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Cited by 159Acute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processesChronic Lymphocytic Leukemia Research

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Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine

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Pollyea, Daniel A., Pratz, Keith W., Wei, Andrew H., Pullarkat, Vinod, Jonas, Brian A., Recher, Christian, Babu, Sunil, Schuh, Andre C., Dail, Monique, Sun, Yan, Potluri, Jalaja, Chyla, Brenda, DiNardo, Courtney D.·2022·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-22-1183PMC PMC9751752

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Abstract

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt. Patients and Methods: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1–28) + azacitidine (75 mg/m2 days 1–7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally. Results: Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18). For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt. For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively. For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients. Conclusions: In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235

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Crossref · 10.1158/1078-0432.ccr-22-1183

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Figure 1. Study design and molecular classification. Abbreviations: Aza, azacitidine; mut, mutated; Pbo, placebo; wt, wild-type; Ven, venetoclax.
Figure 1. Study design and molecular classification. Abbreviations: Aza, azacitidine; mut, mutated; Pbo, placebo; wt, wild-type; Ven, venetoclax.CC BY-NC-ND · PubMed Central
Figure 2. Response rates. A, CR+CRi in patients with poor-risk cytogenetics. B, CR+CRi in patients with intermediate-risk cytogenetics. C, Transfusion independence in patients with poor-risk cytogenetics. D, Transfusion independence in patients with intermediate-risk cytogenetics. E, MRD <10−3 in patients with poor-risk cytogenetics. F, MRD <10−3 in patients with intermediate-risk cytogenetics. Abbreviations: Aza, azacitidine; CR, complete remission; CRi, CR with incomplete hematologic recovery; mut, mutated; wt, wild-type; Ven, venetoclax.
Figure 2. Response rates. A, CR+CRi in patients with poor-risk cytogenetics. B, CR+CRi in patients with intermediate-risk cytogenetics. C, Transfusion independence in patients with poor-risk cytogenetics. D, Transfusion independence in patients with intermediate-risk cytogenetics. E, MRD <10−3 in patients with poor-risk cytogenetics. F, MRD <10−3 in patients with intermediate-risk cytogenetics. Abbreviations: Aza, azacitidine; CR, complete remission; CRi, CR with incomplete hematologic recovery; mut, mutated; wt, wild-type; Ven, venetoclax.CC BY-NC-ND · PubMed Central
Figure 3. Duration of response and OS. A, Duration of response among patients with poor-risk cytogenetics. B, Duration of response among patients with intermediate-risk cytogenetics. C, OS among patients with poor-risk cytogenetics. D, OS among patients with intermediate-risk cytogenetics. Abbreviations: Aza, azacitidine; mut, mutated; wt, wild-type; Ven, venetoclax.
Figure 3. Duration of response and OS. A, Duration of response among patients with poor-risk cytogenetics. B, Duration of response among patients with intermediate-risk cytogenetics. C, OS among patients with poor-risk cytogenetics. D, OS among patients with intermediate-risk cytogenetics. Abbreviations: Aza, azacitidine; mut, mutated; wt, wild-type; Ven, venetoclax.CC BY-NC-ND · PubMed Central
Figure 4. Response rates and OS by VAF. A, Response rates by VAF among patients with poor-risk cytogenetics and TP53mut treated with venetoclax + azacitidine. B, OS by variant allelic frequency among patients with poor-risk cytogenetics and TP53mut treated with venetoclax + azacitidine. Abbreviations: CR, complete remission; CRi, CR with incomplete hematologic recovery; NE, not evaluable; VAF, variant allele frequency.
Figure 4. Response rates and OS by VAF. A, Response rates by VAF among patients with poor-risk cytogenetics and TP53mut treated with venetoclax + azacitidine. B, OS by variant allelic frequency among patients with poor-risk cytogenetics and TP53mut treated with venetoclax + azacitidine. Abbreviations: CR, complete remission; CRi, CR with incomplete hematologic recovery; NE, not evaluable; VAF, variant allele frequency.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Pollyea, D. A., Pratz, K. W., Wei, A. H., Pullarkat, V., Jonas, B. A., Recher, C., Babu, S., Schuh, A. C., Dail, M., Sun, Y., Potluri, J., Chyla, B., & DiNardo, C. D.
Affiliations
  • University of Colorado Anschutz (US)
  • Abramson Cancer Center (US)
  • The Royal Melbourne Hospital (AU)
  • City Of Hope National Medical Center (US)
  • University of California Davis Medical Center (US)
  • 6Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
  • 7Fort Wayne Medical Oncology and Hematology, Fort Wayne, Indiana.
  • Princess Margaret Cancer Centre (CA)
  • 9Genentech Inc., South San Francisco, California.
  • AbbVie (United States) (US)
  • The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Pollyea, Daniel A.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2022-08-25
Volume
28
Issue
24
Pages
5272-5279
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-22-1183
PMC
PMC9751752
OpenAlex
W4293253462
Cited by
159
References
29
Citations by year
2026: 24 · 2025: 41 · 2024: 44 · 2023: 39 · 2022: 10
FWCI
24.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Clinical Cancer Research (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
Funders
  • AbbVie (NCT02993523)
  • Genentech (NCT02203773)
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 › Hematology › Chronic Lymphocytic Leukemia Research
Keywords
venetoclax, azacitidine, acute myeloid leukemia, poor-risk cytogenetics, TP53 mutation, wild-type p53, combination therapy, remission duration, overall survival, febrile neutropenia, adverse events, treatment-naive patients, elderly patients, prognostic factors, prognostic score
MeSH terms
Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Humans, Mutation, Sulfonamides, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Treatment Outcome, Clinical Trials, Phase I as Topic, Clinical Trials, Phase III as Topic, Bridged Bicyclo Compounds, Heterocyclic, Cytogenetic Analysis

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