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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/m 2 ), doxorubicin (50 mg/m 2 ), and vincristine (1·4 mg/m 2 , 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/m 2 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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects., Methods: In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907., Findings: The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03-119), 6-year event-free survival was 55·8% (95% CI 50·4-60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3-78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5-25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2-90·7] vs 71·0% [65·1-76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6-6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2-6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730)., Interpretation: Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone., Funding: Hoffmann-La Roche., (Copyright © 2011 Elsevier Ltd. All rights reserved.)