Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial.

Autor:	Kersting S; Department of Hematology, HAGA Teaching Hospital, The Hague, Netherlands. Electronic address: s.kersting@hagaziekenhuis.nl., Dubois J; Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam, Netherlands., Nasserinejad K; Department of Hematology, HOVON Data Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands., Dobber JA; Department of Laboratory Special Hematology, Amsterdam University Medical Center, Amsterdam, Netherlands., Mellink C; Department of Human Genetics, Section Cytogenetics, Amsterdam University Medical Center, Amsterdam, Netherlands., van der Kevie-Kersemaekers AF; Department of Human Genetics, Section Cytogenetics, Amsterdam University Medical Center, Amsterdam, Netherlands., Evers LM; Department of Laboratory Special Hematology, Amsterdam University Medical Center, Amsterdam, Netherlands., de Boer F; Department of Internal Medicine, Ikazia Hospital, Rotterdam, Netherlands., Koene HR; Department of Hematology, Antonius Hospital, Nieuwegein, Netherlands., Schreurs J; Department of Internal Medicine, Martini Hospital, Groningen, Netherlands., van der Klift M; Department of Internal Medicine, Amphia Hospital, Breda, Netherlands., Velders GA; Department of Internal Medicine, Gelderland Valley Hospital, Ede, Netherlands., van der Spek E; Department of Internal Medicine, Rijnstate Hospital, Arnhem, Netherlands., van der Straaten HM; Department of Internal Medicine, St Jansdal Hospital, Harderwijk, Netherlands., Hoogendoorn M; Department of Internal Medicine, Medical Center Leeuwarden, Leeuwarden, Netherlands., van Gelder M; Department of Hematology, MUMC, Maastricht, Netherlands., Posthuma EFM; Department of Internal Medicine, RDGG, Delft, Netherlands., Visser HPJ; Department of Internal Medicine, Northwest Clinics, Alkmaar, Netherlands., Houtenbos I; Department of Internal Medicine, Spaarne Gasthuis, Hoofddorp, Netherlands., Idink CAM; Department of Internal Medicine, ZorgSaam hospital, Terneuzen, Netherlands., Issa DE; Department of Internal Medicine, Jeroen Bosch hospital, 's-Hertogenbosch, Netherlands., Dompeling EC; Department of Hematology, Isala Hospital, Zwolle, Netherlands., van Zaanen HCT; Department of Internal Medicine, St Franciscus Hospital, Rotterdam, Netherlands., Veelken H; Department of Hematology, LUMC, Leiden, Netherlands., Levenga H; Department of Internal Medicine, Groene Harthospital, Gouda, Netherlands., Tick LW; Department of Internal Medicine, Maxima MC, Eindhoven, Netherlands., Terpstra WE; Department of Internal Medicine, OLVG, Amsterdam, Netherlands., Tonino SH; Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam, Netherlands., Boyer M; Roche Products Limited, Welwyn Garden City, UK., Mobasher M; Genentech, South San Francisco, CA, USA., Levin MD; Department of Internal Medicine, Albert Schweitzer Hospital, Dordrecht, Netherlands., Kater AP; Department of Hematology, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Amsterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	The Lancet. Haematology [Lancet Haematol] 2022 Mar; Vol. 9 (3), pp. e190-e199.
DOI:	10.1016/S2352-3026(22)00034-5
Abstrakt:	Background: Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status. Methods: We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27). Findings: Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths. Interpretation: Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. Funding: F Hoffmann-La Roche. Competing Interests: Declaration of interests APK reports personal fees from AbbVie, LAVA, Genmab, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb; and research funding from AbbVie, Janssen, AstraZeneca, Roche/Genentech, and Bristol Myers Squibb. EvdS reports honoraria from Janssen and Amgen; and support for attending meetings from Janssen. JD reports research funding from Roche/Genentech. SK reports personal fees from Janssen, AbbVie, Novartis, Gilead, and Celgene; and research funding from AbbVie, Janssen, AstraZeneca, and Roche/Genentech. M-DL reports personal fees from AbbVie, Janssen, and Roche; and research funding from AbbVie, Janssen, AstraZeneca, and Roche/Genentech. SHT reports personal fees from Roche, Takeda, Incyte, Kite/Gilead, and Celgene. All other authors declare no competing interests. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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