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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the optimal dose of total body irradiation combined with specific chemotherapy treatments to prepare patients for a stem cell transplant. It aims to assist those with certain types of leukemia or related disorders that have returned or aren't responding to existing treatments. The goal is to eliminate cancer cells, create space for new blood cells, and prevent complications after the transplant. This trial suits patients with leukemia that has been difficult to treat or has recurred despite previous treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

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.

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

Research has shown that both CLAG-M and FLAG-Ida chemotherapy treatments, when combined with total body irradiation (TBI), have been tested for safety in patients with blood cancers like leukemia.

For CLAG-M treatment, studies have found that the combination of cladribine, cytarabine, filgrastim, and mitoxantrone is generally tolerated. However, some patients may experience side effects common to strong chemotherapy, such as low blood cell counts and a higher risk of infections. These treatments prepare the body for a stem cell transplant, which is crucial for recovery.

Regarding FLAG-Ida treatment, research indicates that this combination, which includes idarubicin and fludarabine, is also generally well-tolerated. Patients might face similar side effects, like low blood counts and infection risks. The goal is to prepare the patient's body effectively for a stem cell transplant.

Both treatments aim to increase the chances of a successful transplant while managing side effects. Potential participants should consult their healthcare team to fully understand the risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard leukemia treatments, which often rely solely on chemotherapy, this trial leverages a combination of chemotherapy, stem cell transplantation, and total-body irradiation. Researchers are excited because this approach not only targets cancer cells more aggressively but also supports the patient's immune system through hematopoietic cell transplantation. This dual action could potentially improve recovery rates and reduce relapse chances. Additionally, the inclusion of graft-versus-host disease (GVHD) prophylaxis aims to minimize complications, making the treatment potentially safer and more effective than traditional options.

What evidence suggests that this trial's treatments could be effective for leukemia and related disorders?

Research shows that combining chemotherapy with stem cell transplants can help treat certain blood cancers. In this trial, participants will be assigned to one of two treatment arms. Arm I involves the CLAG-M treatment, which includes drugs like cladribine and mitoxantrone, and has shown promising results, with 71% of patients living for at least two years without disease recurrence. Arm II involves the FLAG-Ida treatment, which uses drugs like fludarabine and idarubicin, and has a 37% success rate of patients remaining cancer-free for five years. Both treatments aim to destroy cancer cells and support the growth of new healthy cells, potentially improving outcomes for patients with hard-to-treat leukemia. ^{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?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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]

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]

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]

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 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]

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 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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11223948/

Intensive Re-Induction Chemotherapy Followed by Early ... Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplant ...

2. withpower.com withpower.com/trial/phase-1-leukemia-myelomonocytic-juvenile-11-2020-f9055

Chemotherapy + Stem Cell Transplant for Leukemia and Related ... 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 ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT04375631?term=AREA%5BInterventionSearch%5D(ERL%20080)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=2

Study Details | NCT04375631 | CLAG-M or FLAG-Ida ... This phase I trial studies the best dose of total body irradiation when given with cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M) or ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S000649712403012X

CLAG-M or FLAG-Ida Followed Immediately By Allogeneic ... Here, we developed a new HCT platform that combines high-intensity chemotherapy with CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) or ...

5. researchgate.net researchgate.net/publication/374778166_CLAG_combined_with_total_body_irradiation_as_intensive_conditioning_chemotherapy_prior_to_allogeneic_hematopoietic_stem_cell_transplantation_in_patients_with_refractory_or_relapsed_acute_myeloid_leuke

CLAG combined with total body irradiation as intensive ... A total of 70 patients, including 21 primary refractory and 49 relapsed AML, were analyzed. Forty-nine (70%) patients had extramedullary diseases, and 54 (77%) ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04861207

Total Body Irradiation and Cladribine Before Allogeneic ... A single center, prospective, one arm clinical study to assess the tolerance and effectiveness of total body irradiation and cladribine in adult patients ...

7. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2016-00477

Early Allogeneic Hematopoietic Cell Transplantation in ... Drugs used in chemotherapy, such as filgrastim, cladribine, cytarabine and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells ...

8. researchgate.net researchgate.net/publication/355223597_A_novel_intensive_conditioning_regimen_for_allogeneic_hematopoietic_stem_cell_transplantation_in_the_treatment_of_relapsedrefractory_acute_myeloid_leukemia

A novel intensive conditioning regimen for allogeneic ... The 1-year OS and leukemia-free survival (LFS) rates after allo-HSCT were 69.4% and 52.9%, respectively. In another study, patients were ...

9. astctjournal.org astctjournal.org/article/S2666-6367(24)00376-2/fulltext

Intensive Reinduction Chemotherapy Followed by Early ... Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell ...