Treosulfan-Based Conditioning for Bone Marrow Failure

Recruiting at 27 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

40 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests if a combination of three drugs can reduce complications for patients with bone marrow failure diseases. The drugs work by killing harmful cells, stopping their growth, and reducing immune reactions.

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.

What data supports the idea that Treosulfan-Based Conditioning for Bone Marrow Failure is an effective treatment?

The available research shows that Treosulfan-Based Conditioning is effective for treating bone marrow failure disorders. In a study with 14 patients who had various marrow failure disorders, all patients successfully received donor cells, and 13 out of 14 were alive with their diseases corrected after three years. This suggests that the treatment is effective in establishing donor cell acceptance with low side effects and good long-term outcomes. Compared to other treatments, Treosulfan-Based Conditioning has a lower risk of serious complications and high survival rates, making it a promising option for patients with marrow failure disorders. ^{1 2 3 4 5}

What data supports the effectiveness of the drug combination of Treosulfan, Fludarabine, and Thymoglobulin for bone marrow failure?

Research shows that the combination of Treosulfan, Fludarabine, and Thymoglobulin is effective in establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and marrow failure disorders, with a high survival rate and low transplant-related mortality. ^{1 2 3 4 5}

What safety data is available for Treosulfan-based conditioning in bone marrow failure treatment?

Treosulfan-based conditioning, often combined with fludarabine and thymoglobulin, has been studied for its safety and efficacy in hematopoietic cell transplantation. Studies show promising results with good engraftment and low toxicity. In a multicenter trial, 31 patients with nonmalignant diseases received treosulfan, fludarabine, and thymoglobulin, resulting in a 0% transplant-related mortality at day 100 and a 90% survival rate at 2 years. The combination was effective in establishing donor engraftment with low toxicity, although some patients experienced graft-versus-host disease (GVHD). The use of thymoglobulin was associated with a lower incidence of severe acute GVHD. These findings support the safety and potential of treosulfan-based conditioning for bone marrow failure treatment. ^{1 2 3 4 6}

Is Treosulfan-based conditioning generally safe for humans?

Treosulfan-based conditioning, when combined with fludarabine and thymoglobulin, has shown low toxicity and improved survival rates in patients with nonmalignant diseases, with a 2-year survival rate of 90% and no early transplant-related deaths reported in a study. ^{1 2 3 4 6}

Is the drug combination of Fludarabine, Thymoglobulin, and Treosulfan a promising treatment for bone marrow failure?

Yes, the combination of Fludarabine, Thymoglobulin, and Treosulfan is promising for treating bone marrow failure. It has shown to be effective in helping patients recover with low toxicity and high survival rates. This drug combination helps establish donor cells in the patient's body, which is crucial for recovery, and has a good safety profile. ^{1 4 5 7 8}

How is the drug Treosulfan-based conditioning different from other treatments for bone marrow failure?

Treosulfan-based conditioning is unique because it combines treosulfan, fludarabine, and thymoglobulin to prepare patients for bone marrow transplants, offering a lower toxicity profile and improved survival rates compared to traditional myeloablative regimens. This combination is particularly effective for patients with nonmalignant diseases and marrow failure disorders, providing a safer alternative with reduced transplant-related mortality. ^{1 4 5 7 8}

Research Team

Lauri Burroughs, MD

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Margaret MacMillan, MD

Principal Investigator

University of Minnesota

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

References

1. Germany pubmed.ncbi.nlm.nih.gov

A pilot pharmacologic biomarker study of busulfan and fludarabine in hematopoietic cell transplant recipients. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Fludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. [2013]

3. United States 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. [2017]

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

Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. [2021]

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

Allogeneic Hematopoietic Cell Transplantation Using Treosulfan-Based Conditioning for Treatment of Marrow Failure Disorders. [2019]

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

Antithymocyte globulin induction in living donor renal transplant recipients: final report of the TAILOR registry. [2022]

7. Spain pubmed.ncbi.nlm.nih.gov

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

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

Determination of Treosulfan and Fludarabine in Plasma by Turbulent Flow Liquid Chromatography-Tandem Mass Spectrometry (TFLC-MS/MS). [2023]