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

• Busulfan (Drug), also known as Busulfex®: Given IV or PO pre-transplant as part of conditioning regimen
• Busulfan (Drug), also known as Busulfex®: Given IV pre-transplant as part of conditioning regimen
• Fludarabine (Drug), also known as Fludara®: Given IV pre-transplant as part of conditioning regimen
• Total-body irradiation (Radiation), also known as TBI: Administered pre-transplant as part of conditioning regimen
• Cyclophosphamide (Drug), also known as Cytoxan®: Given IV pre-transplant as part of conditioning regimen
• Melphalan (Drug): Given IV pre-transplant as part of conditioning regimen
• PBSC Hematopoietic Stem Cell Transplantation (HSCT) (Procedure), also known as PBSC HSCT, PBSC HCT, PBSC Transplantation: Peripheral blood stem cell graft is infused from a mismatched unrelated donor on Day 0.
• Bone Marrow Hematopoietic Stem Cell Transplantation (Procedure), also known as BM HSCT, BM HCT, Bone Marrow Transplantation: Bone marrow graft is infused from a mismatched unrelated donor on Day 0.
• Post-transplant Cyclophosphamide (Drug), also known as Cytoxan®: Cyclophosphamide (50 mg/kg) is administered on Day +3 and on Day +4 post-transplant as an IV infusion over 1-2 hours.
• Mesna (Drug), also known as Mesnex®: Mesna is given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide.
• Tacrolimus (Drug): Tacrolimus is given at a dose of 0.05 mg/kg PO or an IV dose of 0.03 mg/kg of ideal body weight (IBW) starting on Day +5 post-transplant with taper recommended at 90-100 days post HCT.
• Mycophenolate Mofetil (Drug), also known as MMF, Cellcept®: Mycophenolate mofetil (MMF) is given at a dose of 15 mg/kg three times daily IV or PO from Day +5 to Day +35 post-transplant.
• Patient-Reported Outcomes (Other): Survey assessments will be administered to study participants pre- and post-transplant.

Primary outcomes

• Overall Survival [1 year post HCT]

Secondary outcomes

• 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.
• 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.
• Progression-free survival [1 year post-HCT]
• Cumulative incidence of nonrelapse mortality [Day +100 and 1 year post-HCT]
• Event-Free Survival based on donor HLA match grade and donor age (7/8 versus <7/8) [1 year post-HCT]
• 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.
• 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.
• 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 acute GVHD [Day +100 post-HCT]
• Cumulative incidence of chronic GVHD [1 year post-HCT]
• Cumulative incidence of BK and cytomegalovirus (CMV) viral infections [Days +100 and +180 post-HCT]
• Cumulative incidence of relapse/progression [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
• Cumulative incidence of secondary graft failure [1 year post-HCT]
• 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.

Sex: All, ages: 1 Year to any

Stratum 1 Recipient 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.

• Results publication: Jimenez Jimenez AM, Stanek J, Logan BR, Leckrone E, Stefanski HE, Auletta JJ, Spellman SR, Malmberg C, Askar M, Cusatis RN, Shaffer BC, Modi D, Khimani F, Gooptu M, Hamadani M, Maiers M, Bo-Subait S, Bolanos-Meade J, Rao U, Milner J, Abboud R, Jamieson KJ, Carrum G, Dholaria B, Hogan WJ, Reshef R, Kosuri S, Cook RJ, Ballen K, Loren AW, Larkin K, Arai S, Qayed M, Choi SW, Broglie L, Shaw BE, Devine SM, Al Malki MM. Outcomes after 7/8 and <7/8 mismatched unrelated donor PBSC transplantation with PTCy: results from the ACCESS trial. Blood Adv. 2026 Aug 19:bloodadvances.2026021081. doi: 10.1182/bloodadvances.2026021081. Online ahead of print. PMID 42616616
• Results publication: Auletta JJ, Stanek J, Bo-Subait S, Al Malki MM, Cook R, Gooptu M, Shaffer B, Jimenez AJ, Modi D, Hill JA, Huppler AR, Kou J, Cusatis R, Broglie L, Shaw BE, Stefanski H, Spellman SR, Devine SM. Infection burden in mismatched unrelated donor hematopoietic cell transplantation: results from the ACCESS trial. Blood Adv. 2026 Oct 13;10(19):6551-6563. doi: 10.1182/bloodadvances.2026020882. PMID 42448319
• Results publication: Al Malki MM, Bo-Subait S, Logan B, Olson J, Kou J, Smith S, Leckrone E, Wu J, Stefanski HE, Auletta JJ, Spellman SR, Malmberg C, Askar M, Cusatis R, Shaffer BC, Modi D, Khimani F, Gooptu M, Hamadani M, Madbouly A, Maiers M, Fingerson S, Cook R, Ballen K, Loren A, Larkin K, Arai S, Qayed M, Choi SW, Broglie L, Shaw BE, Devine SM, Jimenez Jimenez AM. Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis After Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation. J Clin Oncol. 2025 Sep;43(25):2772-2781. doi: 10.1200/JCO-25-00856. Epub 2025 Jun 16. PMID 40523209

• Steven Devine, MD, Principal investigator, NMDP/Be The Match