Overview

Pre-transplant conditioning will include targeted total marrow irradiation (TMI) at a dose of 6Gy. Graft-versus-host disease prophylaxis will include cyclophosphamide 50 mg/kg on Day +3 and 4 along with tacrolimus and mycophenolate mofetil

Eligibility

Inclusion Criteria:

1. Patient age 18-75 years
2. Related donor who is, at minimum, Human Leukocyte Antigen (HLA) haploidentical. The donor and recipient must be identical 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 5/10 is therefore required, and will be considered sufficient evidence that the donor and recipient share one HLA haplotype. In addition, unrelated donors who are mismatched at least one of the following loci: HLA-A, HLA-B, HLA-Cw, HLA-or DRB1.
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 e. Mixed lineage and biphenotypic leukemia

4. Adequate end-organ function as measured by:
   1. Left ventricular ejection fraction ≥ 40%
   2. Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST < 5 x ULN
   3. FEV1 and FVC > 50% of predicted

Exclusion Criteria:

1. Presence of significant co morbidity as shown by:
   1. Left ventricular ejection fraction < 40%
   2. Bilirubin > 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST > 5 x ULN
   3. FEV1 and FVC < 50% of predicted or DLCO <50% of predicted once corrected for anemia
   4. Karnofsky score <70
   5. 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)