First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia.

Barbara Eichhorst, Carsten U. Niemann, Arnon P. Kater, Moritz Furstenau, Julia Von Tresckow, Can Zhang, Sandra Robrecht, Michael Gregor, Gunnar Juliusson, Patrick Thornton, Philipp B. Staber, Tamar Tadmor, Vesa Lindstrom, Caspar Da Cunha-Bang, Christof Schneider, Christian B. Poulsen, Thomas Illmer, Bjorn Schottker, Thomas Nosslinger, Ann JanssensIlse Christiansen, Michael Baumann, Henrik Frederiksen, Marjolein Van Der Klift, Ulrich Jager, Maria B.L. Leys, Mels Hoogendoorn, Kourosh Lotfi, Holger Hebart, Tobias Gaska, Harry Koene, Lisbeth Enggaard, Jereon Goede, Josien C. Regelink, Anouk Widmer, Florian Simon, Nisha De Silva, Anna Maria Fink, Jasmin Bahlo, Kirsten Fischer, Clemens Martin Wendtner, Karl A. Kreuzer, Matthias Ritgen, Monika Bruggemann, Eugen Tausch, Mark David Levin, Marinus Van Oers, Christian Geisler, Stephan Stilgenbauer, Michael Hallek

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Background Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. Methods In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. Results A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P=0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P=0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). Conclusions Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 number, NCT02950051; EudraCT number, 2015-004936-36.)

Original languageEnglish
JournalNew England Journal of Medicine
Issue number19
Pages (from-to)1739-1754
Publication statusPublished - 11. May 2023


  • Hematology/Oncology
  • Leukemia/Lymphoma
  • Treatments in Oncology
  • Antineoplastic Agents/administration & dosage
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
  • Antineoplastic Agents, Immunological/administration & dosage
  • Rituximab/administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols/adverse effects
  • Bridged Bicyclo Compounds, Heterocyclic/administration & dosage
  • Cyclophosphamide/administration & dosage
  • Neoplasm, Residual/diagnosis
  • Bendamustine Hydrochloride/administration & dosage


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