Treosulfan-Based Conditioning for Bone Marrow Failure

Not currently recruiting at 28 trial locations

Overseen By Megan Scott

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Disqualifiers: Aplastic anemia, Fanconi anemia, MDS, 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: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether combining treosulfan, fludarabine, and rabbit antithymocyte globulin can make blood or bone marrow transplants safer for individuals with bone marrow failure diseases. These medicines aim to reduce complications by killing harmful cells, stopping their growth, and improving immune function. Individuals with conditions such as Shwachman-Diamond syndrome, Diamond Blackfan anemia, and other bone marrow failure diseases might be suitable candidates, particularly if they experience severe blood-related issues like anemia or frequent infections. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from innovative therapies.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. It's best to discuss your specific medications with the trial team to get a clear answer.

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 to get specific guidance based on your situation.

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

Research has shown that the combination of treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) is generally well-tolerated before a bone marrow transplant. Studies have found that this combination can enhance bone marrow function without causing serious issues. It has been successfully used in patients with bone marrow failure diseases, indicating safety and effectiveness.

Fludarabine is known for its manageable safety profile. It is often used in similar transplant situations with good results, showing high survival rates and few complications. Similarly, rATG has been used in various treatments without increasing the risk of major side effects. It helps control the body's immune response, which is crucial for transplant success.

Overall, studies support the safety and effectiveness of these treatments, making them a promising option for those needing a bone marrow transplant. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatments for bone marrow failure, which often rely on harsher conditioning regimens, the treosulfan-based approach is considered less toxic, potentially reducing harmful side effects. Treosulfan is unique because it combines the effectiveness of traditional chemotherapy with a more favorable safety profile, making it suitable for patients who might not tolerate standard regimens well. Researchers are excited because this approach could offer a gentler yet effective alternative, improving patient outcomes and quality of life during bone marrow or stem cell transplants.

What evidence suggests that this trial's treatments could be effective for bone marrow failure?

In this trial, participants will receive a conditioning regimen of treosulfan, fludarabine, and rabbit antithymocyte globulin (rATG) before undergoing a bone marrow or peripheral blood stem cell transplant. Research has shown that treosulfan, when combined with fludarabine and rATG, is effective for bone marrow transplants. Studies indicate that treosulfan aids donor cell engraftment and has a good safety record, resulting in fewer side effects. Fludarabine is known to improve survival rates in serious bone marrow conditions and is generally well tolerated. rATG enhances bone marrow function and boosts blood cell production. Together, these drugs reduce complications and improve outcomes for patients with bone marrow failure diseases. ^{3 6 7 8 9}

Who Is on the Research Team?

Lauri Burroughs, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Margaret MacMillan, MD

Principal Investigator

University of Minnesota

Are You a Good Fit for This Trial?

This trial is for people aged 1 to under 50 with bone marrow failure diseases treatable by transplant, who have specific genetic mutations or meet diagnostic criteria. Excluded are those with certain other conditions, previous transplants, severe lung function impairment, liver issues, uncontrolled infections, HIV positive status or unwillingness to use contraception.

Inclusion Criteria

I have a SAMD9 or SAMD9L disorder with a confirmed mutation.

My bone marrow failure disorder can be treated with a stem cell transplant from a donor.

I have Shwachman-Diamond syndrome with a confirmed genetic mutation.

Exclusion Criteria

I am HIV positive.

I have had a solid organ transplant.

My bilirubin levels are not more than twice the normal limit, unless due to Gilbert's syndrome.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning Regimen

Patients receive treosulfan, fludarabine, and rATG as part of the conditioning regimen before transplantation

6 days

Daily visits for IV administration

Transplantation

Patients undergo bone marrow or peripheral blood stem cell transplant

1 day

1 visit (in-person)

GVHD Prophylaxis

Patients receive tacrolimus and methotrexate to prevent graft-versus-host disease

180 days

Multiple visits for IV and oral administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Fludarabine
• Thymoglobulin (Rabbit Anti-thymocyte Globulin; rATG)
• Treosulfan

Trial Overview The study tests a pre-transplant conditioning regimen using treosulfan combined with fludarabine and rabbit antithymocyte globulin (rATG) in patients with bone marrow failure diseases. The goal is to see if this combination reduces complications post-transplant.

How Is the Trial Designed?

Group I: Treatment (conditioning regimen; transplant; GVHD prophylaxis) Experimental Treatment 15 Interventions

CONDITIONING REGIMEN: Patients receive treosulfan IV over 120 minutes on days -6 to -4, fludarabine phosphate IV over 60 minutes on days -6 to -2, and rATG IV over 4-6 hours on days -4 to -2. TRANSPLANTATION: Patients undergo bone marrow or peripheral blood stem cell transplant on day 0. GVHD PROPHYLAXIS: Patients receive tacrolimus IV continuously beginning on day -2 and a taper beginning on day 180. Patients may also receive tacrolimus PO. Patients also receive methotrexate IV on days 1, 3, 6, and 11. Patients undergo ECHO or MUGA as well as possible x-ray or CT at baseline and undergo bone marrow biopsy and aspiration at baseline and follow up. Patients also undergo blood sample collection throughout the trial.

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

Approved in European Union as Fludara for:

• Chronic lymphocytic leukemia
• Mantle-cell lymphoma
• Non-Hodgkin's lymphoma

Approved in United States as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma
• Stem Cell Transplant Conditioning

Approved in Canada as Fludara for:

• Chronic lymphocytic leukemia
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

National Marrow Donor Program

Collaborator

Trials

63

Recruited

202,000+

Blood and Marrow Transplant Clinical Trials Network

Collaborator

Trials

51

Recruited

14,600+

Published Research Related to This Trial

In a study involving 31 patients with nonmalignant diseases, a conditioning regimen using treosulfan and fludarabine resulted in 100% engraftment and a 0% early transplant-related mortality (TRM) at 100 days, indicating a safe and effective approach for hematopoietic cell transplantation.

The combination of treosulfan, fludarabine, and thymoglobulin led to a 90% survival rate over two years, with significantly lower rates of severe acute graft-versus-host disease (GVHD) in patients who received thymoglobulin, suggesting improved outcomes and reduced toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. Burroughs, LM., Nemecek, ER., Torgerson, TR., et al.[2021]

In a study involving five patients with severe aplastic anemia, a conditioning regimen of fludarabine, cyclophosphamide, and thymoglobulin resulted in complete donor type hematologic recovery for all participants, indicating high efficacy for bone marrow transplantation.

The combination treatment showed minimal complications, with only one case of mild acute graft-versus-host disease (GVHD) and no serious complications, suggesting a favorable safety profile for this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. Kang, HJ., Shin, HY., Choi, HS., et al.[2013]

The combination of treosulfan and fludarabine (Treo-Flu) shows a good safety profile for patients undergoing hematopoietic stem cell transplantation, with a low risk of severe complications like hepatic venoocclusive disease, despite common grade 4 hematologic toxicities such as leukopenia and neutropenia.

Treo-Flu demonstrates significant myelosuppressive effects, leading to full donor chimerism in most transplant recipients, making it a promising option among reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan in combination with fludarabine as part of conditioning treatment prior to allogeneic hematopoietic stem cell transplantation. Ussowicz, M.[2020]

In a phase II clinical trial involving 14 patients with various marrow failure disorders, the combination of treosulfan, fludarabine, and thymoglobulin resulted in successful donor engraftment for all patients.

At a median follow-up of 3 years, 13 out of 14 patients showed complete correction of their underlying disease, indicating that this conditioning regimen has a low toxicity profile and leads to excellent disease-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders. Burroughs, LM., Shimamura, A., Talano, JA., et al.[2019]

In a study of 2322 living donor renal transplant recipients, the use of rabbit antithymocyte globulin (rATG) induction resulted in high patient and graft survival rates of 99.3% and 99.0% at 6 months, and 98.4% and 98.2% at 12 months, respectively.

The treatment was found to be safe, with only 3.2% of patients experiencing serious adverse events and a low incidence of acute rejection (93.6% freedom from rejection at 5 years), indicating that rATG is an effective immunosuppressive option for kidney transplant recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antithymocyte globulin induction in living donor renal transplant recipients: final report of the TAILOR registry. Gaber, AO., Matas, AJ., Henry, ML., et al.[2022]

In a phase II study involving 16 patients with hematologic malignancies, the addition of rabbit antithymocyte globulin (rATG) to the fludarabine and busulfan conditioning regimen showed low rates of acute and chronic graft versus host disease (GvHD), which is a positive safety outcome.

The study found significant interpatient variability in pharmacologic biomarkers related to busulfan and fludarabine, suggesting that further research is needed to optimize the conditioning regimen for better patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. McCune, JS., Woodahl, EL., Furlong, T., et al.[2021]

Treosulfan, a drug similar to busulfan, shows comparable effectiveness in myeloablation with fewer serious side effects, making it a promising candidate for FDA approval in combination with fludarabine for use before hematopoietic stem cell transplantation.

A new rapid and accurate assay has been developed to simultaneously measure treosulfan and fludarabine levels in human plasma, which is crucial for therapeutic drug monitoring to optimize treatment efficacy and minimize toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of Treosulfan and Fludarabine in Plasma by Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry (TFLC-MS/MS). Hutcherson, SM., Schofield, RC., Carlow, DC.[2023]

In a phase II clinical trial involving 28 patients with severe aplastic anemia, a conditioning regimen of fludarabine, cyclophosphamide, and thymoglobulin led to successful donor-type hematologic recovery in all participants, indicating effective engraftment.

Despite the promising engraftment results, the study reported a high treatment-related mortality rate of 67.9%, with complications such as thrombotic microangiopathy and chronic GVHD, highlighting the need for further research to reduce these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful engraftment with fludarabine, cyclophosphamide, and thymoglobulin conditioning regimen in unrelated transplantation for severe aplastic anemia: A phase II prospective multicenter study. Kang, HJ., Shin, HY., Park, JE., et al.[2017]

Citations

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Impact of Different Fludarabine Doses in the ... High-dose Flu with busulfan suggests superior overall survival and relapse rate. No significant differences in outcome for high versus low-dose Flu with ...

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Impact of Different Fludarabine Doses in the ... The purine analog fludarabine (Flu) plays a central role in reduced-intensity conditioning and myeloablative reduced-toxicity conditioning ...

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Outcome of Fludarabine-Based Conditioning in High-Risk ... Fludarabine-based conditioning is well tolerated, with lower rates of rejection and excellent long-term survival in these high-risk aplastic anemia patients. •.

4. nature.com nature.com/articles/s41409-025-02565-7

Outcomes of attenuated dose fludarabine and melphalan ... The goal of this study was to determine outcomes of fludarabine with attenuated dosed melphalan (<140 mg/m 2 ) (aFM) compared to FM140.

5. ashpublications.org ashpublications.org/bloodneoplasia/article/1/3/100030/517045/Effect-of-clofarabine-and-fludarabine-exposure-on

Effect of clofarabine and fludarabine exposure on outcome ... We recently reported that CloFluBu is a good alternative for TBI-based conditioning in ALL in first complete remission and an effective, less toxic strategy.

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Early Results of a Cyclophosphamide Dose Deescalation ... The lethal organ toxicities (primarily pulmonary) seen in the CY 150 mg/kg cohort were unexpected, given that the safe use of similar (and even higher) doses of ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/32444864/

Conditioning regimen for allogeneic bone marrow ... The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively.

8. astctjournal.org astctjournal.org/article/S1083-8791(17)31442-8/fulltext

Efficacy and Safety of Hematopoietic Stem Cell ... Our data suggest that RIC with fludarabine, thiotepa, melphalan, and rATG prior to MSD and MUD HSCT for SAA and CAMT is effective with a tolerable safety ...

9. nature.com nature.com/articles/s41409-024-02323-1

Efficacy and safety of outpatient fludarabine ... The FCR regimen in SAA was well tolerated, even in older adults, with 100% disease-free survival with low GVHD and infection rates.