Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

Courtney D. DiNardo, Keith Pratz, Vinod Pullarkat, Brian Jonas, Martha Arellano, Pamela S. Becker, Olga Frankfurt, Marina Konopleva, Andrew H. Wei, Hagop M. Kantarjian, Tu Xu, Wan Jen Hong, Brenda Chyla, Jalaja Potluri, Daniel A. Pollyea, Anthony Letai

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Abstract

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 5 145) 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) 1 CR with incomplete count recovery (CRi), with a CR 1 CRi rate of 73% in the venetoclax 400 mg 1 HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR 1 CRi rates of 60% and 65%, respectively. The median duration of CR 1 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).

Original languageEnglish (US)
Pages (from-to)7-17
Number of pages11
JournalBlood
Volume133
Issue number1
DOIs
StatePublished - Jan 3 2019

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decitabine
Azacitidine
Acute Myeloid Leukemia
Cytogenetics
Therapeutics
Survival
Cells
Tumor Lysis Syndrome
Chemotherapy
Febrile Neutropenia
Hypokalemia
B-Cell Lymphoma
Appetite
Myeloid Cells
Constipation
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Tumors
Leukocyte Count
Blood
Nausea

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. / DiNardo, Courtney D.; Pratz, Keith; Pullarkat, Vinod; Jonas, Brian; Arellano, Martha; Becker, Pamela S.; Frankfurt, Olga; Konopleva, Marina; Wei, Andrew H.; Kantarjian, Hagop M.; Xu, Tu; Hong, Wan Jen; Chyla, Brenda; Potluri, Jalaja; Pollyea, Daniel A.; Letai, Anthony.

In: Blood, Vol. 133, No. 1, 03.01.2019, p. 7-17.

Research output: Contribution to journalArticle

DiNardo, CD, Pratz, K, Pullarkat, V, Jonas, B, Arellano, M, Becker, PS, Frankfurt, O, Konopleva, M, Wei, AH, Kantarjian, HM, Xu, T, Hong, WJ, Chyla, B, Potluri, J, Pollyea, DA & Letai, A 2019, 'Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia', Blood, vol. 133, no. 1, pp. 7-17. https://doi.org/10.1182/blood-2018-08-868752
DiNardo, Courtney D. ; Pratz, Keith ; Pullarkat, Vinod ; Jonas, Brian ; Arellano, Martha ; Becker, Pamela S. ; Frankfurt, Olga ; Konopleva, Marina ; Wei, Andrew H. ; Kantarjian, Hagop M. ; Xu, Tu ; Hong, Wan Jen ; Chyla, Brenda ; Potluri, Jalaja ; Pollyea, Daniel A. ; Letai, Anthony. / Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. In: Blood. 2019 ; Vol. 133, No. 1. pp. 7-17.
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T1 - Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia

AU - DiNardo, Courtney D.

AU - Pratz, Keith

AU - Pullarkat, Vinod

AU - Jonas, Brian

AU - Arellano, Martha

AU - Becker, Pamela S.

AU - Frankfurt, Olga

AU - Konopleva, Marina

AU - Wei, Andrew H.

AU - Kantarjian, Hagop M.

AU - Xu, Tu

AU - Hong, Wan Jen

AU - Chyla, Brenda

AU - Potluri, Jalaja

AU - Pollyea, Daniel A.

AU - Letai, Anthony

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N2 - 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 5 145) 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) 1 CR with incomplete count recovery (CRi), with a CR 1 CRi rate of 73% in the venetoclax 400 mg 1 HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR 1 CRi rates of 60% and 65%, respectively. The median duration of CR 1 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).

AB - 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 5 145) 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) 1 CR with incomplete count recovery (CRi), with a CR 1 CRi rate of 73% in the venetoclax 400 mg 1 HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR 1 CRi rates of 60% and 65%, respectively. The median duration of CR 1 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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