Study of Intensity Modulated Total Marrow Irradiation (IM-TMI) in Addition to Fludarabine/Busulfan Conditioning for Allogeneic Transplantation in High Risk AML and Myelodysplastic Syndromes

NCT03121014 | Active Not Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: 2017-0001
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

Brief Summary

The study is a Phase II clinical trial. Patients will receive intensity modulated total marrow irradiation (TMI) at a dose of 9 Gy with standard myeloablative fludarabine/ i.v. targeted busulfan (FluBu) conditioning prior to allogeneic hematopoietic stem cell transplant (HSCT).

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (1)

• Relapse free survival of approximately 30% in high-risk patients conditioned with the Fludarabine/ Busulfan regimen

  Using a Simon 2 stage optimal design with α of 0.05 and power of 0.8, 15 patients will be enrolled in the first stage. If greater than 5 patients survive to 1 year without relapse the study will continue into stage 2. Recruitment will then continue to a total of 46 patients. In this expanded cohort, if a total of 18 or more patients survive to 1 year without relapse, the treatment will be judged efficacious and worthy of further study.

  Up to 1 year

Secondary Outcomes (3)

• Relapse free survival

  Up to 1 year

• Overall survival

  Up to 1 year

• Transplant related mortality rate

  Up to 1 year

Study Arms (1)

Patient Treatment

EXPERIMENTAL

Patients will receive fludarabine 40 mg/m2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2, IV busulfan targeting a 4800μM/min/ day from day -5 through day -2, and ATG (Thymoglobulin®) at 0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1 (Only for recipients of stem cells from unrelated or mismatched donors). In addition to the above conditioning regimen all patients will receive TMI at a dose of 3Gy on days -3, -2 and -1. On day 0, the stem cell product will be infused according to BMT unit policy. Graft versus host disease (GVHD) prophylaxis will consist of administration of tacrolimus and methotrexate. Post-transplant evaluation will be done as per standard care with study data collected at day 30, 60, 90, 180, 365 and 2 years.

Drug: Fludarabine; Drug: Busulfan; Drug: ATG; Radiation: Total Marrow Irradiation; Procedure: Stem Cell Product Infusion; Drug: Tacrolimus; Drug: Methotrexate

Interventions

Fludarabine DRUG

40 mg/m\^2 IVBP daily for day -5 (5 days before stem cell infusion) through Day -2

Also known as: Fludara®

Patient Treatment

Busulfan DRUG

targeting a 4800μM/min/ day from day -5 through day -2

Also known as: Busulfex®

Patient Treatment

ATG DRUG

0.5 mg/kg IV on day -3, and 2 mg/kg on days -2 and day -1

Also known as: Thymoglobulin®

Patient Treatment

Total Marrow Irradiation RADIATION

dose of 3Gy on days -3, -2 and -1

Patient Treatment

Stem Cell Product Infusion PROCEDURE

Day 0 according to BMT unit policy

Patient Treatment

Tacrolimus DRUG

The starting dose is at 0.03 mg/kg/day IV continuous infusion over 24 hr from 4 PM on day -2. Dose will be adjusted to target trough levels of 5-15 ng/mL. More information is available in the protocol document.

Also known as: FK-506, Prograf®

Patient Treatment

Methotrexate DRUG

5mg/m\^2 on Day 1, 5 mg/m\^2 on Days 3, 6 and 11

Also known as: Trexall®

Patient Treatment

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18-65 years
• Patients with AML or MDS who meet the following criteria:
• a. Relapsed or refractory AML (including AML in CR2)
• b. Poor-risk AML in first remission, with remission defined as \<5% bone marrow blasts morphologically:
• AML arising from MDS or a myeloproliferative disorder, or secondary AML
• Poor risk molecular features including 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
• c. Primary refractory disease
• d. MDS with at least one of the following poor-risk features:
• Poor-risk cytogenetics including 3q abnormalities, 7/7q minus or complex cytogenetics (\>3 abnormalities)
• Current or previous INT-2 or high IPSS score
• Treatment-related MDS
• MDS diagnosed before age 21 years
• Progression on or lack of response to standard DNA-methyltransferase inhibitor therapy
• Life-threatening cytopenias, including those requiring regular PRBC or platelet transfusions e. CML with a history of accelerated or blast phase

You may not qualify if:

• Presence of significant co morbidity as shown by:
• Left ventricular ejection fraction \< 50%
• Creatinine clearance \<30ml/min
• Bilirubin \> 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST \> 5 x ULN
• FEV1 and FVC \< 50% of predicted or DLCO \<50% of predicted once corrected for anemia
• f. Karnofsky score \<70 (appendix C)
• g. Hematopoietic cell transplantation comorbidity index \>3
• h. Active viral hepatitis or HIV infection
• j. Cirrhosis
• Pregnancy
• Patients unable to sign informed consent
• Patient who have previously received radiation to \>20% of bone marrow containing areas.
• \. DONOR ELIGIBILITY AND SELECTION
• Donor Selection
• Donor evaluation and selection is by standard for normal clinical practice. No study procedures are to be performed on donors. All donors must be willing to donate peripheral blood stem cells and meet institutional or NMDP criteria for donation.

Sponsors & Collaborators

• University of Illinois at Chicago: lead

Study Sites (1)

University of Illinois at Chicago

Chicago, Illinois, 60612, United States

Location

Related Publications (1)

• Maahs L, Avila AM, Koshy M, Sweiss K, Ahn KH, Chen Z, Uzoka C, Galvez C, Sanchez M, Rubinstein P, Quigley J, Zucchetti E, Mahmud N, Aydogan B, Patel P, Rondelli D. Intensified conditioning with high-dose total marrow irradiation and myeloablative chemotherapy reduces risk of relapse without increasing toxicity in allogeneic hematopoietic stem cell transplant for high-risk myeloid malignancies: a phase II study. Haematologica. 2026 Jan 1;111(1):177-183. doi: 10.3324/haematol.2025.287457. Epub 2025 Jun 19.

  PMID: 40534485 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

fludarabine; fludarabine phosphate; Busulfan; thymoglobulin; Tacrolimus; Methotrexate

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Butylene Glycols; Glycols; Alcohols; Organic Chemicals; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Hydrocarbons; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Macrolides; Lactones; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Damiano Rondelli, MD

  University of Illinois at Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Hematology

Study Record Dates

• First Submitted: April 14, 2017
• First Posted: April 19, 2017
• Study Start: April 24, 2017
• Primary Completion: April 1, 2026
• Study Completion: April 1, 2026
• Last Updated: January 13, 2026

Record last verified: 2026-01

Locations

US (1)