Clinical Trial: Use of G-CSF to Obtain Blood Cell Precursors

This study is currently recruiting patients.

Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by: Warren G Magnuson Clinical Center (CC)

Purpose

This protocol is designed to study the techniques needed to develop gene therapy or other treatments for certain inherited immune system diseases.

Healthy normal volunteers between 18 and 65 years of age and patients with chronic granulomatous disease (CGD), X-linked severe combined immune deficiency (X-SCID), leukocyte adhesion deficiency (LAD), interferon gamma receptor deficiency (IGR-deficiency) or other inherited diseases affecting precursor blood cells-bone marrow cells that generate blood cells-may be eligible for this study. Patients who have had repeated severe infections possibly due to an inherited blood cell abnormality may also participate. Candidates will be screened with a medical history, physical examination and blood tests.

Patients with an active infection will be hospitalized during this study. Uninfected participants will be seen as outpatients at the NIH Clinical Center. Participants will have the following procedures:

- G-CSF administration - All participants will have daily injections of granulocyte-colony stimulating factor (G-CSF). This drug is a genetically engineered hormone that stimulates the bone marrow to release white blood cells and white cell precursors into the bloodstream. The injections are given under the skin in the arm or leg, using a very small needle. Patients will have injections for 6 or 7 days, normal volunteers for 5. A small blood sample will be drawn each day of the injections to monitor white cell counts and changes in the number of blood cell precursors. (Smaller children and all children under 10 years of age may have blood drawn on alternate days or less to reduce the number of needle sticks and the amount of blood taken.). Larger blood draws will be taken on days 6 and/or 7 for patients and on days 5 and/or 6 for normal volunteers.

- Leukapheresis - This procedure for collecting larger numbers of circulating blood precursor cells is optional and may take the place of the larger blood draw described above. Patients 5 years old or older may have leukapheresis. Whole blood is collected through a needle in an arm vein. The blood circulates through a machine that separates it into its components. The desired cells are then removed and the rest of the blood is returned to the body, either through the same needle or through a second one placed in the other arm. The cells obtained will be used to purify blood precursors for growing in culture and to examine the ability to transfer new genes into these precursor cells. For patients whose arm veins are too scarred to for needle placement, a vein in the groin area (femoral vein) may be used instead.

- Bone marrow aspiration - This procedure for obtaining a bone marrow sample is optional. Normal volunteers who agree to the procedure may undergo aspiration up to three times. The hip area is anesthetized and a small sample of bone marrow is drawn through a special needle inserted in the hipbone. The first aspiration is done on a day before the G-CSF injections are started; the second is done soon after the last injection (day 6 or 7), and the third is done from 7 to 10 days after the last injection.

- Repeat blood tests - At day 6 or 7 some of the blood tests done at the beginning of the study will be repeated to check blood counts and liver and kidney function.

Four months or more after the end of the study, participants will be asked to repeat the entire procedure to examine the effects of two cycles of G-CSF mobilization in the same individual. This second cycle is optional.

Condition
Chronic Granulomatous Disease
Healthy
Immunologic Disease
Leukocyte Adhesion Deficiency Syndrome
Severe Combined Immunodeficiency

MedlinePlus related topics:  Immune System and Disorders

Study Type: Observational
Study Design: Natural History

Official Title: Recruitment of Peripheral Blood Hematopoietic Progenitors by Granulocyte Colony Stimulating Factor (GCSF)

Further Study Details: 

Expected Total Enrollment:  180

Study start: February 9, 1994

We will collect and study CD34+ hematopoietic progenitors from blood and bone marrow of patients with inherited immune deficiencies and of normal volunteers. We wish to improve harvest, purification, and ex vivo culture and gene transduction of mobilized CD34+ peripheral blood stem cells (PBSC) and to compare them to CD34+ stem cells obtained from bone marrow. These studies will allow development of gene therapy methods targeting hematopoietic progenitors for treatment of immune deficiencies. Most patients will have one of these disorders: chronic granulomatous disease (CGD), X-lined severe combined immune deficiency (X-SCID), leukocyte adhesion deficiency (LAD), and interferon gamma receptor deficiency (IGR deficiency). Normal subjects will be healthy adults of both sexes from 18 to 65 years of age. Patient subjects of both sexes will have an inherited disorder of immune blood cells, will be 5-50 years of age and greater than or equal to 15 kg body weight. All subjects may have up to three study cycles of mobilization and collection of PBSC with each cycle greater than or equal to 4 months apart. A cycle of mobilization and collection of PBSC takes a week including: Day -10 to 0, entry evaluation; Days 1-6, administration of granulocyte-colony stimulating factor (G-CSF); Day 5, apheresis; Day 6, apheresis. During a study cycle subjects will receive a single daily subcutaneous injection of G-CSF at 10 micrograms/kg body-weight/day for 6 days. Subjects will undergo a three-blood-volume apheresis to collect CD34+ PBSC on days 5 and 6. Most patients will be healthy during study, but some may have an active infection. The purpose of apheresis is to obtain sufficient CD34+ PBSC for study of harvest, purification, culture and efficiency of gene transfer into PBSC. For non-infected patients with X-SCID a portion of purified CD34+ PBSC will be cryopreserved and stored by the NIH CC Transfusion Medicine Department following clinical standard operating procedure for potential future use of these PBSC in an X-SCID gene therapy clinical trial that is under development. However, the procedures encompassed in this current protocol do not involve the re-infusion of any cells back into patients. Finally, some normal donors and patients will have 2 bone marrow aspirates up to 7-15 ml each (proportionately less for children) at greater than or equal to 2 weeks apart at some time before or after one of the three mobilization cycles. The biological properties of bone marrow stem cells will be compared with PBSC to determine which might be the best target for gene therapy correction.

Eligibility

Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

INCLUSION CRITERIA:
NORMAL VOLUNTEERS:
Healthy adults (18 to 65 years of age) without active infection or history of recurrent infections.
Normal renal function (creatinine less than or equal to 1.5 mg/dl; less than or equal to 1+ proteinuria); normal hepatic function (bilirubin less than or equal to 1.5 mg/dl); normal hematologic function (WBC greater than or equal to 2500/mm(3)); granulocytes greater than or equal to 1200/mm(3); platelets greater than or equal to 120,000; hematocrit greater than or equal to 38).
Normal female volunteers of childbearing potential may be entered if using effective contraception and having a negative serum pregnancy test within one week of beginning G-CSF administration.
Normal volunteers must weigh greater than 50 kg (110 lbs).
PATIENTS:
CGD patients must have a demonstrated specific cellular defect in oxidant production by phagocytic cells and history of recurrent infections compatible with a diagnosis of CGD. Specifically, patients must have had studies at NIH confirming abnormal oxidase activity consistent with a diagnosis of CGD.
LAD patients must have a FACS analysis demonstrating deficiency of leukocyte integrins (CD11a,b,c/CD18).
X-SCID patients must have a documented abnormality or deficiency of the common gamma chain of the IL2 receptor or defects in numbers and function of B lymphocyte and/or T lymphocytes consistent with XSCID.
IGR deficiency patients must demonstrate an absence or deficiency of this receptor as assessed by flow cytometry or Western immunoblot, or a defined mutation in the interferon gamma receptor by sequencing analysis, or a defect in function of the receptor for interferon gamma as evidenced by a lack or deficiency of stat-1 protein phosphorylation in response to stimulation of monocytes with interferon gamma.
Other patients may be enrolled who have a history of recurrent infection where an inherited phagocytic cell defect might be the underlying abnormality.
Some patients may have active bacterial or fungal infection at the time of study entry.
Preserved renal function (creatinine less than or equal to 2.5 mg/dl; less than or equal to 3+ proteinuria); preserved hepatic function (bilirubin less than or equal to 2.0 mg/dl); preserved hematologic function (WBC greater than or equal to 1000/mm(3); granulocytes greater than or equal to 500/mm(3); platelets greater than or equal to 100,000; hematocrit greater than or equal to 25).
Patients of childbearing potential may be entered if using effective contraception and having a negative serum pregnancy test within one week of beginning G-CSF administration.
All patients will be maintained on their normal regimen of prophylactic medications (i.e. prophylactic antibiotics for all patients, interferon gamma or prednisone for CGD, IVIg for XSCID patients).
EXCLUSION CRITERIA:
NORMAL VOLUNTEERS:
Volunteers with active bacterial, fungal or viral infection as evidenced by history, physical exam (temperature greater than 38 degrees Celsius) or WBC greater than 9000 are excluded.
Female volunteers who are pregnant or lactating as determined by history and/or pregnancy test are excluded.
History of vasculitis or similar disorder.
Must be negative by routine blood donor eligibility testing criteria including tests for syphilis (RPR) and TTV Recipient Transplant Panel (includes hepatitis B and C, HIV and syphilis (RPR) and TTV Recipient Transplant Panel (includes hepatitis B and C, HIV and HTLV). (These are routine tests for blood bank donors).
Volunteers without peripheral venous access in arm veins adequate for apheresis.
PATIENTS:
Patients hemodynamically unstable (systolic or diastolic blood pressure fall of 20 mm Hg from the stable patient's baseline measurement) or requiring mechanical respiratory assistance are excluded.
Patients requiring granulocyte transfusions are excluded.
Female patients who are pregnant or lactating as determined by history and/or positive pregnancy test are excluded.
History of vasculitis or similar disorder.
Must be negative by routine blood donor eligibility testing criteria including tests for syphilis (RPR) and TTV Donor Transplant Panel testing (includes hepatitis B and C, HIV and HTLV. XSCID patients do not make antibodies and false positives may occur because they receive periodic infusions of pooled donations of IVIG. We have observed positive anti-HBc testing in these patients. If this occurs, more specific DNA or antigen testing will be done and must be negative.

Location and Contact Information


Maryland
      National Institute of Allergy and Infectious Diseases (NIAID), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting
Patient Recruitment and Public Liaison Office  1-800-411-1222    prpl@mail.cc.nih.gov 
TTY  1-866-411-1010 

More Information

Detailed Web Page

Publications

Sekhsaria S, Fleisher TA, Vowells S, Brown M, Miller J, Gordon I, Blaese RM, Dunbar CE, Leitman S, Malech HL. Granulocyte colony-stimulating factor recruitment of CD34+ progenitors to peripheral blood: impaired mobilization in chronic granulomatous disease and adenosine deaminase--deficient severe combined immunodeficiency disease patients. Blood. 1996 Aug 1;88(3):1104-12.

Sekhsaria S, Malech HL. Recombinant human stem cell factor enhances myeloid colony growth from human peripheral blood progenitors. Blood. 1993 Apr 15;81(8):2125-30.

Schwinger W, Mache C, Urban C, Beaufort F, Toglhofer W. Single dose of filgrastim (rhG-CSF) increases the number of hematopoietic progenitors in the peripheral blood of adult volunteers. Bone Marrow Transplant. 1993 Jun;11(6):489-92.

Study ID Numbers:  940073; 94-I-0073
Record last reviewed:  February 7, 2005
Last Updated:  February 14, 2005
Record first received:  November 3, 1999
ClinicalTrials.gov Identifier:  NCT00001405
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08


Source: ClinicalTrials.gov
Cache Date: April 9, 2005

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