Conditioning Regimen for Allogeneic Hematopoietic Stem-Cell Transplantation

Inclusion Criteria: * Diagnoses: * Hemoglobinopathies (e.g. thalassemia or sickle cell disease), * Cytopenias (e.g.Diamond-Blackfan anemia, congenital or acquired neutropenia, congenital or acquired thrombocytopenia, congenital or acquired anemia, and others, regardless clonality), * Hemophagocytic lymphohistiocytosis, * Primary immunodeficiencies (e.g. Wiscott Aldrich Syndrome, chronic granulomatous disease, common variable immune deficiency, X-linked lymphoproliferative disease, NK+ severe combined immune deficiencies), * Metabolic disorders (Hurler's syndrome, mannosidosis, adrenal leuko-dystrophy) * Other non-malignant disorders for which there is published evidence that HSCT (hematopoietic stem cell transplant) is a curative therapy. * Donor Requirements * Related or unrelated donor who is suitable and willing to donate bone marrow or peripheral blood stem cells. HLA typing should be done by high-resolution typing at A, B, C, DrB1 and DQ loci and the donor should be at a minimum ≥8/10 match (with one antigen/allele mismatch allowed at A, B, or C-loci and other at DQ loci). * Cord blood units must be matched at a minimum of 6/8 antigens/alleles at A, B, C and DrB1 loci. High resolution typing at all loci is required. The minimum TNC dose pre-cryopreservation must be ≥3.7 x10\^7/kg of recipient's weight, if a single cord blood unit is used, or at least 2x10\^7/kg per unit, if two cord blood units are used. The mismatches cannot be at the same loci (e.g. double A mismatch). * Haploidentical related stem cell donor who is suitable and willing to donate peripheral blood stem cells. T-cell depletion is required if haploidentical donors are used. Pharmacologic GVHD prophylaxis will not be used for T-cell depleted transplant recipients. * Adequate organ function defined as: * Cardiac: ejection fraction ≥55% or shortening fraction ≥30% * creatinine clearance ≥70 ml/min/1.73m2 * Pulse oximetry \>95% on room air or FEV1/DLCO \>60% * LFTs \< 3 x ULN, Total bilirubin \<3 mg/dl (unless due to non-hepatic cause (e.g. Gilbert's syndrome or hemolysis) * Lansky/Karnofsky score ≥60% * Written informed consent obtained from the subject or parental/guardian permission ± child's assent per institutional guidelines * Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy for at least 1 month after completion of conditioning. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as: * Amenorrhea that has lasted for ≥ 12 consecutive months without another cause, or * For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL. * Males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, or vasectomy) for at least one month after completion of conditioning. Exclusion Criteria: * Diagnoses that do not require myeloablative transplant for cure (e.g. NK- SCID patients), unless the subject previously did not engraft with non-myeloablative or reduced intensity conditioning transplant. * Known or suspected sensitivity to chemotherapy or radiation (e.g Fanconi's anemia, Dyskeratosis congenita, Ligase IV deficiency, etc). * Subjects with fast-progressing neurodegenerative disorders (e.g. Krabbe disease or adrenal leukodystrophy with Loes score of ≥10) * Cytopenias with increased blasts (\>5%) * Presence of anti-donor HLA antibodies (positive anti-donor HLA antibody is defined as a positive cross-match test of any titer (by complement-dependent cytotoxicity or flow cytometric testing) or the presence of anti-donor HLA antibody to the high expression loci HLA-A, B, C, DRB1 with mean fluorescence intensity (MFI)\>3000 by solid phase * Prior allogeneic stem cell transplant, except for patients with immune deficiencies who underwent previous non-myeloablative or reduced intensity transplants. * Haploidentical donor using in vivo T-cell depletion (e.g. post-transplant cyclophosphamide). * Uncontrolled bacterial, viral, or fungal infection at the time of enrollment. Uncontrolled is defined as currently taking medication and with progression or no clinical improvement on adequate medical treatment. * Seropositive for HIV * Active Hepatitis B or C determined by a detectable viral load of HBV or HCV by PCR * Bridging fibrosis or liver cirrhosis * Females or males of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 1 months after the end of conditioning * Females who are pregnant or breastfeeding * History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician. * Subjects demonstrating an inability to understand the study and comply with the study and/or follow-up procedures