Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Nov 21;144(21):2211-2222.
doi: 10.1182/blood.2024024944.

Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine

Hartmut Döhner  1 , Keith W Pratz  2 , Courtney D DiNardo  3 , Andrew H Wei  4 , Brian A Jonas  5 , Vinod A Pullarkat  6 , Michael J Thirman  7 , Christian Récher  8 , Andre C Schuh  9 , Sunil Babu  10 , Xiaotong Li  11 , Grace Ku  12 , Zihuan Liu  11 , Yan Sun  11 , Jalaja Potluri  11 , Monique Dail  12 , Brenda Chyla  11 , Daniel A Pollyea  13
Affiliations

Genetic risk stratification and outcomes among treatment-naive patients with AML treated with venetoclax and azacitidine

Hartmut Döhner et al. Blood. .

Abstract

The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most patients as adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). Although outcomes with venetoclax-azacitidine improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine. The mutational status of TP53, FLT3 internal tandem duplication (FLT3-ITD), NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% confidence interval (CI), 20.2-32.7]; 12.1 months [95% CI, 7.3-15.2]; and 5.5 months [95% CI, 2.8-7.6], respectively). ELN prognostic classifiers did not provide clinically meaningful risk stratification of OS outcomes in patients treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows the classification of these patients into 3 risk groups with distinct differences in median OS. These trials were registered at www.clinicaltrials.gov as #NCT02993523 and #NCT02203773.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: H.D. reports advisory role for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, Bristol Myers Squibb (BMS), Celgene, GEMoaB, Gilead Sciences, Janssen, Jazz Pharmaceuticals, Novartis, and Syndax and research funding from AbbVie, Agios, Amgen, Astellas, BMS, Jazz Pharmaceuticals, Kronos Bio, and Novartis. K.W.P. reports research funding from AbbVie, Agios, Daiichi Sankyo, and Millennium and advisory board membership for AbbVie, Astellas, AstraZeneca, Boston Biomedical, BMS, Celgene, Novartis, Jazz Pharmaceuticals, and Servier. C.D.D. reports research funding from AbbVie, Astex, BeiGene, BMS, Cleave, Foghorn, Jazz Pharmaceuticals, Loxo, and Servier and advisory role for AbbVie, Astellas, BMS, GlaxoSmithKline, Genmab, Genentech, Jazz Pharmaceuticals, Loxo, Servier, and Schrodinger. A.H.W. has served on advisory boards for Novartis, AstraZeneca, Astellas, Janssen, Jazz Pharmaceuticals, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead Sciences, BMS, and BeiGene; has consulted for AbbVie, Servier, Novartis, Shoreline, and Aculeus; receives research funding to institution from Novartis, AbbVie, Servier, BMS, Syndax, Astex, AstraZeneca, and Amgen; serves on speaker’s bureaus for AbbVie, Novartis, BMS, Servier, and Astellas; is an employee of the Walter and Eliza Hall Institute (WEHI; WEHI receives milestone and royalty payments related to the development of venetoclax, and current and past employees of WEHI may be eligible for financial benefits related to these payments); and receives such financial benefit. B.A.J. reports consultancy/advisory role for AbbVie, BMS, Daiichi Sankyo, Genentech, Gilead Sciences, GlycoMimetics, Kymera, Kura, Rigel, Schrodinger, Syndax, and Treadwell; protocol steering committee membership for GlycoMimetics; data monitoring committee membership for Gilead Sciences; travel reimbursement/support from Rigel; and research funding to institution from AbbVie, Amgen, AROG, Aptose, Biomea Fusion, BMS, Celgene, F. Hoffmann-La Roche, Forma, Forty Seven, Genentech/Roche, Gilead Sciences, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Kymera, Loxo, Pfizer, Pharmacyclics, and Treadwell. V.A.P. reports consultancy fees and honoraria from AbbVie, Jazz Pharmaceuticals, Novartis, and Rigel. M.J.T. reports research funding from AbbVie, Gilead Sciences, Janssen, Merck, Pharmacyclics, Syndax, and TG Therapeutics and consultancy fees from AbbVie, AstraZeneca, Celgene, Janssen, Pharmacyclics, and Roche/Genentech. C.R. reports research funding from AbbVie, BMS, Jazz Pharmaceuticals, Astellas, and IQVIA and advisory role for AbbVie, Jazz Pharmaceuticals, Astellas, Novartis, BMS, Takeda, and Servier. A.C.S. reports clinical trial funding from AbbVie, Amgen, AstraZeneca, BMS, GlycoMimetics, Kite/Gilead Sciences, Loxo, Novartis, Pfizer, Servier, Syndax, and Syros and advisory board membership for AbbVie, Amgen, Astellas, BMS, Jazz Pharmaceuticals, Novartis, Pfizer, and Teva. G.K. and M.D. report employment by Genentech Inc and may own stock/options in Roche. X.L., Z.L., Y.S., J.P., and B.C. report employment by AbbVie and may own stock or other options. D.A.P. reports research funding from AbbVie, Teva, Karyopharm, and BMS; consultancy or advisory board membership for LINK, Daiichi Sankyo, Aptevo, Rigel, Novartis, Sumitomo, Adicet, AbbVie, Syros, Qihan, Seres, Gilead Sciences, OncoVerity, BMS, Boehringer Ingelheim, Sanofi, Karyopharm, MEI Pharma, Inc, and Syndax; and support from the Leukemia and Lymphoma Society Scholar in Clinical Research and the Robert H. Allen MD Chair in Hematology research. S.B. declares no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Response rates with Ven-Aza or Pbo-Aza in favorable-, intermediate-, and adverse-risk groups. CR/CRi rate in patients treated with Ven-Aza or Pbo-Aza by (A) ELN 2017 and (B) ELN 2022. OS in patients treated with Ven-Aza or Pbo-Aza in the ELN 2022 (C) favorable-, (D) intermediate-, and (E) adverse-risk groups. Aza, azacitidine; NR, not reached; Pbo, placebo; Ven, venetoclax.
Figure 2.
Figure 2.
OS in patients treated with Ven-Aza in favorable-, intermediate-, and adverse-risk groups. OS in patients treated with Ven-Aza by risk group per (A) ELN 2017 and (B) ELN 2022.
Figure 3.
Figure 3.
Response in patients treated with Ven-Aza or Pbo-Aza by risk stratification. (A) Remission rates in patients treated with Ven-Aza or Pbo-Aza in the higher-, intermediate-, and lower-benefit groups. (B) OS in patients treated with Ven-Aza in the higher-, intermediate-, and lower-benefit groups.
Figure 4.
Figure 4.
OS in patients treated with Ven-Aza or Pbo-Aza by risk stratification. (A) Higher-, (B) intermediate-, and (C) lower-benefit groups.
Figure 5.
Figure 5.
OS in patients treated with Ven-Aza in the higher- and intermediate-benefit groups with recurrent mutations. Data are for patients with (A) NPM1 mutations, (B) RUNX1 mutations, (C) IDH1 mutations, and (D) IDH2 mutations.
See this image and copyright information in PMC

References

    1. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629. - PubMed
    1. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. - PMC - PubMed
    1. Pratz KW, Jonas BA, Pullarkat V, et al. Long-term follow-up of VIALE-A: venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia. Am J Hematol. 2024;99(4):615–624. - PubMed
    1. Metzeler KH, Herold T, Rothenberg-Thurley M, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128(5):686–698. - PubMed
    1. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med. 2016;374(23):2209–2221. - PMC - PubMed

MeSH terms

Associated data