This is a single arm phase II clinical trial. 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). In addition the 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.
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)
