Reduced-Intensity Conditioning (RIC) and Myeloablative Conditioning (MAC) for HSCT in AML/MDS

INCLUSION CRITERIA: Individuals must meet all the following criteria to be eligible for this study. * Subject, parent, or legal guardian, if applicable, must have given written informed consent. For patients ≤ 17 years of age who are developmentally able, assent or affirmation will be obtained. * Age 0-26, inclusive, at time of consent. * Diagnosis of myelodysplastic syndrome or acute myeloid leukemia, either high-risk (defined below), relapsed or primary refractory, MRD-positive without circulating myeloblasts or active extramedullary disease at the time of transplant. Active marrow disease is permitted. High-risk AML features are defined by the following: RAM phenotype; adverse cytogenetic abnormalities of monosomy 5, monosomy 7, 5q deletion, or other unfavorable prognostic markers according to cytogenetics, FISH, or next generation sequencing (NGS); presence of FLT3 positive internal tandem duplication (FLT3/ITD+), particularly high allelic ratio; treatment-related AML; or positive minimal residual disease (MRD) at end of Induction I. * Stem cell sources include bone marrow, peripheral blood stem cells, or umbilical cord blood. Related bone marrow, peripheral blood stem cell, or cord blood unit: sibling should be HLA-matched at A, B, and DR-B1 loci. Unrelated cord blood unit should be at a minimum of 4/6 matched at antigen level on HLA A and B, and allele level at HLA DR-B1 loci. Unrelated bone marrow or peripheral blood stem cell donor should be HLA allele level matched at DR-B1. * Minimum pre-freezing cell dose for cord blood units: 3 x 10\^7 total nucleated cells/kg and 1.5 x 10\^5 CD34+ cells/kg. If this is not attainable, then double cord blood transplant should be considered. * Subject must have adequate performance status: Lansky score ≥60% for patients \<16 years, Karnofsky score ≥60% for patients ≥16 years. * Subject must have adequate pre-transplant organ function to undergo one of the two conditioning regimens, either the myeloablative conditioning (MAC) OR reduced-intensity conditioning (RIC) regimen. If a subject does not meet the following organ function criteria for the MAC regimen, the RIC regimen will be considered if eligibility criteria is met. The RIC regimen may also be considered, regardless of MAC eligibility, if deemed appropriate by the Principal Investigator and/or treating physician. Pre-transplant organ function criteria for Myeloablative Conditioning regimen: * Renal: creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2. * Hepatic: total bilirubin ≤2.0 mg/dL unless the increase in bilirubin is attributable to Gilbert's syndrome; and SGOT (AST), SGPT (ALT), and Alkaline Phosphatase \<4 x upper limit of normal (ULN) for age. * Cardiac: normal cardiac function by echocardiogram or radionuclide scan, as defined by left ventricular ejection fraction at rest \>45% or shortening fraction \>26%. * Pulmonary: FEV1, FVC, and DLCO (corrected for hemoglobin) ≥50% of predicted; if unable to perform pulmonary function tests, then oxygen saturation ≥92% on room air. OR Pre-transplant organ function criteria for Reduced-Intensity Conditioning regimen: * Renal: creatinine clearance or radioisotope GFR ≥70 mL/min/1.73 m2. * Hepatic: total bilirubin ≤2.5 mg/dL unless the increase in bilirubin is attributable to Gilbert's syndrome; and SGOT (AST), SGPT (ALT), and Alkaline Phosphatase \<5 x upper limit of normal (ULN) for age. * Cardiac: normal cardiac function by echocardiogram or radionuclide scan, as defined by left ventricular ejection fraction at rest \>40% or shortening fraction \>26%. * Pulmonary: FEV1, FVC, and DLCO (corrected for hemoglobin) ≥40% of predicted; if unable to perform pulmonary function tests, then oxygen saturation ≥92% on room air. * HIV and HTLV negative, by either PCR or serology. * Negative pregnancy test for females ≥10 years old or who have reached menarche. * All females of childbearing potential and sexually active males must agree to use an FDA approved method of birth control for up to 12 months after HSCT or for as long as they are taking any medication that may harm a pregnancy, an unborn child or may cause a birth defect. EXCLUSION CRITERIA: Individuals who meet any of the following criteria are not eligible for this protocol. * Uncontrolled bacterial, viral, fungal, or other infection at the time of cytoreduction, defined by positive blood cultures and/or fevers \>38.0 within 24 hours of start of conditioning therapy. * Females who are pregnant or who are lactating. * Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality or interpretation of the data obtained from the study. Additional Exclusion Criteria for Myeloablative Conditioning (MAC) Only Individuals who meet any of the following criteria are not eligible for the MAC regimen. * Recipient of either an autologous or allogeneic stem cell transplant within 3 months of the start of conditioning. * Patients with any inherited bone marrow failure syndrome including, but not limited to, Fanconi anemia, Shwachman-Diamond syndrome, dyskeratosis congenita or Down syndrome (defined as either constitutional trisomy 21 or constitutional mosaicism of trisomy 21).