Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia
Open accessAbstract
BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively. CONCLUSIONS: In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).
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Azacitidine + venetoclax is standard of care for AML with CRc rate in mTP53 AML of 55% (CR ~20%) but without improvement of OS (<6 months).
“Azacitidine (AZA) + venetoclax (VEN) is the standard of care for AML with a composite CR (CRc) rate in mTP53 AML of 55% (albeit CR rate of ~20%) but without improvement of OS (<6 months).”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [18]
The Secondary End Points section (page unavailable) reports a 55.3% composite complete-remission rate with azacitidine–venetoclax in patients with TP53 mutations. Figure 3 gives a TP53-subgroup overall-survival hazard ratio of 0.76 (95% CI, 0.40–1.45), which does not establish an OS improvement in that subgroup. Our copy does not report the claimed ~20% TP53 complete-remission rate or <6-month TP53 median OS, and the trial studied previously untreated patients ineligible for intensive therapy, not AML generally. (LLM, conf=0.88)
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- Authors
- DiNardo, C. D., Jonas, B. A., Pullarkat, V., Thirman, M. J., Garcia, J. S., Wei, A. H., Konopleva, M., Döhner, H., Letai, A., Fenaux, P., Koller, E., Havelange, V., Leber, B., Esteve, J., Wang, J., Pejsa, V., Hájek, R., Porkka, K., Illés, Á., Lavie, D., Lemoli, R. M., Yamamoto, K., Yoon, S.-S., Jang, J.-H., Yeh, S.-P., Turgut, M., Hong, W.-J., Zhou, Y., Potluri, J., & Pratz, K. W.
- Affiliations
- City Of Hope National Medical Center (US)
- From the Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (C.D.D., M.K.); the Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento (B.A.J.), the Department of Hematology and Hematopoietic Cell Transplantation and Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte (V. Pullarkat), and Genentech, South San Francisco (W.-J.H.)...
- ORCID
- DiNardo, Courtney D.
- Jonas, Brian A.
- Pullarkat, Vinod
- Thirman, Michael J.
- Garcia, Jacqueline S.
- Wei, Andrew H.
- Konopleva, Marina
- Döhner, Hartmut
- Letai, Anthony
- Fenaux, Pierre
- Havelange, Violaine
- Leber, Brian
- Esteve, Jordi
- Wang, Jianxiang
- Hájek, Roman
- Porkka, Kimmo
- Illés, Árpád
- Lemoli, Roberto M.
- Yamamoto, Kazuhito
- Yoon, Sung-Soo
- Jang, Jun-Ho
- Yeh, Su-Peng
- Turgut, Mehmet
- Hong, Wan-Jen
- Zhou, Ying
- Potluri, Jalaja
- Pratz, Keith W.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2020-08-13
- Volume
- 383
- Issue
- 7
- Pages
- 617-629
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3048827006
- Cited by
- 2,900
- References
- 30
- Citations by year
- 2026: 450 · 2025: 537 · 2024: 501 · 2023: 515 · 2022: 454 · 2021: 363 · 2020: 69 · 2019: 2 · 2014: 1
- FWCI
- 221.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- University of Debrecen Electronic Archive (University of Debrecen) (submittedVersion)
- DIAL (Catholic University of Leuven) (submittedVersion, other-oa)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Funders
- AbbVie
- Genentech
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Health Sciences › Medicine › Pharmacology › Flavonoids in Medical Research
- Keywords
- acute myeloid leukemia, azacitidine, venetoclax, treatment-naive patients, elderly patients, overall survival, complete remission, hypomethylating agents, combination therapy, adverse events, febrile neutropenia, thrombocytopenia, nausea, BCL-2 inhibition, BCL-2 inhibitor
- MeSH terms
- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Double-Blind Method, Female, Follow-Up Studies, Humans, Leukopenia, Male, Middle Aged, Pneumonia, Recurrence, Remission Induction, Sulfonamides, Thrombocytopenia, Leukemia, Myeloid, Acute, Bridged Bicyclo Compounds, Heterocyclic, Kaplan-Meier Estimate, Intention to Treat Analysis
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