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

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.

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

Eligibility Criteria:
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