Donor Stem Cell Transplantation for Congenital Immunodeficiencies

- INCLUSION CRITERIA:

PATIENTS (RECIPIENT)

- 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

EXCLUSION CRITERIA:

PATIENT (RECIPIENT)

- Eastern Cooperative Oncology Group (ECOG) or equivalent performance status of 3 or more (See Supportive Care guidelines, available at http://intranettst2.cc.nih.gov/bmt/clinicalcare).

- 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.