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.

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在积极预后良好的侵袭性B细胞淋巴瘤（FLYER）患者中，将CHOP化疗的四个周期与六个周期的化疗联合六次利妥昔单抗的应用：一项随机，三期，非劣效性试验。

背景技术R-CHOP的六个周期（利妥昔单抗加环磷酰胺，阿霉素，长春新碱和泼尼松）是侵袭性B细胞非霍奇金淋巴瘤的标准治疗方法。在FLYER试验中，我们评估了在预后良好的B细胞非霍奇金淋巴瘤患者群体中，四个周期的CHOP加六次利妥昔单抗是否不逊于六个周期的R-CHOP。方法这项两臂，开放标签，国际性，多中心，前瞻性，随机性第3期非劣效性试验在丹麦，以色列，意大利，挪威和德国的138个临床地点进行。我们招募了年龄在18至60岁之间，患有I-II期疾病，血清乳酸脱氢酶浓度正常，ECOG功能状态为0-1，无大块疾病（最大肿瘤直径<7·5 cm）的患者。随机化是基于计算机的，在中心，阶段（I vs II）和淋巴外部位（否与是）分层之后，使用Pocock最小化算法以1：1的比例集中进行。患者被分配接受六个周期的R-CHOP或四个周期的R-CHOP加上两剂利妥昔单抗。CHOP包括环磷酰胺（750 mg / m2），阿霉素（50 mg / m2）和长春新碱（1·4 mg / m2，最大总剂量为2 mg），均在第1天静脉内给药，再加上口服泼尼松或泼尼松龙在第1-5天服用的研究者（100 mg）酌情决定。利妥昔单抗的剂量为体表面积375 mg / m2。每21天重复一次循环。除睾丸淋巴瘤治疗外，未计划放疗。主要终点是3年后无进展生存。初步分析是在意向性治疗人群中进行的。在接受至少一剂指定治疗的所有患者中评估安全性。选择的非劣性余量为-5·5％。该试验已完成，预期已在ClinicalTrials.gov上注册为NCT00278421。结果在2005年12月2日至2016年10月7日之间，共有592例患者入组，其中295例患者被随机分配接受6个周期的R-CHOP治疗，297例患者被分配接受4个周期的R-CHOP治疗和2剂量的利妥昔单抗治疗。四周期组中的四名患者在开始治疗前撤回了知情同意书，因此有588名患者被纳入了意向性治疗分析。在平均随访66个月（IQR 42-100）之后，进行了四个周期的R-CHOP加两次利妥昔单抗治疗的患者的3年无进展生存率为96％（95％CI 94-99），提高了3％（单侧95％CI的下限因为R-CHOP的六个周期的差异为0％），证明了四周期方案的非劣效性。在四个疗程组中记录了294例血液学不良事件和1036例非血液学上的不良事件，而在六个疗程组中则记录了426例血液学和1280例非血液学不良事件。六个周期组中的两名患者在研究治疗期间死亡。解释在年轻的侵袭性B细胞非霍奇金淋巴瘤患者和预后良好的年轻患者中，四个周期的R-CHOP不劣于六个周期的R-CHOP，并相应降低了毒性作用。因此，可以减少化疗而不会影响该人群的预后。资金筹集德意志·克雷布希尔夫。