BMT-06: Study of 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

• Patient age 18-75 years
• 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.
• Eligible diagnoses are listed below. Patient must have one of the following:

• Relapsed or refractory acute leukemia (including AML or ALL in CR2 and primary refractory leukemia).
• 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
• 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
• 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
• Mixed lineage and biphenotypic leukemia
• 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

• 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
• Patients unable to sign informed consent
• Patient who have previously received radiation to >20% of bone marrow containing areas (assessed by radiation oncology physician)