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

38 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment IM-TMI + Chemotherapy for AML and MDS?

Research shows that adding total body irradiation (TBI) to a regimen with fludarabine and busulfan significantly reduces relapse rates and improves overall survival in patients with acute myelogenous leukemia (AML). Additionally, targeted marrow irradiation (TMI) with fludarabine and busulfan has shown promising survival rates in patients with high-risk blood cancers. ^{1 2 3 4 5}

Is the treatment of IM-TMI + Chemotherapy for AML and MDS generally safe in humans?

Research shows that using lower doses of total body irradiation (TBI) and chemotherapy can reduce toxicity and non-relapse mortality in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Substituting TBI with treosulfan in certain regimens has been found to be safer for elderly patients or those with severe health issues. Additionally, using busulfan as an alternative to TBI has been evaluated for its effectiveness and safety, showing potential as a less toxic option. ^{1 3 4 6 7}

What makes the IM-TMI + Chemotherapy treatment unique for AML and MDS?

The IM-TMI + Chemotherapy treatment is unique because it combines intensity-modulated total marrow irradiation (TMI) with chemotherapy drugs like busulfan and fludarabine, which may allow for targeted radiation to the bone marrow while minimizing damage to other tissues. This approach aims to reduce toxicity and improve outcomes compared to traditional total body irradiation (TBI) regimens. ^{2 4 8 9 10}

What is the purpose of this trial?

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).

Research Team

Damiano Rondelli, MD

Principal Investigator

University of Illinois at Chicago

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

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

2. United States 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. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Targeted Marrow Irradiation Intensification of Reduced-Intensity Fludarabine/Busulfan Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Intermediate intensity conditioning regimen containing FLAMSA, treosulfan, cyclophosphamide, and ATG for allogeneic stem cell transplantation in elderly patients with relapsed or high-risk acute myeloid leukemia. [2013]

5. United States pubmed.ncbi.nlm.nih.gov

Impact of conditioning regimen in allogeneic hematopoetic stem cell transplantation for children with acute myelogenous leukemia beyond first complete remission: a pediatric blood and marrow transplant consortium (PBMTC) study. [2013]

6. United States 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. [2019]

7. Austria pubmed.ncbi.nlm.nih.gov

[High-dose busulfan with subsequent bone marrow transplantation in poor-risk forms of leukemia]. [2013]

8. United States pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem cell transplantation for pediatric patients with treatment-related myelodysplastic syndrome or acute myelogenous leukemia. [2012]

9. United States pubmed.ncbi.nlm.nih.gov

Combination of linear accelerator-based intensity-modulated total marrow irradiation and myeloablative fludarabine/busulfan: a phase I study. [2015]

10. United States 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. [2021]