Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial

Moritz Fürstenau; Carsten Utoft Niemann; Sandra Robrecht; Emelie C Rotbain; Laura Elisabeth Maria Eurelings; Adam Giza; Julia von Tresckow; Can Zhang; Michael Gregor; Patrick Thornton; Philipp B Staber; Tamar Tadmor; Vesa Lindstrom; Gunnar Juliusson; Ann Janssens; Caspar da Cunha-Bang; Christof Schneider; Yair Herishanu; Derville O'Shea; Michael Baumann; Anouk Andrea Widmer; Thomas Nösslinger; Christian Bjørn Poulsen; Henrik Frederiksen; Kourosh Lotfi; Juha Ranti; Lisbeth Enggaard; Gerjo A Velders; Marie-Christiane Madeleine Vekemans; Koen de Heer; Tjeerd J F Snijders; Claire Siemes; Clemens-Martin Wendtner; Wolfgang U Knauf; Alexander Kroeber; Mark-Oliver Zahn; Thomas Illmer; Björn Schöttker; Florian Simon; Anna-Maria Fink; Kirsten Fischer; Ronald D'Brot; Emily Eva Holmes; Karl-Anton Kreuzer; Matthias Ritgen; Monika Brüggemann; Eugen Tausch; Stephan Stilgenbauer; Mark-David Levin; Michael J Hallek; Arnon P Kater; Barbara F Eichhorst

doi:10.1182/blood.2025032160

Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial

Moritz Fürstenau^*
, Carsten Utoft Niemann
, Sandra Robrecht
, Emelie C Rotbain
, Laura Elisabeth Maria Eurelings
, Adam Giza
, Julia von Tresckow
, Can Zhang
, Michael Gregor
, Patrick Thornton
, Philipp B Staber
, Tamar Tadmor
, Vesa Lindstrom
, Gunnar Juliusson
, Ann Janssens
, Caspar da Cunha-Bang
, Christof Schneider
, Yair Herishanu
, Derville O'Shea
, Michael Baumann

Anouk Andrea Widmer, Thomas Nösslinger, Christian Bjørn Poulsen, Henrik Frederiksen, Kourosh Lotfi, Juha Ranti, Lisbeth Enggaard, Gerjo A Velders, Marie-Christiane Madeleine Vekemans, Koen de Heer, Tjeerd J F Snijders, Claire Siemes, Clemens-Martin Wendtner, Wolfgang U Knauf, Alexander Kroeber, Mark-Oliver Zahn, Thomas Illmer, Björn Schöttker, Florian Simon, Anna-Maria Fink, Kirsten Fischer, Ronald D'Brot, Emily Eva Holmes, Karl-Anton Kreuzer, Matthias Ritgen, Monika Brüggemann, Eugen Tausch, Stephan Stilgenbauer, Mark-David Levin, Michael J Hallek, Arnon P Kater, Barbara F Eichhorst

^*Corresponding author for this work

Haematology

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Pages (from-to)	3025-3038
Number of pages	14
Journal	Blood
Volume	147
Issue number	25
Early online date	30 Mar 2026
DOIs	https://doi.org/10.1182/blood.2025032160
Publication status	Published - 18 Jun 2026

Keywords

Adenine/analogs & derivatives
Aged
Aged, 80 and over
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Bendamustine Hydrochloride/administration & dosage
Bridged Bicyclo Compounds, Heterocyclic/administration & dosage
Cyclophosphamide/administration & dosage
Female
Humans
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
Male
Middle Aged
Patient Reported Outcome Measures
Piperidines/administration & dosage
Rituximab/administration & dosage
Sulfonamides/administration & dosage
Vidarabine/analogs & derivatives
Therapy
Obinutuzumab
Rituximab
1st-line treatment
Ibrutinib
Final analysis

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10.1182/blood.2025032160

Cite this

Fürstenau, M., Niemann, C. U., Robrecht, S., Rotbain, E. C., Eurelings, L. E. M., Giza, A., von Tresckow, J., Zhang, C., Gregor, M., Thornton, P., Staber, P. B., Tadmor, T., Lindstrom, V., Juliusson, G., Janssens, A., da Cunha-Bang, C., Schneider, C., Herishanu, Y., O'Shea, D., ... Eichhorst, B. F. (2026). Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial. Blood, 147(25), 3025-3038. https://doi.org/10.1182/blood.2025032160

@article{2e3d4a5a77ff4cce8e45426d77a8bfd2,

title = "Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial",

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.",

keywords = "Adenine/analogs \& derivatives, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols/therapeutic use, Bendamustine Hydrochloride/administration \& dosage, Bridged Bicyclo Compounds, Heterocyclic/administration \& dosage, Cyclophosphamide/administration \& dosage, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy, Male, Middle Aged, Patient Reported Outcome Measures, Piperidines/administration \& dosage, Rituximab/administration \& dosage, Sulfonamides/administration \& dosage, Vidarabine/analogs \& derivatives, Therapy, Obinutuzumab, Rituximab, 1st-line treatment, Ibrutinib, Final analysis",

author = "Moritz F{\"u}rstenau and Niemann, \{Carsten Utoft\} and Sandra Robrecht and Rotbain, \{Emelie C\} and Eurelings, \{Laura Elisabeth Maria\} and Adam Giza and \{von Tresckow\}, Julia and Can Zhang and Michael Gregor and Patrick Thornton and Staber, \{Philipp B\} and Tamar Tadmor and Vesa Lindstrom and Gunnar Juliusson and Ann Janssens and \{da Cunha-Bang\}, Caspar and Christof Schneider and Yair Herishanu and Derville O'Shea and Michael Baumann and Widmer, \{Anouk Andrea\} and Thomas N{\"o}sslinger and \{Bj{\o}rn Poulsen\}, Christian and Henrik Frederiksen and Kourosh Lotfi and Juha Ranti and Lisbeth Enggaard and Velders, \{Gerjo A\} and Vekemans, \{Marie-Christiane Madeleine\} and \{de Heer\}, Koen and Snijders, \{Tjeerd J F\} and Claire Siemes and Clemens-Martin Wendtner and Knauf, \{Wolfgang U\} and Alexander Kroeber and Mark-Oliver Zahn and Thomas Illmer and Bj{\"o}rn Sch{\"o}ttker and Florian Simon and Anna-Maria Fink and Kirsten Fischer and Ronald D'Brot and Holmes, \{Emily Eva\} and Karl-Anton Kreuzer and Matthias Ritgen and Monika Br{\"u}ggemann and Eugen Tausch and Stephan Stilgenbauer and Mark-David Levin and Hallek, \{Michael J\} and Kater, \{Arnon P\} and Eichhorst, \{Barbara F\}",

note = "{\textcopyright} 2026 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.",

year = "2026",

month = jun,

day = "18",

doi = "10.1182/blood.2025032160",

language = "English",

volume = "147",

pages = "3025--3038",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier B.V.",

number = "25",

}

Fürstenau, M, Niemann, CU, Robrecht, S, Rotbain, EC, Eurelings, LEM, Giza, A, von Tresckow, J, Zhang, C, Gregor, M, Thornton, P, Staber, PB, Tadmor, T, Lindstrom, V, Juliusson, G, Janssens, A, da Cunha-Bang, C, Schneider, C, Herishanu, Y, O'Shea, D, Baumann, M, Widmer, AA, Nösslinger, T, Bjørn Poulsen, C, Frederiksen, H, Lotfi, K, Ranti, J, Enggaard, L, Velders, GA, Vekemans, M-CM, de Heer, K, Snijders, TJF, Siemes, C, Wendtner, C-M, Knauf, WU, Kroeber, A, Zahn, M-O, Illmer, T, Schöttker, B, Simon, F, Fink, A-M, Fischer, K, D'Brot, R, Holmes, EE, Kreuzer, K-A, Ritgen, M, Brüggemann, M, Tausch, E, Stilgenbauer, S, Levin, M-D, Hallek, MJ, Kater, AP & Eichhorst, BF 2026, 'Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial', Blood, vol. 147, no. 25, pp. 3025-3038. https://doi.org/10.1182/blood.2025032160

TY - JOUR

T1 - Venetoclax combinations in untreated CLL

T2 - 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial

AU - Fürstenau, Moritz

AU - Niemann, Carsten Utoft

AU - Robrecht, Sandra

AU - Rotbain, Emelie C

AU - Eurelings, Laura Elisabeth Maria

AU - Giza, Adam

AU - von Tresckow, Julia

AU - Zhang, Can

AU - Gregor, Michael

AU - Thornton, Patrick

AU - Staber, Philipp B

AU - Tadmor, Tamar

AU - Lindstrom, Vesa

AU - Juliusson, Gunnar

AU - Janssens, Ann

AU - da Cunha-Bang, Caspar

AU - Schneider, Christof

AU - Herishanu, Yair

AU - O'Shea, Derville

AU - Baumann, Michael

AU - Widmer, Anouk Andrea

AU - Nösslinger, Thomas

AU - Bjørn Poulsen, Christian

AU - Frederiksen, Henrik

AU - Lotfi, Kourosh

AU - Ranti, Juha

AU - Enggaard, Lisbeth

AU - Velders, Gerjo A

AU - Vekemans, Marie-Christiane Madeleine

AU - de Heer, Koen

AU - Snijders, Tjeerd J F

AU - Siemes, Claire

AU - Wendtner, Clemens-Martin

AU - Knauf, Wolfgang U

AU - Kroeber, Alexander

AU - Zahn, Mark-Oliver

AU - Illmer, Thomas

AU - Schöttker, Björn

AU - Simon, Florian

AU - Fink, Anna-Maria

AU - Fischer, Kirsten

AU - D'Brot, Ronald

AU - Holmes, Emily Eva

AU - Kreuzer, Karl-Anton

AU - Ritgen, Matthias

AU - Brüggemann, Monika

AU - Tausch, Eugen

AU - Stilgenbauer, Stephan

AU - Levin, Mark-David

AU - Hallek, Michael J

AU - Kater, Arnon P

AU - Eichhorst, Barbara F

PY - 2026/6/18

Y1 - 2026/6/18

N2 - 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.

AB - 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.

KW - Adenine/analogs & derivatives

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal, Humanized

KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use

KW - Bendamustine Hydrochloride/administration & dosage

KW - Bridged Bicyclo Compounds, Heterocyclic/administration & dosage

KW - Cyclophosphamide/administration & dosage

KW - Female

KW - Humans

KW - Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy

KW - Male

KW - Middle Aged

KW - Patient Reported Outcome Measures

KW - Piperidines/administration & dosage

KW - Rituximab/administration & dosage

KW - Sulfonamides/administration & dosage

KW - Vidarabine/analogs & derivatives

KW - Therapy

KW - Obinutuzumab

KW - Rituximab

KW - 1st-line treatment

KW - Ibrutinib

KW - Final analysis

U2 - 10.1182/blood.2025032160

DO - 10.1182/blood.2025032160

M3 - Article

C2 - 41911073

SN - 0006-4971

VL - 147

SP - 3025

EP - 3038

JO - Blood

JF - Blood

IS - 25

ER -

Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial

Abstract

Keywords

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