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

Stratum 1 Recipient Inclusion Criteria:

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

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

3. Stated willingness to comply with all study procedures and availability for theduration 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) withage ≥ 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-CIfor this trial to allow for the inclusion of patients with secondary ortherapy-related AML or MDS.

8. One of the following diagnoses:

9. Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or otheracute leukemia in 1st remission or beyond with ≤ 5% marrow blasts and nocirculating blasts or evidence of extra-medullary disease. Documentation ofbone marrow assessment will be accepted within 45 days prior to the anticipatedstart of conditioning.

10. Patients with MDS with no circulating blasts and with < 10% blasts in the bonemarrow (higher blast percentage allowed in MDS due to lack of differences inoutcomes with < 5% or 5-10% blasts in MDS). Documentation of bone marrowassessment will be accepted within 45 days prior to the anticipated start ofconditioning.

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

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

13. 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

14. Liver function acceptable per local institutional guidelines

15. 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 informedconsent according to the applicable regulatory and local institutional requirements.

3. Stated willingness to comply with all study procedures and availability for theduration 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) withage ≥ 18 and ≤ 40 years (≤ 35 preferred).

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

7. One of the following diagnoses:

8. Patients with acute leukemia or chronic myeloid leukemia (CML) with nocirculating blasts, no evidence of extramedullary disease, and with < 5% blastsin the bone marrow.Documentation of bone marrow assessment will be accepted within 45 days priorto the anticipated start of conditioning.

9. Patients with MDS with no circulating blasts and with < 10% blasts in the bonemarrow (higher blast percentage allowed in MDS due to lack of differences inoutcomes with < 5% or 5-10% blasts in MDS.) Documentation of bone marrowassessment will be accepted within 45 days prior to the anticipated start ofconditioning.

10. Patients with chronic lymphocytic leukemia (CLL) or other leukemias (includingprolymphocytic leukemia) with chemosensitive disease at time of transplantation

11. Higher risk CMML according to CMML-specific prognostic scoring system or highrisk MDS/MPN not otherwise specified are eligible, provided there is noevidence of high-grade bone marrow fibrosis or massive splenomegaly at the timeof enrollment.

12. Patients with lymphoma with chemosensitive disease at the time oftransplantation

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

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

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

16. Liver function acceptable per local institutional guidelines

17. 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 informedconsent according to the applicable regulatory and local institutional requirements.

3. Stated willingness to comply with all study procedures and availability for theduration 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) withage ≥ 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 withgrade 4 fibrosis are also eligible. Patients with a myelofibrosis diagnosis requiresponsor approval before enrolling.

8. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recentechocardiogram 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 PBSCdonation. 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 screeningrequirements 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 donoravailable

2. Subject unwilling or unable to give informed consent, or unable to comply with theprotocol 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 transplantpreparative regimen

7. Concurrent enrollment on a preventative GvHD and/or infectious disease preventionclinical trial.

8. Subjects who undergo desensitization to reduce anti-donor HLA antibody levels priorto transplant.

9. Patients who are HIV+ with persistently positive viral load. HIV-infected patientson effective anti-retroviral therapy (ART) with undetectable viral load within 6months are eligible for this trial. Patients with well controlled HIV are eligibleprovided resistance panels are negative, the patient is compliant with ART, andtheir disease remains well controlled.

Donor Exclusion Criteria:

1. Donor unwilling or unable to donate.

2. Recipient positive for HLA antibodies against a mismatched HLA in the selected donordetermined by the presence of donor specific HLA antibodies (DSA) to any mismatchedHLA 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 bymicroarray-based single antigen bead testing. In patients receiving red blood cellor platelet transfusions, DSA evaluation must be performed or repeatedpost-transfusion and prior to donor mobilization and initiation of recipientpreparative regimen.