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.

• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Radiation), also known as Total Marrow Irradiation: Experimental: Total marrow irradiation 1.5 Gray (Gy) twice a daily on days -3 and -2
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Drug), also known as Fludarabine: All patients will receive the following standard conditioning regimen: Fludarabine 30 mg/m2 IVPB daily from Day -6 (6 days before stem cell infusion) through Day -2
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Drug), also known as Cyclophosphamide: Cyclophosphamide 14.5 mg/kg intravenously prior to transplant on Days -6 and -5
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Device), also known as Total body irradiation: Total body irradiation 2Gy on Day -1.
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Other), also known as Stem cell transplant: Stem cell infusion on Day 0.
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Drug), also known as Mesna: Mesna 14.5 mg/kg IV starting 30 minutes prior to cyclophosphamide on Days -6 and -5 and continuing for at least 12 hours after end of cyclophosphamide
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Drug), also known as Cyclophosphamide: Cyclophosphamide 50 mg/kg IV on Days 3 and 4 after transplant at a dose of 50mg/kg per day
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Drug), also known as Mesna: Mesna 10 mg/kg IV every 4 hours for 10 doses starting 1 hour prior to cyclophosphamide on Days 3 and 4
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Drug), also known as Tacrolimus: Tacrolimus 0.03 mg/kg IBW Q24H starting on Day 5
• Conditioning regimen with half-matched (haploidentical) stem cell transplant (Drug), also known as Mycophenolate mofetil: Mycophenolate mofetil (MMF) 15 mg/kg PO TID (maximum daily dose of 3g/day) starting on Day 5

Primary outcomes

• Rate of 1 year Graft-Versus-Host Disease (GVHD) free, relapse free survival (GRFS) survival [1 year]: To evaluate the number of patients with acute leukemia or MDS who are GVHD-free, relapse free (GRFS) after 1 year of undergoing undergoing a treatment regimen of haploidentical stem cell transplant with conditioning and total marrow irradiation.

Secondary outcomes

• The number of patients with greater than or equal to grade 4 non-hematologic toxicities [1 year post-stem cell transplant]: Evaluate the incidence of greater than or equal to grade 4 non-hematologic toxicities
• Engraftment rates [30 days post-stem cell transplant]: Engraftment rates at Day 30
• Rates of incidence of full donor chimerism [30 days post-stem cell transplant]: Rates of incidence of full donor chimerism at Day 30
• The rate of overall survival (OS) [1 year post-stem cell transplant]: The rate of overall survival (OS)
• The rate of event free-survival (EFS) [1 year post-stem cell transplant]: The rate of event free-survival (EFS)
• The rate of Grade II-IV and III-IV acute GVHD and limited/extensive chronic GVHD [1 year post-stem cell transplant]: The rate of Grade II-IV and III-IV acute GVHD and limited/extensive chronic GVHD
• The rate of progression at 1 year post transplant [1 year post-stem cell transplant]: The rate of progression at 1 year post transplant
• The rate of relapse at 1 year post transplant [1 year post-stem cell transplant]: The rate of relapse at 1 year post transplant
• The rate of non-morality (NRM) at 1 year post transplant [1 year post-stem cell transplant]: The rate of non-morality (NRM) at 1 year post transplant

Sex: All, ages: 18 Years to 75 Years

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)

• Rondelli Damiano, MD, Principal investigator, University of Illinois at Chicago