| Conditions: |
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Healthy - Blood Component Removal |
| Purpose: |
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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.
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| Study Summary: |
|
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. 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.
The primary objective is to characterize the cellular content and immunological properties
of an AMD3100 mobilized PBPC in donors who have previously under gone mobilization with
G-CSF, and to further study its safety and efficacy as a peripheral blood stem cell
mobilizer.
The primary endpoint is the ratio of Th1 (intracellular IFN-gamma plus) versus Th2
(intracellular IL-4 plus) T-cells in the apheresis products collected from individual donors
undergoing G-CSF and AMD3100 hematopoietic progenitor cell mobilization.
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.
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| Criteria: |
|
- 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 than1.5mg/dl, ALT 6 -41 U/L, AST
9-34 U/L.
5. Normal blood count: WBC 3000-10000/mm(3)
granulocytes greater than 1500/mm(3)
platelets greater than150,000/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 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
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| NCT ID: |
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NCT00075335 |
| Primary Contact: |
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Principal Investigator
Richard W Childs, M.D.
National Heart, Lung, and Blood Institute (NHLBI)
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| Backup Contact: |
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N/A |
| Location Contact: |
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Bethesda, Maryland 20892
United States
There is no listed contact information for this specific location.
Site Status: N/A |