Total Marrow Irradiation for Acute Myeloid Leukemia

(BMT-13 Trial)

Overseen By Marisol Vega, MPH

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: 30

38 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for acute myeloid leukemia (AML) and related blood disorders. It combines total marrow irradiation (a type of precise radiation) with the chemotherapy drugs fludarabine and busulfan before a stem cell transplant. The goal is to determine if this method can benefit patients who haven't responded well to other treatments. Suitable candidates include those with hard-to-treat or recurrent AML, or other specific blood disorders like MDS, where blood cells don't mature correctly. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, since the trial involves specific treatments and medications, it's best to discuss your current medications with the trial team.

What prior data suggests that intensity-modulated total marrow irradiation is safe for acute myeloid leukemia patients?

Research has shown that intensity-modulated total marrow irradiation (TMI) is generally safe at a dose of 9 Gray (Gy). In past studies, patients tolerated this dose well, without reaching unsafe levels. This treatment, combined with fludarabine and busulfan, has been used to prepare patients for stem cell transplants.

Previous studies tested this combination in patients, yielding encouraging safety results. Most patients handled the treatment without major problems.

This treatment is currently in a Phase II trial, so researchers are still gathering safety information. However, the treatments have been used together before, providing some reassurance about their safety based on earlier data. Everyone may react differently, so discussing potential risks with a doctor is always advisable. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment regimen for acute myeloid leukemia because it combines several innovative approaches. Unlike the standard chemotherapy protocols, this regimen includes intensity-modulated total marrow irradiation, which precisely targets the bone marrow, potentially reducing damage to surrounding healthy tissues. Additionally, the integration of targeted doses of Busulfan and Fludarabine with this precise irradiation aims to improve the eradication of leukemia cells. This approach, followed by the infusion of stem cells, offers a comprehensive strategy that could enhance treatment effectiveness and patient outcomes compared to current options.

What evidence suggests that intensity-modulated total marrow irradiation is effective for acute myeloid leukemia?

This trial will evaluate the effectiveness of using intensity-modulated total marrow irradiation (TMI) alongside the drugs busulfan and fludarabine in treating acute myeloid leukemia (AML) before a stem cell transplant. Research has shown that a 9 Gy dose of TMI is safe when combined with these drugs. This approach targets cancer cells more precisely while protecting healthy tissue, preparing the body to accept new stem cells by eliminating existing cancer cells. Although more research is needed, early results suggest this method could improve outcomes for people with AML. ^{1 2 3 4 6}

Who Is on the Research Team?

Matias Sanchez, MD

Principal Investigator

University of Illinois at Chicago

Are You a Good Fit for This Trial?

This trial is for patients with high-risk blood cancers like AML, CML, and MDS who have a fully or partially matched donor for stem cell transplant. Participants must be eligible for myeloablative conditioning and allogeneic HSCT.

Inclusion Criteria

I have a specific type of blood cancer that is not responding well to standard treatments.

Exclusion Criteria

I am unable to sign the consent form myself.

I've had radiation on more than 20% of my bone marrow areas.

Pregnancy or breast feeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Participants receive fludarabine and busulfan conditioning, followed by total marrow irradiation and stem cell infusion

7 days

Daily visits for conditioning and irradiation

Post-Transplant Treatment

Graft-versus-host disease prophylaxis with Cyclophosphamide, tacrolimus, and mycophenolate mofetil

5 days

Daily visits for medication administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

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

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Fludarabine
• Intensity Modulated Total Marrow Irradiation

Trial Overview The study tests if total marrow irradiation (TMI) combined with standard drugs fludarabine, busulfan before stem cell transplant can help treat certain blood cancers. It also looks at using cyclophosphamide, tacrolimus, and mycophenolate mofetil to prevent GVHD post-transplant.

How Is the Trial Designed?

Group I: Treatment Regimen Experimental Treatment 4 Interventions

Days -5 through -2: Fludarabine 40 mg/m2 IVPB daily and Busulfan targeting AUC 4800μM/min daily Day -3 through -1: Intensity modulated total marrow irradiation (9Gy fractionated) Day 0: Infuse peripheral blood mobilized stem cells Days +3 and +4: Cyclophosphamide 50 mg/kg/day Day 5: Mycophenolate mofetil and Tacrolimus (dose adjustment dependent on trough level) Day 30: Follow up Day 60: Follow up Day 90: Follow up Day 180: Follow up 1. year: Follow up 2. year: Follow up

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 of 518 patients with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation, the total body irradiation plus fludarabine (TBI8Gy/Flu) regimen showed better overall survival and leukemia-free survival in patients under 50 years old compared to the busulfan plus fludarabine (Bu3/Flu) regimen.

However, TBI8Gy/Flu was associated with a significantly higher risk of non-relapse mortality in patients aged 50 and older, suggesting that while it may be beneficial for younger patients, caution is needed for older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Total body irradiation + fludarabine compared to busulfan + fludarabine as "reduced-toxicity conditioning" for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT. Giebel, S., Labopin, M., Sobczyk-Kruszelnicka, M., et al.[2021]

In a study of 476 patients with active relapsed/refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation, the FLAMSA-Bu conditioning regimen showed a significantly lower relapse incidence (38% vs 49%) and improved leukemia-free survival (42% vs 29%) compared to the FluBu2 regimen.

While FLAMSA-Bu was associated with a higher risk of acute graft-versus-host disease (36% vs 20%), it also resulted in better overall survival rates (47% vs 39%), indicating that FLAMSA-Bu may be a beneficial but more complex treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmented FLAMSA-Bu versus FluBu2 reduced-intensity conditioning in patients with active relapsed/refractory acute myeloid leukemia: an EBMT analysis. Rodríguez-Arbolí, E., Labopin, M., Eder, M., et al.[2022]

A phase I/II trial involving 54 patients with advanced hematologic malignancies found that continuous infusion of busulfan over 90 hours, combined with fludarabine, allows for a higher maximum tolerated dose (MTD) of busulfan, improving treatment efficacy without increasing organ toxicity.

The study identified a dose-limiting toxicity (DLT) of desquamative skin rash and mucositis at doses over 8000 μM/min, but overall, the treatment was well tolerated, suggesting it could be a promising alternative strategy for allogeneic stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Dose-Escalated Busulfan Delivered by Prolonged Continuous Infusion in Allogeneic Transplant Patients. Shea, TC., Walko, C., Chung, Y., et al.[2018]

In a study of 20 patients with acute myeloid leukemia, the busulfan/fludarabine conditioning regimen showed significantly lower incidences of pretreatment toxicity and complications compared to the modified busulfan/cyclophosphamide regimen, indicating a safer option for patients.

Both conditioning regimens achieved successful hematopoietic engraftment with 100% donor chimerism, but busulfan/fludarabine was better tolerated, suggesting it may be a highly effective and low-toxicity alternative for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Different Conditioning Regimens of Haploidentical Hematopoietic Stem Cell Transplant in Patients With Acute Myeloid Leukemia. Jiang, Y., Fang, X., Sui, X., et al.[2019]

In a study of 148 acute myeloid leukemia patients undergoing hematopoietic stem cell transplantation, myeloablative conditioning with fludarabine and higher doses of busulfan (FluBu4) resulted in lower relapse rates compared to reduced intensity conditioning (FluBu2), particularly in patients with poor risk cytogenetics and those over 50 years old.

Despite the higher intensity of the FluBu4 regimen, the rates of nonrelapse mortality were similar to those of the FluBu2 group, suggesting that the myeloablative approach can improve overall survival (53% vs 34% at 5 years) without increasing toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic transplantation with myeloablative FluBu4 conditioning improves survival compared to reduced intensity FluBu2 conditioning for acute myeloid leukemia in remission. Magenau, JM., Braun, T., Reddy, P., et al.[2015]

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 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]

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]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S1083879114005606

Combination of Linear Accelerator–Based Intensity ... Total marrow irradiation is added to myeloablative chemotherapy in a phase 1 dose escalation. •. Total marrow irradiation 9 Gy is the maximum tolerated dose ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10400409/

Total body irradiation versus busulfan based intermediate ... Total body irradiation versus busulfan based intermediate intensity conditioning for stem cell transplantation in ALL patients >45 years

3. astctjournal.org astctjournal.org/article/S2666-6367(22)01192-7/fulltext

Targeted Marrow Irradiation Intensification of Reduced- ... Combination of linear accelerator-based intensity-modulated total marrow irradiation and myeloablative fludarabine/busulfan: a phase I study.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT03121014?tab=table

Study of Intensity Modulated Total Marrow Irradiation (IM- ... 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 ...

5. trialx.com trialx.com/clinical-trials/listings/228118/study-of-intensity-modulated-total-marrow-irradiation-im-tmi-in-addition-to-fludarabinebusulfan-conditioning-for-allogeneic-transplantation-in-high-risk-aml-and-myelodysplastic-syndromes/

Study of Intensity Modulated Total Marrow Irradiation (IM ... 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 ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/36460819/

Total body irradiation plus fludarabine versus busulfan ... We aimed to compare retrospectively, total body irradiation (12 Gy) plus Flu (FluTBI12) versus busulfan (Bu) plus Flu (FB4) as a myeloablative conditioning ...