This study is being done to see if the addition of a targeted form of radiation to standard conditioning regimen will increase the amount of cancer cells that are killed off in the bone marrow and reduce the chances that your disease may return. This description is called Intensity Modulated Total Marrow Irradiation (IM-TMI).

This is a single arm phase II clinical trial. The usual conditioning regimen for haploidentical transplant is the use of chemotherapy (fludarabine/cyclophosphamide) before the transplant and further chemotherapy with cyclophosphamide after the transplant. In addition, a small dose of radiation is also given.

Patients will receive a standard conditioning regimen with fludarabine, cyclophosphamide and total body irradiation (Flu/Cy/TBI) prior to haploidentical hematopoietic stem cell transplant (HSCT). Graft-versus-host disease prophylaxis will include cyclophosphamide 50 mg/kg on Day +3 and 4 along with tacrolimus and mycophenolate mofetil.

Inclusion Criteria:

1. Patient age 18-75 years

2. Related donor who is, at minimum, Human Leukocyte Antigen (HLA) haploidentical or mismatched unrelated donor.

   • Haploidentical: The donor and recipient must be identical in at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. A minimum match of 4/8 if using HLA-A,-B,-DRB1,-Cw, or 5/10 if using HLA-A,-B,-Cw ,-DRB1, and -DQB1, will be considered evidence that the donor and recipient share one HLA haplotype.
   • Unrelated donors: unrelated donors who are mismatched in one or more of the following loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1,HLA-DQB1- can be included with a maximum of 4/8 or 5/10 mismatches.

3. Eligible diagnoses are listed below. Patient must have one of the following:

   1. Relapsed or refractory acute leukemia (including AML or ALL in CR2 and primary refractory leukemia).

   2. Poor-risk AML in first remission:

      • AML arising from MDS or a myeloproliferative disorder, or secondary AML
      • Poor risk molecular features including but not limited to presence of FLT3 internal tandem duplication mutation.
      • 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

   3. Poor risk ALL in first remission:

      • Poor risk cytogenetics: Philadelphia Chromosome, t(4;11), KMT2A translocation, t(8;14), complex karyotype (⩾ 5 chromosomal abnormalities) and low hypodiploidy (30-39 chromosomes)/near triploidy (60-78 chromosomes)
      • Philadelphia-like ALL
      • Presentation WBC >30 × 109 for B-ALL or >100 109 for T-ALL
      • Age>35
      • Poor MRD clearance, defined as levels >1 × 10-3 after induction and levels >5 × 10-4 after early consolidation by flow cytometry

   4. Myelodysplastic syndromes (MDS) with at least one of the following poor-risk features:

      • i. Poor-risk cytogenetics (including but not limited to 7/7q minus or complex cytogenetics)
      • ii. IPSS score of INT-2 or greater
      • iii. Treatment-related or Secondary MDS
      • iv. MDS diagnosed before age 21 years
      • v. Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy
      • vi. Life-threatening cytopenias, including those generally requiring greater than weekly transfusions
      • vii. Poor risk molecular features including but not limited to the presence of BCOR, ASXL1, p53 or RUNX1 mutations

   5. Mixed lineage and biphenotypic leukemia

4. Adequate end-organ function as measured by:

   • a. Left ventricular ejection fraction ≥ 40%
   • b. Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST < 5 x ULN
   • c. FEV1 and FVC > 50% of predicted

Exclusion Criteria:

1. Presence of significant co morbidity as shown by:

   • a. Left ventricular ejection fraction < 40%
   • b. Bilirubin > 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST > 5 x ULN
   • c. FEV1 and FVC < 50% of predicted or DLCO <50% of predicted once corrected for anemia
   • d. Karnofsky score <70
   • e. History of cirrhosis

2. Patients unable to sign informed consent

3. Patient who have previously received radiation to >20% of bone marrow containing areas (assessed by radiation oncology physician)