Precision-T: A Randomized Study of Orca-T in Recipients Undergoing Allogeneic Transplantation for Hematologic Malignancies

Key Inclusion Criteria: * Matched to a related or unrelated donor who is an 8/8 match for HLA-A, -B, -C, and DRB1 * Diagnosed with one of the following diseases: * Acute myeloid, lymphoid 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 * Myelodysplastic syndromes (MDS) that are indicated for alloHSCT per 2017 International Expert Panel recommendations and/or have therapy-related/secondary MDS, with ≤ 10% blast burden in the bone marrow * Planned to undergo MA-alloHCT including one of the following myeloablative conditioning regimens: * TBI/Cy * TBI/Etoposide * BFT * Cardiac ejection fraction at rest ≥ 45% or shortening fraction of ≥ 27% by echocardiogram or radionuclide scan (MUGA) * Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥ 50% * Negative serum or urine beta-HCG test in females of childbearing potential * ALT/AST \< 3 times ULN * Recipients in screening must screen negative for SARS-CoV-2 RNA using a PCR-based test * Disease Risk Index (DRI) overall risk categorization of intermediate or high * Total bilirubin ≤ upper limit of normal (ULN) * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/minute Key Exclusion Criteria: * Prior allogeneic HCT * Currently receiving corticosteroids or other immunosuppressive therapy. Topical corticosteroids or oral systemic corticosteroid doses less than or equal to 10 mg/day are allowed. * Planned donor lymphocyte infusion (DLI) * Planned pharmaceutical in vivo or ex vivo T cell depletion * Recipient positive anti-donor HLA antibodies against a mismatched allele in the selected donor * Karnofsky performance score \< 70% * Hematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) \> 4 * Uncontrolled bacterial, viral or fungal infections at time of enrollment * Seropositive for HIV-1 or -2, HTLV-1 or -2, Hepatitis B sAg, Hepatitis C antibody * Known allergy or hypersensitivity to, or intolerance of, tacrolimus * Documented allergy or hypersensitivity to iron dextran or bovine, murine, algal or Streptomyces avidinii proteins * Any uncontrolled autoimmune disease requiring active immunosuppressive treatment * Concurrent malignancies or active disease within 1 year, except non-melanoma skin cancers that have been curatively resected * Psychosocial circumstances that preclude the patient being able to go through transplant or participate responsibly in follow up care * Women who are pregnant or breastfeeding * Women of childbearing potential (WOCBP) or men who have sexual contact with WOCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation