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Reduction of Chemotherapy in Aggressive Non-Hodgkin's Lymphoma with Favorable Prognosis

140 Pages Posted: 24 Jun 2019

See all articles by Viola Poeschel

Viola Poeschel

Westpfalz Hospital

Gerhard Held

Westpfalz Hospital - Department of Internal Medicine 1

Marita Ziepert

University of Leipzig

Mathias Witzens-Harig

Heidelberg University

Harald Holte

University of Oslo - Oslo University Hospital

Lorenz Thurner

Saarland University - Department of Internal Medicine 1

Peter Borchmann

University of Cologne - University Hospital of Cologne

Andreas Viardot

University Hospital Ulm

Martin Soekler

University of Tübingen - University Hospitals Tübingen

Ulrich Keller

Rechts der Isar Hospital

Christian Schmidt

Munich University Hospital

Lorenz Trümper

University of Göttingen

Rolf Mahlberg

Hospital Motherhouse of the Borromäerinnen

Reinhard Marks

University of Freiburg - Medical Center

Heinz-Gert Hoeffkes

Klinikum-Fulda gAG

Bernd Metzner

University of Oldenburg

Judith Dierlamm

University of Hamburg - University Medical Center Hamburg-Eppendorf

Norbert Frickhofen

Dr. Horst-Schmidt-Klinik

Mathias Hänel

Küchwald Hospital Chemnitz

Andreas Neubauer

University Hospital Marburg

Michael Kneba

Schleswig-Holstein University - University Hospital Center

Francesco Merli

Hematology AUSL-IRCCS Reggio Emilia

Alessandra Tucci

Hematology ASST Spedali Civili Brescia

Peter de Nully Brown

University of Copenhagen - Rigshospitalet

Massimo Federico

Università degli studi di Modena e Reggio Emilia (UNIMORE)

Eva Lengfelder

University Hospital Mannheim

Alice di Rocco

Sapienza University of Rome

Ralf Trappe

Evang. Diakonie-Krankenhaus

Andreas Rosenwald

University of Wuerzburg - Institute of Pathology

Christian Berdel

Saarland University - Medical School

Martin Maisenhölder

University Hospital of North Norway

Ofer Shpilberg

Tel Aviv University - Rabin Medical Center

Josif Amam

Saarland University - Department of Internal Medicine 1

Konstantinos Christofyllakis

Saarland University - Department of Internal Medicine 1

Frank Hartmann

Saarland University - Department of Internal Medicine 1

Niels Murawski

Saarland University - Department of Internal Medicine 1

Stephan Stilgenbauer

Saarland University - Department of Internal Medicine 1

Norbert Schmitz

Asklepios Klinik St. Georg

Bettina Altmann

University of Leipzig

Markus Loeffler

University of Leipzig

Michael Pfreundschuh

Saarland University - Department of Internal Medicine 1

FLYER Trial Investigators

Independent

More...

Abstract

Background: Six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) or R-CHOP-like chemotherapy are the standard treatment for aggressive B-cell non-Hodgkin's lymphoma. We hypothesized that four cycles of CHOP plus six applications of rituximab (4x R-CHOP+2xR) are non-inferior to six cycles of R-CHOP in a population with favorable prognosis.

Methods: We randomized patients 18 to 60 years of age, stage I-II disease, normal serum lactate dehydrogenase concentration, good ECOG performance status 0-1, without bulky disease (maximal tumor diameter <7.5 cm) to receive 6x R-CHOP or 4x R-CHOP+2xR. The primary endpoint was progression-free survival after three years.

Findings: After a median follow-up of 66 months, 3-years progression-free survival of patients with 4x R-CHOP+2xR was 96% (95% confidence interval [CI]: 94%; 99%), which was 3% (95% CI (one-sided): 0%; 6%) better than 6x R-CHOP, demonstrating the non-inferiority of 4x R-CHOP+2xR. Survival after 3 years was 99% (95% CI: 98% - 100%) with 4x R-CHOP+2xR versus 98% (95% CI: 96% - 99%) with 6x R-CHOP. Relapse rates were 4% (95% CI: 2% -7%) in the 4x R-CHOP+2xR group versus 5% (95% CI: 3% - 8%) in the 6x R-CHOP group, respectively.

Interpretation: In young patients with aggressive B-cell non-Hodgkin's lymphoma and favorable prognosis outcome after 4 cycles of R-CHOP is non-inferior compared to 6 cycles of R-CHOP, with relevant reduction of toxicity. Thus, chemotherapy can be reduced without compromising outcome in this population.

Trial Registration: ClinicalTrials.gov number, NCT00278421.

Funding Statement: It was coordinated by the German Study Group for high-grade Non-Hodgkin Lymphoma (DSHNHL) and funded by a German non-profit foundation, the “Deutsche Krebshilfe” (German Cancer Aid), reference number 106369.

Declaration of Interests: Referring the Work under Consideration for Publication/During the Conduct of the study: Grants: V. Poeschel: Deutsche Krebshilfe (Non-Profit/Charity Organization); H. Holte: Deutsche Krebshilfe, Roche; Personal Fees: U. Keller: Roche; Relevant financial activities outside the submitted work: Personal Fees: V. Poeschel: Hexal; G. Held: BMS, Roche, Amgen, Spectrum, MSD; A. Viardot: Roche, Kite/Gilead, Pfizer, BMS, Amgen; C. Schmidt: Novartis AG, Gilead, Takeda; L. Truemper: Takeda; U. Keller: Janssen Cilag, BMS, Gilead, Takeda, Amgen, Hexal, Celgene, Astra Zeneca, MSD; R. Marks: Roche, Servier, Merck; M. Kneba: Astra Zeneca; F. Merli: Roche, Takeda, Celgene, Janssen, Gilead, Mundipharma; P. de Nully Brown: Roche; F. Hartmann: BMS, Roche, Boehringer Ingelheim, Sanofi, Celgene, Novartis, Ipsen, Janssen, Gilead; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Grants: V. Poeschel: Abbvie, Amgen, Roche; G. Held: BMS, Roche; C. Schmidt: Janssen Cilag, Gilead, Takeda; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis; Non-financial support: C. Schmidt: Janssen Cilag, Gilead, Takeda; F. Merli: Takeda, Celgene; S. Stilgenbauer: Abbvie, Amgen, Astra Zeneca, Celgene, Gilead, GSK, Roche, Janssen, Novartis, Pharmacyclics, Sunesis All other authors declared no conflicts of interest.

Ethics Approval Statement: The study was conducted in accordance with the Helsinki declaration. The protocol and its amendments were approved by the ethics committee of each participating center.

Suggested Citation

Poeschel, Viola and Held, Gerhard and Ziepert, Marita and Witzens-Harig, Mathias and Holte, Harald and Thurner, Lorenz and Borchmann, Peter and Viardot, Andreas and Soekler, Martin and Keller, Ulrich and Schmidt, Christian and Trümper, Lorenz and Mahlberg, Rolf and Marks, Reinhard and Hoeffkes, Heinz-Gert and Metzner, Bernd and Dierlamm, Judith and Frickhofen, Norbert and Hänel, Mathias and Neubauer, Andreas and Kneba, Michael and Merli, Francesco and Tucci, Alessandra and Brown, Peter de Nully and Federico, Massimo and Lengfelder, Eva and Rocco, Alice di and Trappe, Ralf and Rosenwald, Andreas and Berdel, Christian and Maisenhölder, Martin and Shpilberg, Ofer and Amam, Josif and Christofyllakis, Konstantinos and Hartmann, Frank and Murawski, Niels and Stilgenbauer, Stephan and Schmitz, Norbert and Altmann, Bettina and Loeffler, Markus and Pfreundschuh, Michael and Investigators, FLYER Trial, Reduction of Chemotherapy in Aggressive Non-Hodgkin's Lymphoma with Favorable Prognosis (June 19, 2019). Available at SSRN: https://ssrn.com/abstract=3408065 or http://dx.doi.org/10.2139/ssrn.3408065

Viola Poeschel

Westpfalz Hospital

Germany

Gerhard Held (Contact Author)

Westpfalz Hospital - Department of Internal Medicine 1 ( email )

Germany

Marita Ziepert

University of Leipzig

Marschnerstrasse 31
D-04109 Leipzig, DE 04109
Germany

Mathias Witzens-Harig

Heidelberg University

Grabengasse 1
Heidelberg, 69117
Germany

Harald Holte

University of Oslo - Oslo University Hospital

Kirkeveien 166
Building 2H
Oslo, N-0450
Norway

Lorenz Thurner

Saarland University - Department of Internal Medicine 1

Germany

Peter Borchmann

University of Cologne - University Hospital of Cologne

Building 47, 9th floor Kerpener Str.
Herderstrasse 52
Cologne, 50931
Germany

Andreas Viardot

University Hospital Ulm

Ulm
Germany

Martin Soekler

University of Tübingen - University Hospitals Tübingen

Geschwister-Scholl-Platz
Tübingen, 72074
Germany

Ulrich Keller

Rechts der Isar Hospital

Germany

Christian Schmidt

Munich University Hospital

Germany

Lorenz Trümper

University of Göttingen

Platz der Gottinger Sieben 3
Gottingen, D-37073
Germany

Rolf Mahlberg

Hospital Motherhouse of the Borromäerinnen

Germany

Reinhard Marks

University of Freiburg - Medical Center

Breisacher Str. 64
Freiburg, 79106
Germany

Heinz-Gert Hoeffkes

Klinikum-Fulda gAG

Germany

Bernd Metzner

University of Oldenburg

Ammerländer Heerstraße 114-118
Oldenburg, D-26111
Germany

Judith Dierlamm

University of Hamburg - University Medical Center Hamburg-Eppendorf

Martinistrasse 52
Hamburg, D - 20246
Germany

Norbert Frickhofen

Dr. Horst-Schmidt-Klinik

Wiesbaden
Germany

Mathias Hänel

Küchwald Hospital Chemnitz

Germany

Andreas Neubauer

University Hospital Marburg

Germany

Michael Kneba

Schleswig-Holstein University - University Hospital Center

Kiel
Germany

Francesco Merli

Hematology AUSL-IRCCS Reggio Emilia

Italy

Alessandra Tucci

Hematology ASST Spedali Civili Brescia

Italy

Peter de Nully Brown

University of Copenhagen - Rigshospitalet

Copenhagen
Denmark

Massimo Federico

Università degli studi di Modena e Reggio Emilia (UNIMORE)

Viale A. Allegri 9
Modena, Modena 42121
Italy

Eva Lengfelder

University Hospital Mannheim

Germany

Alice di Rocco

Sapienza University of Rome

Piazzale Aldo Moro, 5
Rome, 00185
Italy

Ralf Trappe

Evang. Diakonie-Krankenhaus

Germany

Andreas Rosenwald

University of Wuerzburg - Institute of Pathology

Law Faculty
Domerschulstraße 16
Würzburg, Bavaria D-97070
Germany

Christian Berdel

Saarland University - Medical School

Germany

Martin Maisenhölder

University Hospital of North Norway

Tromsø
Norway

Ofer Shpilberg

Tel Aviv University - Rabin Medical Center

Tikva
Israel

Josif Amam

Saarland University - Department of Internal Medicine 1

Germany

Konstantinos Christofyllakis

Saarland University - Department of Internal Medicine 1

Germany

Frank Hartmann

Saarland University - Department of Internal Medicine 1

Germany

Niels Murawski

Saarland University - Department of Internal Medicine 1

Germany

Stephan Stilgenbauer

Saarland University - Department of Internal Medicine 1

Germany

Norbert Schmitz

Asklepios Klinik St. Georg

Germany

Bettina Altmann

University of Leipzig

Marschnerstrasse 31
D-04109 Leipzig, DE 04109
Germany

Markus Loeffler

University of Leipzig

Marschnerstrasse 31
D-04109 Leipzig, DE 04109
Germany

Michael Pfreundschuh

Saarland University - Department of Internal Medicine 1

Germany

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