2019年12月21日，德国萨尔兰大学医学院Viola Poeschel联合Westpfalz-Klinikum医院Gerhard Held研究团队在《柳叶刀》杂志发表论文，比较了4周期或6周期CHOP化疗+6剂利妥昔单抗治疗侵袭性B细胞淋巴瘤患者的预后。

六个周期的R-CHOP（利妥昔单抗+环磷酰胺+阿霉素+长春新碱+泼尼松）是治疗侵袭性B细胞非霍奇金淋巴瘤的标准方案。在先前的试验中，研究组发现四个周期CHOP联合六个周期利妥昔单抗治疗B细胞非霍奇金淋巴瘤的预后不劣于六个周期的R-CHOP治疗。

2005年12月2日至2016年10月7日，研究组在丹麦、以色列、意大利、挪威和德国的138个临床试验点进行了一项双臂、开放标签、国际性、多中心、前瞻性、随机、临床3期的非劣效性试验，共招募了592名18-60岁的B细胞非霍奇金淋巴瘤患者，I-II期，血清乳酸脱氢酶水平正常，ECOG表现状态0-1，最大肿瘤直径小于7.5厘米。将其按1：1随机分组，其中295名患者接受6个周期的R-CHOP方案治疗，297名患者接受4个周期的R-CHOP+2剂利妥昔单抗方案治疗。

共有588名患者纳入最终的意向治疗分析。中位随访66个月后，4周期R-CHOP+2剂利妥昔单抗组的3年无进展生存率为96%，比6周期R-CHOP组好3%，符合非劣效性标准。4周期组共发生294例血液学和1036例非血液学不良事件，6周期组则分别为426例和1280例。6周期组中有2名患者在治疗期间死亡。

总之，对于侵袭性B细胞非霍奇金淋巴瘤的年轻患者，4周期R-CHOP治疗的预后不劣于6周期R-CHOP，且毒性显著降低，值得临床推广。

附：英文原文

Title: 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

Author: Viola Poeschel, Gerhard Held, Marita Ziepert, Mathias Witzens-Harig, Harald Holte, Lorenz Thurner, Peter Borchmann, Andreas Viardot, Martin Soekler, Ulrich Keller, Christian Schmidt, Lorenz Truemper, Rolf Mahlberg, Reinhard Marks, Heinz-Gert Hoeffkes, Bernd Metzner, Judith Dierlamm, Norbert Frickhofen, Mathias Haenel, Andreas Neubauer, Michael Kneba, Francesco Merli, Alessandra Tucci, Peter de Nully Brown, Massimo Federico, Eva Lengfelder, Alice di Rocco, Ralf Trappe, Andreas Rosenwald, Christian Berdel, Martin Maisenhoelder, Ofer Shpilberg, Josif Amam, Konstantinos Christofyllakis, Frank Hartmann, Niels Murawski, Stephan Stilgenbauer, Maike Nickelsen, Gerald Wulf, Bertram Glass, Norbert Schmitz, Bettina Altmann, Markus Loeffler, Michael Pfreundschuh

Issue&Volume: 2019/12/21

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/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.

DOI: 10.1016/S0140-6736(19)33008-9

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)33008-9/fulltext