Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab + Venetoclax (RVe) Versus Obinutuzumab (GA101) + Venetoclax (GVe) Versus Obinutuzumab + Ibrutinib + Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic Lymphocytic Leukemia (CLL) Without Del(17p) or TP53 Mutation

Summary

The aim of this study is to evaluate if standard chemoimmunotherapy (FCR, BR) in frontline treatment of physically fit CLL patients without del17p or TP 53 mutation can be replaced by combinations of targeted drugs (Venetoclax, Ibrutinib) with anti-CD20-antibodies (Rituximab, Obinutuzumab), which may induce extremely long lasting remissions.

Timeline

Start

2016-12-13

Primary completion

2024-02-29

Completion

2024-02-29

Outcome

Met primary endpoint

paper The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001). PMID 38821083 ↗

paper At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group PMID 37163621 ↗

paper Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. PMID 37163621 ↗

Publications

• Results Furstenau M, Kater AP, Robrecht S, von Tresckow J, Zhang C, Gregor M, Thornton P, Staber PB, Tadmor T, Lindstrom V, Juliusson G, Janssens A, Levin MD, da Cunha-Bang C, Schneider C, Goldschmidt N, Vandenberghe E, Rossi D, Benz R, Nosslinger T, Heintel D, Poulsen CB, Christiansen I, Frederiksen H, Enggaard L, Posthuma EFM, Issa DE, Visser HPJ, Bellido M, Kutsch N, Durig J, Stehle A, Vohringer M, Bottcher S, Schulte C, Simon F, Fink AM, Fischer K, Holmes EE, Kreuzer KA, Ritgen M, Bruggemann M, Tausch E, Stilgenbauer S, Hallek M, Niemann CU, Eichhorst B. First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2024 Jun;25(6):744-759. doi: 10.1016/S1470-2045(24)00196-7.
• Results Eichhorst B, Niemann CU, Kater AP, Furstenau M, von Tresckow J, Zhang C, Robrecht S, Gregor M, Juliusson G, Thornton P, Staber PB, Tadmor T, Lindstrom V, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schottker B, Nosslinger T, Janssens A, Christiansen I, Baumann M, Frederiksen H, van der Klift M, Jager 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 AM, Bahlo J, Fischer K, Wendtner CM, Kreuzer KA, Ritgen M, Bruggemann M, Tausch E, Levin MD, 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. First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia. N Engl J Med. 2023 May 11;388(19):1739-1754. doi: 10.1056/NEJMoa2213093.
• Furstenau M, Niemann CU, Robrecht S, Rotbain EC, Eurelings L, 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 A, Nosslinger T, Poulsen CB, Frederiksen H, Lotfi K, Ranti J, Enggaard L, Velders G, Vekemans MC, de Heer K, Snijders TF, Siemes C, Wendtner CM, Knauf W, Kroeber A, Zahn MO, Illmer T, Schottker B, Simon F, Fink A, Fischer K, D'Brot R, Holmes E, Kreuzer KA, Ritgen M, Bruggemann M, Tausch E, Stilgenbauer S, Levin MD, Hallek M, Kater AP, Eichhorst B. Venetoclax combinations in untreated CLL: 5-year results and patient-reported outcomes analysis of the CLL13/GAIA trial. Blood. 2026 Jun 18;147(25):3025-3038. doi: 10.1182/blood.2025032160.
• Langerbeins P, Giza A, Robrecht S, Cramer P, von Tresckow J, Al-Sawaf O, Fink AM, Furstenau M, Kutsch N, Simon F, Goede V, Hoechstetter M, Niemann CU, da Cunha-Bang C, Kater A, Dubois J, Gregor M, Staber PB, Tausch E, Schneider C, Stilgenbauer S, Eichhorst B, Fischer K, Hallek M. Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies. Blood. 2024 Jun 20;143(25):2588-2598. doi: 10.1182/blood.2023022564.
• Furstenau M, Thus YJ, Robrecht S, Mellink CHM, van der Kevie-Kersemaekers AM, Dubois J, von Tresckow J, Patz M, Gregor M, Thornton P, Staber PB, Tadmor T, Levin MD, da Cunha-Bang C, Schneider C, Poulsen CB, Illmer T, Schottker B, Janssens A, Christiansen I, Nosslinger T, Baumann M, Hebart H, Gaska T, Regelink JC, Dompeling EC, Lindstrom V, Juliusson G, Widmer A, Goede J, Goldschmidt N, Simon F, De Silva N, Fink AM, Fischer K, Wendtner CM, Ritgen M, Bruggemann M, Tausch E, Spaargaren M, Eldering E, Stilgenbauer S, Niemann CU, Hallek M, Eichhorst B, Kreuzer KA, Kater AP. High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations. Blood. 2023 Aug 3;142(5):446-459. doi: 10.1182/blood.2023019634.
• Furstenau M, Langerbeins P, De Silva N, Fink AM, Robrecht S, von Tresckow J, Simon F, Hohloch K, Droogendijk J, van der Klift M, van der Spek E, Illmer T, Schottker B, Fischer K, Wendtner CM, Tausch E, Stilgenbauer S, Niemann CU, Gregor M, Kater AP, Hallek M, Eichhorst B. COVID-19 among fit patients with CLL treated with venetoclax-based combinations. Leukemia. 2020 Aug;34(8):2225-2229. doi: 10.1038/s41375-020-0941-7. Epub 2020 Jun 29. No abstract available.

Drugs

Evaluation	Drug	Modality	Dose	Route
Comparator	Bendamustine	Small molecule	90 mg/m2	Intravenous
Comparator	Cyclophosphamide	Other / unclassified	250 mg/m2	Intravenous
Comparator	Fludarabine	Small molecule	25 mg/m2	Intravenous
Subject	Ibrutinib	Small molecule	420 mg	Oral
Subject	Obinutuzumab	Monoclonal antibody	1000 mg	Intravenous
Subject	Rituximab	Monoclonal antibody	500 mg/m2	Intravenous
Subject	Venetoclax	Small molecule	400 mg	Oral

Indications