HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation With Post-Transplantation Cyclophosphamide

Phase 2

Recruiting

• Conditions: Chronic Myelogenous Leukemia; Mixed Phenotype Acute Leukemia; Acute Leukemia; Acute Lymphoblastic Leukemia; Chronic Lymphocytic Leukemia; Acute Myelogenous Leukemia; Myelodysplastic Syndromes; Lymphoma
• Interventions: Drug: Busulfan; Radiation: Total-body irradiation; Drug: Melphalan; Drug: Cyclophosphamide; Drug: Fludarabine; Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT); Procedure: Bone Marrow Hematopoietic Stem Cell Transplantation; Drug: Post-transplant Cyclophosphamide; Drug: Mesna; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Other: Patient-Reported Outcomes

• Registration Number: NCT04904588
• Lead Sponsor: Center for International Blood and Marrow Transplant Research

Brief Summary

This is a prospective, multi-center, Phase II study of hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-mismatched unrelated donors (MMUD) for peripheral blood stem cell transplant in adults and bone marrow stem cell transplant in children. Post-transplant cyclophosphamide (PTCy), tacrolimus and mycophenolate mofetil (MMF) will be used for for graft versus host disease (GVHD) prophylaxis. This trial will study how well this treatment works in patients with hematologic malignancies.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2021-05-17
• Study First Submitted QC: 2021-05-26
• Study First Posted: 2021-05-27
• Study Start: 2021-09-30
• Status Verified: 2024-05
• Last Update Submitted: 2024-05-22
• Last Update Posted: 2024-05-23
• Primary Completion: 2024-07
• Study Completion: 2024-07

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. Age > 18 years and < 66 years (chemotherapy-based conditioning) or < 61 years (total body irradiation [TBI]-based conditioning) at the time of signing informed consent

2. Planned MAC regimen as defined per protocol

3. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age < 35 years

4. Product planned for infusion is PBSC

5. HCT Comorbidity Index (HCT-CI) < 5

6. One of the following diagnoses:

   1. Acute myeloid leukemia (AML) acute lymphoblastic leukemia (ALL), or other acute leukemia in 1st remission or beyond with ≤ 5% marrow blasts and no circulating blasts or evidence of extra-medullary disease. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
   2. Patients with myelodysplastic syndrome (MDS) with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS). Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.

7. Cardiac function: Left ventricular ejection fraction > 45% based on most recent echocardiogram or multigated acquisition scan (MUGA) results

8. Estimated creatinine clearance > 60 mL/min calculated by equation

9. Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin > 50% and forced expiratory volume in first second (FEV1) predicted > 50% based on most recent pulmonary function test results

10. Liver function acceptable per local institutional guidelines

11. Karnofsky performance status (KPS) of > 70%

12. Subjects ≥ 18 years of age or legally authorized representative must have the ability to give informed consent according to applicable regulatory and local institutional requirements.

Stratum 2 Recipient Inclusion Criteria

1. Age > 18 years at the time of signing informed consent

2. Planned NMA/RIC regimen as defined per protocol

3. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age < 35 years

4. Product planned for infusion is PBSC

5. One of the following diagnoses:

   1. Patients with acute leukemia or chronic myeloid leukemia (CML) with no circulating blasts, no evidence of extramedullary disease, and with < 5% blasts in the bone marrow. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
   2. Patients with MDS with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS.) Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
   3. Patients with chronic lymphocytic leukemia (CLL) or other leukemias (including prolymphocytic leukemia) with chemosensitive disease at time of transplantation
   4. Patients with lymphoma with chemosensitive disease at the time of transplantation

6. Cardiac function: Left ventricular ejection fraction > 45% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure

7. Estimated creatinine clearance > 60 mL/min calculated by equation

8. Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted > 50% based on most recent pulmonary function test results

9. Liver function acceptable per local institutional guidelines

10. KPS of > 60%

11. Subjects ≥ 18 years of age or legally authorized representative must have the ability to give informed consent according to applicable regulatory and local institutional requirements.

Stratum 3 Recipient Inclusion Criteria

1. Age > 1 years and < 21 years at the time of signing informed consent

2. Partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age < 35 years

3. Product planned for infusion is BM

4. Planned MAC regimen as defined per protocol

5. One of the following diagnosis:

   1. AML in 1st remission or beyond with ≤ 5% marrow blasts, no circulating blasts or evidence of extra-medullary disease. Pre-transplant MRD testing will be performed as per standard of practice at the treating institution. Patients with any MRD status are eligible and should be enrolled at the discretion of provider. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
   2. Patients MDS with no circulating blasts and less than 10% blasts in the bone marrow. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
   3. ALL in 1st remission or beyond with ≤ 5% marrow blasts, no circulating blasts, or evidence of extra-medullary disease. Pre-transplant MRD testing will be performed as standard practice at the treating institution with the goal of achieving MRD of <0.01%. Patients with any MRD status are eligible and should be enrolled at the discretion of provider. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
   4. Other leukemia (mixed-phenotype acute leukemia [MPAL], CML, or other leukemia) in morphologic remission with ≤ 5% marrow blasts and no circulating blasts or evidence of extramedullary disease. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning.
   5. Chemotherapy sensitive lymphoma in at least partial remission (PR)

6. KPS or Lansky performance score ≥ 70%

7. Cardiac function: Left ventricular ejection fraction of ≥ 50% and shortening fraction of ≥ 27% based on most recent echocardiogram

8. Glomerular Filtration Rate (GFR) of ≥ 60ml/min/1.73m2 measured by nuclear medicine scan or calculated from a 24 hour urine collection

9. Pulmonary function: DLCO corrected for hemoglobin, FEV1, and Forced Vital Capacity (FVC) of ≥50% if able to perform pulmonary function tests. If unable to perform pulmonary function tests, must have a resting pulse oximetry of >92% without supplemental oxygen.

10. Hepatic: Total bilirubin ≤ 2.5 mg/dL and alanine aminotransferase (ALT), aspartate aminotransferase (AST) < 3x the upper limit of normal

11. Legal guardian permission must be obtained for subjects < 18 years of age. Pediatric subjects will be included in age appropriate discussion in order to obtain assent.

12. Subjects ≥ 18 years of age or legally authorized representative must have the ability to give informed consent according to applicable regulatory and local institutional requirements.

Donor Inclusion Criteria:

1. Must be unrelated to the subject and high-resolution HLA-matched at 4/8, 5/8, 6/8, or 7/8 (HLA-A, -B, -C, and -DRB1)
2. Donor must be typed at high-resolution for a minimum of HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1
3. Age > 18 years and < 35 years at the time of signing informed consent
4. Meet the donor registries' medical suitability requirements for PBSC or BM donation
5. Must undergo eligibility screening according to current Food and Drug Administration (FDA) requirements. Donors who do not meet one or more of the donor screening requirements may donate under urgent medical need.
6. Must agree to donate PBSC (or BM for stratum 3)
7. Must have the ability to give standard (non-study) informed consent according to applicable donor regulatory requirements

Recipient Exclusion Criteria (Strata 1, 2 and 3):

1. Suitable HLA-matched related or 8/8 high-resolution matched unrelated donor available
2. Subject unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing
3. Primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia, polycythemia vera, or MDS with grade 4 marrow fibrosis
4. Subjects with a prior allogeneic HSC transplant
5. Subjects with an autologous HSC transplant within the past 3 months
6. Females who are breast-feeding or pregnant
7. Uncontrolled bacterial, viral or fungal infection at the time of the transplant preparative regimen
8. Concurrent enrollment on other interventional GVHD clinical trial (enrollment on supportive care trials may be allowed after discussion with Principal Investigators)
9. Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant.
10. Patients who are HIV+ with persistently positive viral load. HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

Donor

Exclusion Criteria

1. Donor unwilling or unable to donate
2. Recipient positive anti-donor HLA antibodies against a mismatched HLA in the selected donor determined by the presence of donor specific HLA antibodies (DSA) to any mismatched HLA allele/antigen at any of the following loci (HLA-A, -B, -C, -DRB1, DRB3, DRB4, DRB5, -DQA1, -DQB1, -DPA1, -DPB1) with median fluorescence intensity (MFI) >3000 by microarray-based single antigen bead testing. In patients receiving red blood cell or platelet transfusions, DSA evaluation must be performed or repeated post-transfusion and prior to donor mobilization and initiation of recipient preparative regimen.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	Patient-Reported Outcomes	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	Post-transplant Cyclophosphamide	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	Total-body irradiation	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Total-body irradiation	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	Tacrolimus	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	Patient-Reported Outcomes	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	Patient-Reported Outcomes	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Post-transplant Cyclophosphamide	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	Post-transplant Cyclophosphamide	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	Post-transplant Cyclophosphamide	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	Post-transplant Cyclophosphamide	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	Melphalan	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	Patient-Reported Outcomes	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	Mycophenolate Mofetil	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Bone Marrow Hematopoietic Stem Cell Transplantation	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Patient-Reported Outcomes	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Post-transplant Cyclophosphamide	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Patient-Reported Outcomes	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Post-transplant Cyclophosphamide	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Patient-Reported Outcomes	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Bone Marrow Hematopoietic Stem Cell Transplantation	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Total-body irradiation	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Cyclophosphamide	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Mesna	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	Busulfan	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	Fludarabine	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	Mesna	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	Tacrolimus	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	Tacrolimus	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	Fludarabine	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen A (MAC: busulfan and fludarabine, PBSC HCT)	Mycophenolate Mofetil	Patients receive: * Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	Fludarabine	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	Mycophenolate Mofetil	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen B (MAC: Fludarabine and TBI; PBSC HCT)	Mesna	Patients receive: * Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 * Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	Busulfan	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	Mesna	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen C (RIC: Fludarabine and Busulfan; PBSC HCT)	Mycophenolate Mofetil	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -6 to -2 * Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Fludarabine	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	Fludarabine	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	Mesna	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen D (RIC: Fludarabine and Melphalan; PBSC HCT)	Tacrolimus	Patients receive: * Fludarabine (120-180 mg/m2 total dose) IV on days -7 to -3 * Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Cyclophosphamide	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Mesna	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Busulfan	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Tacrolimus	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen E (NMA: Fludarabine, Cyclophosphamide, TBI; PBSC HCT)	Mycophenolate Mofetil	Patients receive: * Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 * Cyclophosphamide (29-50 mg/kg) IV on days -6 and -5 * TBI (200 cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Tacrolimus	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Mesna	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Cyclophosphamide	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen F (MAC: Busulfan and Cyclophosphamide; BM HCT)	Mycophenolate Mofetil	Patients receive: * Busulfan (dosed by age and weight per institutional standards to target goal pharmacokinetic (PK) in range noted in protocol.) on days -6 to -3 * Cyclophosphamide (100 mg/kg total dose) IV on days -2 and -1 Patients receive a bone marrow (BM) graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Tacrolimus	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.
Regimen G (MAC: Cyclophosphamide and TBI; BM HCT)	Mycophenolate Mofetil	Patients receive: * Cyclophosphamide (100 mg/kg total dose) IV on days -5 and -4 * TBI (1200 cGy total dose) on days -3, -2 and -1 Patients receive a BM graft infusion from a mismatched unrelated donor on Day 0.

Primary Outcome Measures

Name	Time	Method
Overall Survival	1 year post HCT

Secondary Outcome Measures

Name	Time	Method
Cumulative incidence of relapse/progression	1 year post-HCT
GVHD, relapse free survival	1 year post-HCT	Defined as relapse or progression of underling disease, graft failure, grade III-IV acute GVHD, chronic GVHD requiring systemic immune suppression, or death by any cause.
Modified GVHD, relapse free survival	1 year post-HCT	Defined as relapse or progression of underling disease, graft failure, grade III-IV acute GVHD, NIH moderate or severe chronic GVHD, or death by any cause.
Event-Free Survival based on donor HLA match grade and donor age (7/8 versus <7/8)	1 year post-HCT
Kinetics of platelet recovery	Day +100 post-HCT	Defined as the evaluation of the time it takes for platelet count recovery to occur in the study subjects.
Overall Toxicity	1 year post-HCT	To tabulate adverse events (AEs) experienced by recipients, defined as grade 3-5 unexpected and Grade 5 expected AEs, according to CTCAE version 5.0.
Event-free survival	1 year post-HCT	Defined as graft failure, relapse or progression of underlying disease, death, grade 3-4 acute GVHD, or NIH-severe chronic GVHD.
Overall Survival based on donor HLA match grade and donor age (7/8 versus <7/8)	1 year post-HCT
Cumulative incidence of neutrophil recovery	Day +100 post-HCT	Defined as neutrophil count ≥500/mm\^3 for 3 consecutive days post-HCT.
Kinetics of neutrophil recovery	Day +100 post-HCT	Defined as the evaluation of the time it takes for neutrophil count recovery to occur in the study subjects.
Cumulative incidence of platelet recovery	Day +100 post-HCT	Defined as platelet count ≥20,000/mm\^3 or ≥50,000/mm\^3 with no platelet transfusions within seven days.
Cumulative incidence of primary graft failure	Day +28 post-HCT
Donor chimerism	Day +100 post-HCT	Strata 2 and 3 only. Percent of donor chimerism via peripheral blood
Cumulative incidence of nonrelapse mortality	Day +100 and 1 year post-HCT
Cumulative incidence of acute GVHD	Day +100 post-HCT
Cumulative incidence of chronic GVHD	1 year post-HCT
Incidence of cytokine release syndrome (CRS)	Day +14 post-HCT	Overall incidence of CRS of any grade and grade 3 or 4 CRS post-transplant
Progression-free survival	1 year post-HCT
Cumulative incidence of BK and cytomegalovirus (CMV) viral infections	Days +100 and +180 post-HCT
Cumulative incidence of secondary graft failure	1 year post-HCT

Trial Locations

Locations (40)

Levine Cancer Institute; 🇺🇸 Charlotte, North Carolina, United States

Ohio State Medical Center, James Cancer Center; 🇺🇸 Columbus, Ohio, United States

City of Hope National Medical Center; 🇺🇸 Duarte, California, United States

Children's Healthcare of Atlanta; 🇺🇸 Atlanta, Georgia, United States

The University of Chicago; 🇺🇸 Chicago, Illinois, United States

Cincinnati Children's Hospital; 🇺🇸 Cincinnati, Ohio, United States

University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States

Thomas Jefferson University Sidney Kimmel Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

-Baylor College of Medicine - Texas Children's Hospital and Houston Methodist; 🇺🇸 Houston, Texas, United States

University of Virginia; 🇺🇸 Charlottesville, Virginia, United States

University of Wisconsin Hospital and Clinic; 🇺🇸 Madison, Wisconsin, United States

University of Maryland Medical Center; 🇺🇸 Baltimore, Maryland, United States

Colorado Blood Cancer Institute; 🇺🇸 Denver, Colorado, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

TriStar BMT; 🇺🇸 Nashville, Tennessee, United States

TriStar Medical Group Children's Specialists; 🇺🇸 Nashville, Tennessee, United States

Vanderbilt University Medical Center; 🇺🇸 Nashville, Tennessee, United States

Texas Transplant Institute; 🇺🇸 San Antonio, Texas, United States

Froedtert & the Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

Mayo Clinic Rochester; 🇺🇸 Rochester, Minnesota, United States

H. Lee Moffitt Cancer Center and Research Institute; 🇺🇸 Tampa, Florida, United States

University of California San Francisco; 🇺🇸 San Francisco, California, United States

Stanford University; 🇺🇸 Stanford, California, United States

Emory University Medical Center; 🇺🇸 Atlanta, Georgia, United States

University of Miami Sylvester Cancer Center; 🇺🇸 Miami, Florida, United States

Northwestern University; 🇺🇸 Chicago, Illinois, United States

Tufts Medical Center; 🇺🇸 Boston, Massachusetts, United States

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; 🇺🇸 Baltimore, Maryland, United States

University of Michigan Medical Center - Mott Children's Hospita; 🇺🇸 Ann Arbor, Michigan, United States

Dana Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Washington University/Barnes Jewish Hospital; 🇺🇸 Saint Louis, Missouri, United States

Karmanos Cancer Institute; 🇺🇸 Detroit, Michigan, United States

Roswell Park Comprehensive Cancer Center; 🇺🇸 Buffalo, New York, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Columbia University Medical Center; 🇺🇸 New York, New York, United States

University of North Carolina Chapel Hill; 🇺🇸 Chapel Hill, North Carolina, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Virginia Commonwealth University; 🇺🇸 Richmond, Virginia, United States

St. David's South Austin Medical Center; 🇺🇸 Austin, Texas, United States

University of Florida Health Shands Hospital; 🇺🇸 Gainesville, Florida, United States