IM-TMI + Chemotherapy for AML and MDS

Overseen By Damiano Rondelli, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Illinois at Chicago

Disqualifiers: Heart failure, Kidney failure, Liver disease, Lung disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 36

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for certain blood cancers, specifically AML (a fast-growing cancer of the blood and bone marrow) and MDS (a group of disorders caused by poorly formed or dysfunctional blood cells). It combines a special form of radiation therapy called Total Marrow Irradiation (TMI) with chemotherapy before a stem cell transplant. The goal is to determine if this combination is safe and effective in improving patient outcomes. Ideal candidates for this trial are those with relapsed or hard-to-treat AML or MDS who have a matching stem cell donor. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both busulfan and fludarabine have FDA approval for treating acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), indicating their safety is well understood. One study found that using busulfan and fludarabine together (BuFlu) is less harmful than other treatments, making it a popular choice for stem cell transplants. Patients receiving this combination have demonstrated promising results in achieving remission.

Regarding total marrow irradiation (TMI), previous studies have shown it can be safely used in patients with high-risk leukemia and MDS. Specifically, one study reported a low rate of deaths unrelated to cancer recurrence, suggesting TMI is relatively safe.

Overall, the treatments in this trial have been studied and used before, aiding in understanding their safety. Participants should still discuss any concerns with their healthcare providers. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Busulfan, Fludarabine, and Total Marrow Irradiation (TMI) for treating Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) because it offers a unique approach compared to standard chemotherapy regimens. Unlike traditional treatments, which often involve just chemotherapy, this regimen incorporates TMI, a targeted form of radiation therapy, aiming to precisely irradiate the bone marrow. This precision allows for a potentially more effective eradication of cancerous cells while sparing surrounding healthy tissue. Additionally, the integration of TMI with high-dose chemotherapy could enhance the conditioning process before stem cell transplantation, potentially improving patient outcomes.

What evidence suggests that this trial's treatments could be effective for AML and MDS?

Research has shown that using busulfan and fludarabine together can help patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) achieve long-term remission. In this trial, participants will receive these drugs before a stem cell transplant to improve outcomes. Studies have found that adding total marrow irradiation (TMI) to this treatment can increase survival rates. TMI targets the bone marrow more precisely than traditional radiation methods, potentially offering better disease control. Early results suggest that this combination effectively treats advanced AML and MDS by improving survival chances. ^{6 7 8 9 10}

Who Is on the Research Team?

Damiano Rondelli, MD

Principal Investigator

University of Illinois at Chicago

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with high-risk Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS), including those with specific genetic mutations, poor response to prior treatments, or severe blood cell shortages. Participants need a compatible stem cell donor and must be in relatively good health without serious heart, liver, lung conditions, active infections like hepatitis or HIV, and not pregnant.

Inclusion Criteria

My leukemia or myelodysplastic syndrome is in a difficult-to-treat stage or has returned after treatment.

I have a stem cell donor who matches the required HLA criteria.

Exclusion Criteria

I do not have active viral hepatitis or HIV.

My health is significantly impaired; I need assistance for self-care.

I am unable to give my consent for treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Patients receive fludarabine, busulfan, and TMI as part of the conditioning regimen before stem cell transplantation

5 days

Daily visits for 5 days

Transplantation

Stem cell product is infused according to BMT unit policy

1 day

1 visit (in-person)

Post-transplant Follow-up

Participants are monitored for safety and effectiveness after transplantation with evaluations at specified intervals

2 years

Visits at day 30, 60, 90, 180, 365, and 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Fludarabine
• Tacrolimus
• Total Marrow Irradiation

Trial Overview The study tests adding Intensity Modulated Total Marrow Irradiation (IM-TMI) at a dose of 9 Gy to the standard Fludarabine/Busulfan conditioning before allogeneic hematopoietic stem cell transplant. This Phase II trial aims to see if this combination improves outcomes for patients with high-risk AML/MDS.

How Is the Trial Designed?

Group I: Patient Treatment Experimental Treatment 7 Interventions

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.

Busulfan is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Malignant lymphoma
• Bone marrow transplantation conditioning

Approved in European Union as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Canada as Busulfex for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Approved in Japan as Busulfan for:

• Chronic myeloid leukemia
• Acute myeloid leukemia
• Bone marrow transplantation conditioning

Who Is Running the Clinical Trial?

University of Illinois at Chicago

Lead Sponsor

Trials

653

Recruited

1,574,000+

Published Research Related to This Trial

In a study involving 179 patients undergoing allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia, the addition of 400 cGy of total body irradiation (TBI) to a regimen of fludarabine and busulfan significantly reduced relapse rates (hazard ratio 0.29) without increasing nonrelapse mortality.

The inclusion of TBI also improved overall survival (hazard ratio 0.50) and disease-free survival (hazard ratio 0.43), demonstrating that enhancing regimen intensity can lead to better outcomes in AML treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The addition of 400 cGY total body irradiation to a regimen incorporating once-daily intravenous busulfan, fludarabine, and antithymocyte globulin reduces relapse without affecting nonrelapse mortality in acute myelogenous leukemia. Russell, JA., Irish, W., Balogh, A., et al.[2013]

Intensifying the reduced-intensity conditioning regimen of fludarabine/busulfan with targeted marrow irradiation (TMI) is feasible and shows a low transplantation-related mortality rate of 8.5% in high-risk hematologic malignancy patients, suggesting it is a safe option for medically frail individuals.

The study found that the one-year disease-free survival rate was 55% and overall survival rate was 65%, indicating that this intensified treatment approach can effectively improve outcomes for patients who are ineligible for myeloablative transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Marrow Irradiation Intensification of Reduced-Intensity Fludarabine/Busulfan Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation. Ali, N., Sharma, AA., de Rezende, ACP., et al.[2022]

Total marrow irradiation (TMI) at doses up to 15 Gy combined with chemotherapy (etoposide and cyclophosphamide) showed acceptable toxicity levels and resulted in complete remission in 11 out of 12 patients in the first trial, indicating its potential efficacy for patients with advanced leukemia.

In contrast, TMI combined with busulfan and etoposide resulted in dose-limiting toxicities at 13.5 Gy, suggesting that this combination may not be safe for further dose escalation, highlighting the importance of selecting appropriate chemotherapy regimens for TMI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose escalation of total marrow irradiation with concurrent chemotherapy in patients with advanced acute leukemia undergoing allogeneic hematopoietic cell transplantation. Wong, JY., Forman, S., Somlo, G., et al.[2021]

The studies compared the efficacy of busulfan versus total body irradiation (TBI) as preparative treatments for hematopoietic transplantation in patients with acute myeloid leukemia (AML).

The findings from these comparisons could provide insights into the optimal conditioning regimens for improving treatment outcomes in AML patients undergoing transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Busulfan or TBI: answer to an age-old question. Champlin, RE.[2021]

In a study involving 100 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), the combination of treosulfan/fludarabine with low-dose total body irradiation (TBI) significantly improved progression-free survival, leading to a 1-year overall survival rate of 80% compared to 69% for those without TBI.

The addition of TBI particularly benefited patients with AML, showing a lower 1-year relapse incidence of 16% compared to 35% in the non-TBI group, highlighting the treatment's efficacy in high-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia. Deeg, HJ., Stevens, EA., Salit, RB., et al.[2019]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/23562738/

Busulfan dose intensity and outcomes in reduced ... Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity.

2. sciencedirect.com sciencedirect.com/science/article/pii/S1083879113001420

Busulfan Dose Intensity and Outcomes in Reduced ... Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity.

3. astctjournal.org astctjournal.org/article/S2666-6367(23)01469-0/fulltext

Myeloablative Dose of Busulfan and Fludarabine ... FB4 can safely offer durable remission of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients age 55 with HCT-CI <2.

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7051

Myeloablative fractionated busulfan-based conditioning ... Results: A total of 116 patients were randomized, 59 to the shorter day -13 arm and 57 to the longer day -20 arm. Median age was 59 in the day - ...

5. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT00005866?draw=2&rank=1

Study Details | NCT00005866 | S9920 Busulfan Compared ... OBJECTIVES: I. Compare event free survival after total body irradiation (TBI) plus busulfan versus TBI plus cyclophosphamide followed by allogeneic peripheral ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT01471444

Fludarabine-IV Busulfan ± Clofarabine and Allogeneic ... This is an investigational study. Busulfan and fludarabine are both FDA approved and commercially available for the treatment of AML and MDS. Clofarabine is FDA ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11907693/

Myeloablative Fractionated Busulfan With Fludarabine in ... The OS decreased between 1 and 3 years in almost all diseases (except lymphoma), with a substantial decline noted in AML patients in CR.

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18545

myelodysplastic syndrome undergoing stem cell transplant ... Busulfan-Fludarabine (BuFlu) has emerged as a less toxic alternative. This meta-analysis compares the efficacy and safety of BuCy and BuFlu in ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2666636723014690

Adult Myeloablative Dose of Busulfan and Fludarabine ... FB4 can safely offer durable remission of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients age 55 with HCT-CI <2.

10. astctjournal.org astctjournal.org/article/S1083-8791(13)00142-0/fulltext

Busulfan Dose Intensity and Outcomes in Reduced ... Comparisons of myeloablative conditioning versus reduced-intensity conditioning (RIC) have demonstrated a tradeoff between relapse and toxicity.