This study will evaluate the safety, tolerability, and efficacy of Orca-T, an allogeneic stem cell and T-cell immunotherapy biologic manufactured for each patient (transplant recipient) from the mobilized peripheral blood of a specific, unique donor. It is composed of purified hematopoietic stem and progenitor cells (HSPCs), purified regulatory T cells (Tregs), and conventional T cells (Tcons) in participants undergoing myeloablative allogeneic hematopoietic cell transplant transplantation for hematologic malignancies.

Key Inclusion Criteria:

Recipients must meet all of the following criteria:

1. Patients must be diagnosed with 1 of the following histopathologically confirmed diseases, for which a myeloablative hematopoietic stem cell transplant (HCT) is planned:

   A) Acute myeloid, lymphoid, or mixed phenotype/undifferentiated leukemia who are not in CR or CRi (active disease) and/or MDS with >10% to <20% bone marrow blast burden (ages 18 to 75 years)

   B) Acute leukemia in CR/CRi or MDS that is DRI intermediate to high risk (ages 66 to 75 years)

   C) BPDCN (ages 18 to 65 years)

   D) Participants aged 18 to 65 who would be eligible for the Phase 3 component of Precision-T except for mild impairments of renal and/or hepatic function as defined by an eGFR of 50 to <60 mL/min and/or a total bilirubin of >ULN to ≤2 x ULN and diagnosed with either of the following:

   i. Acute myeloid, lymphoid, or mixed phenotype/undifferentiated leukemia that is in CR/CRi and DRI intermediate to high risk

   a) MDS that is DRI intermediate to high risk

   E) Acute or chronic leukemia in remission that is DRI low risk (ages 18 to 65 years), including the following:

   i. CML in chronic phase but with a history of accelerated phase or blast crisis or who are resistant to or intolerant of more than 1 first- and second-generation tyrosine kinase inhibitors

   ii. Acute myeloid leukemia (AML) with inv(16) without accompanying complex cytogenetics

2. Patients must be matched to a 8/8 HLA-matched related or unrelated donor

3. Estimated glomerular filtration rate (eGFR) >50 mL/minute

4. Cardiac ejection fraction at rest ≥45% or shortening fraction of ≥27% by echocardiogram or radionuclide scan (MUGA)

5. Diffusing capacity of the lung for carbon monoxide (DLCO) (adjusted for hemoglobin) ≥50%

6. Total bilirubin <2 times upper limit of normal (ULN) (patients with Gilbert's syndrome may be included where hemolysis has been excluded) and ALT/AST <3 times ULN

Key Exclusion Criteria:

Recipients meeting any of the following exclusion criteria will not be eligible:

1. History of prior allogeneic HCT
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. Pre-planned donor lymphocyte infusion (DLI)
4. Planned pharmaceutical in vivo or ex vivo T cell depletion
5. Positive for anti-donor HLA antibodies against an allele in the selected donor
6. Karnofsky performance score <70%
7. Hematopoietic cell transplantation-specific Comorbidity Index (HCT-CI) >4
8. Uncontrolled bacterial, viral or fungal infections (currently taking antimicrobial therapy and with progression or no clinical improvement) at time of enrollment
9. Seropositive for HIV-1 or -2 antibody, HTLV-1 or -2 antibody, Hepatitis B sAg, or Hepatitis C antibody
10. Any uncontrolled autoimmune disease requiring active immunosuppressive treatment
11. Concurrent malignancies or active disease within 1 year, except non-melanoma skin cancers that have been curatively resected
12. Women who are pregnant or breastfeeding