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
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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. / Poeschel, Viola; Held, Gerhard; Ziepert, Marita; Witzens-Harig, Mathias; Holte, Harald; Thurner, Lorenz; Borchmann, Peter; Viardot, Andreas; Soekler, Martin; Keller, Ulrich; Schmidt, Christian; Truemper, Lorenz; Mahlberg, Rolf; Marks, Reinhard; Hoeffkes, Heinz-Gert; Metzner, Bernd; Dierlamm, Judith; Frickhofen, Norbert; Haenel, Mathias; Neubauer, Andreas; Kneba, Michael; Merli, Francesco; Tucci, Alessandra; de Nully Brown, Peter; Federico, Massimo; Lengfelder, Eva; di Rocco, Alice; Trappe, Ralf; Rosenwald, Andreas; Berdel, Christian; Maisenhoelder, Martin; Shpilberg, Ofer; Amam, Josif; Christofyllakis, Konstantinos; Hartmann, Frank; Murawski, Niels; Stilgenbauer, Stephan; Nickelsen, Maike; Wulf, Gerald; Glass, Bertram; Schmitz, Norbert; Altmann, Bettina; Loeffler, Markus; Pfreundschuh, Michael; FLYER Trial Investigators.
in: LANCET, Jahrgang 394, Nr. 10216, 21.12.2019, S. 2271-2281.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - 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
AU - Poeschel, Viola
AU - Held, Gerhard
AU - Ziepert, Marita
AU - Witzens-Harig, Mathias
AU - Holte, Harald
AU - Thurner, Lorenz
AU - Borchmann, Peter
AU - Viardot, Andreas
AU - Soekler, Martin
AU - Keller, Ulrich
AU - Schmidt, Christian
AU - Truemper, Lorenz
AU - Mahlberg, Rolf
AU - Marks, Reinhard
AU - Hoeffkes, Heinz-Gert
AU - Metzner, Bernd
AU - Dierlamm, Judith
AU - Frickhofen, Norbert
AU - Haenel, Mathias
AU - Neubauer, Andreas
AU - Kneba, Michael
AU - Merli, Francesco
AU - Tucci, Alessandra
AU - de Nully Brown, Peter
AU - Federico, Massimo
AU - Lengfelder, Eva
AU - di Rocco, Alice
AU - Trappe, Ralf
AU - Rosenwald, Andreas
AU - Berdel, Christian
AU - Maisenhoelder, Martin
AU - Shpilberg, Ofer
AU - Amam, Josif
AU - Christofyllakis, Konstantinos
AU - Hartmann, Frank
AU - Murawski, Niels
AU - Stilgenbauer, Stephan
AU - Nickelsen, Maike
AU - Wulf, Gerald
AU - Glass, Bertram
AU - Schmitz, Norbert
AU - Altmann, Bettina
AU - Loeffler, Markus
AU - Pfreundschuh, Michael
AU - FLYER Trial Investigators
N1 - Copyright © 2019 Elsevier Ltd. All rights reserved.
PY - 2019/12/21
Y1 - 2019/12/21
N2 - 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.
AB - 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.
U2 - 10.1016/S0140-6736(19)33008-9
DO - 10.1016/S0140-6736(19)33008-9
M3 - SCORING: Journal article
C2 - 31868632
VL - 394
SP - 2271
EP - 2281
JO - LANCET
JF - LANCET
SN - 0140-6736
IS - 10216
ER -