TACrolimus Targeted Immunosuppression Cessation in ALlogeneic HCT

Inclusion Criteria:

* Eligible diseases:

  * Acute myeloid leukemia (AML) in complete remission (CR), CR with incomplete hematologic recovery (CRi), or MLFS.
  * Myelodysplasic syndrome (MDS) myelodysplastic syndromes eligible for alloHSCT based on IPSS-M of intermediate or higher, or IPSS-R of intermediate or higher, or refractory disease to standard growth factor or hypomethylating agent-based therapy
  * Myelofibrosis (MF)
  * Chronic myeloid leukemia (CML) in chronic phase with a prior history of accelerated phase or blast crisis or CML in chronic phase refractory to standard TKI therapy
  * Chronic myelomonocytic leukemia (CMML)
* Age ≥ 18 and ≤ 80 years at the time of enrollment.
* Planned for first myeloablative or reduced intensity allogenic transplant using a conditioning regimen listed in Appendix B.
* Has a related or unrelated donor available who is 8/8 HLA match at HLA-A, -B, -C, and -DRB1, all typed using DNA-based high-resolution methods.
* Estimated glomerular filtration rate (eGFR) ≥ 50 mL/minute or creatinine \< 2 mg/dL.

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%.
* Total bilirubin \< 2 times upper limit of normal (ULN) (patients with Gilbert's syndrome may be included once hemolysis has been excluded).
* Karnofsky Performance Score ≥70%
* Negative serum or urine beta-HCG test in females of childbearing potential (FCBP) within 3 weeks of enrollment.

A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

-Ability to understand and the willingness to provide written informed consent.

Exclusion Criteria:

* Prior allogeneic HCT.
* Planned donor lymphocyte infusion (DLI).
* Recipient positive anti-donor HLA antibodies against a mismatched allele in the selected donor determined by either:

  1. Positive crossmatch test of any titer (by complement-dependent cytotoxicity or flow cytometric testing), or
  2. Presence of anti-donor HLA antibody to any of the following HLA loci: HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, or -DPA1, with mean fluorescence intensity (MFI) \>1000 by solid phase immunoassay.
* Uncontrolled bacterial, viral, or fungal infections at time of enrollment including known, active tuberculosis infection.
* Seropositive for HIV-1 or -2, HTLV-1 or -2, Hepatitis B sAg, and/or Hepatitis C antibody.

  \*History of hepatitis B or hepatitis C is permitted if viral load is undetectable per quantitative PCR and/or NAT.

Known allergy or hypersensitivity to planned GVHD prophylactic medications including PTCy, tacrolimus

* Any uncontrolled autoimmune disease requiring active immunosuppressive treatment.
* Concurrent malignancy diagnosed within 12 months of enrollment, except non-melanoma skin cancers or other early-stage solid tumors that have been curatively resected or treated to curative intent. Patients with history of low grade concurrent blood cancers that are controlled will be eligible.
* Females of childbearing potential (FCBP) or men who have sexual contact with FCBP unwilling to use effective forms of birth control or abstinence for one year after transplantation.

(FCBP definition: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months).

-Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the recipient's safe participation in and completion of the study, or which could affect compliance with the protocol or interpretation of results.

\* All subject files must include supporting documentation to confirm subject eligibility.