Stem Cell Transplant for Blood Cancers

Overseen By Filippo Milano

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Investigational agents

Disqualifiers: Active infections, Other malignancies, Pregnancy, 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: 29

60 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase II trial studies how well a donor stem cell transplant, treosulfan, fludarabine, and total-body irradiation work in treating patients with blood cancers (hematological malignancies). Giving chemotherapy and total-body irradiation before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.

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 this is a stem cell transplant trial, it's possible that some medications might need to be adjusted. Please consult with the trial coordinators for specific guidance.

What data supports the effectiveness of the treatment for blood cancers?

Research shows that adding fludarabine to total body irradiation (TBI) before stem cell transplantation improves survival rates and reduces relapse in patients with blood cancers. Additionally, a combination of treosulfan, fludarabine, and TBI has been effective in reducing relapse rates in patients with myelodysplastic syndrome and acute myeloid leukemia. ^{1 2 3 4 5}

Is stem cell transplant for blood cancers generally safe in humans?

Fludarabine, a drug used in stem cell transplants, can cause damage to certain cells and increase immune responses, which may lead to complications. High levels of fludarabine in the blood are linked to higher treatment-related mortality, suggesting that careful dosing is important to minimize risks. Treosulfan, another drug used in these treatments, has shown fewer serious side effects compared to similar drugs, but monitoring is needed to ensure safe and effective dosing. ^{2 3 4 6 7}

What makes the stem cell transplant treatment with Fludarabine, Total-Body Irradiation, and Treosulfan unique for blood cancers?

This treatment combines Fludarabine and Treosulfan, which are known for their myeloablative (bone marrow destroying) and immunosuppressive effects, with Total-Body Irradiation to prepare patients for stem cell transplantation. Treosulfan is noted for causing fewer serious side effects compared to similar agents, and the combination aims to reduce toxicity while maintaining effectiveness. ^{1 2 3 6 8}

Research Team

Filippo Milano

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

This trial is for patients with various blood cancers who have responded poorly to other treatments or are in remission. They must be over 6 months old, have good heart and lung function, normal liver enzymes, acceptable kidney function, and a Karnofsky/Lansky score indicating they can carry out daily activities. Pregnant women and those with uncontrolled infections or hypersensitivity to the drugs used in the trial cannot participate.

Inclusion Criteria

My large cell lymphoma is in its second or later remission.

I am at least 6 months old.

I have been diagnosed with myelodysplastic syndromes.

Exclusion Criteria

I have another cancer with a survival rate less than 75% in 5 years.

Dosing with another investigational agent within 30 days prior to entry in the study

My leukemia in the brain didn't respond to initial treatments.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Preparative Regimen

Patients receive treosulfan, fludarabine, and total-body irradiation before stem cell transplantation

7 days

Daily visits for treatment administration

Transplantation

Allogeneic hematopoietic stem cell transplantation is performed

1 day

1 visit (in-person)

Post-Transplantation Treatment

Patients receive cyclophosphamide, cyclosporine, mycophenolate, and filgrastim to support engraftment and prevent GVHD

35 days

Frequent visits for monitoring and medication administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Visits at 28, 56, 84, 365, and 730 days post-transplant

Treatment Details

Interventions

• Cyclosporine
• Fludarabine
• Mycophenolate Mofetil
• Mycophenolate Sodium
• Total-Body Irradiation
• Treosulfan

Trial Overview The study tests if chemotherapy (treosulfan and fludarabine), total-body irradiation, followed by donor stem cell transplant is effective for treating blood cancers. The treatment aims to destroy cancer cells and make space for new stem cells from a donor that match the patient's immune system.

Participant Groups

Group I: Arm B (low dose treosulfan) Experimental Treatment 15 Interventions

Patients receive low dose treosulfan IV over 120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo total-body irradiation and allogeneic hematopoietic stem cell transplantation, and receive cyclophosphamide, cyclosporine, mycophenolate sodium or mycophenolate mofetil, and filgrastim as in Arm A. Additionally, patients undergo bone marrow aspiration and biopsy, and echocardiography at baseline and blood sample collection and CT or PET/CT on study.

Group II: Arm A (high dose treosulfan) Experimental Treatment 15 Interventions

Patients receive high dose treosulfan IV over 120 minutes on days -6 to -4 and fludarabine IV over 60 minutes on days -6 to -2. Patients then undergo total-body irradiation on day -1 and allogeneic hematopoietic stem cell transplantation on day 0. Patients then receive cyclophosphamide IV over 1-2 hours on days 3-4. Beginning on day 5, patients receive cyclosporine IV BID or TID over 1-2 hours or PO (after 3 months, in the absence of GVHD, cyclosporine tapering will start by 5-10% per week, until drug withdrawal at 6 months post-transplant). Beginning on day 5, patients also receive mycophenolate sodium PO TID or mycophenolate mofetil IV or PO TID until day 35 (may be continued if active GVHD is present). Beginning on day 5, patients also receive filgrastim until the absolute neutrophil count is \> 1,000/uL for 3 consecutive days. Additionally, patients undergo bone marrow aspiration and biopsy, and echocardiography at baseline and blood sample collection and CT or PET/CT on study.

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+

medac GmbH

Industry Sponsor

Trials

40

Recruited

9,300+

Findings from Research

In a study of 85 patients with hematological malignancies, adding fludarabine to a 2-Gy total body irradiation (TBI) regimen before stem cell transplantation resulted in better overall survival (65% vs. 54%) and lower relapse rates compared to TBI alone.

The combination of fludarabine and TBI led to significantly higher levels of donor T cell and NK cell chimerism, indicating improved donor engraftment and a stronger graft-versus-tumor effect, which is crucial for successful transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. Kornblit, B., Maloney, DG., Storb, R., et al.[2021]

In a study of 89 hematopoietic cell transplantation recipients, higher levels of the active metabolite of cyclophosphamide (PM AUC0-8 hr) were linked to worse nonrelapse mortality and overall survival, indicating that careful monitoring of this metabolite is crucial for patient outcomes.

Patients with low levels of the active metabolite of fludarabine (F-ara-ADay-4) and low PM AUC0-8 hr had significantly lower nonrelapse mortality, suggesting that optimizing drug exposure could improve safety and efficacy in reduced-intensity conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. Takahashi, T., Scheibner, A., Cao, Q., et al.[2021]

Fludarabine, while used to reduce toxicity in bone marrow transplantation, can actually damage human endothelial and epithelial cells and provoke a proinflammatory response, which may complicate transplantation outcomes.

Defibrotide has been identified as a protective agent against the harmful effects of fludarabine, potentially allowing for safer pretransplant conditioning without compromising its antileukemic properties.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. Eissner, G., Multhoff, G., Gerbitz, A., et al.[2021]

In a study involving three children with refractory severe aplastic anemia (SAA), a radiotherapy-free conditioning regimen using fludarabine and other agents was effective in preparing them for hemopoietic cell transplantation (HCT) without the development of graft-versus-host disease (GVHD).

All patients achieved normal blood counts and complete donor chimerism after the transplant, demonstrating that fludarabine-based conditioning can be a safe and effective option for children undergoing HCT from alternative donors, even after previous transplant failures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. Urban, C., Benesch, M., Sykora, KW., et al.[2013]

In a study involving 100 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), the combination of treosulfan/fludarabine with low-dose total body irradiation (TBI) significantly improved progression-free survival, leading to a 1-year overall survival rate of 80% compared to 69% for those without TBI.

The addition of TBI particularly benefited patients with AML, showing a lower 1-year relapse incidence of 16% compared to 35% in the non-TBI group, highlighting the treatment's efficacy in high-risk populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia. Deeg, HJ., Stevens, EA., Salit, RB., et al.[2019]

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 study of 87 adult hematopoietic cell transplantation recipients, higher plasma concentrations of fludarabine (F-ara-A) were linked to an increased risk of treatment-related mortality (TRM) and reduced overall survival (OS), indicating the need for careful monitoring of drug levels.

Patients with renal insufficiency experienced higher F-ara-A exposures, suggesting that individualized dosing strategies are essential to prevent toxicity and optimize outcomes in HCT recipients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation. Long-Boyle, JR., Green, KG., Brunstein, CG., et al.[2021]

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]

References

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

Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial. [2021]

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

Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy. [2021]

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

Fludarabine induces apoptosis, activation, and allogenicity in human endothelial and epithelial cells: protective effect of defibrotide. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Non-radiotherapy conditioning with stem cell transplantation from alternative donors in children with refractory severe aplastic anemia. [2013]

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

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia. [2019]

6. 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]

7. England pubmed.ncbi.nlm.nih.gov

High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation. [2021]

8. Spain pubmed.ncbi.nlm.nih.gov

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