Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia
Open accessAbstract
Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).
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Historical outcomes with HMA treatment, including azacitidine or low-dose cytarabine administered with venetoclax, had median overall survival of 7.2 and 3.7 months, respectively.
“These findings compare favourably to historical outcomes with HMA treatment, including azacitidine or low-dose cytarabine administered with venetoclax where median OS was 7.2 and 3.7 months, respectively.32,33”
From Eprenetapopt (APR-246) and Azacitidine in <i>TP53</i> -Mutant Myelodysplastic Syndromes (2021) · cites this paper as [32]
The Efficacy section (page not available) reports median overall survival of 15.2 months or not reached for the azacitidine–venetoclax cohorts, contrary to the claimed 7.2 months. This study tested venetoclax with azacitidine or decitabine, not low-dose cytarabine; it does not report the claimed 3.7-month outcome. (LLM, conf=0.86)
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- Authors
- DiNardo, C. D., Pratz, K., Pullarkat, V., Jonas, B. A., Arellano, M., Becker, P. S., Frankfurt, O., Konopleva, M., Wei, A. H., Kantarjian, H. M., Xu, T., Hong, W.-J., Chyla, B., Potluri, J., Pollyea, D. A., & Letai, A.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Johns Hopkins University (US)
- City Of Hope National Medical Center (US)
- UC Davis Comprehensive Cancer Center (US)
- Emory University (US)
- University of Washington (US)
- Northwestern University (US)
- The Alfred Hospital (AU)
- AbbVie (United States) (US)
- Genentech (US)
- University of Colorado Anschutz (US)
- Dana-Farber Cancer Institute (US)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2019-01-03
- Volume
- 133
- Issue
- 1
- Pages
- 7-17
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC6318429
- OpenAlex
- W2898284215
- Cited by
- 1,825
- References
- 40
- Citations by year
- 2026: 103 · 2025: 177 · 2024: 220 · 2023: 245 · 2022: 256 · 2021: 288 · 2020: 335 · 2019: 186 · 2018: 7 · 2017: 2 · 2016: 1
- FWCI
- 146.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (acceptedVersion, other-oa)
- Funders
- National Institutes of Health (DP1OD003958)
- Genentech
- National Cancer Institute (P30CA016672, P30CA093373, P01CA066996)
- 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 › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- venetoclax, decitabine, azacitidine, acute myeloid leukemia, elderly patients, BCL-2 inhibition, hypomethylating agents, complete remission, overall survival, dose escalation, adverse events, poor-risk cytogenetics
- MeSH terms
- Decitabine, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Female, Follow-Up Studies, Humans, Male, Prognosis, Sulfonamides, Cohort Studies, Leukemia, Myeloid, Acute, Survival Rate, Bridged Bicyclo Compounds, Heterocyclic, Maximum Tolerated Dose
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