The purpose of this study is to determine the safety and effectiveness of Umbilical Cord Blood Transplant (UCBT) to treat the patient's disease, and to see if this treatment can decrease the incidence of GVHD.

This study is for patients that were born with a disease that affects their body's metabolism or immune system. The doctor plans to treat the patient for this illness with a stem cell transplant.

While improved medical care has allowed many people with these diseases to live longer, the only way to truly cure the diseases is by means of a stem cell transplant from a donor who does not have the disease. A stem cell transplant will replace sick cells with new healthy donor cells. Stem cells grow into different types of blood cells that people need, including red blood cells, white blood cells, and platelets. In a stem cell transplant, the patients own stem cells would be killed by chemotherapy drug and then replaced by stem cells from the donor. Stem cells can be collected from the bone marrow, peripheral blood or umbilical cords. In this study, umbilical cords will be the source of the stem cells.

Currently, large inventories of umbilical cord blood units are available in public banks for transplantation in those lacking bone marrow donors. UCB transplants offer several advantages over adult bone marrow or peripheral blood stem cell transplants, including:

1. Rapid availability,
2. Absence of donor risk,
3. Low risk of transmissible infectious diseases,
4. Low risk of acute GvHD (as compared to recipients of unrelated donor marrow and peripheral blood cells).

The two main causes of death after umbilical cord blood transplantation for disorders for these kinds of patients, are graft failure and infection.

In this study we are trying to address these two problems by using different drugs to prepare patients for the transplant.

To help improve engraftment (cells begin to grow), we will include the drug Fludarabine to the usually used Busulfan and Cytoxan that the study patients will receive before their transplant.

We will try to decrease the chance of developing graft-versus-host disease (GvHD) by using Cyclosporin A (CSA) and Mycophenolate Mofetil (MMF), instead of Anti-Thymocyte Globulin (ATG) which is normally used.

Patients will be examined to make sure that they meet the requirements of this study. There will be tests of the heart and of the lungs. X-rays will be taken of the lungs and other organs, depending on the disease. An MRI and consultations with different specialists will also be conducted.

Patients also must have a negative pregnancy test before entering this study if they are a woman of childbearing potential. The blood will be tested for viruses and to look at the functioning of the liver and kidneys. The examination also includes HIV testing. If the patient has HIV, they will not be able to be treated on this protocol.

After we have determined that the patient is eligible for treatment on this study and a suitable UCB stem donor has been found, they will have a central line placed.

After placement of the central line, the following chemotherapy will be given to after admission to the hospital:

• 9 days before the infusion through 6 days before the infusion: Busulfan every 6 hours for 16 total doses.
• 5 days before the infusion through 2 days before the infusion: Cytoxan given daily for 4 days over 2 hours. (It can be given over 1 to 4 hours if needed as decided by the physician). Mesna will be given per standards.
• 4 days before the infusion through 1 day before the infusion: Fludarabine given daily for 4 days over 1 hour.

Stem cell transplant (infusion of the UCB stem cells) - defined as Day 0 of the treatment. All other "numbered" days relate to this infusion date. For example, Day 1 is the first day after the stem cell transplant.

Standard Therapy: Phenytoin will be given according to the standards of the TCH formulary.

Cyclosporin A (CSA) will be given starting 2 days prior to the stem cell infusion. It will be given daily over 2 hours every 12 hours, and then tapered if no GvHD is present.

Administration of Mycophenolate Mofetil (MMF) will start on the day the stem cell infusion is completed, and will continue daily for 45 days unless the patient develops GvHD.

Intravenous Immunoglobulins (IVIG) will be given as per CAGT SOP for infections prophylaxis.

Granulocyte Colony-Stimulating Factor (GCSF) will be given daily starting at Day +7 until ANC is greater than 2,500 for three consecutive days.

Study Evaluation: Patients will have various study evaluations, including blood samples, before and after the transplant.

Follow-Up: After year 1, the patients will be asked to return to the clinic once a year for consultations. These consultations with specialists will be similar to the ones the patients had before their transplant.

INCLUSION CRITERIA:

• Patients less than 18 years of age.
• Patients with a congenital or acquired immunologic, hematological, or metabolic pediatric disease (including SCID) in which stem cell transplantation has been beneficial.
• Related or Unrelated Umbilical Cord Blood Unit with 0-1 antigen mismatch, 5-6 HLA- A and B (at low to intermediate resolution) and DRB1 (at high resolution).
• Total cryopreserved HSC graft cell dose must be 5 x 10^7 or greater nucleated cells per kilogram recipient body weight.
• Lansky/Karnofsky scores 60 or greater.
• Patient has DLCO > 50% predicted or FEV1 > 50%, if applicable.
• Written informed consent and/or signed assent line from patient, parent or guardian.

EXCLUSION CRITERIA:

• Patients with uncontrolled infections as assessed by the principal investigator only. For bacterial infections, patients must be receiving definitive therapy and have no signs of progressing infection for 72 hours prior to starting conditioning. For fungal infections patients must be receiving definitive systemic antifungal therapy and have no signs of progressing infection for 1 week prior to enrollment. Progressing infection is defined as hemodynamic instability attributable to sepsis or new symptoms, worsening physical signs or radiographic findings attributable to infection. Persisting fever without other signs or symptoms will not be interpreted as progressing infection.
• Severe renal disease (creatinine > 3X normal for age).
• Severe hepatic disease (direct bilirubin > 3 mg/dL or SGOT > 500).
• Patients with symptomatic cardiac failure unrelieved by medical therapy or evidence of significant cardiac dysfunction by echocardiogram (shortening fraction < 20%).
• HIV positive.

The analysis included 38 evaluable participants who completed conditioning and received transplant. Two participants who were enrolled but considered not evaluable for the study were excluded from the analysis. One participant died before receiving transplant. The other was diagnosed with aplastic anemia without signs of malignancy at the time of enrollment, but later showed signs of MDS and progressed to AML, which made the participant not evaluable for this study.

We have recorded all grade 3 and 4 toxicities, except hematological toxicities, fever, abnormal glucose, ALT, GGT, and K levels from the day conditioning started until day 30 post-transplant. SAEs were reported up to day 100. Our study primary outcome is Overall Survival (OS) up to 3 years after transplant. The use of AEs up to 100 days is the standard measurement after a stem cell transplant. OS will capture any major toxicity up to 3 years after transplant that will lead to mortality.