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Acute myeloid leukemia

Dual inhibition of JAK1/2 kinases and BCL2: a promising therapeutic strategy for acute myeloid leukemia

Leukemia volume 32, pages 2025–2028 (2018)Cite this article

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Acute myeloid leukemia (AML) is a blood cancer resulting from the enhanced proliferation and impaired differentiation of hematopoietic stem and progenitor cells. Chemotherapy consisting of cytarabine and anthracyclines has been the standard of AML care for decades, with a 5-year overall survival rate of 25% [1]. Outcomes in older patients, who represent the majority of patients with this disease, are poor with a median survival of 5 to 10 months. Owing to their inability to tolerate intensive chemotherapy, many older patients do not receive any anti-leukemic therapy [2]. Although the development of drugs targeted to specific pathways offers the promise of improved treatment options, resistance to individual inhibitors has limited their effectiveness. This is in part the result of the substantial disease heterogeneity and clonality underlying AML and underscores the need for combinations of targeted therapies to achieve durable responses.

Our group and others have previously established the utility of ex vivo screening platforms to identify effective targeted treatments for leukemia patients [3]. We adapted this approach to test combinations of targeted drugs in a fixed molar concentration series of seven dose points. This work identified several candidate combinations with enhanced efficacy in myeloid leukemia samples, many of which included the BCL2 inhibitor venetoclax [4]. Given the many complex subtypes of AML, we performed expanded studies on the combination of ruxolitinib plus venetoclax (Rux + Ven) because of its broad effectiveness on a majority of AML samples tested.

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Acknowledgements

Funding for this project was provided in part by a Leukemia Lymphoma Therapy Acceleration Grant to BJD and JWT, and by support provided by the Knight Cancer Research Institute (Oregon Health & Science University, OHSU). Also, this study was supported by grants from the National Cancer Institute (1U01CA217862, 1U54CA224019, 3P30CA069533-18S5). JWT received grants from the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, and the National Cancer Institute (1R01CA183947).

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Authors and Affiliations

  1. Division of Hematology & Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Stephen E. Kurtz, Christopher A. Eide, Cristina E. Tognon, Uma Borate & Brian J. Druker

  2. Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR, USA

    Christopher A. Eide, Cristina E. Tognon & Brian J. Druker

  3. Biostatistics Shared Resource, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Andy Kaempf & Motomi Mori

  4. Oregon Health & Science University–Portland State University School of Public Health, Portland, OR, USA

    Motomi Mori

  5. Department of Cell, Development & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA

    Jeffrey W. Tyner

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  1. Stephen E. Kurtz
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Corresponding author

Correspondence to Jeffrey W. Tyner.

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Conflict of interest

JWT receives research support from Agios, Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Seattle Genetics, Syros, Takeda; JWT is a co-founder of Leap Oncology. 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 without input from any of our industry partners. The remaininig authors declare that they have no conflict of interest.

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Kurtz, S.E., Eide, C.A., Kaempf, A. et al. Dual inhibition of JAK1/2 kinases and BCL2: a promising therapeutic strategy for acute myeloid leukemia. Leukemia 32, 2025–2028 (2018). https://doi.org/10.1038/s41375-018-0225-7

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