Intensity Modulated Total Marrow Irradiation for Acute Leukemia and MDS

BMT-06: Phase II Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Cyclophosphamide and Post-Transplant Cyclophosphamide Conditioning for Partially HLA Mismatched Allogeneic Transplantation in Patients With Acute Leukemia and Myelodysplastic Syndrome (MDS)

This study is testing a new type of radiation treatment before a stem cell transplant to see if it helps people with acute leukemia or myelodysplastic syndromes do better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 27 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: University of Illinois at Chicago (Academic / other)
• Drugs / interventions: radiation, chemotherapy, cyclophosphamide, fludarabine
• Locations: 1 site (Chicago, Illinois)
• Trial ID: NCT04187105 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness of intensity-modulated total marrow irradiation (IM-TMI) as part of the pre-transplant conditioning regimen for patients with acute leukemia or myelodysplastic syndromes (MDS). Participants will receive a combination of fludarabine, cyclophosphamide, and total body irradiation, along with targeted TMI at a dose of 6Gy. The study aims to improve outcomes by using a haploidentical hematopoietic stem cell transplant (HSCT) approach, with specific graft-versus-host disease prophylaxis measures in place. It is a single-arm phase II trial, focusing on a defined patient population with specific genetic matching criteria for donors.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18-75 with relapsed or refractory acute leukemia or poor-risk AML, who have a haploidentical donor.

Not a fit: Patients without a suitable haploidentical donor or those with conditions not specified in the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could enhance transplant outcomes and reduce complications for patients with acute leukemia and MDS.

How similar studies have performed: While the use of total marrow irradiation is established, this specific approach with IM-TMI in the context of haploidentical HSCT is novel and has not been extensively tested in prior studies.

Eligibility criteria

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)

Where this trial is running

Chicago, Illinois

• University of Illinois Cancer Center — Chicago, Illinois, United States (Recruiting)

Study contacts

• Principal investigator: Rondelli Damiano, MD — University of Illinois at Chicago
• Study coordinator: Rondelli Damiano, MD

Conditions Acute Leukemia; MDS; Stem Cell Transplant; Half-matched stem cell transplant