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Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia.

Authors
  • Eide, Christopher A1, 2
  • Kurtz, Stephen E1
  • Kaempf, Andy3
  • Long, Nicola1
  • Agarwal, Anupriya1
  • Tognon, Cristina E1, 2
  • Mori, Motomi3, 4
  • Druker, Brian J1, 2
  • Chang, Bill H1
  • Danilov, Alexey V1
  • Tyner, Jeffrey W5, 6
  • 1 Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 2 Howard Hughes Medical Institute, Portland, OR, USA.
  • 3 Biostatistics Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
  • 4 Portland State University and Oregon Health & Science University School of Public Health, Portland, OR, USA.
  • 5 Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. [email protected]
  • 6 Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR, USA. [email protected]
Type
Published Article
Journal
Leukemia
Publisher
Springer Nature
Publication Date
Sep 01, 2020
Volume
34
Issue
9
Pages
2342–2353
Identifiers
DOI: 10.1038/s41375-020-0764-6
PMID: 32094466
Source
Medline
Language
English
License
Unknown

Abstract

Acute myeloid leukemia (AML) results from the enhanced proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Using an ex vivo functional screening assay, we identified that the combination of the BTK inhibitor ibrutinib and BCL2 inhibitor venetoclax (IBR + VEN), currently in clinical trials for chronic lymphocytic leukemia (CLL), demonstrated enhanced efficacy on primary AML patient specimens, AML cell lines, and in a mouse xenograft model of AML. Expanded analyses among a large cohort of hematologic malignancies (n = 651 patients) revealed that IBR + VEN sensitivity associated with selected genetic and phenotypic features in both CLL and AML specimens. Among AML samples, 11q23 MLL rearrangements were highly sensitive to IBR + VEN. Analysis of differentially expressed genes with respect to IBR + VEN sensitivity indicated pathways preferentially enriched in patient samples with reduced ex vivo sensitivity, including IL-10 signaling. These findings suggest that IBR + VEN may represent an effective therapeutic option for patients with AML.

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