Universität zu Köln

Eichhorst, Barbara, Fink, Anna-Maria, Bahlo, Jasmin, Busch, Raymonde, Kovacs, Gabor, Maurer, Christian, Lange, Elisabeth, Koeppler, Hubert, Kiehl, Michael, Soekler, Martin, Schlag, Rudolf, Vehling-Kaiser, Ursula, Koechling, Georg, Ploeger, Christoph, Gregor, Michael, Plesner, Torben, Trneny, Marek ORCID: 0000-0002-6952-6073, Fischer, Kirsten, Doehner, Harmut, Kneba, Michael, Wendtner, Clemens-Martin, Klapper, Wolfram, Kreuzer, Karl-Anton, Stilgenbauer, Stephan, Boettcher, Sebastian and Hallek, Michael (2016). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol., 17 (7). S. 928 - 943. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1474-5488

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Abstract

Background Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab is the standard therapy for physically fit patients with advanced chronic lymphocytic leukaemia. This international phase 3 study compared the efficacy and tolerance of the standard therapy with a potentially less toxic combination consisting of bendamustine and rituximab. Methods Treatment-naive fit patients with chronic lymphocytic leukaemia (aged 33-81 years) without del(17p) were enrolled after undergoing a central screening process. Patients were randomly assigned (1: 1) with a computer-generated randomisation list using randomly permuted blocks with a block size of eight and were stratified according to participating country and Binet stage. Patients were allocated to receive six cycles of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days or to intravenous bendamustine (90 mg/m(2) per day) for the first 2 days of each cycle. Rituximab 375 mg/m(2) was given intravenously in both groups on day 0 of cycle 1 and subsequently was given at 500 mg/m(2) during the next five cycles on day 1. The primary endpoint was progression-free survival with the objective to assess non-inferiority of bendamustine and rituximab to the standard therapy. We aimed to show that the 2-year progression-free survival with bendamustine and rituximab was not 67.5% or less with a corresponding non-inferiority margin of 1.388 for the hazard ratio (HR) based on the 90.4% CI. The final analysis was done by intention to treat. The study is registered with ClinicalTrials.gov, number NCT 00769522. Findings 688 patients were recruited between Oct 2, 2008, and July 11, 2011, of which 564 patients who met inclusion criteria were randomly assigned. 561 patients were included in the intention-to-treat population: 282 patients in the fludarabine, cyclophosphamide, and rituximab group and 279 in the bendamustine and rituximab group. After a median observation time of 37.1 months (IQR 31.0-45.5) median progression-free survival was 41.7 months (95% CI 34.9-45.3) with bendamustine and rituximab and 55.2 months (95% CI not evaluable) with fludarabine, cyclophosphamide, and rituximab (HR 1.643, 90.4% CI 1.308-2.064). As the upper limit of the 90.4% CI was greater than 1.388 the null hypothesis for the corresponding non-inferiority hypothesis was not rejected. Severe neutropenia and infections were more frequently observed with fludarabine, cyclophosphamide, and rituximab (235 [84%] of 279 vs 164 [59%] of 278, and 109 [39%] vs 69 [25%], respectively) during the study. The increased frequency of infectious complications with fludarabine, cyclophosphamide, and rituximab was more pronounced in patients older than 65 years. Interpretation The combination of fludarabine, cyclophosphamide, and rituximab remains the standard front-line therapy in fit patients with chronic lymphocytic leukaemia, but bendamustine and rituximab is associated with less toxic effects.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Eichhorst, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Fink, Anna-Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Bahlo, Jasmin UNSPECIFIED UNSPECIFIED UNSPECIFIED Busch, Raymonde UNSPECIFIED UNSPECIFIED UNSPECIFIED Kovacs, Gabor UNSPECIFIED UNSPECIFIED UNSPECIFIED Maurer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Lange, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Koeppler, Hubert UNSPECIFIED UNSPECIFIED UNSPECIFIED Kiehl, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Soekler, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlag, Rudolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Vehling-Kaiser, Ursula UNSPECIFIED UNSPECIFIED UNSPECIFIED Koechling, Georg UNSPECIFIED UNSPECIFIED UNSPECIFIED Ploeger, Christoph UNSPECIFIED UNSPECIFIED UNSPECIFIED Gregor, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Plesner, Torben UNSPECIFIED UNSPECIFIED UNSPECIFIED Trneny, Marek UNSPECIFIED orcid.org/0000-0002-6952-6073 UNSPECIFIED Fischer, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Doehner, Harmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Kneba, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Wendtner, Clemens-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Klapper, Wolfram UNSPECIFIED UNSPECIFIED UNSPECIFIED Kreuzer, Karl-Anton UNSPECIFIED UNSPECIFIED UNSPECIFIED Stilgenbauer, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Boettcher, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-271647
DOI:	10.1016/S1470-2045(16)30051-1
Journal or Publication Title:	Lancet Oncol.
Volume:	17
Number:	7
Page Range:	S. 928 - 943
Date:	2016
Publisher:	ELSEVIER SCIENCE INC
Place of Publication:	NEW YORK
ISSN:	1474-5488
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PREVIOUSLY UNTREATED PATIENTS; FRONTLINE FLUDARABINE; PROGRESSION-FREE; INITIAL THERAPY; FREE SURVIVAL; COMBINATION; IBRUTINIB Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/27164