Treo/Flu/TBI With Donor Stem Cell Transplant for Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

A Randomized Phase II Study of Treosulfan, Fludarabine and Low-Dose TBI as Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients With Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

This randomized phase II trial studies how well treosulfan and fludarabine phosphate, with or without total body irradiation before donor stem cell transplant works in treating patients with myelodysplastic syndrome or acute myeloid leukemia. Giving chemotherapy, such as treosulfan and fludarabine phosphate, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus before and mycophenolate mofetil after the transplant may stop this from happening.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Myelomonocytic Leukemia; Myelodysplastic Syndrome; Myelodysplastic/Myeloproliferative Neoplasm; Minimal Residual Disease; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Acute Myeloid Leukemia in Remission
• Intervention / Treatment: Radiation: Total-Body Irradiation; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Laboratory Biomarker Analysis; Procedure: Allogeneic Bone Marrow Transplantation; Drug: Fludarabine Phosphate; Drug: Treosulfan

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the better of two treosulfan-based conditioning regimens in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), by comparing 6-month progression-free survival.

SECONDARY OBJECTIVES:

I. Determine the effects of two conditioning regimens on changes in gene expression profiles, and evaluate the association of gene expression profiles and disease relapse.

II. Determine the incidence of progression-free survival at 1 year and 2 years after hematopoietic cell transplantation (HCT).

III. Evaluate overall survival (OS) at 6 months, at 1 year and at 2 years after HCT.

IV. Determine the incidence of grades II-IV acute graft-versus-host disease (GVHD).

V. Determine the incidence of chronic GVHD.

VI. Determine donor chimerism around days +28 and +84.

CONDITIONING REGIMEN:

Arm A: Patients receive treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2.

Arm B: Patients receive treosulfan and fludarabine phosphate as in Arm A and undergo low-dose total-body irradiation (TBI) on day 0.

TRANSPLANT: Patients in both arms undergo allogeneic peripheral blood stem cell (PBSC) transplant or bone marrow transplant on day 0.

GVHD PROPHYLAXIS: Patients with a related donor receive tacrolimus orally (PO) every 8 or 12 hours on days -3 to 56 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 12 hours to day 28. Patients with an unrelated donor receive tacrolimus PO every 8 or 12 hours on days -3 to 100 with taper to day 180. Beginning 4-6 hours after PBSC infusion, patients also receive mycophenolate mofetil PO every 8 hours to day 40 with taper to day 96.

NOTE: Patients with related donors eligible for FHCRC protocol 2545 may receive cyclosporine IV, instead of tacrolimus, beginning on day -3 to day 50 with a taper to day 180.

After completion of study treatment, patients are followed up periodically.

• Study Type: Interventional
• Enrollment (Actual): 102
• 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: No older than 70 years (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• MDS, myelodysplastic syndrome/myeloproliferative neoplasia overlap disorders (including chronic myelomonocytic leukemia [CMML], and MDS/myeloproliferative neoplasm [MPN] unclassifiable syndromes)
• AML, other than acute promyelocytic leukemia (APL), in first or second remission or with minimal residual disease
• With Karnofsky index or Lansky Play-Performance scale > 70% on pre-transplant evaluation
• Able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)
• Patients with previous autologous or allogeneic HCT are allowed to enroll
• DONOR: Human leukocyte antigen (HLA)-identical related donors or
• DONOR: Unrelated donors matched for HLA-A, B, C, DRB1, and DQB1 as defined by high resolution deoxyribonucleic acid (DNA) typing; mismatch for one HLA allele is allowed
• DONOR: Donors able to undergo peripheral blood stem cell collection or bone marrow harvest
• DONOR: Donors in good general health, with a Karnofsky or Lansky play performance score > 90%
• DONOR: Donors able to give informed consent (if > 18 years), or with a legal guardian capable of giving informed consent (if < 18 years)

Exclusion Criteria:

• Receiving umbilical cord blood
• With impaired cardiac function as evidenced by 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
• With impaired pulmonary function as evidenced by partial pressure of oxygen (pO2) < 70 mm Hg and carbon monoxide diffusing capability test (DLCO) < 70% of predicted or pO2 < 80 mm Hg and DLCO < 60% of predicted; (or, for pediatric patients unable to perform pulmonary function tests, then oxygen (O2) saturation < 92% on room air), or receiving supplementary continuous oxygen
• With impaired renal function as evidenced by creatinine-clearance < 50% for age, weight, height or serum creatinine > 2 x upper limit of normal or dialysis-dependent
• With hepatic dysfunction as evidenced by total bilirubin > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis
• With hepatic dysfunction as evidenced by aspartate aminotransferase (AST) > 2.0 x upper limit of normal or evidence of synthetic dysfunction or severe cirrhosis
• With active infectious disease requiring deferral of conditioning, as recommended by an infectious disease specialist
• With human immunodeficiency virus (HIV)-positivity or active infectious hepatitis
• With central nervous system (CNS) leukemic involvement not clearing with intrathecal chemotherapy, cranial irradiation or both prior to initiating conditioning (day -6)
• Patients with active non-hematological malignancies (except non-melanoma skin cancers) or those with non-hematological malignancies who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 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
• Women who are pregnant or lactating
• With known hypersensitivity to treosulfan or fludarabine (fludarabine phosphate)
• Receiving another experimental drug within 4 weeks before initiation of conditioning (day -6)
• Unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent
• DONOR: Individuals deemed unable to undergo marrow harvesting or PBSC mobilization and leukapheresis
• DONOR: Individuals who are HIV-positive
• DONOR: Individuals with active infectious hepatitis
• DONOR: Females with a positive pregnancy test
• DONOR: Persons unable to give informed consent (if > 18 years) or with a legal guardian (if < 18 years) unable to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Arm A: Treosulfan, Fludarabine Phosphate Treosulfan intravenously (IV) over 2 hours on days -6 to -4 and fludarabine phosphate IV over 30 minutes on days -6 to -2.	Radiation: Total-Body Irradiation; Undergo TBI; Other Names: Whole-Body Irradiation; TOTAL BODY IRRADIATION; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSC transplant; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; Other: Laboratory Biomarker Analysis; Correlative Studies; Procedure: Allogeneic Bone Marrow Transplantation; Undergo allogeneic bone marrow transplant; Other Names: Allo BMT; Allogeneic BMT; Drug: Fludarabine Phosphate; Intravenously administered Fludarabine Phosphate; Other Names: 2-F-ara-AMP; Beneflur; Fludara; SH T 586; Drug: Treosulfan; Intravenously administered Treosulfan; Other Names: 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-; Dihydroxybusulfan; Ovastat; Treosulphan; Tresulfon
Experimental: Arm B; Arm B: Treosulfan, Fludarabine Phosphate, TBI Treosulfan and fludarabine phosphate as in Arm A and undergo low -dose total-body irradiation (TBI) on day 0	Procedure: Peripheral Blood Stem Cell Transplantation; Undergo allogeneic PBSC transplant; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; Other: Laboratory Biomarker Analysis; Correlative Studies; Procedure: Allogeneic Bone Marrow Transplantation; Undergo allogeneic bone marrow transplant; Other Names: Allo BMT; Allogeneic BMT; Drug: Fludarabine Phosphate; Intravenously administered Fludarabine Phosphate; Other Names: 2-F-ara-AMP; Beneflur; Fludara; SH T 586; Drug: Treosulfan; Intravenously administered Treosulfan; Other Names: 1,2,3, 4-Butanetetrol, 1,4-dimethanesulfonate, [R-(R*,S*)]-; Dihydroxybusulfan; Ovastat; Treosulphan; Tresulfon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants That Did Not Progress Within 6 Months	Progression is defined as relapse	At 6 months post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Acute GVHD, Graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0		Up to 84 days
Incidence of Chronic GVHD Graded by the NCI CTCAE Version 4.0		Up to 5 year
Incidence of Relapse/Progression		Up to 5 year
NRM		Up to 5 years
Overall Survival (OS)		Up to 2 year
Change in Gene Expression Profiles	Differences between arms in the changes in gene expression will be compared. 80% power to detect mean differences of approximately 1.4 standard deviation units, at the 2-sided 0.05 level of significance (with Bonferroni correction for 50 genes).	Baseline and at day 0 within 6 hours of conditioning prior to transplant
Relapse Risk as Measured by Degree of Change in Gene Expression Profiles	Among genes identified whose expression is modified by conditioning, degree of change in expression will be evaluated to determine if it is correlated with relapse risk and offers improved prediction of relapse risk over that obtained with standard clinical parameters (cytogenetics, blast count, International Prognostic Scoring System score, minimal residual disease. To account for censoring and the competing risk of non-relapse mortality (NRM), the analysis will be a time-to-event analysis of relapse using Cox regression, with change in expression as a continuous covariate (on a log scale). 8	Baseline and at day 0 within 6 hours of conditioning prior to transplant

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: H. Joachim Deeg, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start: November 1, 2013
• Primary Completion (Actual): January 9, 2017
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: July 1, 2013
• First Submitted That Met QC Criteria: July 3, 2013
• First Posted (Estimate): July 10, 2013

Study Record Updates

• Last Update Posted (Actual): June 3, 2021
• Last Update Submitted That Met QC Criteria: May 13, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Disease; Bone Marrow Diseases; Hematologic Diseases; Neoplastic Processes; Precancerous Conditions; Neoplasms; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myeloproliferative Disorders; Myelodysplastic-Myeloproliferative Diseases; Neoplasm, Residual; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Fludarabine; Fludarabine phosphate; Busulfan; Treosulfan
• Other Study ID Numbers: 2524.00 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); 2524; NCI-2013-01261 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); K12HL087165 (U.S. NIH Grant/Contract)