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

Christopher A. Eide; Stephen E. Kurtz; Andy Kaempf; Nicola Long; Anupriya Agarwal; Cristina E. Tognon; Motomi Mori; Brian J. Druker; Bill H. Chang; Alexey V. Danilov; Jeffrey W. Tyner

doi:10.1038/s41375-020-0764-6

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

Christopher A. Eide, Stephen E. Kurtz, Andy Kaempf, Nicola Long, Anupriya Agarwal, Cristina E. Tognon, Motomi Mori, Brian J. Druker, Bill H. Chang, Alexey V. Danilov, Jeffrey W. Tyner

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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.

Original language	English (US)
Pages (from-to)	2342-2353
Number of pages	12
Journal	Leukemia
Volume	34
Issue number	9
DOIs	https://doi.org/10.1038/s41375-020-0764-6
State	Published - Sep 1 2020

ASJC Scopus subject areas

Hematology
Oncology
Cancer Research

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title = "Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia",

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.",

author = "Eide, {Christopher A.} and Kurtz, {Stephen E.} and Andy Kaempf and Nicola Long and Anupriya Agarwal and Tognon, {Cristina E.} and Motomi Mori and Druker, {Brian J.} and Chang, {Bill H.} and Danilov, {Alexey V.} and Tyner, {Jeffrey W.}",

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doi = "10.1038/s41375-020-0764-6",

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T1 - Simultaneous kinase inhibition with ibrutinib and BCL2 inhibition with venetoclax offers a therapeutic strategy for acute myeloid leukemia

AU - Eide, Christopher A.

AU - Kurtz, Stephen E.

AU - Kaempf, Andy

AU - Long, Nicola

AU - Agarwal, Anupriya

AU - Tognon, Cristina E.

AU - Mori, Motomi

AU - Druker, Brian J.

AU - Chang, Bill H.

AU - Danilov, Alexey V.

AU - Tyner, Jeffrey W.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

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

Abstract

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