Treosulfan-Based vs Clofarabine-Based Conditioning for Leukemia

Overseen By Phuong Vo

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fred Hutchinson Cancer Research Center

Must not be taking: Amphotericin B, Active triazoles

Disqualifiers: Circulating blasts, Organ dysfunction, CNS leukemia, 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: 28

80 Participants Needed

Trial Summary

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 effectiveness of the drug combination of Treosulfan and Clofarabine for leukemia treatment?

Research shows that using Treosulfan and Clofarabine as a conditioning regimen before stem cell transplantation is feasible, with a 78% one-year overall survival rate in patients with low to intermediate risk scores. This combination also allows for rapid engraftment and has a favorable safety profile, although relapse remains a concern for high-risk patients. ^{1 2 3 4 5}

Is the combination of Treosulfan and Clofarabine safe for use in humans?

The combination of Treosulfan and Clofarabine has been studied in clinical trials and is generally considered safe, with manageable side effects. Common side effects include infections and liver enzyme changes, but serious complications like organ toxicity are relatively low. The treatment has been well-tolerated in both adults and children, with specific attention to dose adjustments based on age and kidney function. ^{1 3 4 6 7}

What makes the Treosulfan-based conditioning treatment unique for leukemia?

Treosulfan-based conditioning is unique because it offers a reduced-toxicity option with strong immunosuppressive effects, leading to lower rates of organ toxicity and graft-versus-host disease (a condition where the donor cells attack the recipient's body) compared to traditional regimens. This makes it a promising choice for patients who are not eligible for standard myeloablative conditioning, with favorable survival rates and consistent engraftment. ^{1 3 5 8 9}

What is the purpose of this trial?

This phase II trials studies the effect of treosulfan-based versus clofarabine-based conditioning regimens before donor hematopoietic stem cell transplant in treating patients with myelodysplastic syndromes or acute myeloid leukemia. Chemotherapy drugs, such as treosulfan, fludarabine, and clofarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy and total-body irradiation before a donor hematopoietic stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. When the healthy stem cells from a donor are infused into a patient, they may help the patient's bone marrow make more healthy cells and platelets and may help destroy any remaining cancer cells. This study may help doctors determine whether treosulfan-based or clofarabine-based conditioning regimen works better before donor hematopoietic stem cell transplant in treating patients with myelodysplastic syndromes or acute myeloid leukemia.

Research Team

Phuong Vo

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

Adults aged 18-70 with myelodysplastic syndromes or acute myeloid leukemia, having less than 5% marrow blasts and a Karnofsky performance score of at least 60%. Participants must have compatible donors for stem cell transplant. Exclusions include severe non-cancer illnesses, active infections, HIV/hepatitis positivity, certain heart/lung/kidney diseases, pregnant or breastfeeding women, and those unwilling to use contraception.

Inclusion Criteria

My donor matches me closely in genetic markers for transplant.

Patients with previous autologous or allogeneic HCT may enroll

Able to give informed consent

Exclusion Criteria

My fungal infection has worsened despite treatment.

Known hypersensitivity to specific drugs

I am unable to understand and agree to the study's details on my own.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning and Transplantation

Patients receive chemotherapy and total-body irradiation followed by hematopoietic cell transplantation

7 days

Daily visits for chemotherapy administration and transplantation

Follow-up

Participants are monitored for safety and effectiveness after transplantation

5 years

Visits at days 28, 56, 84, 180, years 1 and 1.5, then annually

Treatment Details

Interventions

• Clofarabine
• Hematopoietic Cell Transplantation
• Total-Body Irradiation
• Treosulfan

Trial Overview The trial compares two pre-transplant chemotherapy regimens: treosulfan-based vs clofarabine-based conditioning. These treatments aim to eliminate cancer cells and make space in the bone marrow for donor stem cells which can regenerate healthy blood cells and help destroy any remaining cancer.

Participant Groups

Group I: Arm B (clofarabine, TBI, HCT) Experimental Treatment 9 Interventions

Patients receive clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.

Group II: Arm A (treosulfan, fludarabine, TBI, HCT) Experimental Treatment 10 Interventions

Patients receive treosulfan IV over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo TBI followed by HCT on day 0. Patients undergo ECHO or MUGA and lumbar puncture pre-transplant and undergo bone marrow aspiration, bone marrow biopsy, and collection of blood samples at pre-transplant and post-transplant.

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

Approved in United States as Clolar for:

• Acute lymphoblastic leukemia (ALL) in pediatric patients

Approved in European Union as Evoltra for:

• Acute lymphoblastic leukemia (ALL) in pediatric patients

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+

Medexus Pharma, Inc.

Industry Sponsor

Trials

4

Recruited

190+

Findings from Research

In a Phase II study involving 44 patients with hematologic malignancies, the conditioning regimen of clofarabine and treosulfan before allogeneic hematopoietic stem cell transplantation (allo-HSCT) demonstrated feasibility, achieving a 1-year overall survival rate of 78% in patients with low-intermediate Disease Risk Index scores.

The study reported a 100-day nonrelapse mortality rate of 18%, primarily due to bacterial infections, highlighting the need for improved strategies to manage infection risks and reduce relapse rates, especially in patients with high-very high Disease Risk Index scores.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine and Treosulfan as Conditioning for Matched Related and Unrelated Hematopoietic Stem Cell Transplantation: Results from the Clo3o Phase II Trial. Peccatori, J., Mastaglio, S., Giglio, F., et al.[2021]

Clofarabine-based reduced intensity conditioning (RIC) for allogeneic stem cell transplantation showed promising 2-year survival rates for patients with acute myeloid leukemia (AML), with an overall survival rate of 64.5% and disease-free survival rate of 57.2% among 84 patients studied over a median follow-up of 31 months.

For patients with AML in complete remission, the 2-year overall survival rate was even higher at 74.2%, indicating that the CloB2A1/A2 RIC regimen could be an effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofarabine/busulfan-based reduced intensity conditioning regimens provides very good survivals in acute myeloid leukemia patients in complete remission at transplant: a retrospective study on behalf of the SFGM-TC. Le Bourgeois, A., Labopin, M., Leclerc, M., et al.[2023]

Treosulfan, used in combination with fludarabine, shows a favorable toxicity profile and effective engraftment in allogeneic hematopoietic stem cell transplantation (SCT), with non-relapse mortality rates between 9-28%.

The regimen demonstrates low relapse rates (5-30%) and promising survival outcomes (40-80%), particularly in patients with myelodysplastic syndrome (36-70% survival) and leukemia in remission (60-70% survival), indicating its potential as a safer alternative to standard conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. Danylesko, I., Shimoni, A., Nagler, A.[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 multicenter trial involving 56 patients with hematologic malignancies, treosulfan was safely administered as a conditioning agent for stem-cell transplantation, with no cases of engraftment failure and low nonrelapse mortality (20%) over 2 years.

The study found that treosulfan at a dose of 14 g/m² showed promising results, combining low toxicity with a lower incidence of relapse, making it a candidate for further research in conditioning regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. Casper, J., Wolff, D., Knauf, W., et al.[2019]

Clofarabine is a nucleoside analog effective for treating pediatric relapsed or refractory acute lymphoblastic leukemia, with pharmacokinetics showing rapid absorption and a bioavailability of 57.5%.

The pharmacokinetics of clofarabine differ significantly between adults and children, with adults experiencing higher drug exposure at similar doses, indicating that dose adjustments may be necessary for patients with renal impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer. Bonate, PL., Cunningham, CC., Gaynon, P., et al.[2018]

In a phase I clinical trial involving 15 patients with recurrent/refractory leukemia, clofarabine was well tolerated at a dose of 50 mg/m/d for 5 days, showing minimal treatment-related mortality in this high-risk group.

The treatment led to quick hematopoietic recovery, with median times to neutrophil and platelet engraftment of 11 and 16 days, respectively, although 73.3% of patients ultimately died, primarily due to disease relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Haploidentical Donor Transplantation Using a Novel Clofarabine-containing Conditioning Regimen for Very High-risk Hematologic Malignant Neoplasms. Sharma, A., Kang, G., Sunkara, A., et al.[2019]

In a phase II trial involving 65 children with various hematological malignancies, treosulfan-based conditioning demonstrated a high rate of complete donor chimerism (98.4%) and a low non-relapse mortality rate (3.1%) at 36 months, indicating its safety and efficacy.

The overall survival rate was 83.0% at 36 months, with manageable rates of acute and chronic graft-versus-host disease, supporting the recommendation of treosulfan/fludarabine/thiotepa for myeloablative conditioning in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies. Kalwak, K., Mielcarek, M., Patrick, K., et al.[2021]

A new reduced-toxicity conditioning regimen using treosulfan and fludarabine was tested in 75 patients with acute myeloid leukemia (AML), showing promising safety and efficacy with a 2-year overall survival rate of 61%.

The regimen resulted in primary engraftment of neutrophils after a median of 20 days, with manageable adverse events, including a 21% incidence of acute graft-versus-host disease (GVHD) and a 34% relapse rate after 2 years.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning. Casper, J., Holowiecki, J., Trenschel, R., et al.[2013]

References

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

Clofarabine and Treosulfan as Conditioning for Matched Related and Unrelated Hematopoietic Stem Cell Transplantation: Results from the Clo3o Phase II Trial. [2021]

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

Clofarabine/busulfan-based reduced intensity conditioning regimens provides very good survivals in acute myeloid leukemia patients in complete remission at transplant: a retrospective study on behalf of the SFGM-TC. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning before hematopoietic SCT: more than a BU look-alike. [2013]

4. Spain pubmed.ncbi.nlm.nih.gov

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

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

Allogeneic hematopoietic stem-cell transplantation in patients with hematologic malignancies after dose-escalated treosulfan/fludarabine conditioning. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer. [2018]

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

Haploidentical Donor Transplantation Using a Novel Clofarabine-containing Conditioning Regimen for Very High-risk Hematologic Malignant Neoplasms. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Treosulfan-fludarabine-thiotepa-based conditioning treatment before allogeneic hematopoietic stem cell transplantation for pediatric patients with hematological malignancies. [2021]

9. England pubmed.ncbi.nlm.nih.gov

Allogeneic hematopoietic SCT in patients with AML following treosulfan/fludarabine conditioning. [2013]