AMD 3100 (Mozobil Plerixafor) to Mobilize Stem Cells for Donation
AMD 3100 (Mozobil Plerixafor) to Mobilize Stem Cells for Donation
Peripheral blood progenitor cells (PBPC) have become the preferred source of hematopoetic
 stem cells for allogeneic transplantation because of technical ease of collection and shorter
 time required for engraftment. Traditionally, granulocyte-colony stimulating factor (G-CSF)
 has been used to procure the peripheral blood stem cell graft. Although regimens using G-CSF
 usually succeed in collecting adequate numbers of PBPC from healthy donors, 5%-10% will
 mobilize stem cells poorly and may require multiple large volume apheresis or bone marrow
 harvesting. Although G-CSF is generally well tolerated in healthy donors, it may be
 associated with bone pain, headache, myalgia and rarely life threatening side effects like
 stroke, myocardial infarction and splenic rupture.

 AMD3100, is a bicyclam compound that inhibits the binding of stromal cell derived factor-1
 (SDF-1) to its cognate receptor CXC- chemokine receptor 4 (CXCR4). CXCR4 is present on
 cluster of differentiation 34 (CD34)+ hematopoetic progenitor cells and its interaction with
 stromal cell derived factor 1 (SDF-1) plays a pivotal role in the homing of CD34+ cells in
 the bone marrow. Inhibition of the CXCR4-SDF1 axis by AMD3100 releases CD34+ cells into the
 circulation, which can then be collected easily by apheresis.

 Recently, a published report demonstrated that large numbers of CD34+ cells were rapidly
 mobilized in healthy volunteers following a single subcutaneous injection of AMD3100.
 Remarkably, the number of CD34+ cells collected by apheresis following a single injection of
 AMD3100 was comparable to the number of CD34+ cells collected from historical controls
 receiving 5 days of G-CSF prior to stem cell mobilization.

 In this study we will collect PBPCs following a single subcutaneous injection of AMD3100 from
 healthy donors who have previously had PBPC collected using standard G-CSF mobilization. The
 AMD3100 mobilized cells, G-CSF mobilized cells, and circulating cells prior to both AMD3100
 and G-CSF mobilization will be analyzed in terms of cellular content and function of
 lymphocytes, natural killer (NK) cells, and antigen presenting cells. AMD3100 mobilized PBPC
 will be collected for the purpose of research studies and will not be used for therapeutic
 purposes.
Peripheral blood progenitor cells (PBPC) have become the preferred source of hematopoietic
 stem cells for allogeneic transplantation because of technical ease of collection and shorter
 time required for engraftment. Traditionally, granulocyte-colony stimulating factor (G-CSF)
 has been used to procure the peripheral blood stem cell graft. Although regimens using G-CSF
 usually succeed in collecting adequate numbers of PBPC from healthy donors, 5%-10% will
 mobilize stem cells poorly and may require multiple large volume apheresis or bone marrow
 harvesting. Although G-CSF is generally well tolerated in healthy donors, it may be
 associated with bone pain, headache, myalgia and rarely life threatening side effects like
 stroke, myocardial infarction and splenic rupture.

 AMD3100 is a bicyclam compound that inhibits the binding of stromal cell derived factor-1
 (SDF-1) to its cognate receptor CXCR4. CXCR4 is present on CD34+ hematopoietic progenitor
 cells and its interaction with SDF-1 plays a pivotal role in the homing of CD34+ cells in the
 bone marrow. Inhibition of the CXCR4-SDF1 axis by AMD3100 releases CD34+ cells into the
 circulation, which can then be collected easily by apheresis. Recently, a published report
 demonstrated that large numbers of CD34+ cells were rapidly mobilized in healthy volunteers
 following a single subcutaneous injection of AMD3100. Remarkably, the number of CD34+ cells
 collected by apheresis following a single injection of AMD3100 was comparable to the number
 of CD34+ cells collected from historical controls receiving 5 days of G-CSF prior to stem
 cell mobilization. Although the study population is relatively small, side-effects to this
 agent have been mild and transient with no serious complications having been reported. The
 ability to collect a large quantity of PBPC with a single injection of this drug makes this
 an attractive agent for mobilizing donors of allogeneic PBPC. However, the immunologic
 profiles of AMD3100 mobilized cells, in terms of lymphocyte content (T cell, B cell, NK cell,
 immuno-regulatory T cell), T cell polarization status (TH1 versus TH2), status of antigen
 presenting cells (DC1 versus DC2), alloreactive potential, and preservation of reactivity to
 infectious agents [e.g. Epstein Barr Virus (EBV), Cytomegalovirus (CMV)] are unknown.
 Consequently, whether AMD3100 mobilized PBPC would be suitable for use as an allograft is
 uncertain. In this study we will collect PBPCs following a single subcutaneous injection of
 AMD3100 from healthy donors who have previously had PBPC collected using standard G-CSF
 mobilization. The AMD3100 mobilized cells, G-CSF mobilized cells, and circulating cells prior
 to both AMD3100 and G-CSF mobilization will be analyzed in terms of cellular content and
 function of lymphocytes, NK cells, and antigen presenting cells. AMD3100 mobilized PBPC will
 be collected for the purpose of research studies and will not be used for therapeutic
 purposes.

 The primary objective is to characterize the immunological properties of AMD3100 mobilized
 (cytokine gene expression profiles) T-cells compared to G-CSF mobilized T-cells.

 Secondary endpoints include the cellular content and other immune properties of AMD3100
 mobilized cells yields of hematopoietic progenitor cells, immune cells, and other cellular
 subsets collected by apheresis in subjects undergoing G-CSF and AMD3100 mobilization and the
 safety profile of AMD3100.
-  INCLUSION CRITERIA:

 1. Mobilization and collection of PBPC using G-CSF at least 60 days prior to
 protocol enrollment (stem cell donors enrolled on Branch transplant protocols or
 healthy volunteers enrolled on 96-H-0049: Use of granulocyte colony stimulating
 factor mobilized leukapheresis collections from healthy volunteers).

 2. Ages greater than or equal to 18 years and less than or equal to 80 years.

 3. Normal renal function: creatinine less than 1.5 mg/dl.

 4. Normal liver function: total bilirubin less than 1.5mg/dl, alanine
 aminotransferase (ALT) 6 -41 U/L, aspartate aminotransferase (AST) 9-34 U/L.

 5. Normal blood count: white blood cell (WBC) 3000-10000/mm(3)

 granulocytes greater than 1500/mm(3)

 platelets greater than 150,000/mm(3)

 hemoglobin (females greater than 11.1 g/dl, males greater than 12.7 g/dl).

 6. Subject must be eligible for normal blood donation and fit to undergo apheresis
 procedure (antecubital veins must be adequate for peripheral access during
 apheresis).

 7. Ability to comprehend the investigational nature of the study and provide
 informed consent.

 EXCLUSION CRITERIA: Any of the Following

 1. Active infection or history of recurrent infection- hepatitis B and C (HBsAg,
 Anti-HBc, Anti-HCV), HIV and human T- lymphocytic virus (HTLV-1).

 2. History of autoimmune disease such as rheumatoid arthritis, systemic lupus
 erythematous.

 3. History of cancer within the past 5 years excluding basal cell or squamous cell
 carcinoma of the skin.

 4. History of any hematologic disorders including thromboembolic disease.

 5. History of cardiac disease such as uncontrolled hypertension, peripheral vascular
 disease, myocardial infarction, cardiac arrhythmias OR related symptoms such as
 tachycardia, chest pain, shortness of breath which have required medical intervention
 OR treatment or a Framingham coronary disease risk prediction score of greater than
 10% 10 year coronary heart disease (CHD) risk.

 6. History of cerebrovascular disease, transient ischemic attack, or stroke.

 7. Pregnant or lactating.

 8. Severe psychiatric illness: mental deficiency sufficiently severe as to make informed
 consent impossible