HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Reduced Dose Post Transplantation Cyclophosphamide GvHD Prophylaxis

Phase 2

Recruiting

• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myeloid Leukemia; Chronic Lymphocytic Leukemia; Chronic Myelomonocytic Leukemia; Acute Leukemia; Pro-Lymphocytic Leukemia; Acute Lymphoblastic Leukemia; Myelofibrosis; Myeloproliferative Neoplasm
• Interventions: Drug: Busulfan; Drug: Fludarabine; Procedure: PBSC Hematopoietic Stem Cell Transplantation (HSCT); Drug: Post-Transplant Cyclophosphamide; Drug: Mesna; Drug: Tacrolimus; Drug: Mycophenolate Mofetil; Other: Patient Reported Outcomes; Radiation: Total-body irradiation; Drug: Melphalan; Drug: Cyclophosphamide

• Registration Number: NCT06001385
• Lead Sponsor: Center for International Blood and Marrow Transplant Research

Brief Summary

The goal of this clinical trial is to determine the effectiveness of Reduced Dose Post-Transplant Cyclophosphamide (PTCy) in patients with hematologic malignancies after receiving an HLA-Mismatched Unrelated Donor (MMUD) . The main question\[s\] it aims to answer are:
...

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2023-08-14
• Study First Submitted QC: 2023-08-14
• Study First Posted: 2023-08-21
• Study Start: 2023-12-08
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-25
• Last Update Posted: 2024-11-27
• Primary Completion: 2026-02-01
• Study Completion: 2026-06-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 190

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. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and institutional requirements.

3. Stated willingness to comply with all study procedures and availability for the duration of the study.

4. Planned MAC regimen as defined per study protocol

5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred).

6. Product planned for infusion is MMUD T-cell replete PBSC allograft

7. HCT-CI < 5. The presence of prior malignancy will not be used to calculate HCT-CI for this trial to allow for the inclusion of patients with secondary or therapy-related AML or MDS.

8. 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 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.

9. Cardiac function: Left ventricular ejection fraction ≥ 45% based on most recent echocardiogram or multi-gated acquisition scan (MUGA) results.

10. Estimated creatinine clearance ≥ 45mL/min calculated by equation.

11. 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 (PFT) results

12. Liver function acceptable per local institutional guidelines

13. KPS of ≥ 70%

Stratum 2 Recipient Inclusion Criteria:

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

2. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements.

3. Stated willingness to comply with all study procedures and availability for the duration of the study.

4. Planned NMA/RIC regimen per study protocol

5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred).

6. Product planned for infusion is MMUD T-cell replete PBSC allograft

7. 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. Higher risk CMML according to CMML-specific prognostic scoring system or high risk MDS/MPN not otherwise specified are eligible, provided there is no evidence of high-grade bone marrow fibrosis or massive splenomegaly at the time of enrollment.

   5. Patients with lymphoma with chemosensitive disease at the time of transplantation

8. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure

9. Estimated creatinine clearance ≥ 45mL/min calculated by equation

10. Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted >50% based on most recent PFT results

11. Liver function acceptable per local institutional guidelines

12. KPS of ≥ 60%

Stratum 3 Recipient Inclusion Criteria:

1. Age ≥18 years at the time of signing informed consent
2. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements.
3. Stated willingness to comply with all study procedures and availability for the duration of the study.
4. Planned NMA/RIC regimen per study protocol
5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred).
6. Product planned for infusion is MMUD T-cell replete PBSC allograft
7. Diagnosis of primary myelofibrosis with risk features making them eligible for HCT. Myelofibrosis secondary to essential thrombocythemia, polycythemia vera, or MDS with grade 4 fibrosis are also eligible. Patients with a myelofibrosis diagnosis require sponsor approval before enrolling.
8. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure
9. Estimated creatinine clearance ≥ 45 mL/min calculated by equation
10. Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted >50% based on most recent PFT results
11. Liver function acceptable per local institutional guidelines
12. KPS of ≥ 60%

Donor Inclusion Criteria (note: donors are not research subjects):

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, -DQB1, and -DPB1.
3. Age ≥ 18 years and ≤ 40 years at the time of signing informed consent for PBSC donation. Note: donors are preferred to be ≤ 35.
4. Meet the donor registries' medical suitability requirements for PBSC 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.
7. Must have the ability to give informed consent according to 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. Subjects with a prior allogeneic transplant
4. Subjects with an autologous transplant within the past 3 months
5. Females who are breast-feeding or pregnant
6. Uncontrolled bacterial, viral, or fungal infection at the time of the transplant preparative regimen
7. Concurrent enrollment on a preventative GvHD and/or infectious disease prevention clinical trial.
8. Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant.
9. Patients who are HIV+ with persistently positive viral load. HIV-infected patients on effective anti-retroviral therapy (ART) with undetectable viral load within 6 months are eligible for this trial. Patients with well controlled HIV are eligible provided resistance panels are negative, the patient is compliant with ART, and their disease remains well controlled.

Donor

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Exclusion Criteria

1. Donor unwilling or unable to donate.
2. Recipient positive for 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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy	Post-Transplant Cyclophosphamide	Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy	Patient Reported Outcomes	Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy	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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy	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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy	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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy	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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy	Busulfan	Patients receive: Fludarabine (150-180 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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: Fludarabine (150-180 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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy	Post-Transplant Cyclophosphamide	Patients receive: Fludarabine (150-180 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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy	Patient Reported Outcomes	Patients receive: Fludarabine (150-180 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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: Fludarabine (125-150 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy	Post-Transplant Cyclophosphamide	Patients receive: Fludarabine (125-150 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy	Patient Reported Outcomes	Patients receive: Fludarabine (125-150 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	PBSC Hematopoietic Stem Cell Transplantation (HSCT)	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Post-Transplant Cyclophosphamide	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Patient Reported Outcomes	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Total-body irradiation	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy	Fludarabine	Patients receive: Fludarabine (150-180 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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy	Busulfan	Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy	Fludarabine	Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy	Tacrolimus	Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy	Mycophenolate Mofetil	Patients Receive: 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy	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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy	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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy	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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy	Tacrolimus	Patients receive: Fludarabine (150-180 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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy	Mycophenolate Mofetil	Patients receive: Fludarabine (150-180 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 peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy	Fludarabine	Patients receive: Fludarabine (125-150 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy	Tacrolimus	Patients receive: Fludarabine (125-150 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy	Mycophenolate Mofetil	Patients receive: Fludarabine (125-150 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy	Melphalan	Patients receive: Fludarabine (125-150 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. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Tacrolimus	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Fludarabine	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Mesna	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Mycophenolate Mofetil	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.
Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy	Cyclophosphamide	Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant.

Primary Outcome Measures

Name	Time	Method
Infection Free Survival	100 days post-HCT	Survival at 100 days without grades 2-3 infections (per BMT CTN grading criteria)

Secondary Outcome Measures

Name	Time	Method
Cumulative incidence of chronic GvHD	1-year post-HCT
Cumulative incidence of grade 2-3 bacterial, fungal, and viral infections	Day 100 and 1-year post-HCT	Defined as grades 2-3 infection as defined by BMT CTN grading criteria.
Cumulative incidence of relapse/progression	1-year post-HCT	Defined as disease relapse or progression from Day 0 to 1-year post-HCT
Incidence and Severity of cytokine release syndrome	within 14 days post-HCT	Defined and graded using the ASTCT grading criteria.
Non-relapse mortality	1-year post-HCT	Defined as death without evidence of disease progression or recurrence
Overall Survival	1-year post-HCT	Defined as time interval between date of transplant and death from any cause
Progression-free survival	1-year post-HCT	Defined as disease relapse or progression, or death by any cause
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 v5
Cumulative incidence of neutrophil recovery	Day 28 post-HCT	Defined as achieving an absolute neutrophil count (ANC) greater than or equal to 500/mm3 for three consecutive measurements on three different days
Cumulative incidence of platelet recovery	Day 28 post-HCT	Defined as platelet count ≥20,000/mm\^3 or ≥50,000/mm\^3 with no platelet transfusions within seven days.
Donor T-Cell Chimerism	Day 28, 100 and 365 post-HCT	Defined as percent of donor chimerism via peripheral blood
Infection-free survival	1-year post-HCT	Defined as death and grades II-III infection (per BMT CTN criteria)
Graft versus host disease relapse free survival	1-year post-HCT	Defined as relapse or progression of underling disease (by 1 year), grade III-IV acute GvHD (by 6 months), chronic GvHD requiring systemic immune suppression (by 1 year), or death by any cause (by 1 year).
Cumulative incidence of primary and secondary graft failure	Day 28 and 1-year post-HCT	Primary graft failure is defined as no neutrophil recovery to ≥ 500 cells/mm3 by Day 28 post HCT.; ...
Cumulative incidence of acute GvHD	Day 100 and Day 180 post-HCT	Defined as cumulative incidence of grades II-IV acute GvHD
Cumulative incidence of grades 2-3 BK virus hemorrhagic cystitis	1-year post-HCT	Defined as incidence of BK virus hemorrhagic cystitis per BMT CTN grading criteria

Trial Locations

Locations (24)

Mayo Clinic Arizona; 🇺🇸 Phoenix, Arizona, United States

Colorado Blood Cancer Institute at Presbyterian St. Luke's; 🇺🇸 Denver, Colorado, United States

City of Hope; 🇺🇸 Duarte, California, United States

Stanford University; 🇺🇸 Stanford, California, United States

Mayo Clinic - Jacksonville; 🇺🇸 Jacksonville, Florida, United States

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

Moffitt Cancer Center; 🇺🇸 Tampa, Florida, United States

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

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

University of Minnesota; 🇺🇸 Minneapolis, Minnesota, United States

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

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

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

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

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

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

Abramson Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

TriStar Centennial; 🇺🇸 Nashville, Tennessee, United States

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

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Methodist Hospital San Antonio; 🇺🇸 San Antonio, Texas, United States

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

Fred Hutchinson Cancer Center; 🇺🇸 Seattle, Washington, United States

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