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Targeting CXCR4 in Chronic Lymphocytic Leukemia: Preclinical Rationale and Early Clinical Experience

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Novel Developments in Stem Cell Mobilization

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Abstract

Chronic lymphocytic leukemia (CLL) cells express high levels of CXCR4, a seven transmembrane G-protein coupled chemokine receptor. Bone marrow stromal cells (BMSCs) and other mesenchymal stromal cells (MSCs) at extramedullary sites constitutively secrete stromal cell-derived factor-1 (SDF-1, now called CXCL12), the ligand for CXCR4. Activation of CXCR4 induces CLL cell migration and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with BMSC which provide growth and drug-resistance signals. CXCR4 antagonists, such as plerixafor (Mozobil®, AMD3100) and T140 analogs, can disrupt adhesive tumor–stroma interactions and mobilize CLL cells from their protective niches into the blood, making them more accessible to conventional drugs. This approach, to mobilize and then target tumor cells outside of their microenvironment, is also called “chemo-sensitization.” The CXCR4–CXCL12 axis is now targeted in a first, ongoing clinical trial in CLL patients who are treated with plerixafor in combination with the anti-CD20 antibody rituximab. The fact that CLL cells express high levels of CXCR4 and readily respond to CXCL12, along with easy access to circulating leukemia cells for monitoring of leukemia cell mobilization, makes CLL a particularly well-suited disease model for studying the effects of CXCR4 antagonists in leukemia. This chapter summarizes preclinical and preliminary clinical experience with CXCR4 antagonists in CLL.

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Acknowledgments

This study was supported by an ASCO Career Development Award, a CLL Global Research Foundation grant, and a Cancer Prevention and Research Institute of Texas (CPRIT) research award (to J.A.B.).

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  1. Department of Leukemia, Unit 428, The University of Texas M.D. Anderson Cancer Center, 301402, Houston, TX, 77230-1402, USA

    Jan A. Burger

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  1. Jan A. Burger
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Correspondence to Jan A. Burger .

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  1. , Zentrum für Tumordiagnostik und –therapi, Paracelsus-Klinik, Am Natruper Holz 69, Osnabrück, 49076, Germany

    Stefan Fruehauf

  2. Deutsches Krebsforschungszentrum (G360), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    W. Jens Zeller

  3. Private, Cresco, 18326, Pennsylvania, USA

    Gary Calandra

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Burger, J.A. (2012). Targeting CXCR4 in Chronic Lymphocytic Leukemia: Preclinical Rationale and Early Clinical Experience. In: Fruehauf, S., Zeller, W., Calandra, G. (eds) Novel Developments in Stem Cell Mobilization. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-1960-0_19

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