ibrutinib transformed treatment for chronic lymphocytic leukemia (CLL) when introduced in 2014. While it continues to be widely used, the Bruton’s tyrosine kinase (BTK) inhibitor is associated with a significant risk of cardiac adverse events, particularly cardiac arrhythmias.
Consequently, patients frequently require dose reduction or interruption. Recently developed guidelines help manage cardiac toxicity with structured dose reductions. In addition, the National Institutes of Health (NIH) are studying the use of a short course of fludarabine in conjunction with continuous ibrutinib in 29 treatment-naïve patients with CLL as a way to minimize cardiac issues.
At the 64th American Society of Hematology Annual Meeting in New Orleans on Dec. 10, Andy Itsara, MD, of the NIH’s National Heart, Lung, and Blood Institute, presented results of cardiac screening in this study as a means of identifying asymptomatic patients at higher risk of serious cardiac events.
The study called for patients to receive ibrutinib 420 mg orally once daily on 28-day cycles until disease progression or intolerable side effects with fludarabine 25 mg/m2/day administered intravenously on days 1-5 of cycles three and four. All patients completed combination therapy and continued on an extension of the study with ibrutinib monotherapy.
Because two patients died suddenly of cardiac events during the study, screening was added for the 21 remaining patients, all of whom were asymptomatic. Each had an echocardiogram, exercise stress test or stress MRI, and heart monitoring with a patch recorder or Holter monitor. As of Dec. 31, 2021, participants had a median follow-up duration of 54.5 months. Progression-free survival was 90% at four years.
The testing revealed no notable finding in 17 patients, all of whom continued on ibrutinib uninterrupted. Screening found no unexpected, clinically significant structural abnormalities or new ischemic heart disease.
Four patients, however, had results that led to changes in treatment. One patient showed 2% ventricular ectopy burden and intermittent ventricular tachycardia on 24-hour Holter. After six weeks off the drug, monitoring revealed ventricular ectopy of less than 1%. Screening showed a second patient had a 3.5% ventricular ectopy burden, which increased to 4.1% four months after discontinuation. Both patients remained off therapy and progression-free after stopping ibrutinib. Screening detected sinus pauses as long as 5.6 seconds as well as second-degree atrioventricular block in a third patient, who discontinued ibrutinib temporarily to receive a pacemaker. Stress testing revealed that a fourth patiens had previously undiagnosed atrial fibrillation. A beta-blocker was started but anticoagulation was not required.
Screening detected no notable results in a fifth patient, but three months later that patient presented with syncope and a motor vehicle accident. On admission, ibrutinib was discontinued. The patient was diagnosed with sick sinus syndrome, experienced an episode of bradycardic arrest requiring cardiopulmonary resuscitation and underwent pacemaker placement.
The study team, which included members from the Uniformed Services University of the Health Sciences and Dana-Farber Cancer Institute as well as NIH, concluded that “further research is warranted to identify efficient monitoring and risk mitigation strategies for cardiac toxicities on ibrutinib and potentially other BTK inhibitors. Future studies should incorporate the recent dose reduction guidelines, pre-treatment cardiac evaluation, and comparison groups, including patients not on treatment and on alternative targeted therapy.”
- Itsara A, Sun C, Ahn IE Soto S, Rosing D, Haigney M, Wiestner A. Comprehensive Cardiac Testing in Asymptomatic Chronic Lymphocytic Leukemia (CLL) Patients on Ibrutinib. Abstract 1318. 2022 ASH Annual Meeting. Dec. 10, 2022.