Treosulfan-Based Versus Clofarabine-Based Conditioning Before Donor Hematopoietic Stem Cell Transplant for the Treatment of Myelodysplastic Syndromes or Acute Myeloid Leukemia

A Phase II Randomized Study to Assess Outcomes With Treosulfan-Based Versus Clofarabine-Based Conditioning in Patients With Myelodysplastic Syndromes With Excess Blasts (MDS-EB), or Acute Myeloid Leukemia (AML) Undergoing Allogeneic Hematopoietic Cell Transplantation (HCT)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Lumbar Puncture; Drug: Fludarabine; Radiation: Total-Body Irradiation; Procedure: Hematopoietic Cell Transplantation; Drug: Treosulfan; Drug: Clofarabine; Procedure: Multigated Acquisition Scan; Procedure: Bone Marrow Aspiration; Procedure: Bone Marrow Biopsy; Procedure: Echocardiography Test

Detailed Description

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine IV over 30 minutes on days -6 to -2. Patients also undergo total-body irradiation (TBI) followed by HCT on day 0. Patients undergo echocardiography (ECHO) or multigated acquisition scan (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.

ARM B: 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.

After completion of study intervention, patients are followed up at days 28, 56, 84 and 180, years 1 and 1.5 and then annually for 5 years.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age >= 18 years and =< 75 years
• Diagnosis of MDS-EB or AML: must have < 5% marrow blasts (by morphology and/or flow cytometry) at time of transplant
• Karnofsky performance score (KPS) >= 60% on pre-HCT evaluation
• Able to give informed consent
• Patients with previous autologous or allogeneic HCT may enroll
• DONOR: Human leukocyte antigen (HLA)-identical related donors or unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high resolution deoxyribonucleic acid (DNA) typing; mismatch for only one HLA allele at class I is allowed
• DONOR: Donors able to undergo peripheral blood stem cell collection. Only granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cell (PBSC) will be permitted as an hematopoietic stem cell (HSC) source on this protocol

Exclusion Criteria:

• Presence of circulating blasts (in the blood) detected by standard pathology for patients with AML
• Presence of >= 5% circulating leukemic blasts (in the blood) detected by standard pathology for patients with MDS-EB
• Patients with promyelocytic AML

• Organ dysfunction

  • Cardiac: Ejection fraction < 35% (or, if unable to obtain ejection fraction, shortening fraction of < 26%) or cardiac insufficiency requiring treatment or symptomatic coronary artery disease. Patients with a shortening fraction < 26% may be enrolled if approved by a cardiologist

  • Pulmonary:

    • Diffusion capacity of the lung for carbon monoxide (DLCO) < 40%, total lung capacity (TLC) < 40%, forced expiratory volume in 1 second (FEV1) < 40% and/or receiving supplementary continuous oxygen. When pulmonary function test (PFT)s cannot be obtained, the 6-minute walk test (6 minute walk functional test [6MWT], also known as exercise oximetry) will be used: Any patient with oxygen saturation on room air of < 89% during a 6MWT will be excluded
    • The principal investigator (PI) must approve enrollment of all patients with pulmonary nodules
  • Renal: Serum creatinine should be within normal limits as specified by Standard Practice guidelines. For subjects with serum creatinine > upper limit of normal, a 24-hour creatinine clearance will be performed and should be equal to or more than the lower limit of normal
  • Hepatic: Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension. Patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin > 3 mg/dL, or symptomatic biliary disease
• With active infectious disease requiring deferral of conditioning, as recommended by an infectious disease specialist
• Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
• With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis because of possible risk of lethal infection when treated with immunosuppressive therapy
• With central nervous system (CNS) leukemia at the time of treatment
• Patients with active non-hematologic malignancies (except non-melanoma skin cancers) or those with non-hematologic malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease but have a greater than 20% chance of having disease recurrence within five years. This exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
• With life expectancy severely limited by diseases other than malignancy
• Fertile men and women unwilling to used contraceptive techniques during treatment and for 12 months following
• Women who are pregnant or lactating
• With known hypersensitivity to treosulfan, fludarabine, or clofarabine
• The use of non-Food and Drug Administration (FDA) approved investigational drugs would not be allowed within 4 weeks of the initiation of conditioning (day -6 for both arms)
• Unable to give informed consent
• Patients suitable for and willing to receive a standard high intensity preparative regimen
• DONOR: Donor (or centers) who will exclusively donate marrow
• DONOR: Donors who are HIV-positive and/or, medical conditions that would result in increased risk for G-CSF mobilization and harvest of PBSC
• DONOR: Donors are excluded when preexisting immunoreactivity is identified that would jeopardize donor hematopoietic cell engraftment. This determination is based on the standard practice of the individual institution. The recommended procedure for patients with 10 of 10 HLA allele level (phenotypic) match is to obtain a panel reactive antibody (PRA) screens to class I and class II antigens for all patients before HCT. If the PRA shows > 10% activity, then flow cytometric or B and T cell cytotoxic cross matches should be obtained. The donor should be excluded if any of the cytotoxic cross match assays are positive. For those patients with an HLA Class I allele mismatch, flow cytometric or B and T cell cytotoxic cross matches should be obtained regardless of the PRA results. A positive anti-donor cytotoxic cross match is an absolute donor exclusion
• DONOR: Donor is excluded if a patient is homozygous in the graft-rejection vector against the donor's mismatched HLA class I allele

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (treosulfan, fludarabine, TBI, HCT); 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.	Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; spinal tap; Drug: Fludarabine; Given IV; Other Names: Fluradosa; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Procedure: Hematopoietic Cell Transplantation; Undergo HCT; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Hematopoietic Stem Cell Infusion; Stem Cell Transplant; Drug: Treosulfan; Given IV; Other Names: 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-; Dihydroxybusulfan; Ovastat; Trecondi; Treosulphan; Tresulfon; Grafapex; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: MUGA; MUGA Scan; Multi-Gated Acquisition Scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Procedure: Echocardiography Test; Undergo ECHO; Other Names: EC
Experimental: Arm B (clofarabine, TBI, HCT); 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.	Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Procedure: Lumbar Puncture; Undergo lumbar puncture; Other Names: LP; spinal tap; Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Total Body Irradiation; TBI; SCT_TBI; Whole Body Irradiation; Whole-Body Irradiation; Procedure: Hematopoietic Cell Transplantation; Undergo HCT; Other Names: HSCT; HCT; Hematopoietic Stem Cell Transplantation; stem cell transplantation; Hematopoietic Stem Cell Infusion; Stem Cell Transplant; Drug: Clofarabine; Given IV; Other Names: Clofarex; Clolar; Procedure: Multigated Acquisition Scan; Undergo MUGA; Other Names: MUGA; MUGA Scan; Multi-Gated Acquisition Scan; Procedure: Bone Marrow Aspiration; Undergo bone marrow aspiration; Procedure: Bone Marrow Biopsy; Undergo bone marrow biopsy; Procedure: Echocardiography Test; Undergo ECHO; Other Names: EC

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Relapse-free survival	At 6 months after transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	At 1 year after transplant
Rate of non-relapse mortality	At 1 year after transplant
Relapse rate	At 1 year after transplant
Incidence of acute graft versus host disease	At 1 year after transplant
Duration of hospitalization	Up to day 100 post hematopoietic stem cell transplantation

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: Medexus Pharma, Inc.
• Investigators: Principal Investigator: Phuong Vo, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2023
• Primary Completion (Actual): January 22, 2026
• Study Completion (Estimated): July 16, 2026

Study Registration Dates

• First Submitted: July 29, 2021
• First Submitted That Met QC Criteria: July 29, 2021
• First Posted (Actual): August 6, 2021

Study Record Updates

• Last Update Posted (Actual): January 26, 2026
• Last Update Submitted That Met QC Criteria: January 23, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Bone Marrow Diseases; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Investigative Techniques; Therapeutics; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Nucleic Acids, Nucleotides, and Nucleosides; Biopsy; Transplantation; Purines; Nucleosides; Arabinonucleosides; Radiotherapy; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Diagnostic Techniques, Neurological; Ribonucleotides; Nucleotides; Adenine Nucleotides; Purine Nucleotides; Clofarabine; fludarabine; Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Spinal Puncture; Whole-Body Irradiation; treosulfan
• Other Study ID Numbers: RG1121616; NCI-2021-07474 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10598 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No