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Donor Stem Cell Transplantation for Congenital Immunodeficiencies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00426517
Recruitment Status : Completed
First Posted : January 24, 2007
Last Update Posted : November 5, 2019
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Tracking Information
First Submitted Date  ICMJE January 23, 2007
First Posted Date  ICMJE January 24, 2007
Last Update Posted Date November 5, 2019
Study Start Date  ICMJE January 19, 2007
Actual Primary Completion Date November 1, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 27, 2015)
The primary objective for this study is to evaluate the use of immunosuppressive drugs such as Campath -1H or h-ATG, fludarabine, and sirolimus in conjunction with a novel busulfan-based conditioning regimen with or without the addition of radia... [ Time Frame: End of Study ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 23, 2007)
Attain phenotypic correction of the disease
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 27, 2015)
  • To measure the engraftment rate and the engraftment kinetics using such a regimen [ Time Frame: End of Study ]
  • To further elucidate the required dose levels of busulfan as compared to historical controls in conditioning regimens for transplantation in general [ Time Frame: End of Study ]
  • To assess the level and kinetics of immune reconstitution when using these conditioning regimens. To further elucidate the factors involved in the development of graft versus host disease. [ Time Frame: End of Study ]
Original Secondary Outcome Measures  ICMJE
 (submitted: January 23, 2007)
Obtain engraftment without development of graft vs host disease, establish stable mixed chimerism, improve radity of immune reconstitution, determine days to neutrophil recovery, measure incidence of CMV reactivation, measure transfusion requirements
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Donor Stem Cell Transplantation for Congenital Immunodeficiencies
Official Title  ICMJE Allogeneic and Matched Unrelated Donor Stem Cell Transplantation for Congenital Immunodeficiencies or Patients With Autoinflammatory/Immunodysregulatory Conditions: Busulfan-Based Conditioning With Campath- 1H or h-ATG, Radiation, and Sirolimus
Brief Summary

This study uses transplantation to treat patients with problems in their immune system. The immune system cells come from the bone marrow where they grow from special cells called stem cells. Giving patients stem cells from someone else may help to cure many patients with certain immune diseases. This is called 'bone marrow transplantation'. This procedure can have side effects that are life-threatening. To try to make transplantation safer we are using lower doses of the medications used in preparing the patient for the transplant.

'Conditioning' treatments are given to patients to create space in their bone marrow. This lets the cells of the donor go into the bone marrow and produce normal immune cells. This study will use lower doses of a drug called busulfan and lower doses of radiation than what are currently being used in other kinds of bone marrow transplantation for other diseases.

Another problem that can occur with bone marrow transplantation is 'graft-versus-host disease'. This happens when the cells of the donor attacks different parts of the patient s body. This study will use a medicine called sirolimus instead of the usual medicine, cyclosporine, to prevent graft-versus-host disease.

To go onto this study, you must have:

  1. A severe immune deficiency, such as chronic granulomatous disease or leukocyte adhesion deficiency.
  2. Have problems from the disease that call for stem cell transplantation.
  3. You must also be between the ages of 2 and 40 years.

Two groups of patients are included in this study:

  1. Patients who have a brother or sister that have stem cells that match the patient. This is known as an allogeneic matched sibling transplant.
  2. Patients who do not have a matched sibling donor but have a donor that matches in the National Marrow Donor Program. This is know as matched unrelated donor transplantation.

Patients will have the following procedures:

  • To create space in the bone marrow, patients are given two drugs, Campath-1H and busulfan. To prevent the body from getting rid of the donated cells, patients are given sirolimus. On the day before the BMT, patients in the matched unrelated donor group also receive a low-dose of whole-body radiation. This will further improve the chances that the patients body will accept the donor cells.
  • Patients will get the donor stem cells through an intravenous (IV) line that goes into a vein in their body. The cells make their way to the bone marrow space and slowly refill the marrow over the next several weeks. Patients will usually stay in the hospital for 30 days after the transplant.
  • For the first 3 months after the transplant, patients are watched closely. The patients will have frequent visits to the clinic. During these visits the patient will have a physical examination and blood tests. The doctor and nurse will also check any symptoms the patient may have. At day 100 after the transplant a sample of bone marrow is taken.
  • Patients will continue to be followed periodically for at least 5 years after the transplant.
Detailed Description

This is an open-label pilot study of HLA-matched allogneic and matched unrelated donor (MUD) hematopoietic stem cell (HSC) transplant (also referred to as peripheral blood stem cell (PBSC) or bone marrow transplant (BMT)) for patients with X-linked severe combined immune deficiency (XSCID). XSCID is caused by mutations in the IL2RG gene encoding the interleukin receptor signaling gamma chain [gamma c]). The study population are older children (greater than or equal to 2 years of age) and adults (less than or equal to 40 years of age) who are experiencing deteriorating and/or dysfunctional immunity and any of a constellation of severe or chronic medical problems warranting transplantation. The study is designed to evaluate whether the use of uniquely designed transplant conditioning and graft-versus-host disease (GvHD) prevention regimens achieve sufficient engraftment of donor hematopoietic stem cells (HSCs) to facilitate robust restoration of cellular immunity (T cell/NK cell number and function) including thymic function, and humoral immunity (B cell number and function) while at the same time enhancing tolerance of the donor graft in a fashon that reduces the occurrence of GvHD but not at significantly enhancing the risk of post-transplant virus infection. One target population are XSCID patients who received matched sibling or haploidentical lymphocyte-depleted transplants as infants with little or no myeloid conditioning, resulting in variable restoration of T cell immunity, but little or no restoration of NK or B cell immunity. Another target population are XSCID patients with partial production or function of gamma c or XSCID patients with clonal somatic reversion of the mutation in the IL2RG gene, who have less severe immune deficiency in childhood. A subset of patients from all of these target XSCID populations may experience progressive deterioration of immune function leading to acute and chronic medical problems that warrant consideration of allogeneic or MUD transplant to restore immunity.

The conditioning and GvHD prevention regimens for this HSC transplant protocol are designed to use mobilized peripheral blood stem cells (PBSC) or bone marrow (BM) (if mobilization is not possible) from either an HLA-matched related sibling donor (alloPBSC) as first choice or from an HLA matched unrelated donor (MUD) for those without an appropriate HLA-matched related sibling donor. If there is no appropriately matched sibling donor nor MUD adult donor available, then an appropriately matched cord blood from the cord blood registries may be used for small children XSCID recipients. For the alloPBSC (or alloBM) transplantation (referred to as Group 1), we propose using a busulfan-based, nonmyeloablative conditioning regimen combined with horse Anti-human Thymocyte Globulin (h-ATG) immune suppression conditioning plus post-transplant sirolimus for tolerance inducing immunosuppressant to prevent GvHD. For the MUD or unrelated cord blood transplantation (referred to as Group 2), we will use a similar conditioning regimen, with a few modifications that include addition of total body irradiation with shielding and reduction in busulfan dosing, changes designed to address the increased risk of graft rejection with HLA-matched but unrelated donor HSC.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Inherited Immune Deficiencies
Intervention  ICMJE
  • Drug: Fludarabine
    For patients with inflammatory disorders or immunodeficiencies with a predominant inflammatory component, we may use Fludarabine instead of TBI to increase the immunosuppression induced by the regimen as well as to try to decrease the target cells responsible for the inflammatory symptoms
  • Drug: Total Body Irradiation, Busulfan, Campath-1H, or h-ATG, Fludarabine
    Conditioning regimen in various combination based on patient underlining immune deficiency disorder
  • Drug: Sirolimus or equivalent based on response
    post Transplantation immunosuppressants
  • Drug: Granulocyte Colony Stimulating Factor (G-CSF)
    For mobilization of sibling donors
  • Other: hematopoietic progenitor cells
    Allogeneic Stem Cells (sibling donor, Unrelated Donor (MUD) or Cord Blood Unit (CBU)
Study Arms  ICMJE
  • Group 1
    All Sibling BMT
    • Drug: Fludarabine
    • Drug: Total Body Irradiation, Busulfan, Campath-1H, or h-ATG, Fludarabine
    • Drug: Sirolimus or equivalent based on response
    • Other: hematopoietic progenitor cells
  • Group 2
    MUD or Cord Blood Unit BMT
    • Drug: Fludarabine
    • Drug: Total Body Irradiation, Busulfan, Campath-1H, or h-ATG, Fludarabine
    • Drug: Sirolimus or equivalent based on response
    • Other: hematopoietic progenitor cells
  • Group 3
    Sibling Donors for Group 1
    Intervention: Drug: Granulocyte Colony Stimulating Factor (G-CSF)
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 2, 2019)
Original Enrollment  ICMJE
 (submitted: January 23, 2007)
Actual Study Completion Date  ICMJE November 1, 2019
Actual Primary Completion Date November 1, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE


  • Must have confirmed genetic diagnosis of XSCID (common gamma chain disorder) by identification of a mutation in the IL2RG gene or by demonstrating failure to detect gamma c protein in patient immune blood cells.
  • Must have sufficient complications from underlying disease to warrant undergoing transplantation as defined as follows:.

Clinical Criteria: (greater than or equal to 1 must be present)

i. Infections (not including molluscum, warts or mucocutaneous candidiasis; see vii and viii below): 3 significant new or chronic active infections during the 2 years preceding evaluation for enrollment, with each infection accounting for one criteria.

Infections are defined as an objective sign of infection (fever >38.30C [1010F] or neutrophilia or pain/redness/swelling or radiologic/ultrasound imaging evidence or typical lesion or histology or new severe diarrhea or cough with sputum production). In addition to one or more of these signs/symptoms of possible infection, there also must be at least 1 of the following criteria as evidence of the attending physician s intent to treat a significant infection (a. and b.) or objective evidence for a specific pathogen causing the infection (c.)

  1. Treatment (not prophylaxis) with systemic antibacterial, antifungal or antiviral antibiotics . 14 days OR
  2. Hospitalization of any duration for infection OR
  3. Isolation of a bacteria, fungus, or virus from biopsy, skin lesion, blood, nasal washing, bronchoscopy, cerebrospinal fluid or stool likely to be an etiologic agent of infection

ii. Chronic pulmonary disease as defined by:

  1. Bronchiectasis by x-ray computerized tomography OR
  2. Pulmonary function test (PFT) evidence for restrictive or obstructive disease that is . 60% of Predicted for Age OR
  3. Pulse oximetry . 94% in room air (if patient is too young to comply with performance of PFTs).

iii. Gastrointestinal enteropathy:

  1. Diarrhea-watery stools . 3 times per day (of at least 3 months duration that is not a result of infection as defined in criterion # i. above) OR
  2. Endoscopic evidence (gross and histologic) for enteropathy (endoscopy will only be performed if medically indicated) OR
  3. Other evidence of enteropathy or bacterial overgrowth syndrome: including malabsorption of fat soluble vitamin(s), abnormal D-xylose absorption, abnormal hydrogen breath test, evidence of protein losing enteropathy (for example increasingly high or frequent dosing of intravenous gamma globulin supplement required to maintain blood IgG level).

iv. Poor nutrition: Requires G-tube or intravenous feeding supplement to maintain weight or nutrition.

v. Auto- or allo-immunity: Examples must include objective physical findings that include, but are not limited to any one of alopecia, severe rashes, uveitis, joint pain with redness or swelling or limitation of movement that is not a result of infection, lupus-like lesions, and granulomas (Does not include auto- or allo-immune enteropathy which is criterion iii). Where possible and appropriate, diagnosis will be supported by histopathology or other diagnostic modality.

vi. Failure to grow in height: . 3rd percentile for age

vii. Skin molluscum contagiosum OR warts (this criterion is satisfied if molluscum consists of 10 lesions or there are two or more lesions at each of two or more widely separated anatomic sites; or there are 3 warts at different anatomic sites at the same time; or the patient has both

molluscum and warts)

viii. Mucocutaneous candidiasis (chronic oral thrush or candida esophagitis or candida intertriginous infection or candida nail infections; must be culture positive to satisfy this criterion)

ix. Hypogammaglobulinemia: requires regular IgG supplementation

Ages 2 years 40 years.

HLA-matched family donor available or an HLA matched unrelated PBSC graft (10/10 or 9/10 mismatch) available, or a minimum of 4/6 HLA matched cord blood product. (If the size of the cord blood graft is less than 3.0 x 10(7) cells, a second appropriate 4/6 or greater match cord blood product must be available).

Must be HIV negative.

Must be able to stay within one hour s travel of the NIH for the first 3 months after transplantation and have a family member or other designated companion to stay with during the post transplant period.

Must provide a durable power of attorney for health care decisions to an appropriate adult relative or guardian in accordance to NIH -200 NIH Durable Power of Attorney for Health Care Decision Making.

If of child-bearing potential, must agree to consistently use contraception throughout study participation and for 3 months post-study. Acceptable forms of contraception are:

  • Condoms, male or female, with or without a spermicide
  • Diaphragm or cervical cap with spermicide
  • Intrauterine device
  • Contraceptive pills or patch, Norplant, Depo-Provera, or other FDA-approved contraceptive method
  • Male partner has previously undergone a vasectomy



  • Eastern Cooperative Oncology Group (ECOG) or equivalent performance status of 3 or more (See Supportive Care guidelines, available at
  • Left ventricular ejection fraction less than 40%.
  • Transaminases greater than 5 times upper limit of normal based on the patient s clinical situation and at the discretion of the investigator.
  • Liver alkaline phosphatase >10x upper limit of normal based on the patient s clinical situation and at the discretion of the investigator
  • Psychiatric disorder or mental deficiency severe enough as to make compliance with the BMT treatment unlikely, and/or making informed consent impossible.
  • Major anticipated illness or organ failure incompatible with survival from AlloPBSC, MUD or unrelated cord blood transplant
  • Pregnant or lactating.
  • HIV positive.
  • Uncontrolled seizure disorder.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years to 40 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00426517
Other Study ID Numbers  ICMJE 070075
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Elizabeth M Kang, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date November 1, 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP