“This is exactly the population we need to be looking at more closely for cardiac issues,” she said, adding that the Italian scoring system could prove to be a good tool, especially for identifying high-risk patients with CLL.

Although Bruton tyrosine kinase is a high-value molecular target, it’s not the only one researchers have identified in CLL, said Adrian Wiestner, MD, PhD, who is a senior investigator at the National Heart, Lung, and Blood Institute. Nor is ibrutinib the only drug in the pipeline “with the same broad approval” for treatment. But, for most patients with CLL, ibrutinib remains the treatment of choice for now, Dr Wiestner said, with randomized trials showing it improves progression-free survival compared with chemotherapy.3

Still poorly understood is the mechanism by which ibrutinib causes these erratic heart rhythms that damage the heart, or other heart problems, such as hypertension, he and others said. A more pressing concern, they suggested, is the excessive bleeding that can occur once AFib emerges.

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“Doctors are caught between a rock and a hard place,” Dr Archibald said — torn between administering anticoagulants to patients to reduce stroke risk and the risk these present regarding thinning the blood too much. In the Mayo study, he said, doctors navigated this delicate balance without mishap —an encouraging sign that lower doses of Ibrutinib could be combined with anticoagulants in a way patients can tolerate. Overall, however, researchers did see shorter event-free survival and shorter overall survival in patients with new-onset atrial fibrillation.

Of the 3 prediction models evaluated in the Mayo study, Mayo researchers developed 1 of them, while the other 2 were developed specifically as risk models in heart disease, not for use in cancer, according to NCI’s Dr Minasian. Going forward, she said, new cancer-specific designs are needed to balance out heart and cancer outcomes in the chronic disease setting of CLL and other cancers.

“Right now, in oncology trials, we don’t review heart problems as carefully as we do cancer progression,” and that needs to change, she said. “That’s why the Mayo Clinic did this study. We need predictive tools.”

As to the study’s small size, few investigators felt it mattered. “The [study] size is fine,” Dr Wiestner said, but the study’s findings are limited because of the lack of a CLL patient control group, matched by age, sex, and risk factors for AFib that are not being treated with ibrutinib. “The rate of AFib observed in a similar patient group not on this drug should be expressed, for example, as incidence of AFib per 100 patient years, to adjust for different observation times,” Dr Wiestner said.

This criticism is “certainly fair,” said Dr Archibald. 

“We had difficulty identifying a proper control group,” he said, because CLL patients enrolled in randomized clinical trials tend to be healthier than “real-world” patients, eliminated from study cohorts for preexisting heart disease or other comorbidities. Investigators also had trouble finding sufficient numbers of patients among those treated at the clinic who were not on Ibrutinib for their disease, he said.

According to Dr Archibald, the next likely step will be a prospective study using aggressive screening tests to evaluate risk factors for atrial fibrillation, before patients start ibrutinib. Those considered at highest risk for these heart events might even be encouraged to wear an Apple Watch or some other monitoring device to track AFib, he said. “I hadn’t thought of it before, but it’s a great idea”

Not everyone’s so sure, especially if monitoring includes tracking AFib in the general population.

“Because the technology now exists to find AFib in patients not otherwise suspected of having it,” said Leonard Lichtenfeld, MD, acting chief medical and scientific officer at the American Cancer Society in Atlanta, Georgia, “we need to look holistically at the care we can offer them” — weighing benefits of early detection in asymptomatic patients against the potential harm of overtreating them. 

“Do we really want to subject everyone out there to anticoagulants?” he asked. Or, more importantly, “Will doing so save lives or prevent more strokes? We don’t know.”


  1. National Institutes of Health. Heart problems: investigating the cardiac side effects of cancer treatments. Published September 21, 2018. Accessed June 30, 2119. 
  2. Hayek SS, Ganatra S, Lenneman C, et al. Preparing the cardiovascular workforce to care for oncology patients: JACC review topic of the week. J Am Coll Cardiol. 2019;73(17):2226-2235.
  3. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425-2437.