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The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells

Leukemia volume 26, pages 2554–2557 (2012)Cite this article

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Chronic lymphocytic leukemia (CLL) represents the most prevalent type of adult leukemia and is currently incurable with available therapies. The introduction of fludarabine, fludarabine/cyclophosphamide and either of these combined with rituximab has improved the outcome for younger patients with CLL. Treatment options available for patients in the setting of relapsed disease following receipt of chemoimmunotherapy are less where most patients have high-risk genomic findings including IgVH un-mutated disease, del(17p13.1) and del(11q22.3) associated with poor treatment response (reviewed in Grever et al.1). Identifying therapies with novel mechanisms of action for this patient group is important.

One class of drugs that has promise for the treatment of relapsed CLL is the cyclin-dependent kinases (CDK) inhibitors. Flavopiridol is the first member of this group to be extensively tested based upon pre-clinical work by several groups,2, 3, 4 which, although having a narrow therapeutic window, was shown to be clinically active in high-risk genomic patients with a dose-limiting side effect of hyper-acute tumor lysis syndrome.5, 6 A multicenter phase II trial confirmed the activity of flavopiridol, including in patients with del(17p13.1), but also toxicity associated with its narrow therapeutic index (American Society of Hematology Annual meeting 2010). These results provide support for development of CDK inhibitors that have an improved therapeutic index.

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Acknowledgements

We thank all of the patients who donated blood for these studies and also the clinical support staff who collected them. All statistical evaluation was done by the OSU Center for Biostatistics. This work was supported by Specialized Center of Research from the Leukemia and Lymphoma Society, K12 CA133250, P50-CA140158, P01 CA95426, P01 CA8153 and P01 CA101956 from the National Cancer Institute, Pelotonia Fellowship Program and The D Warren Brown Foundation. AJJ is a Paul Calabresi Scholar and Y-YY is a Pelotonia post-doctoral fellow.

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Authors and Affiliations

  1. Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    A J Johnson, Y-Y Yeh, L L Smith, A J Wagner, J Hessler, J Flynn, J Jones, M R Grever & J C Byrd

  2. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    A J Johnson & J C Byrd

  3. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    S Gupta

  4. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    X Zhang

  5. Merck and Company, Oncology Clinical Research, Kenilworth, NJ, USA

    R Bannerji

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Correspondence to A J Johnson.

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RB is an employee of Merck and Co.

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Authorship Contribution

LLS, AJW, JH, and Y-YY performed the experiments. LLS, AJJ, and JCB analyzed the results and made the figures. XZ performed the statistical analysis. JF, JJ, MRG, and JCB provided clinical samples. AJJ, RB, MRG and JCB designed the research and wrote the paper.

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Johnson, A., Yeh, YY., Smith, L. et al. The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells. Leukemia 26, 2554–2557 (2012). https://doi.org/10.1038/leu.2012.144

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