Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist

Abstract

Stromal cell-derived factor 1 (SDF1/ CXCL12) and its cognate receptor, CXCR4, play key regulatory roles in CD34 ؉ cell trafficking. We investigated whether AMD3100, a selective CXCR4 antagonist, could mobilize hematopoietic progenitor cells from marrow to peripheral blood in healthy human volunteers. Initially, 10 persons each received a single dose of AMD3100 (80 g/kg subcutaneously), which induced rapid, generalized leukocytosis associated with an increase in peripheral blood CD34 ؉ cells, representing pluripotent hematopoietic progenitors by in vitro colony-forming unit assays, from 3.8 ؎ 0.5/L to 20.7 ؎ 3.5/L at 6 hours. Subsequent dose-response studies showed a maximum increase in circulating CD34 ؉ cells from 2.6 ؎ 0.3/L to 40.4 ؎ 3.4/L at 9 hours after 240 g/kg AMD3100. Serial administration of AMD3100 (80 g/kg/d for 3 days) resulted in consistent, reversible increases in peripheral blood CD34 ؉ cells. AMD3100 was well tolerated and caused only mild, transient toxicity. These findings suggest potential clinical application of AMD3100 for CD34 ؉ cell mobilization and collection for hematopoietic stem cell transplantation.

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…Instead, AnorMED explored AMD3100 as a mobilizing agent for HSC, 88 and a subsequent series of preclinical and clinical trials demonstrated that AMD3100 alone and in combination with G-CSF mobilizes HSC. 34,89,90 AMD3100 (recently re-named as Plerixafor or Mozobil) is now owned by Genzyme Corporation (Cambridge, MA, USA) after a recent takeover of AnorMED by Genzyme in late 2006. Plerixafor is currently used in phase III trials in lymphoma and multiple myeloma patients undergoing autologous stem cell mobilization, and current plans are to file for US and European approval of the drug in 2008.…”

Chemokines in cancer related inflammation

“…In pre-clinical settings, CXCR4 antagonists significantly reduced the size of primary tumors and had anti-metastatic effects in mouse models of melanoma, osteosarcoma, breast and prostate tumors [123][124][125][126][127]. AMD3100 was unexpectedly found to mobilize CD34+ stem cells from the bone marrow [128]. This compound is currently in clinical use for the mobilization of normal hematopoietic stem cells.…”

Safety and preliminary efficacy of plerixafor (Mozobil) in combination with chemotherapy and G-CSF: an open-label, multicenter, exploratory trial in patients with multiple myeloma and non-Hodgkin's lymphoma undergoing stem cell mobilization

“…Early studies with plerixafor showed enhancement of circulating WBCs and PBSCs in healthy volunteers. [1][2][3][4] Flomenberg et al 5 showed the superiority of plerixafor plus G-CSF over G-CSF alone for PBSC mobilization in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). When apheresis yields for the same patient were compared between plerixafor plus G-CSF and G-CSF alone, more CD34 þ cells were collected with plerixafor plus G-CSF and in fewer apheresis days than with G-CSF alone.…”