Expert Point of View: Susan M. O’Brien, MD

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Susan M. O’Brien, MD

Susan M. O’Brien, MD

THE STUDY’S discussant, Susan M. O’Brien, MD, Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center, University of California Irvine Health, said the results of the Alliance North American Intergroup Study A041202—demonstrating that ibrutinib (Imbruvica) is more effective than bendamustine plus rituximab (Rituxan)—are “potentially practice-changing.” The caveat is that the drug already has a broad label, and it is unclear whether oncologists will change the way they use it, she told The ASCO Post.

“What is most important about this study is that it compared ibrutinib with bendamustine/rituximab, which is the most common treatment of chronic lymphocytic leukemia (CLL) in the United States,” she said. Approval of ibrutinib in the front-line setting was based on the RESONATE-2 trial, which compared it with chlorambucil.1

Different Paradigm Than in Lymphoid Malignancies

THE STUDY also showed that ibrutinib alone was as effective as ibrutinib plus rituximab, which is unlike the benefit seen with anti-CD20 antibodies plus chemotherapy in lymphoid malignancies. “It’s very different from the paradigm in lymphoid malignancies (lymphoma, acute lymphocytic leukemia), where when you add an antibody to chemotherapy you have significantly better outcomes,” Dr. O’Brien pointed out. “But the situation may be different for other small molecules. Based on early data, venetoclax (Venclexta) appears to be synergistic with anti-CD20 antibodies. From the current study, it’s very clear that the only advantage of using rituximab with ibrutinib is to produce a much faster response.”

Single-agent ibrutinib often produces lymphocytosis, which must gradually resolve before a response can be confirmed. Resolution happens much faster with an antibody on board, she explained. “We knew this from the phase II studies, but the important question was this: Other than getting a faster response, which arguably may or may not be important, did the combination of ibrutinib plus rituximab result in more durable responses?”

Second Trial to Study This Treatment

THE CURRENT study is the second trial to evaluate ibrutinib with and without rituximab. At the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition, a study from The University of Texas MD Anderson Cancer Center evaluated this approach in previously treated patients with CLL, finding no difference between the single agent and the combination in 24-month progression-free survival (approximately 94% in each arm) or overall survival, although the combination led to faster complete responses.2

“The curves were not only the same; they were overlapping,” Dr. O’Brien said. “But this was in a predominantly relapsed population, and you could argue that they were exposed to rituximab in the first-line setting and could have some resistance to the drug. The current study is in the front-line setting, so there is no issue with prior exposure to rituximab and the impact of that.”

Clinical Implications

DR. O’BRIEN concluded that although the findings of the Alliance trial may lead to more front-line use of ibrutinib as a single agent, some oncologists may still keep the drug in reserve, based on the lack of an overall survival benefit and its strong benefit in the salvage setting.

“If a patient is not likely to be cured, the physician is always thinking about how to sequence the available drugs. I’ve heard physicians say, ‘I can use chemotherapy upfront and get at 2 to 3 years of remission, or even more. I can get 4 years out of bendamustine/rituximab. Then I can give ibrutinib, and I know it works great as a salvage regimen. I’ll still get several more years.’ So, they’d rather give chemotherapy upfront because it’s more difficult to give this when the patient gets older. Some will save ibrutinib for later.”

DISCLOSURE: Dr. O’Brien has consulted for or received research support from Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie, Alexion, Kite, Regeneron, Acerta, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis Pharmaceuticals.


1. Burger JA, Tedeschi A, Barr PM, et al: Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373:2425-2437, 2015.

2. Burger JA, Sivina M, Ferrajoli A, et al: Randomized trial of ibrutinib versus ibrutinib plus rituximab in patients with chronic lymphocytic leukemia (CLL). 2017 ASH Annual Meeting & Exposition. Abstract 427. Presented December 9, 2017.

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