Intensity Modulated Total Marrow Irradiation in Fully Human Leukocyte Antigen (HLA)-Matched and Partially-HLA Mismatched Allogeneic Transplantation Patients with High-Risk Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), and Myelodysplastic Syndrome (MDS)

The study is a Phase II clinical trial. Patients will receive intensity-modulated total marrow irradiation (TMI) at a dose of 9 Gray (Gy) with standard myeloablative fludarabine intravenous (IV) and targeted busulfan (FluBu4) conditioning prior to allogeneic hematopoietic stem cell transplant (HSCT). Graft-versus-host disease (GVHD) prophylaxis will include Cyclophosphamide on Day +3 and +4, tacrolimus, and mycophenolate mofetil.

Patients will receive the following conditioning regimen: fludarabine 40 mg/m2 IV piggyback daily, from day -5 (5 days before stem cell infusion) through Day -2, IV busulfan targeting a 4800 μM/min/ day, from day -5 through day -2. In addition to the above chemotherapy, all patients will receive TMI at a dose of 3Gy on days -3, -2, and -1. On day 0, the stem cell product will be infused according to BMT (Bone Marrow Transplant) unit policy. Graft versus host disease (GVHD) prophylaxis will consist of the administration of Cyclophosphamide 50 mg/Kg on days 3 and 4 and mycophenolate mofetil combined with tacrolimus. Post-transplant evaluation will be done per standard care with study data collected at days 30, 60, 90, 180, 365, and 2 years.

Eligibility Criteria:
Inclusion Criteria:

* 1. Age 18-65 years.
* 2. Patients with CML, AML, or MDS who meet one of the following criteria: 2a. Relapsed or refractory AML (including AML in CR2) 2b. Poor-risk AML in first remission, with remission defined as \<5% bone marrow blasts morphologically:
* AML arising from MDS, a myeloproliferative disorder, or secondary AML
* Poor risk molecular features according to Leukemia Net including ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2
* Poor-risk cytogenetics: Monosomal karyotype, complex karyotype (\> 3 abnormalities), inv (3), t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or abnormalities of chromosome 5 or 7. 2c. Primary refractory disease 2d. MDS with at least one of the following poor-risk features:
* Poor-risk cytogenetics including 3q abnormalities, 7/7q minus or complex cytogenetics (\>3 abnormalities).
* Current or previous INT-2 or high IPSS score.
* Treatment-related MDS.
* MDS diagnosed before the age of 21 years.
* Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy.
* Life-threatening cytopenias, including those requiring regular PRBC or platelet transfusions. 2e. CML with a history of accelerated or blast phase.

Exclusion Criteria:

* 1. Presence of significant co-morbidity as shown by:
* 1a. Left ventricular ejection fraction \< 50%
* 2b. Creatinine clearance \<30ml/min.
* 3c. Bilirubin \> 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \> 5 x ULN.
* 4d. FEV1 and FVC \< 50% of predicted or DLCO \<50% of predicted once corrected for anemia.
* 5e. Karnofsky score \<70
* 6f. Active viral hepatitis or HIV infection.
* 7g. Cirrhosis.
* 2. Pregnancy or breast feeding
* 3. Patients unable to sign informed consent.
* 4. Patients previously received radiation to \>20% of bone marrow-containing areas.