Venetoclax combined with induction chemotherapy in patients with newly diagnosed acute myeloid leukaemia: a post-hoc, propensity score-matched, cohort study.

Autor:	Lachowiez CA; Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Reville PK; Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kantarjian H; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jabbour E; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Borthakur G; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Daver N; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Loghavi S; Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Furudate K; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Xiao L; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Pierce S; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Short NJ; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Maiti A; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yilmaz M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sasaki K; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Takahashi K; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Konopleva M; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Pemmaraju N; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Popat U; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Shpall E; Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Garcia-Manero G; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Ravandi F; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., DiNardo CD; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Kadia TM; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: tkadia@mdanderson.org.
Jazyk:	angličtina
Zdroj:	The Lancet. Haematology [Lancet Haematol] 2022 May; Vol. 9 (5), pp. e350-e360.
DOI:	10.1016/S2352-3026(22)00076-X
Abstrakt:	Background: Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone. Methods: This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and were treated within trials incorporating purine analogues with an anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients in the venetoclax plus intensive chemotherapy cohort were matched with patients in the intensive chemotherapy cohort. Morphological response and measurable residual disease (MRD) was assessed using bone marrow aspiration and biopsy and eight-colour multiparameter flow cytometry. The primary objectives were rate of MRD negative composite complete response and cumulative incidence of transition to allogeneic haematopoietic stem-cell transplantation (HSCT). All patients who had response within two treatment cycles (induction and re-induction) were included in the analyses. Secondary objectives included assessment of event-free and overall survival. Findings: The propensity matched cohort included 279 patients (median age 49 years [IQR 39-57]; 131 [47%] were men and 148 [53%] were women); 85 in the venetoclax plus intensive chemotherapy cohort and 194 in the intensive chemotherapy cohort. After a median follow up of 30 months (95% CI 26-36), 64 (86%) of 74 patients in the venetoclax plus intensive chemotherapy cohort had an MRD-negative composite complete response rate compared with 86 [61%] of 140 patients in the intensive chemotherapy cohort (odd ratio 3·2 [95% CI 1·5-6·7]; p=0·0028). The overall cumulative incidence of allogeneic HSCT in responding patients was higher with venetoclax plus intensive chemotherapy than intensive chemotherapy (79% [95% CI 67-88] vs 57% [49-65]; hazard ratio [HR] 1·52 [95% CI 1·11-2·08]; p=0·012). Venetoclax plus intensive chemotherapy improved event-free survival (median not reached [NR; 95% CI NR-NR] vs 14·3 months [10·7-33·5]; HR 0·57 [95% CI 0·34-0·95]; p=0·030), but overall survival did not significantly differ between the two cohorts (median NR [95% CI 24-NR] vs 32 months [19-NR]; HR 0·63 [95% CI 0·35-1·1], p=0·13). Interpretations: Venetoclax combined with intensive induction chemotherapy induced deep MRD-negative remissions, allowing transition to allogeneic HSCT in first remission, and improvement in event-free survival. These results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy across European LeukemiaNet risk groups, and serve as a benchmark to inform enrolment on future confirmatory prospective clinical trials. Funding: None. Competing Interests: Declaration of interests GB reports consultancy fees from Protagonist Therapeutics, research funding from Ryvu, membership on an entity's Board of Directors or advisory committees from Takeda, research funding from Astex, membership on an entity's Board of Directors or advisory committees from ArgenX, current employment by University of Texas MD Anderson Cancer Center, consultancy and membership on an entity's Board of Directors or advisory committees from Novartis, and consultancy from GSK. MY reports research funding from Daiichi-Sankyo and Pfizer. NP reports consultancy from DAVA Oncology, LFB Biotechnologies, MustangBio, Stemline Therapeutics, Affymetrix, Roche Diagnostics, Blueprint Medicines, Clearview Healthcare Partners, Novartis Pharmaceuticals, Celgene Corporation, Incyte, Protagonist Therapeutics, Abbvie Pharmaceuticals, Aptitude Health, Bristol-Myers Squibb, ImmunoGen, Pacylex Pharmaceuticals, and CareDx; membership on the Board of Directors or advisory committees of ASCO Leukemia Advisory Panel, Dan's House of Hope, Stemline Therapeutics, Abbvie Pharmaceuticals, ASH Communications Committee, and HemOnc Times/Oncology Times; and grants or contracts from Sager Strong Foundation, MustangBio, Daiichi Sankyo, Springer Science + Business Media, Stemline Therapeutics, Samus, Novartis Pharmaceuticals, Abbvie Pharmaceuticals, Plexxicon, and Cellectis S.A. ADR; research funding from Cellectis S.A. ADR, Daiichi Sankyo, Affymetrix, Samus, Novartis Pharmaceuticals, Abbvie Pharmaceuticals, Plexxicon, and Stemline Therapeutics; and research support from Novartis Pharmaceuticals. UP reports research funding from Bayer, Abbvie, Novartis, and Incyte. ES reports honoraria from Magenta, Novartis, and Bayer HealthCare Pharmaceuticals; consultancy from Navan, Axio, Adaptimmune, Magenta, and Novartis; and patents and royalties from Affimed and Takeda. CDD reports membership on an entity's Board of Directors or advisory committees from GlaxoSmithKline and Notable Labs; current stock options in a privately-held company in Notable Labs, honoraria from ImmuneOnc, Bristol Myers Squibb, Agios/Servier, Takeda, Novartis, Foghorn, Celgene a Bristol Myers Squibb company, and Forma; research funding from ImmuneOnc, and Bristol Myers Squibb, AbbVie, Agios/Servier, Foghorn, Celgene a Bristol Myers Squibb company, and Forma; and consultancy for AbbVie and Agios/Servier. TMK reports consultancy from Abbvie, Sanofi-Aventis, Liberum, Jazz, Genentech, Daiichi Sankyo, Novartis, Pfizer, and Aglos; grant or research support from Abbvie, Genentech, Bristol Myers Squibb, and Amgen; speaker's bureau fees from Cure, and research support from Genfleet, Cellonkos, Astellas, AstraZeneca, Ascentage, and Pulmotech. ND reports consultancy for Novartis, Trovagene, Abbvie, Genentech, Amgen, Pfizer, Bristol Myers Squibb, Astellas, Daiichi Sankyo, Sevier, ImmunoGen, Gilead Sciences, Trillium, Dava Oncology (Arog), Celgene, Syndax, Shattuck Labs, Agios, Kite Pharmaceuticals, SOBI, STAR Therapeutics, and Jazz Pharmaceuticals; member of the Data Monitoring Committee for Jazz Pharmaceuticals; research funding from Trovagene, Genentech, FATE Therapeutics, Hanmi, Amgen, Pfizer, Bristol Myers Squibb, Novimmune, Astellas, Daiichi Sankyo, Sevier, ImmunoGen, Glycomimetics, Gilead Sciences, Trillium, Karyopharm, Newave, and Abbvie. NJS reports consultancy for Takeda Oncology, Jazz Pharmaceuticals, NGMBio, AstraZeneca, and Amgen; research funding from Takeda Oncology and Astellas; honoraria from Amgen, and Novartis. MK reports grant support from Agios, Rafael Pharmaceuticals, Cellectis, Ascentage, AstraZeneca, Sanofi, Ablynx, Genentech, Forty Seven, AbbVie, F Hoffmann-La Roche, and Calithera; research funding from Agios, Rafael Pharmaceuticals, KisoJi, Eli Lilly, Ascentage, AstraZeneca, Sanofi, Ablynx, Genentech, Forty Seven, AbbVie, Stemline Therapeutics, and Calithera; intellectual property rights from Eli Lilly, Novartis, and Reata Pharmaceuticals; current stock options in Reata Pharmaceuticals; pending research funding from Novartis; consultancy for Genentech, F Hoffmann-La Roche, and AbbVie; honoraria from Genentech, F Hoffmann-La Roche, and AbbVie. FR reports honoraria from Astex, Taiho, Bristol Myers Squibb, Xencor, Agios, AstraZeneca, Novartis, AbbVie, Celgene, Jazz, Syros Pharmaceuticals, and Amgen; research funding from Astex, Taiho, Bristol Myers Squibb, Xencor, Agios, Prelude, AbbVie, Celgene, Jazz, Syros Pharmaceuticals, and Amgen; membership on the Board of Directors or advisory committees of Bristol Myers Squibb and Celgene; consultancy for Syros Pharmaceuticals. KT reports consultancy for Novartis, Celgene/BMS, GSK, and Symbio Pharmaceuticals; and membership on Symbio Pharmaceuticals’ Board of Directors or advisory committee. SL reports current equity in publicly-traded Abbvie; honoraria from Curio Sciences and Peerview; and consultancy for Gerson Lehrman Group, Guidepoint, and Qualworld. KS reports consultancy for Novartis; research funding from Novartis; membership on the Board of Directors or advisory committees of Pfizer and Daiichi-Sankyo. HK reports honoraria from AbbVie, Ipsen Pharmaceuticals, AstraZeneca, KAHR Medical, Aptitude Health, Pfizer, Astellas Health, Novartis, NOVA Research, Precision Biosciences, Taiho Pharmaceutical Canada, and Amgen; research funding from AbbVie, Immunogen, BMS, Jazz Pharmaceuticals, Ascentage, Daiichi-Sankyo, Pfizer, Novartis, and Amgen. All other authors declare no competing interests. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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