ArticlesIntensified 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
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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