Trial of Orca-T Following Reduced Intensity or Nonmyeloablative Conditioning in Patients With Acute Myeloid Leukemia or Myelodysplastic Syndrome

Inclusion Criteria: 1. Age ≥18 years at the time of enrollment 2. Diagnosed with 1 of the following diseases: 1. Acute myeloid, or mixed phenotype leukemia in complete remission (CR) or CR with incomplete hematologic recovery (CRi), with or without the presence of known minimal residual disease. 2. Myelodysplastic syndrome that is indicated for alloHCT per the 2017 International Expert Panel recommendations and/or therapy-related/secondary MDS as defined by the World Health Organization (WHO) classification of myeloid malignancies, with ≤10% blast burden in the bone marrow. 3. Planned to undergo 1 of the following preparative regimens as per Investigator discretion: 1. RIC cohort: Planned RIC-alloHCT including RIC regimen with TBI/thiotepa/fludarabine 2. NMA cohort: Planned NMA-alloHCT including NMA regimen with fludarabine/cyclophosphamide/TBI 4. Identified related or unrelated donor who is an 8/8 match for HLA-A, -B, -C, and -DRB1 5. Estimated glomerular filtration rate ≥30 mL/minute 6. Cardiac ejection fraction at rest ≥40% or shortening fraction of ≥22% by echocardiogram or radionuclide scan (MUGA) 7. Diffusing capacity of the lung for carbon monoxide (adjusted for hemoglobin) ≥40% 8. Negative serum or urine β-HCG test in persons of childbearing potential 9. Alanine transaminase (ALT)/aspartate transaminase (AST) \<5 times the upper limit of normal (ULN) 10. Total bilirubin \<3 × ULN 11. Deemed ineligible for a fully myeloablative alloHCT per assessment of the principal investigator Exclusion Criteria: 1. Prior alloHCT 2. Currently receiving corticosteroids or other immunosuppressive therapy. Topical corticosteroids or oral systemic corticosteroid doses less than or equal to 10 mg/day are allowed. 3. Planned donor lymphocyte infusion (DLI) 4. Planned pharmaceutical in vivo or ex vivo T-cell depletion 5. Recipient-positive antidonor HLA antibodies against a mismatched allele in the selected donor 6. Karnofsky performance score \<60% 7. For RIC cohort only: HCT-Specific Comorbidity Index (HCT-CI) ≥6 8. Uncontrolled bacterial, viral, or fungal infection (currently taking antimicrobial therapy and with progression or no clinical improvement) at the time of enrollment 9. Seropositive for HIV-1 or -2, HTLV-1 or -2, hepatitis B surface antigen, or HCV antibody unless previously treated with curative therapy and are HCV NAT negative 10. Known allergy or hypersensitivity to or intolerance of tacrolimus 11. Documented allergy or hypersensitivity to iron dextran or bovine, murine, algal, or Streptomyces avidinii proteins 12. Any uncontrolled autoimmune disease requiring active immunosuppressive treatment 13. Concurrent malignancy within 1 year except nonmelanoma skin cancer that has been curatively resected 14. Psychosocial circumstances that preclude the participant being able to go through transplantation or participate responsibly in follow-up care 15. Persons who are pregnant or breastfeeding 16. Person of childbearing potential (POCBP) or men who have sexual contact with POCBP who are unwilling to use effective forms of birth control or abstinence for 1 year after transplantation. 17. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's or medical monitor's judgment, precludes the recipient's safe participation in and completion of the trial or which could affect compliance with the protocol or interpretation of results