Stem Cell Transplantation for Blood Cancers

Overseen By Margaret MacMillan

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Pregnant, HIV, Hepatitis B/C, 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: Unknown

Duration: 6 weeks

70 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new stem cell transplant method to treat blood cancers like leukemia. It evaluates the procedure's safety and feasibility for patients. The study includes several treatment plans that combine drugs like Fludarabine and Busulfan with stem cell infusions. Individuals with blood cancers, such as acute leukemias or myelodysplastic syndromes (conditions where blood cells don't mature properly), might be suitable candidates for this trial. As a Phase 2 trial, this research measures 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 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 shows that the treatment combinations in this trial have been studied for safety in previous research.

For the Fludarabine and Total Body Irradiation (TBI) regimen, studies indicate it is generally well-tolerated. Many patients have successfully received this treatment, with manageable side effects.

The Fludarabine and Busulfan combination has also been studied. Some research found it may be linked to higher risks of serious side effects, depending on the dose used.

When Fludarabine is combined with Busulfan and Melphalan, evidence suggests a higher risk of serious side effects. However, this combination is used in specific cases where the benefits may outweigh the risks.

Doctors have experience managing side effects from these treatments, as they have been used in other situations. Discuss any concerns with the medical team to understand what this means for you. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they explore the use of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells in combination with powerful chemotherapy agents like Fludarabine, Busulfan, Melphalan, and Total Body Irradiation. Unlike traditional treatments for blood cancers, which often rely solely on chemotherapy or radiation, this approach aims to enhance the immune system’s ability to fight cancer by infusing specially prepared stem cells. Additionally, the inclusion of ATG (Anti-Thymocyte Globulin) in some regimens could potentially reduce the risk of transplant rejection and complications. These innovative strategies might improve outcomes and expand treatment options for both adult and pediatric patients with blood cancers.

What evidence suggests that this trial's treatments could be effective for blood cancers?

This trial studies various treatment arms to manage blood cancers through stem cell transplantation. Research has shown that using fludarabine with total body irradiation (TBI), as in Arm 1A and Arm 1B, effectively supports stem cell transplants, leading to successful integration of new cells and good patient tolerance. Arm 2A and Arm 2B explore the combination of fludarabine with busulfan, which studies indicate helps stop cancer cells from growing before a stem cell transplant. Arm 3A and Arm 3B, which include melphalan with fludarabine and busulfan, have shown improved survival rates in patients with high-risk conditions. Research on busulfan and cyclophosphamide, as in Arm 4B, shows they work well together, with outcomes similar to other treatment plans. Finally, Arm 5B, which combines cyclophosphamide with TBI, has shown promising results in improving survival and reducing the chances of cancer returning. These treatments are being evaluated for their effectiveness in managing blood cancers through different stem cell transplant methods. ^{6 7 8 9 10}

Who Is on the Research Team?

Margaret MacMillan, MD

Principal Investigator

University of Minnesota Masonic Cancer Center

Are You a Good Fit for This Trial?

This trial is for children and adults up to 60 years old with various blood cancers, including leukemia and myelodysplasia. Participants must have confirmed hematological malignancies, be in a specific health condition (Karnofsky performance status ≥ 70% or Lansky play score ≥ 50%), and have adequate organ function. Pregnant individuals, those with active infections or known HIV/Hepatitis B/C, prior transplants, CML blast crisis, or CNS malignancy cannot join.

Inclusion Criteria

I am 60 years old or younger.

My leukemia is considered low risk based on specific criteria.

I have been diagnosed with Acute Myeloid Leukemia or a related condition.

Exclusion Criteria

I have an active brain or spinal cord tumor.

Pregnant or breastfeeding

Known seropositive for HIV or known active Hepatitis B or C infection with detectable viral load by PCR

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive T cell receptor alpha/beta depletion (α/β TCD) peripheral blood stem cell transplantation

6 weeks

Multiple visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment, including GVHD incidence and engraftment

12 months

Regular follow-up visits

Long-term follow-up

Participants are monitored for overall survival and non-relapse mortality

85 months

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Fludarabine
• Levetiracetam
• Melphalan
• Rituximab

Trial Overview The study tests T cell receptor alpha/beta depletion PBSC transplantation using drugs like Fludarabine, Busulfan, Melphalan, Rituximab & Levetiracetam on patients with blood cancers. It's an open-label phase II trial aiming to see how well this treatment works for these conditions.

How Is the Trial Designed?

Group I: Arm 5B: ATG, Cyclophosphamide (CY), Total Body Irradiation (TBI) Experimental Treatment 4 Interventions

Patients will be treated on the most medically appropriate regimen with a preference for ATG/CY/TBI Arm followed by an infusion at Day 0 of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells.

Group II: Arm 4B: ATG, Busulfan (BU), Cyclophosphamide (CY) Experimental Treatment 5 Interventions

Patients will be treated on the most medically appropriate regimen with a preference for ATG/BU/CY Arm followed by an infusion at Day 0 of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells.

Group III: Arm 3B: ATG, Fludarabine (flu), Busulfan (bu), Melphalan (Mel) Regimen for Pediatric Patients Only Experimental Treatment 6 Interventions

ATG/Flu/Bu/Mel will the preference for patients with JMML or infants with leukemia.

Group IV: Arm 3A: Fludarabine (flu), Busulfan (bu), Melphalan (Mel) Regimen for Pediatric Patients Only Experimental Treatment 5 Interventions

Flu/Bu/Mel will the preference for patients with JMML or infants with leukemia. , Closed to Accrual

Group V: Arm 2B: ATG, Fludarabine (flu), Busulfan (bu), Flu/Bu Regimen Experimental Treatment 5 Interventions

Patients will be treated on the most medically appropriate regimen with a preference for ATG/Flu/BU/TBI Arm followed by an infusion at Day 0 of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells.

Group VI: Arm 2A: Fludarabine (flu), Busulfan (bu), Flu/Bu Regimen, Closed to Accrual Experimental Treatment 4 Interventions

Patients will be treated on the most medically appropriate regimen with a preference for Flu/TBI Arm followed by an infusion at Day 0 of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells.

Group VII: Arm 1B: ATG, Fludarabine (flu), Total Body Irradiation (TBI), Flu/TBI Regimen Experimental Treatment 4 Interventions

Patients will be treated on the most medically appropriate regimen with a preference for ATG/Flu/TBI Arm followed by an infusion at Day 0 of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells.

Group VIII: Arm 1A: Fludarabine (flu), Total Body Irradiation (TBI), Flu/TBI Regimen, Closed to Accrual Experimental Treatment 4 Interventions

Patients will be treated on the most medically appropriate regimen with a preference for Flu/TBI Arm followed by an infusion at Day 0 of Alpha/Beta T Cell-Depleted Hematopoietic Stem Cells.

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?

Masonic Cancer Center, University of Minnesota

Lead Sponsor

Trials

285

Recruited

15,700+

Published Research Related to This Trial

Fludarabine and melphalan (Flu/Mel) is a more tolerable conditioning regimen for allogeneic stem cell transplant patients with acute myelogenous leukemia (AML) compared to busulfan and cyclophosphamide (Bu/Cy), based on a review of 156 patients from 2005 to 2014.

While both regimens showed similar effectiveness in terms of relapse rates and survival outcomes, Bu/Cy was linked to higher non-relapse mortality, suggesting that Flu/Mel could be a safer option for certain patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myeloablative busulfan/cytoxan conditioning versus reduced-intensity fludarabine/melphalan conditioning for allogeneic hematopoietic stem cell transplant in patients with acute myelogenous leukemia. Dhere, V., Edelman, S., Waller, EK., et al.[2019]

In a study of 30 adult patients undergoing allogeneic hematopoietic stem cell transplant, fludarabine combined with full-dose busulfan (FluBu) and fludarabine with melphalan (FluMel) showed similar levels of hematological toxicity, indicating that both regimens are comparably safe.

The timing and duration of severe neutropenia were similar between the two groups, with both regimens resulting in a comparable recovery time for neutrophils and platelets post-transplant, suggesting that FluBu can be an effective alternative to standard reduced intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparable kinetics of myeloablation between fludarabine/full-dose busulfan and fludarabine/melphalan conditioning regimens in allogeneic peripheral blood stem cell transplantation. Chunduri, S., Dobogai, LC., Peace, D., et al.[2013]

The FLU/BU4/MEL conditioning regimen, which includes fludarabine, busulfan, and melphalan, demonstrated curative potential in patients with advanced myeloid malignancies, achieving complete chimerism within one month after transplantation.

In a study of 42 patients, the 4-year overall survival rate was 66.0% and the disease-free survival rate was 59.5%, indicating that this regimen is effective even for those who were not in complete remission at the time of transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of melphalan to fludarabine/busulfan (FLU/BU4/MEL) provides survival benefit for patients with myeloid malignancy following allogeneic bone-marrow transplantation/peripheral blood stem-cell transplantation. Ueda, T., Maeda, T., Kusakabe, S., et al.[2020]

In a study of 846 patients who underwent allogeneic hematopoietic stem cell transplantation, adding melphalan to the Flu/Bu4 regimen improved 5-year overall survival rates, with 34.2% survival in the Flu/Bu4/Mel group compared to 30.1% in the Flu/Bu4 group.

The addition of melphalan was linked to a lower incidence of relapse and relapse-associated mortality, indicating that it enhances the effectiveness of the treatment without increasing non-relapse mortality.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adding melphalan to fludarabine and a myeloablative dose of busulfan improved survival after allogeneic hematopoietic stem cell transplantation in a propensity score-matched cohort of hematological malignancies. Shimomura, Y., Hara, M., Yamamoto, H., et al.[2021]

In a study comparing two treatment regimens for children undergoing hematopoietic cell transplantation, the combination of fludarabine and busulfan (FluBu) showed similar survival rates to busulfan and cyclophosphamide (BuCy), with 2-year survival rates of 82% for FluBu and 78% for BuCy.

The FluBu regimen was associated with significantly lower toxicity, including reduced rates of lung injury, veno-occlusive disease, and infections, as well as a shorter duration of neutropenia, indicating it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Bartelink, IH., van Reij, EM., Gerhardt, CE., et al.[2014]

A conditioning regimen of busulfan, fludarabine, and melphalan was safely administered to 6 patients aged 1 to 19 years with very high-risk myeloid malignancies, resulting in complete donor engraftment even with small umbilical cord blood grafts.

All patients remained in remission without experiencing acute or chronic graft-versus-host disease during a median follow-up of 24 months, suggesting strong disease control and safety of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alternative Donor Hematopoietic Cell Transplantation Conditioned With Myeloablative Busulfan, Fludarabine, and Melphalan is Well Tolerated and Effective Against High-risk Myeloid Malignancies. Katsanis, E., Sapp, LN., Pelayo-Katsanis, L., et al.[2022]

In a study of 32 patients with acute myeloid leukemia in first complete remission, the busulfan/fludarabine (Bu/Flu) conditioning regimen resulted in significantly lower transplant-related toxicity compared to the busulfan/cyclophosphamide (Bu/Cy) regimen, with a lower incidence of severe side effects (68.8% vs. 25.0%).

Both regimens showed similar efficacy in terms of overall survival and event-free survival rates, indicating that Bu/Flu is a safer option without compromising treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A comparison of toxicity and efficacy between busulfan plus fludarabine and busulfan plus cyclophosphamide for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia]. Liu, H., Fan, ZP., Jiang, QL., et al.[2014]

In a study of 394 acute myeloid leukemia patients undergoing allogeneic stem cell transplantation, the fludarabine plus melphalan (FM) regimen showed a significantly lower relapse incidence compared to fludarabine plus busulfan (FB), indicating better control of the disease.

Despite the differences in relapse rates, both FM and FB regimens resulted in similar overall survival rates, suggesting that while FM may be more effective in preventing relapse, both treatments are comparably effective in terms of long-term survival outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning with fludarabine and busulfan versus fludarabine and melphalan for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Baron, F., Labopin, M., Peniket, A., et al.[2015]

The study compared outcomes of 67 patients treated with intravenous busulfan-cyclophosphamide to 148 patients treated with busulfan-fludarabine before allogeneic stem cell transplantation, finding that the busulfan-fludarabine regimen resulted in significantly improved safety and recovery from side effects.

Patients receiving the busulfan-fludarabine treatment had extremely low one-year treatment-related mortality and high overall and event-free survival rates, suggesting that this regimen may be a better option than conventional chemotherapy for those in first complete remission of acute myeloid leukemia or myelodysplastic syndrome.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-toxicity conditioning therapy with allogeneic stem cell transplantation for acute leukemia. Andersson, BS., de Lima, M., Thall, PF., et al.[2021]

In a meta-analysis of 1955 patients, both fludarabine with busulfan (FB) and fludarabine with melphalan (FM) showed similar overall survival rates in allogeneic stem cell transplantation, indicating both regimens are effective options.

However, FM was associated with lower relapse rates in patients with acute myelogenous leukemia/myelodysplastic syndrome, while FB resulted in lower nonrelapse mortality, suggesting a trade-off between the two regimens regarding safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Choosing a Reduced-Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation, Fludarabine/Busulfan versus Fludarabine Melphalan: A Systematic Review and Meta-Analysis. Jain, T., Alahdab, F., Firwana, B., et al.[2020]

Citations

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Busulfan and cyclophosphamide for autologous stem cell ... This study aimed to compare the efficacy of the BU/CY and MEL-200 regimens in patients with MM who underwent ASCT after treatment with PIs and/or IMIDs.

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Busulfan and Cyclophosphamide (Bu/Cy) as a Preparative ... Our data indicate that in patients with NHL undergoing ASCT, Bu/Cy has efficacy and toxicity comparable to that of other reported regimens.

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6. clinicaltrials.gov clinicaltrials.gov/study/NCT00619645

Donor Peripheral Stem Cell Transplant, Fludarabine, and ... Giving chemotherapy drugs, such as fludarabine and busulfan, before a donor peripheral stem cell transplant helps stop the growth of cancer cells.

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40096889/

Fludarabine plus myeloablative dose of busulfan regimen ... Fludarabine plus myeloablative dose of busulfan regimen was associated with high nonrelapse mortality in allogeneic hematopoietic stem cell ...

8. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e18546

Efficacy and safety of busulfan-fludarabine versus ... Efficacy and safety of busulfan-fludarabine versus busulfan-cyclophosphamide as a conditioning regimen prior to hematopoietic stem cell ...

9. clinicaltrials.gov clinicaltrials.gov/study/NCT01471444

Fludarabine-IV Busulfan ± Clofarabine and Allogeneic ... Busulfan is designed to kill cancer cells by binding to DNA (the genetic material of cells), which may cause cancer cells to die. Busulfan is commonly used in ...

10. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3280823/

A Pilot Pharmacologic Biomarker Study of Busulfan and ... Sixteen patients diagnosed with various hematologic malignancies participated in a phase II study evaluating the addition of rabbit antithymocyte globulin ...