Elsevier

The Lancet

Volume 378, Issue 9806, 26 November–2 December 2011, Pages 1858-1867
The Lancet

Articles
Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial

https://doi.org/10.1016/S0140-6736(11)61040-4Get rights and content

Summary

Background

The outcome of diffuse large B-cell lymphoma has been substantially improved by the addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy regimens. We aimed to assess, in patients aged 18–59 years, the potential survival benefit provided by a dose-intensive immunochemotherapy regimen plus rituximab compared with standard treatment plus rituximab.

Methods

We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18–59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595.

Findings

One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75–86) in the R-ACVBP group and 67% (59–73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38–0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81–91] vs 73% [66–79]; HR 0·48 [0·30–0·76]; p=0·0015) and overall survival (92% [87–95] vs 84% [77–89]; HR 0·44 [0·28–0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3–4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183]).

Interpretation

Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18–59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable.

Funding

Groupe d'Etudes des Lymphomes de l'Adulte and Amgen.

Introduction

Diffuse large B-cell lymphoma is the most common haemopoietic malignancy, accounting for 25% of all lymphoid neoplasms.1 The clinical course of diffuse large B-cell lymphoma has greatly changed over the past 10 years, since the introduction of the chimeric monoclonal anti-CD20 antibody rituximab for the treatment of patients with lymphoma. A pivotal trial done in 1998 by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) showed that combining rituximab with standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy significantly improved response, event-free survival, and overall survival compared with CHOP alone in patients older than 60 years.2, 3 These favourable results have been confirmed by three additional randomised trials in patients both younger and older than 60 years with diffuse large B-cell lymphoma.4, 5, 6 However, despite these significant improvements, some patients are refractory to initial treatment or can relapse after a complete response. In cases where the disease is refractory to immunochemotherapy, the estimate of progression-free survival at 3 years is only 23%, even with subsequent high-dose chemotherapy and autologous stem-cell transplantation.7 This situation emphasises the importance of first-line treatment when crucial issues are still unresolved, such as establishing the optimum rituximab dose and schedule as well as the optimum chemotherapy regimen to combine with rituximab.

Two randomised studies done in the so-called pre-rituximab era showed that the intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone chemotherapy regimen (ACVBP) with subsequent sequential consolidation, compared with standard CHOP, can improve the outcome both in low-risk8 and high-risk9 groups of patients, according to the International Prognostic Index for aggressive lymphoma.10 Similarly, the Deutsche Studiengruppe Hochmaligne Non-Hodgkin-Lymphome11 showed that the addition of etoposide to CHOP improves the event-free survival of patients younger than 60 years with aggressive lymphoma. However, in a subsequent study assessing the outcomes of a subgroup of patients receiving CHOP plus etoposide in combination with rituximab compared with those receiving CHOP in combination with rituximab, the advantage conferred by CHOP plus etoposide disappeared, leading to the hypothesis that rituximab could have an equalising effect on differences exhibited by chemotherapy regimens.5

To prospectively assess the role of a dose-intensive regimen in combination with rituximab, GELA in 2003 started a multicentre, phase 3, open-label, randomised trial (LNH03-2B), comparing the efficacy and safety of ACVBP plus rituximab (R-ACVBP) versus standard CHOP plus rituximab (R-CHOP) in a selected population of patients aged 18–59 years with diffuse large B-cell lymphoma.

Section snippets

Participants

Between December, 2003, and December, 2008, in accordance with our protocol, we did a phase 3 multicentre randomised trial in 73 haematology or oncology departments of GELA in France, Belgium, and Switzerland. Patients were eligible if they were aged 18–59 years and had untreated diffuse large B-cell lymphoma that had been diagnosed in accordance with the WHO classification.12 We required that patients had only one adverse prognostic factor as defined by the age-adjusted International

Results

Figure 2 shows the trial profile. We enrolled 380 patients into our trial, of which 379 received at least one dose of the protocol-planned treatment. The main characteristics of our patients were similar in the two groups (table 1). The main criteria providing an age-adjusted International Prognostic Index score of 1 were raised lactate dehydrogenase concentration and Ann Arbor stage III–IV in 44% and 55% of patients, respectively. 21 patients had an age-adjusted International Prognostic Index

Discussion

After more than 3 years of follow-up, all our study endpoints were met, with significant improvements of event-free, progression-free, disease-free, and overall survival in patients treated with R-ACVBP.

The introduction of rituximab in association with CHOP chemotherapy has substantially improved the outcome of patients with diffuse large B-cell lymphoma. However, the results of the R-CHOP regimen, which has been widely thought the standard of care, remains suboptimum in the treatment of

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