@article{279e7f03609f43729bf1453d348d6026,
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 Stephen Kurtz 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.}",
note = "Funding Information: Acknowledgements Supported by grants from the National Cancer Institute (1U01CA217862, 1U54CA224019, 3P30CA069533). JWT received grants from the V Foundation for Cancer Research, the Gabrielle{\textquoteright}s Angel Foundation for Cancer Research, and the National Cancer Institute (1R01CA183947). AVD is a Leukemia and Lymphoma Society Scholar in Clinical Research. JWT has received research support from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Petra, Seattle Genetics, Syros, Takeda. BJD serves on the advisory boards for Gilead, Aptose, and Blueprint Medicines. BJD is principal investigator or coinvestigator on Novartis and BMS clinical trials. His institution, OHSU, has contracts with these companies to pay for patient costs, nurse and data manager salaries, and institutional overhead. He does not derive salary, nor does his laboratory receive funds from these contracts. The authors certify that the drugs tested in this study were chosen independently and without input from any of our industry partners. AVD received research support from Gilead Sciences, Genentech, Verastem Oncology, Bayer Oncology, Takeda Oncology, Bristol-Myers Squibb, MEI, Aptose Bioscences, AstraZeneca; honoraria and consulting fees from Abbvie, Pharmacyclics, Gilead Sciences, Verastem Oncology, TG Therapeutics, Celgene, Teva Oncology, AstraZeneca, Curis, Seattle Genetics, not relevant to this work. Funding Information: Conflict of interest This manuscript contains original research, has not been previously published, and is not under consideration for publication elsewhere. AVD has received commercial research grants from Gilead Sciences, Verastem, Takeda, AstraZeneca, and Verastem Oncology, and is a consultant/advisory board member for AbbVie, AstraZeneca, Genentech, Verastem Oncology, Seattle Genetics, TG Therapeutics, Curis, Celgene, Teva Oncology, and Gilead Sciences. BJD serves on the board of directors of Amgen, Burroughs Wellcome Fund, and CureOne; reports receiving other commercial research support from Novartis, Bristol-Myers Squibb, and Pfizer (institutional funding—PI or coinvestigator on clinical trials funded via contract with OHSU); has ownership interest (including stock, patents, etc.) in Amgen, Blueprint Medicines, MolecularMD (inactive—acquired by ICON Laboratories), GRAIL, Patent 6958335 (exclusively licensed to Novartis), Henry Stewart Talks, Merck via Dana-Farber Cancer Institute (royalty payments); is a consultant/advisory board member for Aileron Therapeutics, ALLCRON, Third Coast Therapeutics, Monojul (inactive), Baxalta (inactive), CTI Biopharma (inactive), Aptose, Beta Cat, Blueprint Medicines, Celgene, Cepheid, GRAIL (former), Gilead (former), and Patient True Talk; and is an uncompensated joint steering committee member for Beat AML LLC. JWT has received commercial research grants from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Petra, Seattle Genetics, Syros, and Takeda; has received honoraria from the speakers bureaus of Therapeutic Advances in Childhood Leukemia and Hermedicus—Acute Leukemia Forum. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",
year = "2020",
month = sep,
day = "1",
doi = "10.1038/s41375-020-0764-6",
language = "English (US)",
volume = "34",
pages = "2342--2353",
journal = "Leukemia",
issn = "0887-6924",
publisher = "Nature Publishing Group",
number = "9",
}