Mismatched Related Donor Versus Matched Unrelated Donor Stem Cell Transplantation for Children, Adolescents, and Young Adults With Acute Leukemia or Myelodysplastic Syndrome

• PATIENT INCLUSION CRITERIA FOR ENROLLMENT:
• 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)RA 24 hour urine Creatinine clearance >= 60 mL/min/1.73 m^2RA glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2. GFR must be performed usingdirect measurement with a nuclear blood sampling method OR direct small moleculehod (iothalamate or other molecule per institutional standard): Estimated GFR (eGFR) from serum creatinine, cystatin C or other estimatesble for determining eligibilityum glutamic-oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] orum glutamate pyruvate transaminase (SGPT) aminotransferase [ALT] < 5 x upper limit(ULN) for ageTotal bilirubin < 2.5 mg/dL, unless attributable to Gilbert's Syndromehortening fraction of >= 27% by echocardiogram or radionuclide scan (MUGA)Rjection fraction of >= 50% by echocardiogram or radionuclide scan (MUGA), choice ofding to local standard of careForced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), andd carbon monoxide diffusing capability (DLCO) must all be >= 50% of predictedby pulmonary function tests (PFTs).For children who are unable to perform for PFTs (e.g., due to age ordevelopmental delay), the criteria are: no evidence of dyspnea at rest, oxygen(O2) saturation (Sat) > 92% on room air by pulse oximetry, not on supplemental O2d not on supplemental O2 at restALL high-risk in first complete remission (CR1) for whom transplant is indicated.ude: induction failure, treatment failure as per minimal residual diseaseby flow cytometry > 0.01% after consolidation and not eligible for AALL1721 orAALL1721 not available/unwilling to enroll, hypodiploidy (< 44 chromosomes) with MRD+> 0.01% after induction, persistent or recurrent cytogenetic or molecular evidence ofdisease during therapy requiring additional therapy after induction to achieve(e.g. persistent molecular BCR-ABL positivity), T cell ALL with persistentRD > 0.01% after consolidation.ALL in second complete remission (CR2) for whom transplant is indicated. Examplesude: B-cell: early (=< 36 months from initiation of therapy) bone marrow (BM)BM relapse (>= 36 months) with MRD >= 0.1% by flow cytometry after firstduction therapy; T or B-cell: early (< 18 months) isolated extramedullary (IEM),(>= 18 months) IEM, end-Block 1 MRD >= 0.1%; T-cell or Philadelphia chromosomeve (Ph+): BM relapse at any timeALL in >= third complete remission (CR3)Patients treated with chimeric antigen receptor T-cells (CART) cells for whomdicated. Examples include: transplant for consolidation of CART, lossCART persistence and/or B cell aplasia < 6 months from infusion or have othervidence (e.g., MRD+) that transplant is indicated to prevent relapseAML in CR1 for whom transplant is indicated. Examples include those deemed high riskdescribed in AAML1831:FLT3/ITD+ with allelic ratio > 0.1 without bZIP CEBPA, NPM1FLT3/ITD+ with allelic ratio > 0.1 with concurrent bZIP CEBPA or NPM1 and withvidence of residual AML (MRD >= 0.05%) at end of InductionPresence of RAM phenotype or unfavorable prognostic markers (other than FLT3/ITD)ytogenetics, fluorescence in situ hybridization (FISH), next generationquencing (NGS) results, regardless of favorable genetic markers, MRD status orFLT3/ITD mutation statusAML without favorable or unfavorable cytogenetic or molecular features but withvidence of residual AML (MRD >= 0.05%) at end of InductionPresence of a non-ITD FLT3 activating mutation and positive MRD (>= 0.05%) at endduction 1 regardless of presence of favorable genetic markers.AML in >= CR2DS with < 5% blasts by morphology and flow cytometry (if available) on thebone marrow evaluationComplete remission (CR) is defined as < 5% blasts by morphology and flow cytometry (ifvailable) on the pre-transplant bone marrow evaluation with minimum sustainedbsolute neutrophil count (ANC) of 300 cells/microliter for 1 week or ANC > 500/microliter. We will be collecting data from all approaches to MRD evaluationd including NGS and polymerase chain reaction (PCR)DONOR ELIGIBILITY CRITERIA:hed Unrelated Donors:d 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 ofdditional alleles is recommended according to National Marrow Donor Program (NMDP)guidelines, but will be at the discretion of local centersHaploidentical Matched Family Members:um match level full haploidentical (at least 5/10; HLA-A, -B, -C, -DRB1,DQB1 alleles). The following issues (in no particular order) should bedered in choosing a haploidentical donor:Absent or low patient donor-specific antibodies (DSA)uorescence intensity (MFI) of any anti-donor HLA antibody byd phase immunoassay should be < 2000. Donors with higher levels aregible.g assay against pooled HLA antigens is used, positiveults must be followed with specificity testing using a singlegen assay. The MFI must be < 2000 unless the laboratory hasvalidated higher threshold values for reactivity for HLA antigens(such as HLA-C, -DQ, and -DP), that may be enhanced inhe single antigen assays. Donor anti- recipientbodies are of unknown clinical significance and do not need tobe sent or reported.Consult with Study Chair for the clinical significance of anydonor HLA antibody.unable to perform this type of testing, pleasehe Study Chair to make arrangements for testing.killer immunoglobulin testing (KIR) is performed: KIR status by mismatch,KIR-B, or KIR content criteria can be used according to institutionalguidelines.ABO compatibility (in order of priority):Compatible or minor ABO incompatibilityjor ABO incompatibilityCMV serostatus:For a CMV seronegative recipient: the priority is to use a CMVgative donor when feasibleFor a CMV seropositive recipient: the priority is to use a CMVve donor when feasibleAge: younger donors including siblings/half-siblings, and second degreeves (aunts, uncles, cousins) are recommended, even if < 18 yearsze and vascular access appropriate by center standard for peripheral blood stem cell(PBSC) collection if neededHaploidentical matched family members: screened by center health screens and found tobe eligibled donors: meet eligibility criteria as defined by the NMDP or other unrelateddonor registries. If the donor does not meet the registry eligibility criteria but anble eligibility waiver is completed and signed per registry guidelines, thedonor will be considered eligible for this studyHuman immunodeficiency virus (HIV) negativegnantD donors and post-transplant cyclophosphamide haplo donors should be asked tovide BM. If donors refuse and other donors are not available, PBSC is allowed.TCR-alpha beta/CD19 depleted haplo donors must agree to donate PBSCust give informed consent:Haploidentical matched family members: Institution standard of care donor consentd Protocol-specific Donor Consent for Optional Studiesd donors: standard NMDP Unrelated Donor Consentusion Criteria:PATIENT EXCLUSION CRITERIA FOR ENROLLMENT:Patients with genetic disorders (generally marrow failure syndromes) prone todary AML/ALL with known poor outcomes because of sensitivity to alkylator therapyd/or TBI are not eligible (Fanconi Anemia, Kostmann Syndrome, DyskeratosisCongenita, etc). Patients with Downs syndrome because of increased toxicity withve conditioning regimens.Patients with any obvious contraindication to myeloablative HCT at the time ofFemale patients who are pregnant are ineligible as many of the medications used inhis protocol could be harmful to unborn children and infantsually active patients of reproductive potential who have not agreed to use anve contraceptive method for the duration of their study participationPATIENT EXCLUSION CRITERIA TO PROCEED TO HCT:Patients with uncontrolled fungal, bacterial, viral, or parasitic infections areuded. Patients with history of fungal disease during chemotherapy may proceed ifhey have a significant response to antifungal therapy with no or minimal evidence ofdisease remaining by computed tomography (CT) evaluationPatients with active central nervous system (CNS) leukemia or any other active site ofdullary disease at the time of initiation of the conditioning regimen are notd.: Those with prior history of CNS or extramedullary disease, but with nove disease at the time of pre-transplant workup, are eligiblePregnant or breastfeeding females are ineligible as many of the medications used inhis protocol could be harmful to unborn children and infants