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

Abstract

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.

Australian and New Zealand consensus statement on the management of lymphoma, chronic lymphocytic leukaemia and myeloma during the COVID‐19 pandemic

“…We suggest considering four cycles of R‐CHOP if the end of treatment PET is negative, as a number of studies has demonstrated, this is likely comparable with six cycles of R‐CHOP (II). This is most applicable in patients with an age‐adjusted IPI = 0 and age < 60, although the S1001 study suggests that this approach may be applicable more broadly (III) …”

FDG-PET Imaging for Hodgkin and Diffuse Large B-Cell Lymphoma—An Updated Overview

“…As standard treatment, patients receive six chemotherapy cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone alongside the monoclonal antibody rituximab (R-CHOP). Unlike early-stage disease, which can be considered for brief chemotherapy [19], advanced DLBCL with high risk, as defined by the International Prognostic Index, may require intensified treatment, including central nervous system prophylaxis [20,21]. The role of radiotherapy is still under discussion in DLBCL.…”

Impact on survival through consolidation radiotherapy for diffuse large B-cell lymphoma: a comprehensive meta-analysis

“…36 The FLYER trial established four cycles of R-CHOP to be sufficient for patients with favorable risk (and non-bulky) DLBCLs. 37 Radiotherapy in this trial was limited to the contralateral testis in case of testicular involvement. In the yet unpublished OPTIMAL>60 trial (NCT014778542), radiotherapy (and two additional cycles of chemotherapy) is given just to PET-positive sites after four cycles of chemotherapy.…”

“…According to an interim analysis, this can compensate the inferior outcome of this population. 37 Furthermore, the authors of this trial communicated that radiotherapy to PETnegative bulky disease is not needed. 38 In the latest ESMO guidelines, consolidation radiotherapy for DLBCL patients is recommended for both elderly and intermediate-and high-risk young patients with bulky disease.…”