Elsevier

The Lancet

Volume 381, Issue 9873, 6–12 April 2013, Pages 1203-1210
The Lancet

Articles
Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial

https://doi.org/10.1016/S0140-6736(12)61763-2Get rights and content

Summary

Background

Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.

Methods

We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m2 on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m2 on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.

Findings

274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25–57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69·5 months [26·1 to not yet reached] vs 31·2 months [15·2–65·7]; hazard ratio 0·58, 95% CI 0·44–0·74; p<0·0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0·0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0·0001), infections (96 [37%] vs 127 [50%]); p=0·0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0·0001), and stomatitis (16 [6%] vs 47 [19%]; p<0·0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0·024).

Interpretation

In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.

Funding

Roche Pharma AG, Ribosepharm/Mundipharma GmbH.

Introduction

Non-Hodgkin lymphoma is the sixth most common cancer in the USA, with 66 000 new cases diagnosed every year.1 Indolent or low-grade lymphomas represent 40% of all subtypes of non-Hodgkin lymphoma, of which follicular lymphoma is the most frequent.2 Indolent lymphomas are characterised by a chronic relapsing-remitting disease course, with patients usually exposed to several successive treatment courses. Mantle-cell lymphoma, which accounts for about 3–10% of all non-Hodgkin lymphomas, has a poorer prognosis than other types of non-Hodgkin lymphoma.

Rituximab—an anti-CD20 monoclonal antibody—is established for the treatment of non-Hodgkin lymphoma.3 Chemoimmunotherapy with rituximab is a standard of care for the first-line treatment of patients with advanced follicular and mantle-cell lymphomas in view of it being more effective than chemotherapy alone.4, 5, 6, 7, 8, 9 Guidelines from the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) recommend that in patients with follicular lymphoma, rituximab should be used in combination with one of several chemotherapy regimens, including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), CVP (cyclophosphamide, vincristine, and prednisolone), fludarabine and cyclophosphamide (with or without mitoxantrone), and single-agent fludarabine.10, 11 Although CHOP plus rituximab (R-CHOP) is the most widely used of these regimens,12 there are no randomised comparative study data to show that one regimen is better than another. Treatment choices are usually made on the basis of the patient's ability to tolerate chemotherapy, which is generally guided by age, performance status, and comorbidities. The long-term cardiotoxic potential of anthracyclines can also detract from regimens incorporating doxorubicin.

Although bendamustine is used and has been approved for more than 20 years in Germany, it only gained approval for the management of lymphoid malignancies in the USA in 2008, and the European Union in 2010. As a cytotoxic alkylating drug, bendamustine has a favourable tolerability profile and is highly effective as monotherapy or combined with rituximab for patients with relapsed or refractory lymphoid malignancies.13, 14, 15, 16, 17 On the basis of the longstanding experience with bendamustine in Germany, we postulated that bendamustine plus rituximab would be non-inferior to R-CHOP in terms of efficacy, and would be better tolerated. We therefore assessed the efficacy and safety of bendamustine plus rituximab versus R-CHOP as first-line treatment for patients with indolent or mantle-cell lymphoma.

Section snippets

Study design and patients

We undertook this multicentre, randomised, non-inferiority, open-label, phase 3 study at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years and older with a WHO performance status of 2 or less were eligible for inclusion if they had a histologically confirmed diagnosis of mantle-cell lymphoma or indolent non-Hodgkin lymphoma, including the following CD20-positive subtypes:2 follicular (grade 1 and 2), lymphoplasmacytic (Waldenström's macroglobulinaemia), small

Results

Figure 1 shows the trial profile. 274 patients were assigned to the bendamustine plus rituximab group and 275 to the R-CHOP group. 35 patients were excluded, leaving 514 patients for analysis (figure 1).

Baseline characteristics and numbers of patients in specific histology subgroups were similar between the treatment groups (table 1). More than half the patients had follicular lymphoma and about a fifth had mantle-cell lymphoma (table 1). Within the histological subgroups, the median age of

Discussion

Our findings show that bendamustine and rituximab significantly improved progression-free survival compared with R-CHOP. Furthermore, bendamustine plus rituximab significantly increased rate of complete response and time to next lymphoma treatment. Notably, progression-free survival significantly improved with bendamustine and rituximab in three of four histological subgroups. This improvement is particularly notable for mantle-cell lymphoma, which has a more aggressive disease course than

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