The Chemokine System in Experimental and Clinical Hematology

Gary Calandra, Gary Bridger, Simon Fricker

Pharmacological manipulation of CXCR4 has proven clinically useful for mobilization of stem and progenitor cells and in several preclinical models of disease. It is a key component in the localization of leukocytes and stem cells. For patients with multiple myeloma and non-Hodgkin's Lymphoma, treatment with plerixafor, an inhibitor of CXCL12 binding to CXCR4, plus G-CSF mobilizes stem cells for autologous transplantation to a greater degree than the treatment with G-CSF alone, and in some cases when patients could not be mobilized with cytokines, chemotherapy, or the combination. Stem cells from healthy donors mobilized with single agent plerixafor have been used for allogeneic transplantation in acute myelogenous leukemia (AML) patients, although this is still in the early phase of clinical development. Plerixafor is also undergoing evaluation to mobilize tumor cells in patients with AML and chronic lymphocytic leukemia (CLL) to enhance the effectiveness of chemotherapy regimens. Plerixafor's effect on neutrophils may also restore circulating neutrophil counts to normal levels in patients with chronic neutropenias such as in WHIMs syndrome. Other areas where inhibition of CXCR4 may be useful based upon preclinical or clinical data include peripheral vascular disease, autoimmune diseases such as rheumatoid arthritis, pulmonary inflammation, and HIV.