This phase III trial compares hematopoietic (stem) cell transplantation (HCT) using mismatched related donors (haploidentical [haplo]) versus matched unrelated donors (MUD) in treating children, adolescents, and young adults with acute leukemia or myelodysplastic syndrome (MDS). HCT is considered standard of care treatment for patients with high-risk acute leukemia and MDS. In HCT, patients are given very high doses of chemotherapy and/or radiation therapy, which is intended to kill cancer cells that may be resistant to more standard doses of chemotherapy; unfortunately, this also destroys the normal cells in the bone marrow, including stem cells. After the treatment, patients must have a healthy supply of stem cells reintroduced or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. The healthy stem cells may come from the blood or bone marrow of a related or unrelated donor. If patients do not have a matched related donor, doctors do not know what the next best donor choice is. This trial may help researchers understand whether a haplo related donor or a MUD HCT for children with acute leukemia or MDS is better or if there is no difference at all.

PRIMARY OBJECTIVE:

I. To compare the 1-year cumulative incidence of severe Graft Versus Host Disease (GVHD) (from day of HCT) defined as grade III-IV acute GVHD (aGVHD) and/or chronic GVHD (cGVHD) that requires systemic immunosuppression and to compare the disease free survival (DFS) (from time of randomization) in children and young adults (AYA) with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), mixed phenotype acute leukemia (MPAL), and myelodysplastic syndrome (MDS) who are randomly assigned to haploHCT or to an 8/8 adult MUD-HCT.

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) between children and AYA with AML/ALL/MPAL/MDS randomly assigned to haploHCT and MUD HCT.

II. To compare differences in health-related quality of life (HRQOL) between haploHCT and MUD HCT from baseline (pre-transplant), at 6 months, 1 year and 2 years post-transplant.

EXPLORATORY OBJECTIVES:

I. To compare the median time to engraftment and cumulative incidences of neutrophil engraftment at 30 and 100 days post transplant and platelet engraftment at 60 and 100 days post transplant, primary graft failure by 60 days, secondary graft failure at 1 year post transplant, Grade II-IV and III-IV acute graft versus host disease (aGVHD) requiring systemic immunosuppression at 100 days and 6 months, and cumulative incidences of transplant-related mortality (TRM), relapse, and moderate and severe chronic graft versus host disease (cGVHD) at 6 months, 1 and 2 years after haploHCT and MUD HCT.

II. To estimate 1 year, 18-month and 2-year cumulative incidence of graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) with events defined as occurrence of any of the following from Day 0 of HCT: Grade III-IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse or progression, and death from any cause.

IIa. To compare "chronic GVHD" (GRFS) after haploHCT and MUD HCT using landmark definitions.

IIb. To compare "current" GRFS is defined as the time to onset of any of the following events from Day 0 of HCT: Grade III-IV acute GVHD, chronic GVHD that is STILL requiring systemic immunosuppressive treatment, disease relapse or progression, death from any cause at 18 months and 2 years.

III. To evaluate the influence of key clinical variables: age (<13 years and 13-21.99 years), disease (ALL/MPAL versus [vs.] AML/MDS), haploHCT approach (TCR alpha beta + T cell depletion vs. post-transplant cyclophosphamide [PTCy]); donor age (by ten-year increments), donor sex (maternal vs. paternal for parental donation), pre-HCT minimal residual disease status (MRD + vs MRD -); pediatric disease risk index (low, intermediate, and high, impact on OS and DFS only), conditioning regimen (chemotherapy based versus total-body irradiation [TBI] based), immunosuppressive regimen (anti-thymocyte globulin [ATG] exposure according to the weight and absolute lymphocyte count [ALC] dependent dosing approach vs no ATG exposure) time to transplant (interval between diagnosis/relapse and date of stem cell infusion) graft cell dose, use of relapse prevention therapy (yes or no) and weight on engraftment, OS, DFS, GRFS, relapse, transplant related mortality (TRM), aGvHD and cGvHD at 1 and 2 years after haplo and MUD HCT by performing stratified and multivariate analyses.

IV. To compare other important transplant related outcomes after haplo and MUD HCT, such as:

IVa. Incidence of any significant fungal infections (defined as proven or probable fungal infection) through 1 year post HCT; IVb. Incidence of viremia with or without end organ disease (i.e. cytomegalovirus [CMV], adenovirus, Epstein-Barr virus [EBV], human herpesvirus 6 [HHV-6], BK) requiring hospitalization and/or systemic antiviral therapy and/or cell therapy through 1 year post HCT; IVc. Incidence of sinusoidal obstruction syndrome (SOS) through 100 days post HCT; IVd. As defined by the Cairo criteria; IVe. To compare the incidence and outcome of SOS when different criteria are used (European Bone Marrow Transplant [EBMT], Cairo, Baltimore, and modified Seattle criteria); IVf. Incidence of transplant-associated thrombotic microangiopathy (TA-TMA) through 100 days post HCT.

V. To compare immune recovery after haplo PTCy, haplo alpha-beta T cell depletion, and MUD HCT via:

Va. Pace of reconstitution of T, B, and natural killer (NK) cells and immunoglobulins at 30 days, 60 days, 100 days, 180 days and 365 days after HCT; Vb. Response to vaccinations as determined by vaccination-specific antibody titers at 12-18 months post hematopoietic stem cell transplant (HSCT); Vc. Biobanking blood or marrow to analyze the impact of graft composition on GvHD, relapse and viremia; Vd. Biobanking whole blood and serum to compare immune recovery using extended immune phenotyping and immune functional assessments.

VI. Biobanking whole blood or serum to measure rabbit antithymocyte globulin (rATG) exposure when dosed according to weight and absolute lymphocyte count (ALC) using established pharmacokinetic and pharmacodynamics assays (after last infusion, Day -4, Day 0, Day +7).

VII. To compare resource utilization after haplo and MUD HCT. VIIa. Length of HCT hospital stay from Day 0 and readmissions within the first 100 days (number of readmissions, duration, and reason).

VIIb. Inpatient costs within the first 100 days and at 2 years post HCT. VIII. To describe and compare outcomes (neutrophil and platelet engraftment, graft failure, OS, DFS, GRFS, NRM, relapse, GvHD and health-related quality of life [HRQOL] post HCT) by recipient race/ethnicity, annual household income, primary spoken language and conserved transcriptional response to adversity (CTRA).

IX. To describe HRQoL outcomes in racial/ethnic minorities and compare HRQoL outcomes between White patients receiving haploHCT and racial/ethnic minority patients receiving haploHCT.

X. To assess the feasibility of incorporating total body irradiation (TBI) delivered with volumetric modulated arc therapy (VMAT) or tomotherapy into a multi-institutional study, to describe the toxicities and oncologic outcomes (relapse, DFS, OS, and TRM) of the subgroup of patients treated with this approach, and to compare these outcomes to those of patients treated with conventional TBI.

OUTLINE: Patients who have both a MUD and haplo donor are randomized to Arm A or Arm B. Patients who only have a haplo donor are nonrandomly assigned to Arm C.

ARM A: Patients receive a haplo HCT following a TBI- based or chemotherapy-based myeloablative conditioning regimen with PTCy or alpha beta T cell depletion (center's choice). When PTCy is used, it Is administered on days 3 and 4 after HCT and additional immunsouppression is started on day 5 after SCT.

ARM B: Patients receive a MUD HCT following a TBI-based or chemotherapy-based myeloablative conditioning regimen between days -9 and -2 Patients then receive GVHD prophylaxis on days 1-11.

ARM C: Patients receive a haploHCT following a TBI-based or chemotherapy-based myeloablative conditioning regimen with PTCy or alpha beta T cell depletion (center's choice). When PTCy is used, it Is administered on days 3 and 4 after HCT and additional immunsouppression is started on day 5 after SCT.

Patients in all arms undergo standard HCT screening prior to transplant including disease evaluation (lumbar puncture, bone marrow aspiration), and organ function evaluation including but not limited to echocardiogram (ECHO) or multigated acquisition scan (MUGA), PFTS, and bloodwork.Patients also undergo collection of blood throughout the trial.

After completion of study treatment, patients are followed periodically for up to 5 years from HCT.

Inclusion Criteria:

• PATIENT INCLUSION CRITERIA FOR ENROLLMENT:

• 6 months to < 22 years at enrollment

• Diagnosed with ALL, AML, or MDS or mixed phenotype acute leukemia (MPAL) for which an allogeneic hematopoietic stem cell transplant is indicated. Complete Remission (CR) status will not be confirmed at the time of enrollment. CR as defined in these sections is required to proceed with the actual 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 available for stem cell donation

• Has an eligible haploidentical related family donor based on at least intermediate resolution HLA typing

  • Patients who also have an eligible 8/8 MUD adult donor based on confirmatory high resolution 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 Arm C

• 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 enrolled on other protocols for treatment of high risk and/or relapsed ALL, AML, MPAL and MDS. This is including, but not limited to, COG AAML1831, COG AALL1821, the EndRAD Trial, as well as local institutional trials. We will collect information on all co-enrollments
  • Patients will not be excluded from enrollment on this study if receiving immunotherapy prior to transplant as a way to achieve remission and bridge to transplant. This includes chimeric antigen receptor (CAR) T cell therapy and other 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 patients =< 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

• MPAL in first complete remission (CR1) for whom transplant is indicated. Examples include those patients who are poorly responsive to ALL therapy (end of induction failure( IF-MPAL) to ALL induction (see IF-MPAL note below), end of induction MRD ≥ 5% or end-of-consolidation MRD > 0.01%), as well as patients treated with AML therapy

• IF-MPAL: additional criterion for Induction failure for MPAL ONLY as per ALL1732:

  • An increasing number of circulating leukemia cells on 3 or more consecutive CBCs obtained at daily or longer intervals following day 8 of Induction therapy and prior to day 29 with confirmation by flow cytometry OR development of new sites of extramedullary disease, or other laboratory or clinical evidence of refractory disease or progression prior to the end of Induction evaluation (note that residual testicular disease at the end of Induction is an exception)

• MPAL in > second complete remission (CR2)

• ALL high-risk in 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 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). It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt PCR. It is strongly recommended that MPAL be evaluated using multidimensional flow cytometry and/or (KMT2Ar) qt 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/MPAL 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