Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia

NCT00322101 | Completed Phase 3 Results DMC

• 6 other identifiers: 1992.00NCI-2010-00737P01CA078902K23HL084054P01CA018029P01HL036444
• Study Type: interventional
• Target: 25
• Locations: 2 countries
• Sites: 8

Brief Summary

RATIONALE: Giving chemotherapy, such as fludarabine phosphate, busulfan, and cyclophosphamide, and total-body radiation therapy before a donor peripheral 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. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether low-dose chemotherapy and total-body radiation therapy is more effective than high-dose chemotherapy in treating patients with myelodysplastic syndrome or acute myeloid leukemia. PURPOSE: This phase III trial is studying low-dose conditioning to see how well it works compared to high-dose conditioning followed by peripheral blood stem cell transplant in treating patients with myelodysplastic syndromes or acute myeloid leukemia

Conditions

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Acute Myeloid Leukemia/Transient Myeloproliferative Disorder; Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  At 2 years

Secondary Outcomes (5)

• Progression-free Survival

  After stem cell infusion to date of last follow up.

• Non-relapse Mortality

  At 100 days

• Donor Cell Engraftment

  After stem cell infusion to day 28

• Incidence of Disease Progression/Relapse

  After stem cell infusion to date of last follow up.

• Incidence and Severity of Acute and Chronic Graft-vs-host Disease

  After transplantation

Study Arms (2)

Arm I (Nonmyeloablative regimen)

EXPERIMENTAL

CONDITIONING: Patients receive fludarabine phosphate IV on days -4 to -2 and undergo low-dose total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell (PBSC) infusion on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive cyclosporine every 12 hours on days -3 to 57 with taper on days 57-177 or cyclosporine every 12 hours on days -3 to 100 with taper on days 101-177. Patients also receive oral mycophenolate mofetil every 12 hours on days 0-27 or every 8 hours on days 0-40 with taper on days 41-96.

Radiation: total-body irradiation; Drug: mycophenolate mofetil; Drug: cyclosporine; Drug: fludarabine phosphate; Procedure: peripheral blood stem cell transplantation; Procedure: nonmyeloablative allogeneic hematopoietic stem cell transplantation; Other: laboratory biomarker analysis; Genetic: cytogenetic analysis; Other: flow cytometry; Genetic: fluorescence in situ hybridization; Other: pharmacological study; Genetic: polymorphism analysis

Arm II (Myeloablative regimen)

EXPERIMENTAL

CONDITIONING: Patients are assigned to 1 of 2 treatment groups. Group A: Patients receive fludarabine IV once daily and oral busulfan four times daily or busulfan IV over 3 hours on days -5 to -2. Group B: Patients receive cyclophosphamide IV over 1-2 hours on days -3 and -2 and oral busulfan four times daily or busulfan IV over 3 hours on days -7 to -4. TRANSPLANTATION: Patients undergo PBSC infusion on day 0. GRAFT-VS-HOST DISEASE PROPHYLAXIS: Patients receive tacrolimus IV continuously or orally every 12 hours on days -1 to 56 and taper on days 57-200. Patients also receive methotrexate IV on days 1, 3, 6, and 11.

Procedure: allogeneic hematopoietic stem cell transplantation; Drug: cyclophosphamide; Drug: busulfan; Drug: fludarabine phosphate; Procedure: peripheral blood stem cell transplantation; Other: laboratory biomarker analysis; Other: flow cytometry; Genetic: fluorescence in situ hybridization; Other: pharmacological study; Genetic: polymorphism analysis; Drug: tacrolimus; Drug: methotrexate

Interventions

total-body irradiation RADIATION

Radiation

Also known as: TBI

Arm I (Nonmyeloablative regimen)

allogeneic hematopoietic stem cell transplantation PROCEDURE

Undergo allogeneic transplantation

Arm II (Myeloablative regimen)

cyclophosphamide DRUG

Given IV

Also known as: CPM, CTX, Cytoxan, Endoxan, Endoxana

Arm II (Myeloablative regimen)

mycophenolate mofetil DRUG

Given orally

Also known as: Cellcept, MMF

Arm I (Nonmyeloablative regimen)

busulfan DRUG

Given IV or orally

Also known as: BSF, BU, Misulfan, Mitosan, Myeloleukon

Arm II (Myeloablative regimen)

cyclosporine DRUG

Given IV or orally

Also known as: ciclosporin, cyclosporin, cyclosporin A, CYSP, Sandimmune

Arm I (Nonmyeloablative regimen)

fludarabine phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, Beneflur, Fludara

Arm I (Nonmyeloablative regimen); Arm II (Myeloablative regimen)

peripheral blood stem cell transplantation PROCEDURE

Undergo transplantation

Also known as: PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell

Arm I (Nonmyeloablative regimen); Arm II (Myeloablative regimen)

nonmyeloablative allogeneic hematopoietic stem cell transplantation PROCEDURE

Undergo allogeneic transplantation

Arm I (Nonmyeloablative regimen)

laboratory biomarker analysis OTHER

Correlative studies

Arm I (Nonmyeloablative regimen); Arm II (Myeloablative regimen)

cytogenetic analysis GENETIC

Correlative studies

Arm I (Nonmyeloablative regimen)

flow cytometry OTHER

Correlative studies

Arm I (Nonmyeloablative regimen); Arm II (Myeloablative regimen)

fluorescence in situ hybridization GENETIC

Correlative studies

Also known as: fluorescence in situ hybridization (FISH)

Arm I (Nonmyeloablative regimen); Arm II (Myeloablative regimen)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Arm I (Nonmyeloablative regimen); Arm II (Myeloablative regimen)

polymorphism analysis GENETIC

Correlative studies

Arm I (Nonmyeloablative regimen); Arm II (Myeloablative regimen)

tacrolimus DRUG

Given IV or orally

Also known as: FK 506, Prograf

Arm II (Myeloablative regimen)

methotrexate DRUG

Given IV

Also known as: amethopterin, Folex, methylaminopterin, Mexate, MTX

Arm II (Myeloablative regimen)

Eligibility Criteria

• Age: Up to 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Myelodysplastic syndrome (MDS) or transformed acute myelogenous leukemia (transformed from MDS)
• De novo acute myelogenous leukemia (AML) beyond first remission
• Intermediate or high risk de novo AML in first complete response (at FHCRC unrelated donor recipients only)
• Chemotherapy required prior to HCT for all patients:
• A) Interval between start of a cycle of cytoreductive chemotherapy and infusion of donor stem cells must be at least 30 days; chemotherapy received for disease maintenance will be allowed during this time period
• B) All patients must have \< 5% myeloblasts based on marrow morphology performed within 21 days prior to start of conditioning regimen and at least 3-4 weeks after the start of pre-transplant cytoreductive chemotherapy
• C) All patients must have no circulating peripheral blood myeloblasts present based on morphologic analysis
• Age 65 years or under for patients with related donors; age 60 years or under for patients with unrelated donors
• HCT-Specific Comorbidity Index Score (HCT-CI) \< 3
• Related donor (age \> 12 years, nonsyngeneic) or unrelated donor, HLA phenotypically or genotypically identical at the allele level at A,B,C,DRQ1, and CBQ1
• DONOR: Related or unrelated donors who are genotypically or phenotypically matched by high resolution HLA typing (HLA-A, B, C, DRB1, and DQB1); class 1 single allele mismatch allowed
• DONOR: Patient and donor pairs homozygous at a mismatched allele in the graft rejection vector are considered a two-allele mismatch, i.e., the patient is A\*0101 and the donor is A\*0201, and this type of mismatch is not allowed
• DONOR: Age \>= 12 years
• DONOR: Donors must consent to PBSC mobilization with G-CSF and leukaphereses; bone marrow as a source of stem cells will not be allowed
• DONOR: Donor must have adequate veins for leukaphereses or agree to placement of central venous catheter (femoral, subclavian)

You may not qualify if:

• HIV seropositivity
• Fungal infections with radiographic progression after appropriate therapy for greater than one month
• Organ dysfunction
• Symptomatic coronary artery disease or ejection fraction \< 35%
• DLCO \< 65%, FEV1 \< 65% or receiving supplementary continuous oxygen
• Liver function abnormalities: 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, histology, and the degree of portal hypertension; patients with fulminant liver failure, cirrhosis with evidence of portal hypertension or bridging fibrosis, 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, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL, and symptomatic biliary disease will be excluded
• Karnofsky Performance Score \< 70
• Lansky-Play Performance Score \< 70 for pediatric patients
• Life expectancy severely limited (\< 2 years) by disease other than MDS/AML
• Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment
• Patients with active non-hematological malignancies except:
• A) Patients with follicular or low grade lymphoma will be eligible as long as they have not and do not require active treatment for control of their disease
• B) Patients with localized non-melanoma skin malignancies
• Patients with poorly controlled hypertension who are unable to have blood pressure stabilized below 150/90 mm Hg on standard medication
• Females who are pregnant or breastfeeding

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (8)

HealthOne Presbyterian St. Lukes Medical Center

Denver, Colorado, United States

Location

Emory University

Altanta, Georgia, 30322, United States

Location

Weill Cornell University

New York, New York, 10021, United States

Location

University of Utah

Salt Lake City, Utah, 84112, United States

Location

Veterans Administration Center-Seattle

Seattle, Washington, 98108, United States

Location

Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Medical College Wisconsin

Milwaukee, Wisconsin, United States

Location

Technical University Dresden

Dresden, Saxony, 01307, Germany

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myeloproliferative Syndrome, Transient; Congenital Abnormalities; Chromosome 5q Deletion Syndrome; Myeloproliferative Disorders

Interventions

Whole-Body Irradiation; Cyclophosphamide; Mycophenolic Acid; Busulfan; Cyclosporine; fludarabine phosphate; Peripheral Blood Stem Cell Transplantation; Cytogenetic Analysis; Flow Cytometry; In Situ Hybridization, Fluorescence; Amplified Fragment Length Polymorphism Analysis; Tacrolimus; Methotrexate; merphos

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Investigative Techniques; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Cyclosporins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Transplantation; Surgical Procedures, Operative; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Genetic Techniques; Cell Separation; Cytophotometry; Fluorometry; Luminescent Measurements; Photometry; Chemistry Techniques, Analytical; In Situ Hybridization; Staining and Labeling; Histocytological Preparation Techniques; Histological Techniques; Nucleic Acid Hybridization; DNA Fingerprinting; Polymerase Chain Reaction; Nucleic Acid Amplification Techniques; Macrolides; Lactones; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Bart Lee Scott
• Organization: Fred Hutchinson Cancer Research Center

bscott@fhcrc.org

206-667-1990

Study Officials

• Bart Scott

  Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 2, 2006
• First Posted: May 4, 2006
• Study Start: January 1, 2006
• Primary Completion: April 1, 2012
• Study Completion: October 1, 2014
• Last Updated: October 31, 2014
• Results First Posted: October 28, 2013

Record last verified: 2014-10

Locations

US (7); DE (1)