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