• 6 months to < 22 years at enrollment
• Diagnosed with ALL, AML, or MDS for which an allogeneic hematopoietic stem celldicated. Complete Remission (CR) status will not be confirmed at the. CR as defined in these sections is required to proceed with theual HCT treatment plan
• Has not received a prior allogeneic hematopoietic stem cell transplant
• Does not have a suitable human leukocyte antigen (HLA)-matched sibling donor availabledonation
• Has an eligible haploidentical related family donor based on at least intermediateution HLA typing
  • Patients who also have an eligible 8/8 MUD adult donor based on confirmatory highution HLA typing are eligible for randomization to Arm A or Arm B.
  • Patients who do not have an eligible MUD donor are eligible for enrollment to ArmC
• All patients and/or their parents or legal guardians must sign a written informed
  consent
• All institutional, Food and Drug Administration (FDA), and National Cancer Institute(NCI) requirements for human studies must be met
• Co-Enrollment on other trials
  • Patients will not be excluded from enrollment on this study if already enrolledher protocols for treatment of high risk and/or relapsed ALL, AML and MDS.This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRADTrial, as well as local institutional trials. We will collect information on all
  • Patients will not be excluded from enrollment on this study if receivingunotherapy prior to transplant as a way to achieve remission and bridge to. This includes chimeric antigen receptor (CAR) T cell therapy andher immunotherapies
• PATIENT INCLUSION CRITERIA TO PROCEED TO HCT:
• Karnofsky Index or Lansky Play-Performance Scale >= 60 on pre-transplant evaluation.Karnofsky scores must be used for patients >= 16 years of age and Lansky scores for=< 16 years of age (within 4 weeks of starting therapy)
• A serum creatinine based on age/gender as follows:
  6 months to < 1 year: 0.5 mg/dL (Male); 0.5 mg/dL (Female)
  1. to < 2 years: 0.6 mg/dL (Male); 0.6 mg/dL (Female)
  2. to < 6 years: 0.8 mg/dL (Male); 0.8 mg/dL (Female)

6 to < 10 years: 1 mg/dL (Male); 1 mg/dL (Female) 10 to < 13 years: 1.2 mg/dL (Male);
       1.2 mg/dL (Female) 13 to < 16 years: 1.5 mg/dL (Male); 1.4 mg/dL (Female) >= 16 years:
       1.7 mg/dL (Male); 1.4 mg/dL (Female)
        - OR
     - A 24 hour urine Creatinine clearance >= 60 mL/min/1.73 m^2
        - OR
     - A glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2. GFR must be performed using
       direct measurement with a nuclear blood sampling method OR direct small molecule
       clearance method (iothalamate or other molecule per institutional standard)
        - Note: Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimates
         are not acceptable for determining eligibility
     - Serum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] or
       serum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit
       of normal (ULN) for age
     - Total bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndrome
     - Shortening fraction of >= 27% by echocardiogram or radionuclide scan (MUGA)
        - OR
     - Ejection fraction of >= 50% by echocardiogram or radionuclide scan (MUGA), choice of
       test according to local standard of care
     - Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and
       corrected carbon monoxide diffusing capability (DLCO) must all be >= 50% of predicted
       by pulmonary function tests (PFTs).
        - For children who are unable to perform for PFTs (e.g., due to age or
         developmental delay), the criteria are: no evidence of dyspnea at rest, oxygen
         (O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2
         at rest, and not on supplemental O2 at rest
     - ALL high-risk in first complete remission (CR1) for whom transplant is indicated.
       Examples include: induction failure, treatment failure as per minimal residual disease
       by flow cytometry > 0.01% after consolidation and not eligible for AALL1721 or
       AALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+
       > 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence of
       disease during therapy requiring additional therapy after induction to achieve
       remission (e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistent
       MRD > 0.01% after consolidation.
     - ALL in second complete remission (CR2) for whom transplant is indicated. Examples
       include: B-cell: early (=< 36 months from initiation of therapy) bone marrow (BM)
       relapse, late BM relapse (>= 36 months) with MRD >= 0.1% by flow cytometry after first
       re-induction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM),
       late (>= 18 months) IEM, end-Block 1 MRD >= 0.1%; T-cell or Philadelphia chromosome
       positive (Ph+): BM relapse at any time
     - ALL in >= third complete remission (CR3)
     - Patients treated with chimeric antigen receptor T-cells (CART) cells for whom
       transplant is indicated. Examples include: transplant for consolidation of CART, loss
       of CART persistence and/or B cell aplasia < 6 months from infusion or have other
       evidence (e.g., MRD+) that transplant is indicated to prevent relapse
     - AML in CR1 for whom transplant is indicated. Examples include those deemed high risk
       for relapse as described in AAML1831:
        - FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1
        - FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and with
         evidence of residual AML (MRD >= 0.05%) at end of Induction
        - Presence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD)
         per cytogenetics, fluorescence in situ hybridization (FISH), next generation
         sequencing (NGS) results, regardless of favorable genetic markers, MRD status or
         FLT3/ITD mutation status
        - AML without favorable or unfavorable cytogenetic or molecular features but with
         evidence of residual AML (MRD >= 0.05%) at end of Induction
        - Presence of a non-ITD FLT3 activating mutation and positive MRD (>= 0.05%) at end
         of Induction 1 regardless of presence of favorable genetic markers.
     - AML in >= CR2
     - MDS with < 5% blasts by morphology and flow cytometry (if available) on the
       pre-transplant bone marrow evaluation
     - Complete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (if
       available) on the pre-transplant bone marrow evaluation with minimum sustained
       absolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500
       cells/microliter. We will be collecting data from all approaches to MRD evaluation
       performed including NGS and polymerase chain reaction (PCR)
     - DONOR ELIGIBILITY CRITERIA:
     - Matched Unrelated Donors:
    Unrelated donor candidates must be matched at high resolution at a minimum of 8/8 alleles
    (HLA-A, -B, -C, -DRB1). One-antigen HLA mismatches are not permitted. HLA matching of
    additional alleles is recommended according to National Marrow Donor Program (NMDP)
    guidelines, but will be at the discretion of local centers
     - Haploidentical Matched Family Members:
        - Minimum match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1,
         -DQB1 alleles). The following issues (in no particular order) should be
         considered in choosing a haploidentical donor:
          - Absent or low patient donor-specific antibodies (DSA)
             - Mean fluorescence intensity (MFI) of any anti-donor HLA antibody by
              solid phase immunoassay should be < 2000. Donors with higher levels are
              not eligible.
               - If a screening assay against pooled HLA antigens is used, positive
                 results must be followed with specificity testing using a single
                 antigen assay. The MFI must be < 2000 unless the laboratory has
                 validated higher threshold values for reactivity for HLA antigens
                 (such as HLA-C, -DQ, and -DP), that may be enhanced in
                 concentration on the single antigen assays. Donor anti- recipient
                 antibodies are of unknown clinical significance and do not need to
                 be sent or reported.
               - Consult with Study Chair for the clinical significance of any
                 recipient anti-donor HLA antibody.
               - If centers are unable to perform this type of testing, please
                 contact the Study Chair to make arrangements for testing.
          - If killer immunoglobulin testing (KIR) is performed: KIR status by mismatch,
            KIR-B, or KIR content criteria can be used according to institutional
            guidelines.
          - ABO compatibility (in order of priority):
             - Compatible or minor ABO incompatibility
             - Major ABO incompatibility
          - CMV serostatus:
             - For a CMV seronegative recipient: the priority is to use a CMV
              seronegative donor when feasible
             - For a CMV seropositive recipient: the priority is to use a CMV
              seropositive donor when feasible
          - Age: younger donors including siblings/half-siblings, and second degree
            relatives (aunts, uncles, cousins) are recommended, even if < 18 years
     - Size and vascular access appropriate by center standard for peripheral blood stem cell
       (PBSC) collection if needed
     - Haploidentical matched family members: screened by center health screens and found to
       be eligible
     - Unrelated donors: meet eligibility criteria as defined by the NMDP or other unrelated
       donor registries. If the donor does not meet the registry eligibility criteria but an
       acceptable eligibility waiver is completed and signed per registry guidelines, the
       donor will be considered eligible for this study
     - Human immunodeficiency virus (HIV) negative
     - Not pregnant
     - MUD donors and post-transplant cyclophosphamide haplo donors should be asked to
       provide BM. If donors refuse and other donors are not available, PBSC is allowed.
       TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSC
     - Must give informed consent:
        - Haploidentical matched family members: Institution standard of care donor consent
         and Protocol-specific Donor Consent for Optional Studies
        - Unrelated donors: standard NMDP Unrelated Donor Consent
    Exclusion Criteria:
     - PATIENT EXCLUSION CRITERIA FOR ENROLLMENT:
     - Patients with genetic disorders (generally marrow failure syndromes) prone to
       secondary AML/ALL with known poor outcomes because of sensitivity to alkylator therapy
       and/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, Dyskeratosis
       Congenita, etc). Patients with Downs syndrome because of increased toxicity with
       intensive conditioning regimens.
     - Patients with any obvious contraindication to myeloablative HCT at the time of
       enrollment
     - Female patients who are pregnant are ineligible as many of the medications used in
       this protocol could be harmful to unborn children and infants
     - Sexually active patients of reproductive potential who have not agreed to use an
       effective contraceptive method for the duration of their study participation
     - PATIENT EXCLUSION CRITERIA TO PROCEED TO HCT:
     - Patients with uncontrolled fungal, bacterial, viral, or parasitic infections are
       excluded. Patients with history of fungal disease during chemotherapy may proceed if
       they have a significant response to antifungal therapy with no or minimal evidence of
       disease remaining by computed tomography (CT) evaluation
     - Patients with active central nervous system (CNS) leukemia or any other active site of
       extramedullary disease at the time of initiation of the conditioning regimen are not
       permitted.
        - Note: Those with prior history of CNS or extramedullary disease, but with no
         active disease at the time of pre-transplant workup, are eligible
     - Pregnant or breastfeeding females are ineligible as many of the medications used in
       this protocol could be harmful to unborn children and infants