Reduced Intensity Stem Cell Transplant for Blood Disorders

Overseen By Paul Orchard, M.D.

Age: < 65

Sex: Any

Trial Phase: Academic

Sponsor: Masonic Cancer Center, University of Minnesota

Disqualifiers: Previous irradiation, Pregnant, HIV positive, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a gentler approach to stem cell transplants for individuals with blood disorders who did not achieve successful results from a previous transplant. The goal is to enhance the chances of the new stem cells taking hold by using a less intense treatment plan, which includes medications like busulfan and fludarabine, along with low-dose total body irradiation. This trial suits those needing another transplant due to issues with their first one and who have access to a suitable donor match. As an unphased trial, it provides a unique opportunity to explore innovative treatment options for those seeking alternatives after previous transplant challenges.

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 prior data suggests that this treatment guideline is safe?

Research has shown that the treatment plan using busulfan, fludarabine, and low-dose total body irradiation (TBI) is generally safe and well-tolerated. Previous studies found that combining busulfan and fludarabine is effective and safe, particularly for patients unable to handle more intense treatments. This combination has been successfully used in older patients with various blood disorders.

For total body irradiation, research suggests it is a safe method to prepare patients for a stem cell transplant. It has improved survival rates compared to other methods.

Overall, these treatments have been used in various situations and have demonstrated a good balance between effectiveness and safety. While all treatments carry risks, this combination aims to reduce severe side effects while maintaining efficacy. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about the reduced intensity stem cell transplant for blood disorders because it offers a potentially safer alternative to traditional transplants. Unlike standard high-dose conditioning treatments, this approach uses reduced intensity conditioning (RIC) with busulfan, fludarabine, and total body irradiation, which may reduce the risk of severe side effects. This makes it particularly promising for patients who need a second or subsequent transplant and might not tolerate more aggressive treatments. Additionally, using Keppra for seizure prevention is a proactive step to enhance patient safety during the process. This combination aims to provide effective treatment with fewer complications, offering hope for better patient outcomes.

What evidence suggests that this treatment might be an effective treatment for blood disorders?

This trial will evaluate a treatment plan called reduced-intensity conditioning (RIC), which uses the drugs busulfan and fludarabine, along with low-dose total body irradiation and stem cell transplant. Studies have shown that RIC is effective for patients who cannot handle more intense treatments. Research indicates that this method benefits patients with conditions like acute lymphoblastic leukemia (ALL) who cannot undergo more aggressive treatments that destroy bone marrow. In previous patients with blood disorders like myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML), the RIC regimen supported successful stem cell transplants. This approach can improve the chances of donor cells successfully taking hold in the patient's body, which is crucial for recovery. Early findings suggest that using these medications can increase treatment success for those needing a second or additional stem cell transplant. ^{1 2 4 6 7}

Who Is on the Research Team?

Troy C Lund, MD

Principal Investigator

Masonic Cancer Center, University of Minnesota

Are You a Good Fit for This Trial?

This trial is for individuals aged 0 to 55 needing a second or subsequent stem cell transplant due to inadequate donor chimerism after a previous transplant. It's open to those with matched donors, including siblings and unrelated cord blood units. Pregnant women, HIV-positive individuals, and those who can't safely receive additional radiation are excluded.

Inclusion Criteria

I am between 0 and 55 years old.

Consent: voluntary written consent (adult or parental/guardian)

I have a suitable donor for a transplant according to the University of Minnesota's criteria.

Exclusion Criteria

HIV positive

Pregnant or breastfeeding

I am considering a second transplant less than 6 months after my first intense treatment or 2 months after a milder one.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a second or greater allogeneic hematopoietic stem cell transplant using reduced intensity conditioning, including busulfan, fludarabine, total body irradiation, and stem cell transplant. Keppra is given for seizure prophylaxis.

6 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of graft failure, acute and chronic GVHD, transplant-related mortality, and overall survival.

6 months

Long-term follow-up

Participants are monitored for chronic GVHD and donor chimerism status.

1 year

What Are the Treatments Tested in This Trial?

Interventions

• Busulfan
• Fludarabine
• Stem cell transplant
• Total body irradiation

Trial Overview The study tests a reduced intensity conditioning regimen using Busulfan, Fludarabine, and low-dose total body irradiation aimed at promoting engraftment in patients whose previous transplants didn't take sufficiently. Both bone marrow and peripheral blood grafts are considered.

How Is the Trial Designed?

Group I: Reduced Intensity Conditioning Experimental Treatment 5 Interventions

Includes patients receiving a second or greater allogeneic hematopoietic stem cell transplant (HSCT) using reduced intensity conditioning (RIC). Patients will receive busulfan, fludarabine, total body irradiation and stem cell transplant. Keppra will be given for seizure prophylaxis.

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

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]

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]

In a study of 62 patients undergoing reduced-intensity conditioning for stem cell transplantation, therapeutic dose monitoring of oral busulfan did not significantly impact post-transplant outcomes compared to standard dosing.

The presence of chronic graft-versus-host disease was identified as a strong predictor of overall survival and leukemia-free survival, highlighting its importance in patient outcomes after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. Martino, R., Pérez-Simón, JA., Moreno, E., et al.[2013]

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 156 patients undergoing allogeneic hematopoietic stem cell transplantation, the reduced-intensity conditioning regimens FB2 and FM80 showed comparable overall survival rates and relapse incidences, indicating both are effective options.

However, in patients with high-risk disease, FM80 was associated with a trend towards lower overall survival compared to FB2, suggesting that the choice of regimen may need to be tailored based on disease risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective comparison of hematopoietic stem cell transplantation following reduced-intensity conditioning with fludarabine/low-dose melphalan plus 4 Gy TBI versus fludarabine/ busulfan plus 4 Gy TBI. Yamada, Y., Ikegawa, S., Najima, Y., et al.[2022]

In a study involving 16 patients with hematological malignancies, the pharmacokinetics of fludarabine were assessed before and after administration of busulfan, showing no significant changes in key parameters such as clearance and half-life.

The results suggest that there is unlikely to be a clinically relevant drug interaction between busulfan and fludarabine, supporting their combined use in conditioning regimens for stem cell transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

F-ara-A pharmacokinetics during reduced-intensity conditioning therapy with fludarabine and busulfan. Bonin, M., Pursche, S., Bergeman, T., et al.[2013]

The combination of intravenous busulfan and fludarabine as a conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) demonstrated a high complete remission rate of 85% in patients with active disease.

This regimen showed low regimen-related (1%) and treatment-related (3%) mortality rates, indicating improved safety, while achieving a 1-year overall survival rate of 65% and event-free survival rate of 52% for all patients, suggesting it is an effective and reduced-toxicity option for these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. de Lima, M., Couriel, D., Thall, PF., et al.[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]

In a study of 66 patients undergoing reduced intensity conditioning (RIC) with a regimen including fludarabine, busulfan, and low-dose total body irradiation, high-risk patients had a 2-year overall survival rate of 64.5%, comparable to 70.9% in standard-risk patients.

The Flu-BU2-TBI regimen demonstrated similar therapeutic effects for high-risk patients as seen in standard-risk patients, with low treatment-related mortality rates (6% for high-risk) and lower relapse rates compared to previous RIC regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): clinical efficacy in high-risk patients. Takahata, M., Hashino, S., Okada, K., et al.[2013]

The reduced-intensity conditioning regimen using fludarabine, very low-dose busulfan, and antithymocyte globulin (Flu/ATG/BU) resulted in a lower transplant-related mortality (22%) compared to the classical regimen with total body irradiation (41%), indicating a potentially safer option for patients with lymphoid malignancies.

Patients receiving the Flu/ATG/BU regimen experienced significantly lower rates of severe acute and chronic graft-versus-host disease (15% and 12%, respectively) compared to those on the Flu/TBI regimen (44% and 58%), suggesting improved safety and tolerability of the reduced-intensity approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, antithymocyte globulin, and very low-dose busulfan for reduced-intensity conditioning before allogeneic stem cell transplantation in patients with lymphoid malignancies. Malard, F., Cahu, X., Clavert, A., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7256005/

Reduced-Intensity Conditioning with Busulfan and ... RIC with busulfan and fludarabine is an effective and safe conditioning regimen for adult ALL patients unfit for myeloablation.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12134719/

Allogeneic Haematopoietic Stem Cell Transplantation ... All patients in this study received fludarabine (180 mg/m2 over day −9 to −4), intravenous busulfan (8 mg/kg over day −5 to −3), rabbit ATLG (Grafalon (Neovii, ...

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

Busulfan Dose Intensity and Outcomes in Reduced ... A total of 217 consecutive patients with MDS or AML who underwent reduced-intensity busulfan with fludarabine conditioning PBSCT were included in this analysis.

4. astctjournal.org astctjournal.org/article/S1083-8791(17)30770-X/fulltext

Fludarabine and Busulfan versus ... Using the Center for International Blood and Marrow Transplant Research database, we report the outcomes of the 2 most commonly used RIC approaches, fludarabine ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1465324909702828

Reduced-intensity conditioning allogeneic hematopoietic ... We present a non-randomized retrospective analysis of 37 patients conditioned with oral fludarabine compared with 144 patients conditioned with the i.v. ...

6. eymj.org eymj.org/pdf/10.3349/ymj.2020.61.6.452

Reduced-Intensity Conditioning with Busulfan and Fludarabine ... adult ALL results in a CR rate of 44%, median overall survival. (OS) of 6.3 months, and 5-year OS of 7%.3. Allogeneic hematopoietic stem cell transplantation ( ...

7. ash.confex.com ash.confex.com/ash/2024/webprogram/Paper200303.html

Paper: Steroid Pre-Busulfan Based Reduced-Intensity ... The favorable outcomes may be attributed, in part, to our pre-transplant conditioning regimen, which included a 4-week course of alternate-day prednisone. The ...