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Chronic Lymphocytic Leukemia

The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia

Leukemia volume 23, pages 2034–2041 (2009)Cite this article

Abstract

As chronic lymphocytic leukemia (CLL) is characterized by overexpression of pro-survival BCL2, compounds that mimic its physiological antagonists, the BH3-only proteins, may have a role in treatment of this disease. ABT-737 is a BH3 mimetic compound that selectively targets BCL2 and BCLXL. In the present work, we report that ABT-737 is highly effective (LC50<50 nM) as a single agent against most (21/30) primary CLL samples, but that a sizable minority is relatively insensitive. In vitro sensitivity to ABT-737 could not be simply predicted by the patients' clinical features, including response to prior therapy or known prognostic markers (CD38 expression, 17p deletion), or the relative expression of BCL2 family proteins (BCL2, MCL1, BAX, BIM). Strikingly, co-incubation with cytotoxic agents (dexamethasone, etoposide, fludarabine, doxorubicin) sensitized most CLL samples to ABT-737, but this could not be predicted by responses to either ABT-737 or the cytotoxic agent alone. Of 17 samples least sensitive to ABT-737, 13 were sensitized by co-treatment with at least one cytotoxic agent. These data indicate that combination of ABT-737 with a second anti-leukemic agent would improve response rates and suggest a potential role for combination therapies that include BH3 mimetics for the treatment of this disease.

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Acknowledgements

We are grateful to Ms Naomi Sprigg (Royal Melbourne Hospital) for her assistance with clinical samples, and to Drs Steve Elmore, Saul Rosenberg and colleagues (Abbott Laboratories) for provision of ABT-737 and scientific discussions. This work was supported by Fellowships and Grants from the Australian NHMRC (Fellowships to WDF, DCSH, AWR; Program Grants 461221, 461219), Leukemia and Lymphoma Society (SCOR 7015-02), Australian Cancer Research Foundation (Centre for Therapeutic Target Drug Discovery), Cancer Council of Victoria (Fellowships to KDM, EFL; Grant-in-aid 461239), the Victorian Cancer Agency (Fellowship to KDM); SLK is supported by a HOTT Fellowship (Roche, HSANZ, COSA) and a Royal Melbourne Hospital Haematology and Bone Marrow Transplant Scholarship.

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Authors and Affiliations

  1. Divisions of Cancer and Haematology and Molecular Genetics of Cancer, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia

    K D Mason, S L Khaw, E Chew, E F Lee, W D Fairlie, D C S Huang & A W Roberts

  2. Departments of Diagnostic Haematology, Clinical Haematology and Bone Marrow Transplantation, The Royal Melbourne Hospital, Parkville, Victoria, Australia

    K D Mason, A P Grigg, J Szer & A W Roberts

  3. Faculty of Medicine, School of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia

    S L Khaw, A P Grigg, J F Seymour, J Szer & A W Roberts

  4. Victorian Cancer Cytogenetics Service, St Vincent's Hospital, Fitzroy, Victoria, Australia

    K C Rayeroux

  5. Department of Clinical Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia

    J F Seymour

  6. ACRF Centre for Therapeutic Target Discovery, Parkville, Victoria, Australia

    D C S Huang & A W Roberts

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  1. K D Mason
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Correspondence to D C S Huang or A W Roberts.

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Mason, K., Khaw, S., Rayeroux, K. et al. The BH3 mimetic compound, ABT-737, synergizes with a range of cytotoxic chemotherapy agents in chronic lymphocytic leukemia. Leukemia 23, 2034–2041 (2009). https://doi.org/10.1038/leu.2009.151

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