Elsevier

The Lancet

Volume 394, Issue 10216, 21 December 2019–3 January 2020, Pages 2271-2281
The Lancet

Articles
Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial

https://doi.org/10.1016/S0140-6736(19)33008-9Get rights and content

Summary

Background

Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.

Methods

This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18–60 years, with stage I–II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0–1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1–5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of −5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.

Findings

Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42–100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94–99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.

Interpretation

In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.

Funding

Deutsche Krebshilfe.

Introduction

In aggressive B-cell non-Hodgkin lymphoma, CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy in combination with rituximab is standard of care.1, 2, 3 Although heterogeneous in its biology, the outcome of the disease can be predicted by the clinical parameters of age, tumour stage, serum lactate dehydrogenase concentration, performance status, and number of involved extralymphatic sites. These characteristics have been subsumed in the international prognostic index (IPI),4 which reliably separates patients into distinct prognostic subgroups.5 For younger patients (≤60 years), the age-adjusted model of the IPI (including LDH, stage, and performance status) has been established. Patients without age-adjusted IPI risk factors and without bulky disease (ie, maximum lymphoma diameter <7·5 cm) have a very favourable prognosis with a 3-year progression-free survival of 95%, an event-free survival of 89%, and an overall survival of 98%, when treated with six cycles of combined immunochemotherapy with R-CHOP-like regimens.2, 6 However, very high cure rates with cytotoxic therapies suggest overtreatment of most patients at least. Accordingly, the benefit in efficacy might come at the cost of unnecessary and potentially severe toxic effects for all patients. Therefore, we hypothesised and tested whether only four cycles of CHOP plus six applications of rituximab are non-inferior to the standard treatment of six cycles of R-CHOP in this population.

Research in context

Evidence before this study

Rituximab in combination with six to eight cycles of CHOP chemotherapy (R-CHOP) has been established as standard treatment for diffuse large B-cell lymphoma. We searched PubMed with the search terms “lymphoma”, “DLBCL”, “trial”, and “rituximab”, in English, published between Jan 1, 2002, and Dec 4, 2019. Three randomised trials demonstrated that rituximab improved event-free, progression-free, and overall survival compared with CHOP chemotherapy alone, resulting in a halving of lymphoma-related deaths in these trials. Since then, many trials have failed to improve therapy, suggesting that a plateau of efficacy has been reached with R-CHOP, especially in the subgroup of patients with good prognosis. Prognosis of aggressive non-Hodgkin lymphoma can be established by the International Prognostic Index (IPI), using the clinical parameters of age, tumour stage, serum lactate dehydrogenase concentration, performance status, and number of involved extralymphatic sites. The IPI was established in the pre-rituximab era. Pooled analyses of prospective, randomised trials confirmed the validity of IPI for R-CHOP regimens as well. Patients younger than 60 years without risk factors such as stage III–IV disease, increased serum lactate dehydrogenase concentration, poor performance status, and bulky disease (defined as maximum lymphoma diameter ≥7·5 cm) had a 3-year progression-free survival of 95% (95% CI 90–99) and an overall survival of 98% (95–100), when treated with six cycles of R-CHOP or R-CHOP-like regimens in the MInT trial.

Added value of this study

To our knowledge, this study is the first phase 3 study in aggressive B-cell lymphoma since rituximab was introduced, which showed that the treatment paradigm of six cycles of R-CHOP can be changed. It demonstrates that CHOP chemotherapy can be safely reduced to four cycles in young patients (≤60 years) with no risk factor according to the age-adjusted IPI and no bulky disease. Given this excellent outcome, it appears that some patients might be overtreated with six to eight cycles of R-CHOP.

Implications of all the available evidence

We consider these results to be potentially practice changing. Based on the current data, four cycles of CHOP combined with six doses of rituximab are non-inferior to six cycles of CHOP combined with six doses of rituximab in young low-risk patients with aggressive B-cell lymphoma.

Section snippets

Study design and participants

The investigator-initiated FLYER study was a two-arm, open-label, international, multicentre, prospective, randomised phase 3 trial from 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. It was coordinated by the German High-grade Non-Hodgkin's Lymphoma Study Group, which is now part of the German Lymphoma Alliance. The study was conducted in accordance with the Helsinki declaration. The protocol and its amendments were approved by the ethics committee of each participating

Results

From Dec 2, 2005, to Oct 7, 2016, 592 patients were enrolled and randomly assigned to either four cycles of R-CHOP plus two cycles of rituximab (n=297) or six cycles of R-CHOP (n=295). Four patients in the four-cycles group withdrew their informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis (figure 1).

Baseline characteristics were well balanced except B symptoms, with 27 (9%) of 293 patients in the four-cycles group and nine (3%)

Discussion

Young patients with aggressive B-cell non-Hodgkin lymphoma and no IPI risk factors, such as the population included in our study, have an excellent prognosis. We showed that reduction of chemotherapy to four cycles of R-CHOP plus two cycles of rituximab from the standard six cycles of R-CHOP results in similar progression-free survival after 3 years, which was the primary endpoint of this study, demonstrating the non-inferiority of four cycles compared with the six cycles. Also, no difference

Data sharing

Individual data will be made available as well as data dictionaries. Data that underlie the main results reported in this Article, will be shared after de-identification. The study protocol is available in the appendix (pp 49–160). Pseudonymised data will be available upon request up to 5 years after publication of this Article to researchers who provide a data sharing agreement that describes a methodically sound proposal and the data necessary for the purpose of the approved proposal.

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    *

    Contributed equally

    Contributed equally

    A complete list of investigators in the FLYER trial is provided in the appendix pp 3–10

    §

    Prof M Pfreundschuh died in March, 2018

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