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

NCT ID: NCT03121014

Last Updated: 2026-01-13

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 38 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-04-24
• Study Completion Date: 2026-04-30

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).

Detailed Description

Patients will receive the following conditioning regimen: 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 (see Section 8). Post-transplant evaluation will be done as per standard care with study data collected at day 30, 60, 90, 180, 365 and 2 years.

Conditions

Acute Myeloid Leukemia; Myelodysplastic Syndromes

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Patient Treatment

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.

Group Type: EXPERIMENTAL

Tacrolimus

Intervention Type: 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.

Methotrexate

Intervention Type: DRUG

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

Fludarabine

Intervention Type: DRUG

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

Busulfan

Intervention Type: DRUG

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

ATG

Intervention Type: DRUG

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

Total Marrow Irradiation

Intervention Type: RADIATION

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

Stem Cell Product Infusion

Intervention Type: PROCEDURE

Day 0 according to BMT unit policy

Interventions

Tacrolimus

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.

Intervention Type: DRUG

Methotrexate

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

Intervention Type: DRUG

Fludarabine

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

Intervention Type: DRUG

Busulfan

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

Intervention Type: DRUG

ATG

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

Intervention Type: DRUG

Total Marrow Irradiation

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

Intervention Type: RADIATION

Stem Cell Product Infusion

Day 0 according to BMT unit policy

Intervention Type: PROCEDURE

Other Intervention Names

Fludara®; Busulfex®; Thymoglobulin®; FK-506, Prograf®; Trexall®

Eligibility Criteria

Inclusion Criteria

1. Age 18-65 years

2. 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

3. Patients must have a related or unrelated peripheral blood stem cell donor as follows:

1. Sibling donor must be a 6/6 match for HLA-A, -B at intermediate (or higher) resolution and -DRB1 at high resolution using DNA based typing

2. Unrelated donors must be at least 7/8 match at HLA-A, -B, -C and DRB1 at high resolution using DNA-based typing

Exclusion Criteria

1. Presence of significant co morbidity as shown by:

1. Left ventricular ejection fraction < 50%

2. Creatinine clearance <30ml/min

3. Bilirubin > 2.0 mg/dL (unless due to Gilbert's syndrome or hemolysis), and ALT and AST > 5 x ULN

4. 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

2. Pregnancy

3. Patients unable to sign informed consent

4. Patient who have previously received radiation to >20% of bone marrow containing areas.

4. DONOR ELIGIBILITY AND SELECTION

4.1. 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.

The following prioritization will be used when selecting donors:

1. When possible, an HLA compatible sibling will be used as a donor.

2. For patients who do not have an HLA compatible sibling, an unrelated donor will be used

3. 8/8 matched unrelated donors are preferred over single antigen mismatched donors.

If more than one potential volunteer unrelated donor is considered suitable further selection of the most suitable donor is at the discretion of the treating physician. The following serves only as a guide for prioritization:

1. Age of donor (18-24 > 25-34 > 35-44 > 45+)

2. Sex and parity of donor (male > female, nulliparous female > parous, multiparous female)

3. Cytomegalovirus (CMV) status, if recipient is CMV seronegative (CMV- > CMV+)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Illinois at Chicago

OTHER

Sponsor Role: lead

Responsible Party

Damiano Rondelli, MD

Professor, Hematology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Damiano Rondelli, MD

Role: PRINCIPAL_INVESTIGATOR

University of Illinois at Chicago

Locations

University of Illinois at Chicago

Chicago, Illinois, United States

Countries

United States

References

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. 2025 Jun 19. doi: 10.3324/haematol.2025.287457. Online ahead of print.

Reference Type: DERIVED

PMID: 40534485 (View on PubMed)

Other Identifiers

2017-0001

Identifier Type: -

Identifier Source: org_study_id