reduced intensity conditioning for umbilical cord blood transplant in pediatric patients with non-malignant disorders

Conditions: Non Malignant Disorders; Immunodeficiencies; Congenital Marrow Failures; Hemoglobinopathies; Inborn Errors of Metabolism; Sickle Cell; Thalassemia; Lysosomal Storage Disease

Summary: 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 \ 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

Keywords: immunodeficiencies congenital marrow failures hemoglobinopathies inborn errors of metabolism scids wiskott aldrich fel hlh ipex lad sickle cell thalassemia omenn's syndrome hurler's syndrome mld ald sanfilippo krabbe hunter's syndrome taysachs diamond blackfan anemia transplant mps gaucher