Donor Stem Cell Transplantation for Congenital Immunodeficiencies

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.

- 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.