Intensive conditioning regimens used in allogeneic hematopoietic cell transplant (HCT) help to eliminate hematologic tumors and reduce the risk of relapse, but are also characterized by high toxicity. Total marrow and lymphoid irradiation (TMLI) is a specialized radiation technique that specifically targets marrow and lymphoid tissue to maximize antitumor efficacy while reducing off target toxicity. Despite these benefits, TMLI is technically challenging and time consuming. The radiation oncology team at Stanford has developed an automated TMLI platform to overcome these challenges. In this phase II trial, automation will be incorporated into a previously validated conditioning regimen of fludarabine/cyclophosphamide/TMLI HCT with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis to confirm the feasibility and safety of automation in patients receiving allogeneic HCT for high-risk myeloid malignancies.

Inclusion Criteria for 20 Gy Arm (Cohort A)

1. Age, Performance Status, and Graft Criteria require all of the following bullet points:

   • Age 18 to 60 years (inclusive)
   • HCT Co-Morbidity score (HCT-CI) < 5 (http://www.qxmd.com/calculate-online/hematology/hct-ci)(31)
   • Adequate performance status is defined as Karnofsky score ≥ 70%
   • Patients must be receiving an allogeneic peripheral blood stem cell graft
   • Patients and selected donor must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors may be an 8/8 matched sibling donor, 8/8 matched unrelated donor, haploidentical related donor, or 7/8 mismatched unrelated donor.

2. Eligible Diseases (Any one of the following)

   Acute Myeloid Leukemia (AML) Must have at least one of the following characteristics:

   • Blasts >5% in the peripheral blood and/or bone marrow after >2 prior lines of AML directed therapy, present during the trial screening window
   • Adverse plus risk by AlloHCT Refined ELN Criteria: defined as having complex cytogenetics, TP53 mutation, or MECOM rearrangement confirmed at any time point.(32)

   Myelodysplastic syndrome Must have at least one of the following characteristics at the time of conditioning:

   • Blasts >10% in the peripheral blood and/or bone marrow after >1 prior line of therapy.
   • TP53 mutation confirmed at any time point

   Myeloproliferative neoplasms (MPN) or MDS/MPN overlap. Must have at least one of the following characteristics:

   • Blasts >10% in the peripheral blood and/or bone marrow during the trial screening window
   • TP53 mutation confirmed at any time point

3. Adequate organ function is defined as all of the following:

   Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 45% confirmed by MUGA or echocardiography Pulmonary: DLCO, FEV1, FVC > 50% predicted, and absence of O2 requirements. Liver: Transaminases < 3 x upper limit of normal (ULN) and total bilirubin ≤ 2 mg/dL except for patients with Gilbert's syndrome or hemolysis (as indicated by provider documentation).

   Renal: Creatinine < 2.0 mg/dL (adults) and creatinine clearance > 40 mL/min.

4. Must be FIRST allogeneic HCT

5. Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment.

6. Voluntary written consent

Inclusion Criteria for 12 Gy Arm (Cohort B)

1. Age, Performance Status, and Graft Criteria require all of the following bullet points:

   Age 18 to 70 years (inclusive) Adequate performance status is defined as Karnofsky score ≥ 70% Patients must be receiving an allogeneic peripheral blood stem cell graft Patients and selected donor must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1. Donors may be an 8/8 matched sibling donor, 8/8 matched unrelated donor, haploidentical related donor, or 7/8 mismatched unrelated donor.

2. Eligible Diseases (Any of the following) Acute Myeloid Leukemia (AML) Myelodysplastic syndrome Myeloproliferative neoplasm MDS/MPN overlap

3. Must have relapse after prior allo HCT

4. Adequate organ function is defined as all of the following:

   Cardiac: Absence of decompensated congestive heart failure, or uncontrolled arrhythmia and left ventricular ejection fraction > 40% confirmed by MUGA or echocardiography Pulmonary: DLCO, FEV1, FVC > 40% predicted, and absence of O2 requirements. Liver: Transaminases < 3 x upper limit of normal (ULN) and total bilirubin ≤ 2 mg/dL except for patients with Gilbert's syndrome or hemolysis (as indicated by provider documentation).

   Renal: Creatinine < 2.0 mg/dL (adults) and creatinine clearance > 40 mL/min. Sexually active females of childbearing potential and males with partners of child-bearing potential must agree to use adequate birth control during study treatment.

5. Voluntary written consent

Exclusion Criteria:

1. Pregnant or breast feeding. The agents used in this study include Pregnancy Category D: known to cause harm to a fetus. Females of childbearing potential must have a negative pregnancy test prior to starting therapy.
2. Untreated active infection. Controlled or asymptomatic infections requiring continued antimicrobial therapy are permissible.
3. Active HIV infection, defined as HIV infection with detectable viral load
4. Active central nervous system malignancy
5. GVHD requiring systemic therapy including > 0.25 mg/kg prednisone (or equivalent) or other systemic therapy for GVHD (e.g., tacrolimus, sirolimus, ruxolitinib, belumosodil, ibrutinib, axatilimab).
6. Any other medical or psychological condition that is deemed serious and unsafe for clinical trial participation.
7. Exposure to prior radiation that is deemed unsafe for clinical trial participation.