Elsevier

The Lancet Oncology

Volume 17, Issue 7, July 2016, Pages 928-942
The Lancet Oncology

Articles
First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial

https://doi.org/10.1016/S1470-2045(16)30051-1Get rights and content

Summary

Background

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab.

Methods

Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33–81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1:1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days or to intravenous bendamustine (90 mg/m2 per day) for the first 2 days of each cycle. Rituximab 375 mg/m2 was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m2 during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67·5% or less with a corresponding non-inferiority margin of 1·388 for the hazard ratio (HR) based on the 90·4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT%2000769522.

Findings

688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37·1 months (IQR 31·0–45·5) median progression-free survival was 41·7 months (95% CI 34·9–45·3) with bendamustine and rituximab and 55·2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1·643, 90·4% CI 1·308–2·064). As the upper limit of the 90·4% CI was greater than 1·388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years.

Interpretation

The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects.

Funding

Roche Pharma AG, Mundipharma, German Federal Ministry of Education and Research.

Introduction

Chronic lymphocytic leukaemia, the most common leukaemia in high-income countries, had been considered as incurable by conventional therapies.1 In general, younger patients with chronic lymphocytic leukaemia have a reduced life expectancy.1 The introduction of antibody-based chemoimmunotherapy has improved the outcome of younger patients by inducing long-lasting and possibly durable remissions with a median progression-free survival of up to 80 months in subgroups of patients.2, 3, 4 Following the results of a phase 2 study by the MD Anderson Cancer Center2 and a phase 3 study by the German CLL Group, the CLL8 study,5 fludarabine, cyclophosphamide, and rituximab have become the standard front-line therapy for physically fit patients with chronic lymphocytic leukaemia. However, this regimen is associated with substantial toxic effects, most importantly severe haematotoxicity in 56% of patients and severe infections in 25% of patients during treatment. A long-term follow-up of patients treated with fludarabine, cyclophosphamide, and rituximab showed prolonged neutropenia in 17–35% and an elevated risk of secondary neoplasia.4, 6, 7

Research in context

Evidence before this study

We searched PubMed between April 1, 2007, and Jan 31, 2008 for reports with the search terms “CLL”, and “clinical trial” and “chemotherapy” and “antibody” without date or language restrictions. Publications showed promising results for chemoimmunotherapy regimens based on purine analogues with or without CD20 antibodies or with the CD52 antibody alemtuzumab. First data from the CLL8 study of the German CLL Study Group presented at the American Society of Hematology Meeting in December, 2007, showed the superiority of the fludarabine, cyclophosphamide, and rituximab regimen over chemotherapy alone. On the other hand, all purine analogue-based combinations were associated with toxic effects. First data from a phase 2 trial evaluating bendamustine and rituximab had favourable results with regard to toxic effects and good efficacy. In 2007, the National Institutes of Health registry for clinical trials listed no clinical trials with a head-to-head comparison of fludarabine, cyclophosphamide, and rituximab with bendamustine and rituximab in chronic lymphocytic leukaemia.

Added value of this study

The CLL10 study is the first trial directly comparing bendamustine-based chemoimmunotherapy with fludarabine and cyclophosphamide-based chemoimmunotherapy. The data confirm data from a meta-analysis suggesting the superiority of fludarabine and cyclophosphamide-based chemoimmunotherapy over bendamustine-based chemoimmunotherapy.

Implications of all the available evidence

In a head-to-head comparison bendamustine and rituximab is less effective than the standard therapy, but can be considered in patients older than 65 years with chronic lymphocytic leukaemia. Higher incidence of adverse events observed with fludarabine, cyclophosphamide, and rituximab in patients older than 65 years and good efficacy with bendamustine and rituximab in this group might support the use of bendamustine and rituximab in fit elderly patients. Moreover, our data show that immunosuppressive effects are long lasting with fludarabine and cyclophosphamide-based therapy. Prophylactic use of co-trimoxazole against Pneumocystis jirovecii pneumonia or virostatics against herpes virus infections in patients with previous infections should be considered in patients receiving front-line chemoimmunotherapy.

The combination of the alkylating agent bendamustine and rituximab has shown promising results in a phase 2 study in front-line therapy of chronic lymphocytic leukaemia with overall responses in 103 (88%) of 117 patients and complete responses in 27 (23%) of 117 patients.8 Event-free survival of 34 months and low incidence of severe neutropenia (20%) and infections (8%) led to the hypothesis that front-line treatment with bendamustine and rituximab might be similarly effective but less toxic compared with the standard treatment.

Therefore, the German CLL Study Group did an international phase 3 study to test the non-inferiority of bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in front-line therapy of fit patients with chronic lymphocytic leukaemia, but without del(17p).

Section snippets

Study design and participants

We did a randomised, open-label, phase 3, non-inferiority study in previously untreated fit patients aged 33–81 years with advanced chronic lymphocytic leukaemia who required treatment according to the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria9 and had an Eastern Cooperative Oncology Group (ECOG) status of 0–2.

Treatment-naive patients diagnosed with chronic lymphocytic leukaemia were registered for central screening, which was done by the German CLL Study Group

Results

688 patients with previously untreated but advanced chronic lymphocytic leukaemia were recruited between Oct 2, 2008, and July 11, 2011 from 158 sites, including university hospitals, community hospitals, and private oncology practices in five countries (Germany, Austria, Switzerland, Denmark, and Czech Republic), participated in the trial (appendix). After central screening, 124 patients were not eligible for trial participation. 564 patients (aged 33–81 years) who met the inclusion criteria

Discussion

This phase 3 study investigating the non-inferiority of chemoimmunotherapy with bendamustine and rituximab compared with the standard front-line therapy of fludarabine, cyclophosphamide, and rituximab regimen for patients with chronic lymphocytic leukaemia with a low comorbidity burden found that bendamustine and rituximab resulted in significantly shorter progression-free survival, and lower proportions of patients achieving complete remission and minimal residual disease negativity. This

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