First-Line Ibrutinib With or Without Rituximab vs Rituximab/Bendamustine in Older Patients With CLL


Key Points

  • Ibrutinib and ibrutinib/rituximab were associated with significantly prolonged progression-free survival vs bendamustine/rituximab.
  • No difference was observed for ibrutinib vs ibrutinib/rituximab.

In a phase III trial reported at the recent American Society of Hematology Annual Meeting & Exposition and in The New England Journal of Medicine by Woyach et al, ibrutinib (Imbruvica) and ibrutinib/rituximab (Rituxan) were associated with superior progression-free survival vs chemoimmunotherapy with rituximab/bendamustine among patients aged ≥ 65 years with untreated chronic lymphocytic leukemia (CLL). No difference was observed between ibrutinib alone and ibrutinib/rituximab.

The trial was coordinated by the Alliance for Clinical Trials in Oncology (Alliance) in collaboration with the National Cancer Institute Cancer Trials Support Unit.

Study Details

In the open-label trial, 547 patients 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 (range = 65–89 years), and 67% were men. Randomization was stratified by ZAP70 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. 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/m2 on the day before day 1 of cycle 1, and then at 500 mg/m2 on day 1 of cycles 2 through 6. Ibrutinib was given at 420 mg/d until unacceptable toxic effects or disease progression. Ibrutinib/rituximab therapy consisted of ibrutinib given before rituximab on days when both 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.

Patients in the bendamustine/rituximab group with disease progression could cross over to ibrutinib within 1 year after progression. The primary endpoint was progression-free survival according to International Workshop on CLL criteria.

Progression-Free Survival

The Alliance data and safety monitoring board made the decision to release the data in the current analysis after the protocol-specified efficacy threshold had been met; the decision was based on the protocol-specified second interim analysis of comparisons of the two ibrutinib-containing regimens with bendamustine/rituximab and first interim analysis for comparison of ibrutinib/rituximab with ibrutinib. Median follow-up was 38 months among the 481 patients who were alive at time of analysis.

Median progression-free survival was reached only with bendamustine/rituximab. Estimated progression-free survival at 2 years was 74% with bendamustine/rituximab vs 87% with ibrutinib alone (hazard ratio [HR] = 0.39, P < .001, vs bendamustine/rituximab) and vs 88% with ibrutinib/rituximab (HR = 0.38, P < .001). No significant difference was observed between ibrutinib/rituximab vs ibrutinib alone (HR = 1.00, P = .49). Subgroup analysis according to CLL risk factors showed a benefit of ibrutinib-containing regimens in all comparisons, although hazard ratios were not significant among patients with ZAP70-methylated disease.

At the time of analysis, there was no significant difference among the three treatment groups with regard to overall survival (P ≥ .65 for all pairwise comparisons). Estimated overall survival at 2 years was 95% with bendamustine/rituximab, 90% with ibrutinib, and 94% with ibrutinib/rituximab. Response rates were 81% with bendamustine/rituximab, 93% with ibrutinib, and 94% with ibrutinib/rituximab; however, complete response rates were 26% with bendamustine/rituximab, 7% with ibrutinib, and 12% with ibrutinib/rituximab.

Adverse Events

The incidence of grade 3 or 4 hematologic adverse events was 61% (grade 4 = 26%) with bendamustine/rituximab, compared with 41% (grade 4 = 8%) with ibrutinib and 39% (grade 4 = 12%) with ibrutinib/rituximab (overall P < .001). The incidence of grade ≥ 3 nonhematologic adverse events was 63% (grade 4 = 11%, grade 5 = 9%) with bendamustine/rituximab, compared with 74% (grade 4 = 7%, grade 5 = 13%) in the ibrutinib group and 74% (grade 4 = 7%, grade 5 = 12%) in the ibrutinib/rituximab group (overall P = .04). The most common grade 3 or 4 hematologic adverse event in the bendamustine/rituximab group was neutropenia (40%). The most common grade ≥ 3 nonhematologic adverse events in the ibrutinib and ibrutinib/rituximab groups were hypertension (29% and 34%) and infections (20% and 20%). 

The investigators concluded, “Among older patients with untreated CLL, treatment with ibrutinib was superior to treatment with bendamustine plus rituximab with regard to progression-free survival. There was no significant difference between ibrutinib and ibrutinib plus rituximab with regard to progression-free survival.”

Disclosure: The study was funded by the National Cancer Institute and Pharmacyclics. The study authors’ full disclosures can be found at

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.