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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of a combination of treatments for blood cancers. Patients receive chemotherapy and total-body irradiation (a type of radiation therapy) before a donor stem cell transplant, which may help destroy cancer cells and rebuild healthy blood cells. The trial includes two groups: one receives a high dose of treosulfan, and the other a low dose, alongside other treatments. This trial may suit individuals with certain blood cancers, such as leukemia or lymphoma, who are currently in remission or have responded well to initial treatments. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to important advancements in blood cancer treatment.

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.

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

Research has shown that treosulfan, whether administered in high or low doses, is generally well-tolerated by patients undergoing stem cell transplants. Studies have found that treosulfan helps patients receive donor stem cells with a low risk of serious side effects. For those receiving high doses, side effects are manageable, though some patients may experience common issues like reduced bone marrow activity, a known side effect of chemotherapy.

When comparing low-dose treosulfan to other similar treatments, studies have found it poses a lower risk of causing long-term graft-versus-host disease, a condition where the donor's cells attack the patient's body, while still being effective. This makes it a safer option for many patients.

Overall, both high and low doses of treosulfan have proven to be safe, with patients experiencing side effects similar to those expected with chemotherapy. Evidence from previous research supports its use in stem cell transplants for blood cancers, focusing on balancing effectiveness and safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using treosulfan in stem cell transplants for blood cancers because it offers a potentially safer alternative to more aggressive conditioning regimens. Unlike traditional options like busulfan, treosulfan is known for its reduced toxicity, particularly affecting the liver, lungs, and gastrointestinal tract, which could lead to fewer complications for patients. The study explores both high and low doses, aiming to balance effectiveness with minimized side effects. This approach could make stem cell transplants accessible to more patients, including those who are older or have pre-existing health conditions.

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

This trial will compare high-dose and low-dose treosulfan as part of the treatment regimen for blood cancers. Research has shown that treosulfan, in both high and low doses, effectively treats blood cancers. In this trial, participants in Arm A will receive high-dose treosulfan. Specifically, studies reported that 84% of patients had no detectable cancer, which is very encouraging. Participants in Arm B will receive low-dose treosulfan, which also yields positive outcomes, with patients experiencing good survival rates and manageable side effects. Treosulfan works well when combined with other treatments like fludarabine and total-body irradiation, aiding the body in accepting donor stem cells and fighting cancer, making it a strong option for those considering stem cell transplants. ^{1 6 7 8 9}

Who Is on the Research Team?

Filippo Milano

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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]

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