“The data reaffirm the long-term efficacy of ibrutinib in CLL,” said Jennifer Woyach, MD, who researches leukemia at Ohio State University Comprehensive Cancer Center, Columbus, and who served as senior author of the study.

OS was harder to determine because of the crossover allowance on the extended study. Six years after randomization, OS was 67.7 months for the ibrutinib arm and 65.1 months for the ofatumumab arm. To isolate the difference between the 2 treatments, the researchers performed an analysis known as rank-preserving structural failure time. The analysis showed “a clear difference between the 2 arms,” says Talha Munir, MD, consultant hematologist at St. James’s Hospital in the United Kingdom and a lead author of the study.

The results confirm the frequent updates of the data over the past few years. In fact, the complete remission rate increased by 11% among patients taking ibrutinib between the initial publication and the final analysis, notes Matthew Davids, MD, assistant professor of medicine at Harvard Medical School, Boston, Massachusetts, and associate director of the CLL Center at Dana-Farber Cancer Institute. However, noted Dr Davids, who was not involved with the study, “indefinite therapy is required to achieve and maintain those responses.” Still, the new study clarifies the initial results. “These data,” said Dr Davids, “support using ibrutinib in preference to ofatumumab in this population.”

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Cardiovascular toxicity has been a major concern with ibrutinib therapy. This side effect was noted in the original RESONATE report, and further investigations have sought to pinpoint exactly which patients are at risk and why. Dr Woyach coauthored a study of ventricular arrhythmias (VA) tied to ibrutinib in the treatment of lymphoid malignancies using 7 years of data from patients treated with the drug.4 Based on the 582 patients included in the data collection in that study, ibrutinib posed a “markedly increased risk of incident VA events in long-term follow-up,” the authors wrote.

More recently, a group of international researchers sought to identify and characterize cardiac toxicity associated with ibrutinib.5 Using an International pharmacovigilance database, the authors found 303 individuals who died from cardiovascular events related to treatment with ibrutinib. The drug, they noted, was tied to supraventricular arrhythmias, central nervous system hemorrhagic events, ventricular arrhythmias, conduction disorders, and other serious cardiovascular issues. “These events should be considered in patient care and in clinical trial designs,” the authors wrote.

Although cardiovascular toxicity is a concerning risk factor with ibrutinib, it doesn’t preclude use of the drug. Newer and more selective inhibitors of Bruton tyrosine kinase (BTK) — the target of ibrutinib — are now in development, noted Dr Davids, and studies will investigate whether they provoke fewer cardiovascular events. In addition, said Dr Munir, the data in the most recent study on cardiac toxicity were based largely on patients who had received multiple lines of prior therapy and therefore, do not necessarily represent the CLL/SLL population as a whole. “The majority of toxicity with ibrutinib is treatable,” noted Dr Munir. The benefit of using an effective drug like ibrutinib still appears to outweigh the risks, said Dr Woyach. Patients need to be monitored closely for cardiovascular toxicity, she added, but the concern should not prevent clinicians from offering the drug to their patients.

Investigators are also focused on other areas of further improvement. For example, some patients develop resistance to ibrutinib through a BTKC481S mutation. Several new drugs, including vecabrutinib, ARQ-531, and LOXO-305, which may overcome this mutation, are now being explored, noted Dr Davids. And combining ibrutinib with venetoclax or another new drug may achieve extensive remissions that enable patients to avoid prolonged therapy.

“Targeted therapy with ibrutinib for relapsed CLL has changed the natural history of the disease,” Dr Munir and colleagues concluded in their paper.2 As the research leads to further treatment advances, that natural history is likely to change even further. 

Disclosure: Some of the authors of the main paper being discussed disclosed the receipt of financial support from various pharmaceutical companies. For a full list of disclosures, please refer to the original paper.


  1. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
  2. Munir T, Brown JR, O’Brien S, et al. Final analysis from RESONATE: up to 6 years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma [published online September 11, 2019]. Am J Hematol. doi: 10.1002/ajh.25638
  3. O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910-1919.
  4. Guha A, Derbala MH, Zhao Q, et al. Ventricular arrhythmias following ibrutinib initiation for lymphoid malignancies. J Am Coll Cardiol. 2018;72(6):697-609.
  5. Salem JE, Manouchehri A, Bretagne M, et al. Cardiovascular toxicities associated with ibrutinib. J Am Coll Cardiol. 2019;74(13):1667-1678.