Universität zu Köln

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 ORCID: 0000-0003-3052-7463, Brown, Peter de Nully ORCID: 0000-0002-6522-4086, Federico, Massimo, Lengfelder, Eva, di Rocco, Alice, Trappe, Ralf ORCID: 0000-0001-7565-7160, Rosenwald, Andreas, Berdel, Christian, Maisenhoelder, Martin, Shpilberg, Ofer, Amam, Josif, Christofyllakis, Konstantinos ORCID: 0000-0002-0308-388X, Hartmann, Frank, Murawski, Niels, Stilgenbauer, Stephan, Nickelsen, Maike, Wulf, Gerald, Glass, Bertram, Schmitz, Norbert, Altmann, Bettina, Loeffler, Markus and Pfreundschuh, Michael (2019). 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. Lancet, 394 (10216). S. 2271 - 2282. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-547X

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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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Poeschel, Viola UNSPECIFIED UNSPECIFIED UNSPECIFIED Held, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Ziepert, Marita UNSPECIFIED UNSPECIFIED UNSPECIFIED Witzens-Harig, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Holte, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Thurner, Lorenz UNSPECIFIED UNSPECIFIED UNSPECIFIED Borchmann, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Viardot, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Soekler, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Keller, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Truemper, Lorenz UNSPECIFIED UNSPECIFIED UNSPECIFIED Mahlberg, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Marks, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeffkes, Heinz-Gert UNSPECIFIED UNSPECIFIED UNSPECIFIED Metzner, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Dierlamm, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Frickhofen, Norbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Haenel, Mathias UNSPECIFIED UNSPECIFIED UNSPECIFIED Neubauer, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Kneba, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Merli, Francesco UNSPECIFIED UNSPECIFIED UNSPECIFIED Tucci, Alessandra UNSPECIFIED orcid.org/0000-0003-3052-7463 UNSPECIFIED Brown, Peter de Nully UNSPECIFIED orcid.org/0000-0002-6522-4086 UNSPECIFIED Federico, Massimo UNSPECIFIED UNSPECIFIED UNSPECIFIED Lengfelder, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED di Rocco, Alice UNSPECIFIED UNSPECIFIED UNSPECIFIED Trappe, Ralf UNSPECIFIED orcid.org/0000-0001-7565-7160 UNSPECIFIED Rosenwald, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Berdel, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Maisenhoelder, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Shpilberg, Ofer UNSPECIFIED UNSPECIFIED UNSPECIFIED Amam, Josif UNSPECIFIED UNSPECIFIED UNSPECIFIED Christofyllakis, Konstantinos UNSPECIFIED orcid.org/0000-0002-0308-388X UNSPECIFIED Hartmann, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Murawski, Niels UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Nickelsen, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Wulf, Gerald UNSPECIFIED UNSPECIFIED UNSPECIFIED Glass, Bertram UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitz, Norbert UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmann, Bettina UNSPECIFIED UNSPECIFIED UNSPECIFIED Loeffler, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Pfreundschuh, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-124060
Journal or Publication Title:	Lancet
Volume:	394
Number:	10216
Page Range:	S. 2271 - 2282
Date:	2019
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1474-547X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language NON-HODGKIN-LYMPHOMA; ELDERLY-PATIENTS; R-CHOP; RESPONSE CRITERIA; PLUS RITUXIMAB; YOUNG-PATIENTS; RADIOTHERAPY; SURVIVAL; THERAPY Multiple languages Medicine, General & Internal Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12406