Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-Hodgkin's lymphoma.

PURPOSE Interactions between the chemokine receptor CXCR4 and its ligand stromal derived factor-1 regulate hematopoietic stem-cell trafficking. AMD3100 is a CXCR4 antagonist that induces rapid mobilization of CD34+ cells in healthy volunteers. We performed a phase I study assessing the safety and clinical effects of AMD3100 in patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Thirteen patients (MM, n=7; NHL, n=6) received AMD3100 at a dose of either 160 microg/kg (n=6) or 240 microg/kg (n=7). WBC and peripheral blood (PB) CD34+ cell counts were analyzed at 4 and 6 hours following injection. RESULTS AMD3100 caused a rapid and statistically significant increase in the total WBC and PB CD34+ counts at both 4 and 6 hours following a single injection. The absolute CD34+ cell count increased from a baseline of 2.6 +/- 0.7/microL (mean +/- SE) to 15.6 +/- 3.9/microL and 16.2 +/- 4.3/microL at 4 hours (P=.002) and 6 hours after injection (P =.003), respectively. The absolute CD34+ cell counts observed at 4 and 6 hours following AMD3100 were higher in the 240 microg/kg group (19.3 +/- 6.9/microL and 20.4 +/- 7.6/microL, respectively) compared with the 160 microg/kg group (11.3 +/- 2.7/microL and 11.3 +/- 2.5/microL, respectively). The drug was well tolerated and only grade 1 toxicities were encountered. CONCLUSION AMD3100 appears to be a safe and effective agent for the rapid mobilization of CD34+ cells in patients who have received prior chemotherapy. Further studies in combination with granulocyte colony-stimulating factor in patients with lymphoid malignancies are warranted.

[1]  B. Wood,et al.  Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. , 2003, Blood.

[2]  T. Papayannopoulou,et al.  The role of G-protein signaling in hematopoietic stem/progenitor cell mobilization. , 2003, Blood.

[3]  J. Lévesque,et al.  Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. , 2003, The Journal of clinical investigation.

[4]  A. Nagler,et al.  Human CD34(+)CXCR4(-) sorted cells harbor intracellular CXCR4, which can be functionally expressed and provide NOD/SCID repopulation. , 2002, Blood.

[5]  O. Kollet,et al.  The essential roles of the chemokine SDF-1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune-deficient NOD/SCID and NOD/SCID/B2mnull mice , 2002, Leukemia.

[6]  E. De Clercq,et al.  Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4 , 2002, FEBS letters.

[7]  I. Petit,et al.  Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. , 2002, Experimental hematology.

[8]  R. Taichman,et al.  G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4 , 2002, Nature Immunology.

[9]  W. Chan,et al.  Autologous transplantation for aggressive non-Hodgkin's lymphoma: results of a randomized trial evaluating graft source and minimal residual disease. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  P. Anderlini,et al.  Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? , 2001, Blood.

[11]  Dominique Schols,et al.  AMD3100, a Potent and Specific Antagonist of the Stromal Cell-Derived Factor-1 Chemokine Receptor CXCR4, Inhibits Autoimmune Joint Inflammation in IFN-γ Receptor-Deficient Mice1 , 2001, The Journal of Immunology.

[12]  D. Schenkein,et al.  Randomized trial of filgrastim versus chemotherapy and filgrastim mobilization of hematopoietic progenitor cells for rescue in autologous transplantation. , 2001, Blood.

[13]  T. Papayannopoulou,et al.  Increase in Circulating SDF‐1 after Treatment with Sulfated Glycans , 2001, Annals of the New York Academy of Sciences.

[14]  T. Lapidot.  Mechanism of Human Stem Cell Migration and Repopulation of NOD/SCID and B2mnull NOD/SCID Mice , 2001, Annals of the New York Academy of Sciences.

[15]  S. Rafii,et al.  Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. , 2001, Blood.

[16]  S. Rafii,et al.  Mobilization of Endothelial and Hematopoietic Stem and Progenitor Cells by Adenovector‐Mediated Elevation of Serum Levels of SDF‐1, VEGF, and Angiopoietin‐1 , 2001, Annals of the New York Academy of Sciences.

[17]  F. Appelbaum,et al.  Experiences of donors enrolled in a randomized study of allogeneic bone marrow or peripheral blood stem cell transplantation. , 2001, Blood.

[18]  T. Schwartz,et al.  Molecular Interactions of Cyclam and Bicyclam Non-peptide Antagonists with the CXCR4 Chemokine Receptor* , 2001, The Journal of Biological Chemistry.

[19]  D. Scadden,et al.  CXCR-4 Desensitization Is Associated with Tissue Localization of Hemopoietic Progenitor Cells1 , 2001, The Journal of Immunology.

[20]  A. Farese,et al.  Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta. , 2001, Blood.

[21]  O. Sezer,et al.  Optimal CD34(+) cell dose in autologous peripheral-blood stem-cell transplantation. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  J. Winter,et al.  Mobilization of peripheral-blood stem cells by concurrent administration of daniplestim and granulocyte colony-stimulating factor in patients with breast cancer or lymphoma. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Edward J. Fuchs,et al.  Pharmacokinetics and Safety of AMD-3100, a Novel Antagonist of the CXCR-4 Chemokine Receptor, in Human Volunteers , 2000, Antimicrobial Agents and Chemotherapy.

[24]  P. Pedrazzoli,et al.  Therapeutic relevance of CD34 cell dose in blood cell transplantation for cancer therapy. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  E. De Clercq,et al.  Role of CXCR4 in Cell-Cell Fusion and Infection of Monocyte-Derived Macrophages by Primary Human Immunodeficiency Virus Type 1 (HIV-1) Strains: Two Distinct Mechanisms of HIV-1 Dual Tropism , 1999, Journal of Virology.

[26]  E. De Clercq,et al.  Bicyclams, Selective Antagonists of the Human Chemokine Receptor CXCR4, Potently Inhibit Feline Immunodeficiency Virus Replication , 1999, Journal of Virology.

[27]  R. Alon,et al.  Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. , 1999, Science.

[28]  R. Bronson,et al.  Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. De Clercq,et al.  Determinants for Sensitivity of Human Immunodeficiency Virus Coreceptor CXCR4 to the Bicyclam AMD3100 , 1998, Journal of Virology.

[30]  Masahiko Kuroda,et al.  Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development , 1998, Nature.

[31]  Kouji Matsushima,et al.  The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract , 1998, Nature.

[32]  E. De Clercq,et al.  T-Cell-Line-Tropic Human Immunodeficiency Virus Type 1 That Is Made Resistant to Stromal Cell-Derived Factor 1α Contains Mutations in the Envelope gp120 but Does Not Show a Switch in Coreceptor Use , 1998, Journal of Virology.

[33]  B. Barlogie,et al.  Comparable engraftment kinetics following peripheral-blood stem-cell infusion mobilized with granulocyte colony-stimulating factor with or without cyclophosphamide in multiple myeloma. , 1998, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  A. Luster,et al.  Chemokines--chemotactic cytokines that mediate inflammation. , 1998, The New England journal of medicine.

[35]  P. Maslak,et al.  Factors affecting mobilization of peripheral blood progenitor cells in patients with lymphoma. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[36]  W. Velasquez,et al.  Randomized comparison of G-CSF + GM-CSF vs G-CSF alone for mobilization of peripheral blood stem cells: effects on hematopoietic recovery after high-dose chemotherapy , 1997, Bone Marrow Transplantation.

[37]  E. Clercq,et al.  Inhibition of T-tropic HIV Strains by Selective Antagonization of the Chemokine Receptor CXCR4 , 1997, The Journal of experimental medicine.

[38]  E. Shpall,et al.  Peripheral blood progenitor cell mobilization using stem cell factor in combination with filgrastim in breast cancer patients. , 1997, Blood.

[39]  E. De Clercq,et al.  Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor fusin/CXCR-4. , 1997, Antiviral research.

[40]  G. Molineux,et al.  Flt-3 ligand synergizes with granulocyte colony-stimulating factor to increase neutrophil numbers and to mobilize peripheral blood stem cells with long-term repopulating potential. , 1997, Blood.

[41]  J. Gabrilove,et al.  Recombinant methionyl human stem cell factor and filgrastim for peripheral blood progenitor cell mobilization and transplantation in non-Hodgkin's lymphoma patients--results of a phase I/II trial. , 1997, Blood.

[42]  D. Blaise,et al.  Peripheral Blood Stem Cell and Bone Marrow Transplantation for Solid Tumors and Lymphomas: Hematologic Recovery and Costs: A Randomized, Controlled Trial , 1997, Annals of Internal Medicine.

[43]  L. To,et al.  The biology and clinical uses of blood stem cells. , 1997, Blood.

[44]  D. Heitjan,et al.  Harvest quality and factors affecting collection and engraftment of CD34+ cells in patients with breast cancer scheduled for high-dose chemotherapy and peripheral blood progenitor cell support. , 1997, Journal of hematotherapy.

[45]  R. Hoffman,et al.  Recombinant human interleukin-3 (rhIL-3) enhances the mobilization of peripheral blood progenitor cells by recombinant human granulocyte colony-stimulating factor (rhG-CSF) in normal volunteers. , 1996, Experimental hematology.

[46]  L. Schwartzberg,et al.  An analysis of engraftment kinetics as a function of the CD34 content of peripheral blood progenitor cell collections in 692 patients after the administration of myeloablative chemotherapy. , 1995, Blood.

[47]  D. Huhn,et al.  Hematopoietic rescue after high-dose chemotherapy using autologous peripheral-blood progenitor cells or bone marrow: a randomized comparison. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  R. Willemze,et al.  Interleukin-8 induces rapid mobilization of hematopoietic stem cells with radioprotective capacity and long-term myelolymphoid repopulating ability. , 1995, Blood.

[49]  N. Davidson,et al.  Predictive factors for peripheral-blood progenitor-cell collections using a single large-volume leukapheresis after cyclophosphamide and granulocyte-macrophage colony-stimulating factor mobilization. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  B. Barlogie,et al.  Peripheral blood stem cell transplants for multiple myeloma: identification of favorable variables for rapid engraftment in 225 patients. , 1995, Blood.

[51]  Hugues Lortat-Jacob,et al.  Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. , 2002, Blood.

[52]  D. Blaise,et al.  Healthy sibling donor anxiety and pain during bone marrow or peripheral blood stem cell harvesting for allogeneic transplantation: results of a randomised study , 2002, Bone Marrow Transplantation.

[53]  E. De Clercq,et al.  Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists. , 2001, Antiviral chemistry & chemotherapy.

[54]  K. Schulman,et al.  Randomized trial of filgrastim, sargramostim, or sequential sargramostim and filgrastim after myelosuppressive chemotherapy for the harvesting of peripheral-blood stem cells. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[55]  J. Moore,et al.  AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor , 1998, Nature Medicine.

[56]  N. Schmitz,et al.  Economic analysis of a randomized clinical trial to compare filgrastim-mobilized peripheral-blood progenitor-cell transplantation and autologous bone marrow transplantation in patients with Hodgkin's and non-Hodgkin's lymphoma. , 1997, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.