Protocol Number: 04-H-0078

Title:

Peripheral Blood Hematopoietic Progenitor Cell Mobilization with AMD3100 in Healthy Volunteers Previously Mobilized with G-CSF

Number:

04-H-0078

Summary:

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 CXCR4. CXCR4 is present on CD34+ hematopoetic 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. EBV, 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.

Sponsoring Institute:

National Heart, Lung and Blood Institute (NHLBI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: Yes

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

1. Mobilization and collection of PBPC using G-CSF at least 60 days prior to protocol enrollment.

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 l.

4. Normal liver function: total bilirubin less than1.5mg/dl, ALT 6 -41 U/L; AST 934 U/L.

5. Normal blood count: WBC 3000-10000/mm3, granulocytes greater than 1500/mm3, platelets greater than150,000/mm3, 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 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 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.

Special Instructions:

Currently Not Provided

Keywords:

Hematopoietic Stem Cells

Mobilization

Alloreactivity

T Cell Polarization

Dendritic Cells

Recruitment Keyword(s):

Healthy Volunteer

HV

Condition(s):

Healthy

Blood Component Removal

Investigational Drug(s):

AMD3100

Investigational Device(s):

None

Intervention(s):

Drug: AMD3100

Supporting Site:

National Heart, Lung and Blood Institute

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Mohle R, Differential expression of L-selectin, VLA-4, and LFA-1 on CD34+ progenitor cells from bone marrow and peripheral blood during G-CSF-enhanced recovery. Exp Hematol. 1995 Dec;23(14):1535-42.

Mohle R, Expression of adhesion molecules and c-kit on CD34+ hematopoietic progenitor cells: comparison of cytokine-mobilized blood stem cells with normal bone marrow and peripheral blood. J Hematother. 1993 Winter;2(4):483-9.

Petit I, G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002 Jul;3(7):687-94. Epub 2002 Jun 17. Erratum in: Nat Immunol2002 Aug;3(8):787.

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