Chemotherapy + Stem Cell Transplant for Leukemia and Related Disorders

Overseen By Filippo Milano

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Fred Hutchinson Cancer Center

Must not be taking: Anti-leukemia agents

Disqualifiers: Active CNS disease, Infections, Pregnancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 101

120 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, concurrent treatment with any other approved or investigational anti-leukemia agent is not allowed.

What data supports the effectiveness of the treatment involving chemotherapy and stem cell transplant for leukemia and related disorders?

Research shows that treosulfan, a component of the treatment, has been effective in reducing relapse rates and improving survival in leukemia patients when used in conditioning regimens before stem cell transplantation. Additionally, total body irradiation, another component, has been used successfully in pediatric hematological malignancies, showing good survival rates and low toxicity. ^{1 2 3 4 5}

Is the combination of chemotherapy and stem cell transplant generally safe for humans?

Research shows that treosulfan, used in combination with other drugs for stem cell transplants, has a favorable safety profile with low rates of organ toxicity and non-relapse mortality. It is associated with moderate toxicity and promising survival rates, making it a potential alternative for patients not eligible for standard treatments. ^{1 6 7 8 9}

What makes the chemotherapy and stem cell transplant treatment for leukemia unique?

This treatment is unique because it combines chemotherapy with stem cell transplantation and uses treosulfan, a drug with strong immunosuppressive and myeloablative (bone marrow destroying) properties, which has shown promising results in reducing toxicity and improving survival rates compared to traditional treatments like busulfan. ^{1 9 10 11 12}

What is the purpose of this trial?

This phase I trial studies the best dose of total body irradiation when given with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) or idarubicin, fludarabine, cytarabine and filgrastim (FLAG-Ida) chemotherapy reduced-intensity conditioning regimen before stem cell transplant in treating patients with acute myeloid leukemia, myelodysplastic syndrome, or chronic myelomonocytic leukemia that has come back (relapsed) or does not respond to treatment (refractory). Giving chemotherapy and total body irradiation before a donor peripheral blood 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. Sometimes the transplanted cells from a donor can attack the body's normal cells called graft versus host disease. Giving cyclophosphamide, cyclosporine, and mycophenolate mofetil after the transplant may stop this from happening.

Research Team

Filippo Milano

Principal Investigator

Fred Hutch/University of Washington Cancer Consortium

Eligibility Criteria

Adults aged 18-75 with certain blood cancers (AML, MDS, CMML) that are resistant to treatment or have returned after treatment. They must have a related donor for stem cell transplant, be in good physical condition with no severe heart, liver or kidney issues and not pregnant. A suitable donor without strong immune reactions against the patient's cells is needed.

Inclusion Criteria

I have a donor match for a stem cell transplant.

My MDS or CMML did not respond to at least one standard treatment.

My donor is a family member who matches me closely in specific genetic markers.

Exclusion Criteria

I have an active brain or spinal cord condition.

I am not currently receiving any other leukemia treatments.

I have an infection, but it is being treated or is under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Chemotherapy and Conditioning

Participants receive chemotherapy (CLAG-M or FLAG-Ida) and total body irradiation before stem cell transplant

9 days

Daily visits (in-person)

Transplantation and GVHD Prophylaxis

Participants undergo hematopoietic cell transplantation and receive GVHD prophylaxis

60 days

Frequent visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Visits at 100 days, 6, 12, and 24 months post-transplant

Treatment Details

Interventions

• Cladribine
• Cyclophosphamide
• Cyclosporine
• Cytarabine
• Hematopoietic Cell Transplantation
• Mitoxantrone
• Mycophenolate Mofetil
• Total-Body Irradiation

Trial Overview The trial tests two chemotherapy regimens (CLAG-M and FLAG-Ida) combined with low-dose total body irradiation before a stem cell transplant from a donor. The goal is to see how well this approach works for treating relapsed/refractory blood cancers by making space in bone marrow for new cells and potentially eliminating remaining cancer.

Participant Groups

Group I: Arm II (FLAG-Ida, TBI, HCT, GVHD prophylaxis) Experimental Treatment 15 Interventions

See detailed description.

Group II: Arm I (CLAG-M, TBI, HCT, GVHD prophylaxis) Experimental Treatment 16 Interventions

See detailed description.

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

Approved in United States as Leustatin for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma
• Multiple sclerosis

Approved in European Union as Litak for:

• Hairy cell leukemia
• Chronic lymphocytic leukemia (CLL)
• Non-Hodgkin's lymphoma

Who Is Running the Clinical Trial?

Fred Hutchinson Cancer Center

Lead Sponsor

Trials

583

Recruited

1,341,000+

Fred Hutchinson Cancer Research Center

Lead Sponsor

Trials

444

Recruited

148,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

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]

In a study involving 14 children with advanced neuroblastomas, total body irradiation (TBI) was administered in tolerable doses alongside standard chemotherapy, showing that the regimen is generally well tolerated despite some cases of toxicity.

Out of the 12 patients who completed the treatment, 4 survived free of disease for over 12 months, indicating that TBI can be an effective adjunctive therapy when carefully managed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cyclic, low-dose total body irradiation for metastatic neuroblastoma. DAngio, GJ., Evans, AE.[2019]

Treosulfan demonstrated significant antitumor activity against both small-cell and non-small-cell lung carcinomas in a study involving various human tumor models, showing growth reductions of 60-98% compared to control tumors.

In head-to-head comparisons, treosulfan outperformed established chemotherapy agents like ifosfamide, cisplatin, and etoposide in reducing tumor growth, suggesting it could be a promising candidate for further clinical trials in lung cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of treosulfan in human lung carcinomas. Köpf-Maier, P., Sass, G.[2019]

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 of 22 children undergoing allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies, a conditioning regimen using fractionated 8-Gy total body irradiation (TBI), fludarabine, and cyclophosphamide resulted in no cases of graft failure and low rates of severe toxicity, with 18 patients experiencing no renal replacement therapy (RRT).

The overall survival rate at two years was 57.1% for acute lymphoblastic leukemia and 91.7% for myeloid leukemia, indicating that this intermediate-dose TBI regimen may provide effective treatment while minimizing toxicity compared to higher-dose regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low toxicity of a conditioning with 8-Gy total body irradiation, fludarabine and cyclophosphamide as preparative regimen for allogeneic hematopoietic stem cell transplantation in pediatric hematological malignancies. Yanagisawa, R., Nakazawa, Y., Sakashita, K., et al.[2013]

In a study of 45 patients with primary myelodysplastic syndromes, a conditioning regimen using treosulfan and fludarabine resulted in a high primary engraftment rate of neutrophils (almost all patients) after a median of 17 days, indicating effective treatment preparation for allogeneic stem cell transplantation.

The 2-year overall survival rate was 71% and disease-free survival was 67%, suggesting that this treosulfan-based regimen is a promising and effective option for treating myelodysplastic syndromes, despite some patients experiencing significant adverse events like infections and graft-versus-host disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial. Ruutu, T., Volin, L., Beelen, DW., et al.[2021]

In a study of 87 pediatric patients undergoing allogeneic hematopoietic stem cell transplant, treosulfan showed a significant relationship between its pharmacokinetics and patient outcomes, with higher drug exposure linked to increased mortality risk.

A cumulative treosulfan area under the curve (AUC) of 4,800 mg hour/L was associated with an 82% probability of successful engraftment and no mortality, suggesting that careful monitoring and dose adjustment may enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial. Chiesa, R., Standing, JF., Winter, R., et al.[2021]

Treosulfan demonstrated greater cytotoxic activity against leukemic cells from 20 children compared to busulfan, suggesting it may be a more effective treatment option for pediatric leukemia.

The combination of treosulfan with fludarabine showed a synergistic effect, enhancing its ability to induce apoptosis in malignant cells, which supports its potential use in myeloablative therapy for children undergoing hematopoietic transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients. Munkelt, D., Koehl, U., Kloess, S., et al.[2016]

A non-TBI-based preparative regimen using treosulfan, etoposide, and cyclophosphamide for allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia (ALL) showed moderate toxicity, with a low non-relapse mortality rate of 8% at one year.

After a median follow-up of 24 months, the regimen demonstrated a cumulative relapse incidence of 36% at one year and 51% at two years, with estimated disease-free and overall survival rates of 36% and 48%, respectively, indicating its potential as a viable alternative to traditional TBI-based therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Allogeneic stem cell transplantation after conditioning with treosulfan, etoposide and cyclophosphamide for patients with ALL: a phase II-study on behalf of the German Cooperative Transplant Study Group and ALL Study Group (GMALL). Kröger, N., Bornhäuser, M., Stelljes, M., et al.[2018]

Treosulfan demonstrated significant antileukaemic activity in pediatric models of acute lymphoblastic leukaemia (ALL), achieving complete regression of tumors and long-term survival in treated mice, outperforming equitoxic doses of busulfan and cyclophosphamide.

While treosulfan caused some myelotoxicity and minor weight loss, these side effects were manageable, suggesting it could be a promising alternative conditioning agent for stem cell transplantation in patients with hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). Fichtner, I., Becker, M., Baumgart, J.[2019]

Busulfan has a well-established role in high-dose chemotherapy for treating hematologic malignancies and has been extensively studied for over 30 years, providing a clear understanding of its efficacy and pharmacokinetics.

Treosulfan, a newer analogue of busulfan, shows promise in treating hematologic malignancies but requires further research to fully understand its complex metabolism and pharmacological activity, particularly its pharmacokinetics and pharmacodynamics in high-dose chemotherapy contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. Galaup, A., Paci, A.[2013]

Treosulfan demonstrated significant myeloablative and immunosuppressive effects in a preclinical study with BALB/c mice, showing greater efficacy in depleting splenic B and T cells compared to busulfan and cyclophosphamide.

The study suggests that treosulfan could be a viable single-agent option for conditioning before allogeneic stem cell transplantation, as it effectively induces myeloablation without the need for bone marrow support.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Myeloablative and immunosuppressive properties of treosulfan in mice. Sjöö, F., Hassan, Z., Abedi-Valugerdi, M., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

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

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

Cyclic, low-dose total body irradiation for metastatic neuroblastoma. [2019]

3. Germany pubmed.ncbi.nlm.nih.gov

Antitumor activity of treosulfan in human lung carcinomas. [2019]

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. Denmark pubmed.ncbi.nlm.nih.gov

Low toxicity of a conditioning with 8-Gy total body irradiation, fludarabine and cyclophosphamide as preparative regimen for allogeneic hematopoietic stem cell transplantation in pediatric hematological malignancies. [2013]

6. Italy pubmed.ncbi.nlm.nih.gov

Reduced-toxicity conditioning with treosulfan and fludarabine in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndromes: final results of an international prospective phase II trial. [2021]

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

Proposed Therapeutic Range of Treosulfan in Reduced Toxicity Pediatric Allogeneic Hematopoietic Stem Cell Transplant Conditioning: Results From a Prospective Trial. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Cytotoxic effects of treosulfan and busulfan against leukemic cells of pediatric patients. [2016]

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

Allogeneic stem cell transplantation after conditioning with treosulfan, etoposide and cyclophosphamide for patients with ALL: a phase II-study on behalf of the German Cooperative Transplant Study Group and ALL Study Group (GMALL). [2018]

10. England pubmed.ncbi.nlm.nih.gov

Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). [2019]

11. England pubmed.ncbi.nlm.nih.gov

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. [2013]

12. Netherlands pubmed.ncbi.nlm.nih.gov

Myeloablative and immunosuppressive properties of treosulfan in mice. [2013]