Front-Line Ibrutinib Improves Progression-Free Survival in Older Patients With Chronic Lymphocytic Leukemia

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IN A PHASE III TRIAL reported during the Plenary Session at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition and published in The New England Journal of Medicine, single-agent ibrutinib and ibrutinib/rituximab were associated with superior progression-free survival vs chemoimmunotherapy with rituximab/bendamustine among patients 65 years and older with untreated chronic lymphocytic leukemia (CLL).1,2 No difference was observed between ibrutinib alone and ibrutinib/rituximab.

Jennifer A. Woyach, MD

Jennifer A. Woyach, MD

The trial was coordinated by the Alliance for Clinical Trials in Oncology (Alliance) in collaboration with the National Cancer Institute Cancer Trials Support Unit. Jennifer A. Woyach, MD, of The Ohio State University Comprehensive Cancer Center, Columbus, presented the data.

Alliance Multicenter Phase III Trial

A TOTAL OF 547 PATIENTS with CLL, from 219 sites in the United States and Canada, were randomly assigned 1:1:1 between December 2013 and May 2016 to receive ibrutinib (n = 182), ibrutinib/rituximab (n = 182), or bendamustine/rituximab (n = 183). Patients had a median age of 71 years (ranging from 65 to 89 years), and 67% were men. Randomization was stratified by ZAP-70 methylation status, risk category according to modified Rai stage, and del(17p13.1) and del(11q22.3) status.

Treatment was given in 28-day cycles. Ibrutinib was given at 420 mg/d until unacceptable toxicity or disease progression. Ibrutinib/rituximab therapy consisted of ibrutinib given before rituximab on days when both drugs were given, with rituximab given at 375 mg/m2 weekly for 4 weeks starting on day 1 of cycle 2 and then on day 1 of cycles 3 through 6. Bendamustine/rituximab therapy consisted of 6 cycles of bendamustine at 90 mg/m2 on days 1 and 2 of each cycle, plus rituximab at 375 mg/ mon the day before day 1 of cycle 1, and then at 500 mg/m2 on day 1 of cycles 2 through 6.

Progression-Free Survival Rates

AT A MEDIAN follow-up of 38 months, the median progression-free survival was 43 months with bendamustine plus rituximab and was not reached for patients receiving ibrutinib alone or ibrutinib plus rituximab (hazard ratio = 0.37; one-sided P < .0001). There were no differences in outcomes for ibrutinib plus rituximab vs single-agent ibrutinib. The 2-year progression-free survival estimates were 74% for bendamustine plus rituximab, 87% for ibrutinib, and 88% for ibrutinib/rituximab, respectively.

Ibrutinib was superior to bendamustine plus rituximab in all subgroups except those with methylated ZAP-70 (which equates to mutated IgVH). Because the addition of rituximab was not beneficial, Dr. Woyach reported that she would consider using the ibrutinib/rituximab combination only in those with autoimmune hemolytic anemia or immune thrombocytopenia purpura or very high white blood cell counts.

At the time the study was reported, follow-up was still short and crossover was allowed. There were no significant differences in overall survival among the arms, and the median overall survival was not reached in any cohort. 

Safety and Toxicity

GRADES 3 TO 5 treatment-emergent adverse events were seen in 428 of 537 evaluable patients. Grade 3 or greater hematologic toxicity, especially neutropenia and thrombocytopenia, was seen in 61% of the bendamustine plus rituximab cohort, 41% of the ibrutinib monotherapy cohort, and 38% of patients receiving ibrutinib plus rituximab (P < .001). High-grade nonhematologic toxicities were observed in 63%, 74%, and 74%, respectively (P = .04). Up to 17% of patients receiving ibrutinib developed atrial fibrillation.

“[Bruton’s tyrosine kinase] inhibition with ibrutinib is not without significant toxicity in older patients, so close monitoring is warranted, and strategies to discontinue therapy are of interest,” Dr. Woyach said.

Clinical Implications

SUSAN M. O’BRIEN, MD, Associate Director for Clinical Science, Chao Family Comprehensive Cancer Center, University of California Irvine Health, was the discussant for the plenary abstract. Dr. O’Brien reported that the results were “potentially practice-changing,” although she cautioned that it is unclear whether oncologists will change the way they use ibrutinib because it already has a broad label.

“What is most important about this study is that it compared ibrutinib with bendamustine/rituximab, which is the most common treatment of CLL in the United States.”
— Susan M. O'Brien, MD

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“What is most important about this study is that it compared ibrutinib with bendamustine/rituximab, which is the most common treatment of CLL in the United States,” she said. Approval of ibrutinib in the front-line setting was based on the RESONATE-2 trial, which compared the drug with chlorambucil.3

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 said. “But the situation may be different for other small molecules. Based on early data, venetoclax 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?”

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 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. Woyach has consulted for Janssen and received research funding from MorphoSys, KaroPharma, Janssen, Ascerta, and AbbVie. Dr. O’Brien has consulted for or received research support from Amgen, Astellas, Celgene, GlaxoSmith-Kline, Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie, Alexion, Kite, Regeneron, Acerta, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis Pharmaceuticals.


1. Woyach JA, Ruppert AS, Heerema NA, et al: Ibrutinib regimens vs chemoimmunotherapy in older patients with untreated CLL. N Engl J Med 379:2517-2528, 2018.

2. Woyach JA, Ruppert AS, Heerma NA, et al: Ibrutinib alone or in combination with rituximab produces superior progression-free survival compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia. 2018 ASH Annual Meeting & Exposition. Abstract 6. Presented December 2, 2018.

3. 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.