Use of G-CSF to Obtain Blood Cell Precursors

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00001405
First received: November 3, 1999
Last updated: April 17, 2014
Last verified: April 2014
  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

Study Type: Observational
Official Title: Recruitment and Apheresis Collection of Peripheral Blood Hematopoietic Stem Cells

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Estimated Enrollment: 250
Study Start Date: February 1994
Detailed Description:

The goal of this study is to obtain CD34+ hematopoietic stem cells (HSC) for clinical and research purposes. We will collect HSC from peripheral blood and/or bone marrow.

Participants include: 1. Patients with any primary immune deficiency (PID); 2. Healthy sibling or other related donor of those patients with PID in need of an allogeneic stem cell transplant; 3. Healthy adult volunteers.

The majority of subjects will have HSC collected from peripheral blood by apheresis. Daily subcutaneous injections of G-CSF (granulocyte colony stimulating factor/filgrastim) for 5 to 6 days is a standard method used to mobilize HSC to the peripheral blood prior to apheresis, and will be used for most subjects. Plerixafor (AMD 3100/Mozobil) has recently been approved for use in combination with G-CSF to mobilize HSC and will be used in those patients or sibling/related donors undergoing clinical collection of HSC by apheresis who do not, or are predicted not to respond adequately to G-CSF.

Some patients and healthy sibling/related donors will have a clinical scale aspiration collection of bone marrow to obtain HSC for clinical use. Some patients and healthy volunteers will have a small sample needle aspiration collection of bone marrow obtained for research purposes.

HSC collection from patients with PID may be used for laboratory research or may be designated for future clinical treatment of the patient. HSC collections from healthy sibling/related donor of those patients with PID in need of an allogeneic stem cell transplant will be designated for clinical treatment of the related patient. HSC collection from healthy volunteers will be designated entirely for laboratory research.

HSC will be used for the following three clinical purposes, where clinical treatments would occur under separate IRB approved protocols: 1. Autologous HSC from patients may be genetically modified and infused into the patient for treatment of an infection or the underlying disease (Gene therapy); 2. Autologous HSC from patients may serve as back up (rescue product) for patients undergoing matched unrelated donor transplantation; 3. HSC from a sibling/related donor may be used as a directed donation for allogeneic transplant of the related patient.

HSC will be used for laboratory research studies that include: Delineating the pathophysiology of inherited immune deficiencies; Delineating the physiology of and improving engraftment of hematopoietic stem cells; Determining how hematopoietic stem cells may be maintained in ex vivo culture without losing pluripotent potential; Delineating the molecular mechanisms responsible for lineage specific differentiation; Developing efficient methods for gene transfer into hematopoietic stem cells for corrective gene therapy.

  Eligibility

Ages Eligible for Study:   2 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • ELIGIBILITY CRITERIA:

Healthy Volunteers:

  1. Healthy adults aged 18-65 without active current infection or history of recurrent infection,
  2. Weighs at least 50kg.
  3. 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).
  4. 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.
  5. Willingness to allow blood cell samples to be stored
  6. Willingness to allow blood and/or bone marrow samples to be modified to iPS cells

Patients (Patients with a genetically defined PID or clinical history consistent with PID):

  1. Patients will have a genetically defined PID or have a clinical history of recurrent infections or other problems suggestive of PID, must be 2-70 years of age,
  2. Is at least 10 kilograms body weight.
  3. Some patients may have active bacterial or fungal infection at the time of study entry.
  4. 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). For those patients with chronic thrombocytopenia for which the collection is intended for clinical treatment (gene therapy or as rescue stem cells in the context of allogeneic stem cell transplant), patients may participate regardless of platelet count, but must have a platelet count > 40,000 on the day of first apheresis following any required platelet transfusion needed to achieve that level.
  5. 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.
  6. Patients may remain on their regimen of prophylactic treatments as deemed necessary by the investigator.
  7. Willingness to allow blood cell samples to be stored
  8. Willingness to allow blood and/or bone marrow samples to be modified to iPS cells

Healthy Donors (HLA matched sibling or other related donor of a patient with PID in need of an allogeneic hematopoietic stem cell transplant):

  1. Healthy sibling or other relative of a patient with PID in need of an allogeneic transplant, between 2-65 years of age,
  2. Is fully or closely HLA tissue matched to the patient with PID that the hematopoietic stem cell PBSC or bone marrow collection is designated to clinically benefit,
  3. Is at least 10 kilograms body weight.
  4. 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).
  5. Normal female donors 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.
  6. Willingness to allow blood cell samples to be stored
  7. Willingness to allow blood and/or bone marrow samples to be modified to iPS cells

EXCLUSIONS:

Healthy Volunteers and Healthy Donors:

  1. Active bacterial, fungal or viral infection as evidenced by history, physical exam (temperature > 38 degrees C), or WBC > 9000 are excluded.
  2. Females who are pregnant or lactating as determined by history and/or pregnancy test are excluded.
  3. History of vasculitis or similar disorder.
  4. Must be negative by routine blood donor eligibility testing criteria including tests for syphilis (RPR) and TTV Recipient Transplant Panel (list is modified periodically, but may include hepatitis B and C, HIV and HTLV, T. cruzi) (These are routine tests for blood bank donors.)
  5. Someone without peripheral venous access in arm veins adequate for apheresis.
  6. If in the opinion of the investigator participation in this study places the healthy volunteer or donor at undue risk.

Patients:

  1. Patients who are 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.
  2. Female patients who are pregnant or lactating as determined by history and/or positive pregnancy test are excluded.
  3. History of vasculitis or similar disorder.
  4. Must be negative by routine blood donor eligibility testing criteria including tests for syphilis (RPR) and TTV Donor Transplant Panel testing (list is modified periodically, but may include hepatitis B and C, HIV and HTLV, T. cruzi).

    • 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.
    • Autologous HSC Transplant patients may be positive for Hepatitis B and C if the investigator deems it necessary to be collected and used as a safety back-up graft.

Patients or Healthy Donors being considered for clinical scale bone marrow harvesting:

  1. Who are unable to lie prone during the bone marrow harvesting procedure.
  2. Who are unable to tolerate general anesthesia during the bone marrow harvesting procedure.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00001405

Contacts
Contact: Patricia L Littel, R.N. (301) 402-5964 plittel@cc.nih.gov
Contact: Harry L Malech, M.D. (301) 480-6916 hmalech@nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL)    800-411-1222 ext TTY8664111010    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Harry L Malech, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
  More Information

Additional Information:
Publications:
ClinicalTrials.gov Identifier: NCT00001405     History of Changes
Other Study ID Numbers: 940073, 94-I-0073
Study First Received: November 3, 1999
Last Updated: April 17, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Chronic Granulomatous Disease
Apheresis
CD34 Cells
Infection
Nadph Oxidase
Normal Volunteer

Additional relevant MeSH terms:
Severe Combined Immunodeficiency
Granuloma
Granulomatous Disease, Chronic
Immune System Diseases
Immunologic Deficiency Syndromes
Leukocyte-Adhesion Deficiency Syndrome
DNA Repair-Deficiency Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked
Hematologic Diseases
Infant, Newborn, Diseases
Leukocyte Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Metabolic Diseases
Pathologic Processes
Phagocyte Bactericidal Dysfunction

ClinicalTrials.gov processed this record on October 21, 2014