Follow-Up Investigation Highlights Need to Better Understand Ibrutinib-Associated Toxicities

A study found an association between treatment with ibrutinib and an increased risk for death from toxicities.

Ibrutinib (Imbruvica) has improved survival for a host of patients with chronic lymphocytic leukemia (CLL)and has proven superior to other treatments, as reported in The New England Journal of Medicinelast December.1

But tucked in the middle of that study, amid the successes, the experts reported a 7% death rate among those taking ibrutinib. That rate was significantly higher than the 1% not taking the drug on the study.

Now, another investigation published in the Journal of The American College of Cardiology, has plunged into that statistical nuance – finding a possible cardiovascular toxicity issue which could play a role in the heightened mortality.

It all started with a careful appraisal of the entirety of the first investigation-the details of data from that first paper: “We were reading (the NEJMarticle), and we were just intrigued,” said senior study author Javid Moslehi, M.D., director of cardio-oncology and associate professor of medicine at Vanderbilt University Medical Center, in an interview with CancerNetwork®. “We were intrigued by the sudden mortality reported in the ibrutinib arms of the NEJMarticle and wondered whether cardiovascular issues contributed to this.”

Moslehi heads a Vanderbilt team focused on toxicities from immunotherapies and other newer treatments-like front-line ibrutinib, a therapy approved for B-cell cancers since it covalently bonds to a protein known as Bruton’s tyrosine kinase, or BTK, which is known to be vital to B-cell cancers.

The study used VigiBase, the World Health Organization’s global database of individual case safety reports (ICSRs). The database yielded 303 ibrutinib-associated cardiovascular deaths catalogued. That link to the cancer drug was made at the point of care by doctors and was listed as such in the WHO pharmacovigilance database. 

“We’re not playing Monday morning quarterback – with every one of these reports, this is the judgment of the doctor who is taking care of the patient for those 300 deaths,” said Moslehi. “…and that is one of the limitations of our study” said Moslehi.“It’s a striking number, when you think about it.”

The deaths came from a variety of associated conditions, including supraventricular arrhythmias (ROR, 23.1; 95% CI, 21.6-24.7), central nervous system (CNS) hemorrhagic events (ROR, 3.7; 95% CI, 3.4-4.1), heart failure (ROR, 3.5; 95% CI, 3.1-3.8), ventricular arrhythmias (ROR, 4.7; 95% CI, 3.7-5.9), conduction disorders (ROR, 3.5; 95% CI, 2.7-4.6), CNS ischemic events (ROR, 2.2; 95% CI, 2.0-2.5), and hypertension (ROR, 1.7; 95% CI, 1.5-1.9).

Jutta Bergler-Klein, M.D., of the Medical University of Vienna, commented in the findings in an accompanying editorial, noting that careful heart monitoring and electrocardiograms should be considered while treatment is underway.3

Moslehi said the work is a matter of raising awareness of the latest novel therapies – which can provide longer leases on life if properly administered, but which may have as-yet unheralded risks. 


“The take-home message is, we need to understand these toxicities better – and I’m not sure they’re being captured in the trials that are being done in oncology,” said Moslehi. 


1. Woyach, J, Ruppert, A, Heerema, N, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Old Patients with Unreated CLL. N Engl J Med. 2018;379:2517-2528.
2. Salem, J, Manouchehri, A, Bretagne, M, et al. Cardiovascular Toxicities Associated with Ibrutinib. JACC. 2019;74(13):1667-1678.
3. Bergler-Klein, J. Real-Life Insight Into Ibrutinib Cardiovascular Events. JACC. 2019;74(13):1679-1681.