Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial
Abstract
Abstract Fixed-duration venetoclax combinations have become a standard first-line treatment in chronic lymphocytic leukemia (CLL). The phase 3 CLL13/GAIA trial assesses 3 time-limited combinations: venetoclax-rituximab (RV), venetoclax-obinutuzumab (GV), and venetoclax-obinutuzumab-ibrutinib (GIV), in comparison with chemoimmunotherapy (CIT). Fit patients with CLL without TP53 aberrations were randomized between 6 cycles of CIT (fludarabine-cyclophosphamide-rituximab [FCR] or bendamustine-rituximab [BR]) or 12 cycles of RV, GV, or GIV (GIV: ibrutinib continuation until cycle 36 if measurable residual disease at months 12/15). In total, 926 patients were randomized (GIV: 231, GV: 229, RV: 237, and CIT: 229 [FCR: 150, BR: 79]). With a median observation time of 63.8 months, 5-year progression-free survival (PFS) rates were 81.3% (GIV), 69.8% (GV), 57.4% (RV), and 50.7% (CIT). PFS was superior for GV and GIV compared with CIT and RV (P< .001 in each case). In addition, GIV showed longer PFS than GV (P = .0046). Venetoclax-based re-treatment after venetoclax-based first-line regimens was efficacious, with 2-year treatment-free survival >80% from second-line treatment. No differences in overall survival were observed between treatment arms (5-year rates: GIV, 94.3%; GV, 93.6%; RV, 94.7%; and CIT, 90.7%). The incidence rates of severe infections were highest with CIT, whereas cardiac events were most frequent with GIV. Compared with patients treated with CIT, those treated with GV or RV reported rapid and significantly greater quality-of-life (QoL) improvements. In the GIV arm, clinically relevant QoL improvements occurred later (month 15, after the end of treatment in most patients) than with GV/RV, likely due to a higher treatment-related symptom burden. This trial was registered at www.clinicaltrials.gov as NCT02950051.
Article Details
Authors (52)
Moritz Fürstenau
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Carsten U. Niemann
Rigshospitalet, Copenhagen University Hospital, Copenhagen
Sandra Robrecht
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Emelie C. Rotbain
2Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Laura Eurelings
3Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, The Netherlands
Adam Giza
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Julia von Tresckow
4Department of Hematology, Oncology and Palliative Care, Katholisches Klinikum Bochum, Ruhr University Bochum, Bochum, Germany
Can Zhang
School of Integrated Circuits and Electronics, MIIT Key Laboratory for Low-Dimensional Quantum Structure and Devices
Michael Gregor
Cantonal Hospital of Lucerne, Lucerne, Switzerland
Patrick Thornton
Cancer Clinical Trials and Research Unit, Cancer Trials Ireland, Beaumont Hospital, Dublin
Philipp B. Staber
Medical University Vienna, Vienna, Austria
Tamar Tadmor
Bnai Zion Medical Center, Technion, Haifa, Israel
Vesa Lindström
Department of Hematology, Comprehensive Cancer Center, Helsinki University Hospital and University of Helsinki, Helsinki
Gunnar Juliusson
Ann Janssens
Universitaire Ziekenhuizen Leuven, Leuven, Belgium
Caspar da Cunha-Bang
Rigshospitalet, Copenhagen University Hospital, Copenhagen
Christof Schneider
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Yair Herishanu
13Faculty of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
Derville O’Shea
14Department of Hematology, Cork University Hospital, Wilton, Ireland
Michael Baumann
HOCH Health Ostschweiz, Kantonsspital St. Gallen, St. Gallen, Switzerland
Anouk Widmer
16Department of Medical Oncology and Haematology, Universitätsspital Zürich, Zürich, Switzerland
Thomas Nösslinger
173rd Medical Department for Hematology and Oncology, Hanusch Krankenhaus, Vienna, Austria
Christian B. Poulsen
Zealand University Hospital, Roskilde, Denmark
Henrik Frederiksen
19Department of Hematology, Odense University Hospital, Odense, Denmark
Kourosh Lotfi
20Department of Hematology, Linköping University Hospital, Linköping, Sweden
Juha Ranti
Turku University Hospital, Turku, Finland
Lisbeth Enggaard
2Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Gerjo Velders
22Department of Hematology, Gelderse Vallei Hospital, Ede, The Netherlands
Marie-Christiane Vekemans
23Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
Koen de Heer
24Department of Internal Medicine, Flevoziekenhuis, Almere, The Netherlands
Tjeerd F. Snijders
25Department of Hematology, Medisch Spectrum Twente, Enschede, The Netherlands
Claire Siemes
26Department of Hematology, Deventer Hospital, Deventer, The Netherlands
Clemens-Martin Wendtner
Ludwig-Maximilians University (LMU), Medical Clinic III, Munich, Germany
Wolfgang Knauf
28Centrum für Hämatologie und Onkologie Bethanien, Frankfurt am Main, Germany
Alexander Kroeber
29Schwerpunktpraxis und Tagesklinik für Hämatologie und Onkologie, Regensburg, Germany
Mark-Oliver Zahn
30MVZ Onkologische Kooperation Harz, Goslar, Germany
Thomas Illmer
Berufsausüebungsgemeinschaft, Gokos, Dresden, Germany
Björn Schöttker
32Hämatologisch-Onkologische Schwerpunktpraxis Würzburg, Würzburg, Germany
Florian Simon
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Anna Fink
Kirsten Fischer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Ronald D’Brot
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Emily Holmes
1Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, German CLL Study Group, University of Cologne, Cologne, Germany
Karl-Anton Kreuzer
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Matthias Ritgen
Universitaetsklinikum Schleswig-Holstein, Medizinische Klinik II, Kiel, Germany
Monika Brüggemann
1Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
Eugen Tausch
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Stephan Stilgenbauer
Division of CLL, Department of Internal Medicine III, Ulm University, Ulm, Germany
Mark-David Levin
Albert Schweitzer Ziekenhuis, Dordrecht, the Netherlands
Michael Hallek
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
Arnon P. Kater
Amsterdam University Medical Center location University of Amsterdam, Department of Hematology
Barbara Eichhorst
Department I of Internal Medicine, Center of Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany