title: Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia.
abstract: We present a phase II, single-arm study evaluating 800 mg daily venetoclax, a highly selective, oral small-molecule B-cell leukemia/lymphoma-2 (BCL2) inhibitor in patients with high-risk relapsed/refractory acute myelogenous leukemia (AML) or unfit for intensive chemotherapy. Responses were evaluated following revised International Working Group (IWG) criteria. The overall response rate was 19%; an additional 19% of patients demonstrated antileukemic activity not meeting IWG criteria (partial bone marrow response and incomplete hematologic recovery). Twelve (38%) patients had isocitrate dehydrogenase 1/2 mutations, of whom 4 (33%) achieved complete response or complete response with incomplete blood count recovery. Six (19%) patients had BCL2-sensitive protein index at screening, which correlated with time on study. BH3 profiling was consistent with on-target BCL2 inhibition and identified potential resistance mechanisms. Common adverse events included nausea, diarrhea and vomiting (all grades), and febrile neutropenia and hypokalemia (grade 3/4). Venetoclax demonstrated activity and acceptable tolerability in patients with AML and adverse features.
  
  
  
  Venetoclax monotherapy demonstrated clinical activity in patients with AML (relapsed/refractory or unfit for intensive chemotherapy) with a tolerable safety profile in this phase II study. Predictive markers of response consistent with BCL2 dependence were identified. Clinical and preclinical findings provide a compelling rationale to evaluate venetoclax combined with other agents in AML. Cancer Discov; 6(10); 1106-17. ©2016 AACRSee related commentary by Pullarkat and Newman, p. 1082This article is highlighted in the In This Issue feature, p. 1069.
authors: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Marina
authors: M
authors: Konopleva
authors: University of Colorado Cancer Center, Aurora, Colorado.
authors: Daniel A
authors: DA
authors: Pollyea
authors: AbbVie, Inc., Chicago, Illinois.
authors: Jalaja
authors: J
authors: Potluri
authors: AbbVie, Inc., Chicago, Illinois.
authors: Brenda
authors: B
authors: Chyla
authors: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Leah
authors: L
authors: Hogdal
authors: AbbVie, Inc., Chicago, Illinois.
authors: Todd
authors: T
authors: Busman
authors: AbbVie, Inc., Chicago, Illinois.
authors: Evelyn
authors: E
authors: McKeegan
authors: AbbVie, Inc., Chicago, Illinois. Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors: Ahmed Hamed
authors: AH
authors: Salem
authors: AbbVie, Inc., Chicago, Illinois.
authors: Ming
authors: M
authors: Zhu
authors: AbbVie, Inc., Chicago, Illinois.
authors: Justin L
authors: JL
authors: Ricker
authors: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
authors: William
authors: W
authors: Blum
authors: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Courtney D
authors: CD
authors: DiNardo
authors: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Tapan
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authors: Kadia
authors: AbbVie, Inc., Chicago, Illinois.
authors: Martin
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authors: Dunbar
authors: AbbVie, Inc., Chicago, Illinois.
authors: Rachel
authors: R
authors: Kirby
authors: AbbVie, Inc., Chicago, Illinois.
authors: Nancy
authors: N
authors: Falotico
authors: AbbVie, Inc., Chicago, Illinois.
authors: Joel
authors: J
authors: Leverson
authors: AbbVie, Inc., Chicago, Illinois.
authors: Rod
authors: R
authors: Humerickhouse
authors: AbbVie, Inc., Chicago, Illinois.
authors: Mack
authors: M
authors: Mabry
authors: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Richard
authors: R
authors: Stone
authors: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Hagop
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authors: Kantarjian
authors: Dana-Farber Cancer Institute, Boston, Massachusetts. anthony_letai@dfci.harvard.edu.
authors: Anthony
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authors: Letai
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; C579720:venetoclax