Standard-of-Care Reduced-Intensity Conditioning (RIC) With 200 Versus 400 cGy of Total Body Irradiation (TBI) in Patients With Acute Leukemia Undergoing First Allogeneic Blood or Marrow Transplantation (BMT)

Inclusion Criteria:

1. Age ≥ 0 years
2. Patients with a diagnosis of acute myeloid leukemia (AML), acute lymphoblastic leukemia or lymphoma (ALL), or acute leukemia of mixed or ambiguous lineage per the 2022 World Health Organization classifications,75,76 with \< 5% blasts on bone marrow morphologic analysis performed within 30 days of planned conditioning initiation

   1. AML is generally defined as ≥ 20% myeloid blasts identified in the peripheral blood and/or bone marrow. Myeloid sarcoma is also recognized as an AML-defining entity. Situations in which AML can be diagnosed without a specific blast threshold met nor myeloid sarcoma present are when fusions involving RUNX1::RUNX1T1, CBFB::MYH11, DEK:NUP214, or RBM15::MRTFA are present; rearrangements involving KMT2A, MECOM, or NUP98 exist; or there is a mutation in NPM1.
   2. B- or T-ALL is defined as the presence of lymphoid blasts identified in the peripheral blood and/or bone marrow with no specific blast threshold needed (acute lymphoblastic leukemia) or the presence of a lymphatic-based collection of lymphoblasts (acute lymphoblastic lymphoma).
   3. Acute leukemia of mixed or ambiguous lineage is defined as mixed or ambiguous lineage blasts identified in the peripheral blood and/or bone marrow or the presence of a lymphatic-based collection (lymphoma) of mixed or ambiguous lineage blasts. A specific blast threshold does not need to be met.
   4. Patients with a documented diagnosis of myeloproliferative neoplasm (MPN), myelodysplastic syndrome or neoplasm (MDS), and/or MDS/MPN-overlap prior to diagnosis of acute leukemia may be included for randomization in this clinical trial so long as the patient has received at least 4 cycles of DNA methyltransferase inhibitor (e.g., azacitidine, decitabine, decitabine/cedazuradine (Inqovi), and/or any other agent that works via this mechanism) or at least one cycle of induction chemotherapy. A list of antecedent diagnoses per the World Health Organization 2022 classification of hematolymphoid tumors that pertain to this inclusion criterion are listed below 75

      * i. MPN includes myelofibrosis, essential thrombocythemia, polycythemia vera, chronic neutrophilic leukemia, chronic eosinophilic leukemia, juvenile myelomonocytic leukemia, chronic myeloid leukemia (CML), or myeloproliferative neoplasm, not otherwise specified
      * ii. Myelodysplastic syndrome or neoplasm (MDS)
      * iii. MDS/MPN-overlap includes chronic myelomonocytic leukemia (CMML), myelodysplastic/myeloproliferative neoplasm with neutrophilia, myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis, or myelodysplastic/myeloproliferative neoplasm, not otherwise specified
      * iv. Of note, patients without a documented history of one of these conditions prior to diagnosis of acute myeloid leukemia with myelodysplastic features would not be restricted to this specific criterion for study inclusion.
3. No active extramedullary leukemia or known active Central Nervous System (CNS) involvement by malignancy. Such disease treated into remission is permitted.
4. Patients must have a related or unrelated bone marrow or peripheral blood donor

   1. Human leukocyte antigen (HLA)-matched (10/10) sibling donor (MSD)
   2. HLA-matched (10/10) unrelated donor (MUD)
   3. HLA-haploidentical (5/10) related donor (Haplo)
   4. HLA-mismatched (5-9/10) unrelated donor (mMUD)
5. Planned allogeneic BMT using post-transplantation cyclophosphamide (PTCy) as a component of GVHD prophylaxis
6. Adequate end-organ function as measured by:

   1. Left ventricular ejection fraction greater than or equal to 35% or shortening fraction \> 25%
   2. Bilirubin ≤ 3.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 5 x Upper Limit of Normal (ULN)
   3. Forced Expiratory Volume in one second (FEV1) and Forced Vital Capacity (FVC) \> 40% of predicted
7. Patients may enroll in other transplant-related trials (e.g., those testing post-transplant maintenance strategies or peri-transplant strategies for the management of donor specific antibodies) as long as other eligibility criteria are met and the requirements do not conflict with the treatment plan as outlined herein. Patients may also receive standard of care post-transplant maintenance therapies.

Exclusion Criteria:

1\) Acute leukemia with promyelocytic leukemia (PML)/retinoic acid receptor α (RARA) fusion 2)2) Documented, clinical diagnosis of myeloproliferative neoplasm (MPN), myelodysplastic syndrome or neoplasm (MDS), and/or MDS/MPN-overlap based on the World Health Organization 2022 classification prior to diagnosis of acute leukemia.75 Patients with a diagnosis of AML with myelodysplastic features based on cytogenetic or genetic features and without an antecedent clinical history of MPN, MDS, and/or MDS/MPN-overlap are not excluded.

3\) Prior allogeneic BMT 4) Eastern Cooperative Oncology Group (ECOG) Performance Status \> 2 or Karnofsky/Lansky score \< 60 5) Patients with an additional active malignancy with a life expectancy \< 2 years due to that disease 6) Symptomatic coronary artery disease 7) Uncontrolled infection 8) Patients who are pregnant or breastfeeding 9) Body mass index (BMI) \> 45 kg/m2