First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia

Barbara Eichhorst; Carsten U Niemann; Arnon P Kater; Moritz Fürstenau; Julia von Tresckow; Can Zhang; Sandra Robrecht; Michael Gregor; Gunnar Juliusson; Patrick Thornton; Philipp B Staber; Tamar Tadmor; Vesa Lindström; Caspar da Cunha-Bang; Christof Schneider; Christian B Poulsen; Thomas Illmer; Björn Schöttker; Thomas Nösslinger; Ann Janssens; Ilse Christiansen; Michael Baumann; Henrik Frederiksen; Marjolein van der Klift; Ulrich Jäger; 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 Brüggemann; Eugen Tausch; Mark-David Levin; Marinus van Oers; Christian Geisler; Stephan Stilgenbauer; Michael Hallek; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland

doi:10.1056/NEJMoa2213093

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia

Barbara Eichhorst^*, Carsten U Niemann, Arnon P Kater, Moritz Fürstenau, Julia von Tresckow, Can Zhang, Sandra Robrecht, Michael Gregor, Gunnar Juliusson, Patrick Thornton, Philipp B Staber, Tamar Tadmor, Vesa Lindström, Caspar da Cunha-Bang, Christof Schneider, Christian B Poulsen, Thomas Illmer, Björn Schöttker, Thomas Nösslinger, Ann JanssensIlse Christiansen, Michael Baumann, Henrik Frederiksen, Marjolein van der Klift, Ulrich Jäger, 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 Brüggemann, Eugen Tausch, Mark-David Levin, Marinus van Oers, Christian Geisler, Stephan Stilgenbauer, Michael Hallek, GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland

^*Corresponding author af dette arbejde

Afdeling for Blodsygdomme

Abstract

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 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

Originalsprog	Engelsk
Tidsskrift	The New England journal of medicine
Vol/bind	388
Udgave nummer	19
Sider (fra-til)	1739-1754
Antal sider	16
ISSN	0028-4793
DOI	https://doi.org/10.1056/NEJMoa2213093
Status	Udgivet - 11 maj 2023

Adgang til dokumentet

10.1056/NEJMoa2213093

Andre filer og links

Link to publication in Scopus

Citationsformater

Eichhorst, B., Niemann, C. U., Kater, A. P., Fürstenau, M., von Tresckow, J., Zhang, C., Robrecht, S., Gregor, M., Juliusson, G., Thornton, P., Staber, P. B., Tadmor, T., Lindström, V., da Cunha-Bang, C., Schneider, C., Poulsen, C. B., Illmer, T., Schöttker, B., Nösslinger, T., ... GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland (2023). First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. The New England journal of medicine, 388(19), 1739-1754. https://doi.org/10.1056/NEJMoa2213093

Eichhorst, B, Niemann, CU, Kater, AP, Fürstenau, M, von Tresckow, J, Zhang, C, Robrecht, S, Gregor, M, Juliusson, G, Thornton, P, Staber, PB, Tadmor, T, Lindström, V, da Cunha-Bang, C, Schneider, C, Poulsen, CB, Illmer, T, Schöttker, B, Nösslinger, T, Janssens, A, Christiansen, I, Baumann, M, Frederiksen, H, van der Klift, M, Jäger, U, Leys, MBL, Hoogendoorn, M, Lotfi, K, Hebart, H, Gaska, T, Koene, H, Enggaard, L, Goede, J, Regelink, JC, Widmer, A, Simon, F, De Silva, N, Fink, A-M, Bahlo, J, Fischer, K, Wendtner, C-M, Kreuzer, KA, Ritgen, M, Brüggemann, M, Tausch, E, Levin, M-D, van Oers, M, Geisler, C, Stilgenbauer, S, Hallek, M & GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland 2023, 'First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia', The New England journal of medicine, bind 388, nr. 19, s. 1739-1754. https://doi.org/10.1056/NEJMoa2213093

@article{89a3ec14765948588edd607c353aa253,

title = "First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia",

abstract = "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 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).",

author = "Barbara Eichhorst and Niemann, {Carsten U} and Kater, {Arnon P} and Moritz F{\"u}rstenau and {von Tresckow}, Julia and Can Zhang and Sandra Robrecht and Michael Gregor and Gunnar Juliusson and Patrick Thornton and Staber, {Philipp B} and Tamar Tadmor and Vesa Lindstr{\"o}m and {da Cunha-Bang}, Caspar and Christof Schneider and Poulsen, {Christian B} and Thomas Illmer and Bj{\"o}rn Sch{\"o}ttker and Thomas N{\"o}sslinger and Ann Janssens and Ilse Christiansen and Michael Baumann and Henrik Frederiksen and {van der Klift}, Marjolein and Ulrich J{\"a}ger and Leys, {Maria B L} and Mels Hoogendoorn and Kourosh Lotfi and Holger Hebart and Tobias Gaska and Harry Koene and Lisbeth Enggaard and Jereon Goede and Regelink, {Josien C} and Anouk Widmer and Florian Simon and {De Silva}, Nisha and Anna-Maria Fink and Jasmin Bahlo and Kirsten Fischer and Clemens-Martin Wendtner and Kreuzer, {Karl A} and Matthias Ritgen and Monika Br{\"u}ggemann and Eugen Tausch and Mark-David Levin and {van Oers}, Marinus and Christian Geisler and Stephan Stilgenbauer and Michael Hallek and {GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland}",

note = "Copyright {\textcopyright} 2023 Massachusetts Medical Society.",

year = "2023",

month = may,

day = "11",

doi = "10.1056/NEJMoa2213093",

language = "English",

volume = "388",

pages = "1739--1754",

journal = "The New England journal of medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "19",

}

TY - JOUR

T1 - First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia

AU - Eichhorst, Barbara

AU - Niemann, Carsten U

AU - Kater, Arnon P

AU - Fürstenau, Moritz

AU - von Tresckow, Julia

AU - Zhang, Can

AU - Robrecht, Sandra

AU - Gregor, Michael

AU - Juliusson, Gunnar

AU - Thornton, Patrick

AU - Staber, Philipp B

AU - Tadmor, Tamar

AU - Lindström, Vesa

AU - da Cunha-Bang, Caspar

AU - Schneider, Christof

AU - Poulsen, Christian B

AU - Illmer, Thomas

AU - Schöttker, Björn

AU - Nösslinger, Thomas

AU - Janssens, Ann

AU - Christiansen, Ilse

AU - Baumann, Michael

AU - Frederiksen, Henrik

AU - van der Klift, Marjolein

AU - Jäger, Ulrich

AU - Leys, Maria B L

AU - Hoogendoorn, Mels

AU - Lotfi, Kourosh

AU - Hebart, Holger

AU - Gaska, Tobias

AU - Koene, Harry

AU - Enggaard, Lisbeth

AU - Goede, Jereon

AU - Regelink, Josien C

AU - Widmer, Anouk

AU - Simon, Florian

AU - De Silva, Nisha

AU - Fink, Anna-Maria

AU - Bahlo, Jasmin

AU - Fischer, Kirsten

AU - Wendtner, Clemens-Martin

AU - Kreuzer, Karl A

AU - Ritgen, Matthias

AU - Brüggemann, Monika

AU - Tausch, Eugen

AU - Levin, Mark-David

AU - van Oers, Marinus

AU - Geisler, Christian

AU - Stilgenbauer, Stephan

AU - Hallek, Michael

AU - GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland

PY - 2023/5/11

Y1 - 2023/5/11

N2 - 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 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

AB - 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 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

UR - http://www.scopus.com/inward/record.url?scp=85160272522&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa2213093

DO - 10.1056/NEJMoa2213093

M3 - Journal article

C2 - 37163621

SN - 0028-4793

VL - 388

SP - 1739

EP - 1754

JO - The New England journal of medicine

JF - The New England journal of medicine

IS - 19

ER -

First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia

Abstract

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater