Reduced Intensity Conditioning for Umbilical Cord Blood Transplant in Pediatric Patients With Non-Malignant Disorders

Myeloablative doses of chemotherapy and/or radiation therapy are employed with the primary
purpose of eradicating malignant cells. Additionally, these regimens exert varying degree of
immunosuppression/immunoablation that aids in reducing the likelihood of rejection by host
hematopoietic cells. However, myeloablative /immunoablative regimens have also been
associated with significant regimen related toxicity (RRT) and regimen related mortality
(RRM) that may cause death in up to 20% of patients and significantly higher rate of severe
organ dysfunction or failure. While most of these RRT occur typically in the first 100 days
[ e.g. VOD (veno occlusive disease), pulmonary or intracranial hemorrhage, multiorgan
failure (MOF)], there are significant long term toxicities of TBI and/or chemotherapy
including growth impairment, gonadal dysfunction/failure, hypothyroidism, cataracts,
neurocognitive impairment, and second malignancies.

The primary objective is to determine the feasibility of attaining acceptable rates of donor
cell engraftment (>25% donor chimerism at 180 days) following reduced intensity conditioning
(RIC) regimens in pediatric patients < 21 years receiving cord blood transplantation for
non-malignant disorders.

The secondary objectives are:

- To describe the pace of neutrophil and platelet recovery

- To evaluate the pace of immune reconstitution.

- To determine the treatment related mortality, overall survival and disease free
survival by days 100 and 180 post-transplant

- To describe incidence of acute Graft Versus Host Disease (GVHD) (II - IV) and chronic
extensive GVHD

- To describe the incidence of grade 3-4 organ toxicity

- To evaluate long-term complications, such as sterility, endocrinopathy, and growth
failure

- To evaluate the incidence of late graft failures at 2 years post-transplant

Inclusion Criteria:

- 0-21 years of age with a diagnosis of a immunodeficiency, congenital marrow failure
syndrome, inborn error of metabolism, or hereditary anemia

- Appropriately matched related or unrelated umbilical cord blood unit with a cell dose
≥ 3 x 10e7cells/kg

- Performance score (lansky or karnofsky) greater than or equal to 70

- Adequate organ function (Creatinine ≤ 2.0 mg/dl and creatinine clearance ≥ 50
ml/min/1.73 m2; Hepatic transaminases (ALT/AST) ≤ 4 x normal; Shortening fraction
>26% or ejection fraction >40% or > 80% of normal value for age; Pulmonary function
tests demonstrating CVC or FEV1/FVC of >60% of predicted for age.)

- Informed consent

- Not pregnant or breast feeding

- Minimum life expectancy of at least 6 months

- HIV negative

- No uncontrolled infections at the time of cytoreduction

- Disease specific inclusion criteria

Exclusion Criteria:

- Patients with hemoglobinopathies > 3 years of age

- UCB unit with a total nucleated cell count < 3 x 10e7/kg or > 2 antigen mismatching

- Available HLA-matched related living donor able to donate without previous UCB
donation

- Allogeneic hematopoietic stem cell transplant within the previous 6 months

- Any active malignancy, MDS, or any history of malignancy

- Severe acquired aplastic anemia

- DLCO < 60% of normal value for age; requirement for supplemental oxygen

- Uncontrolled bacterial, viral or fungal infection (currently taking medication and
progression of clinical symptoms)

- Pregnancy or nursing mother

- HIV/HTLV seropositive, Hep B surface antigen positive, or HCV RNA positive by PCR

- Any condition that precludes serial follow-up