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

Primary Purpose

Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, Acute Myeloid Leukemia/Transient Myeloproliferative Disorder, Adult Acute Myeloid Leukemia in Remission

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
total-body irradiation
allogeneic hematopoietic stem cell transplantation
cyclophosphamide
mycophenolate mofetil
busulfan
cyclosporine
fludarabine phosphate
peripheral blood stem cell transplantation
nonmyeloablative allogeneic hematopoietic stem cell transplantation
laboratory biomarker analysis
cytogenetic analysis
flow cytometry
fluorescence in situ hybridization
pharmacological study
polymorphism analysis
tacrolimus
methotrexate
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome

Eligibility Criteria

undefined - 65 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 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: A positive anti-donor cytotoxic crossmatch or flow cytometric assay is an absolute donor exclusion at FHCRC/SCCA 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) Exclusion Criteria: 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 Patients with systemic, uncontrolled infections Active CNS disease as identified by positive CSF cytospin DONOR: Identical twin DONOR: Age < 12 years DONOR: Pregnancy DONOR: HIV seropositivity DONOR: Inability to achieve adequate venous access DONOR: Known adverse reaction to G-CSF

Sites / Locations

  • HealthOne Presbyterian St. Lukes Medical Center
  • Emory University
  • Weill Cornell University
  • University of Utah
  • Veterans Administration Center-Seattle
  • Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  • Medical College Wisconsin
  • Technical University Dresden

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Arm I (Nonmyeloablative regimen)

Arm II (Myeloablative regimen)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Overall Survival

Secondary Outcome Measures

Progression-free Survival
IWG criteria was used to determine disease progression
Non-relapse Mortality
Donor Cell Engraftment
Chimerism analysis was performed in patients who recieved nonmyeloablative tranplsnat. In this group the definition of engraftment was a CD3 count greater than 50%. In the myeloablative group, engraftment was defined as an absolute neutrophil count greater than 50%.
Incidence of Disease Progression/Relapse
Disease progression/relapse was defined by IWG criteria
Incidence and Severity of Acute and Chronic Graft-vs-host Disease

Full Information

First Posted
May 2, 2006
Last Updated
October 23, 2014
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00322101
Brief Title
Low-Dose or High-Dose Conditioning Followed by Peripheral Blood Stem Cell Transplant in Treating Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia
Official Title
A Multi-center Phase III Study Comparing Myeloablative to Nonmyeloablative Transplant Conditioning in Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia
Study Type
Interventional

2. Study Status

Record Verification Date
October 2014
Overall Recruitment Status
Completed
Study Start Date
January 2006 (undefined)
Primary Completion Date
April 2012 (Actual)
Study Completion Date
October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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
Detailed Description
OBJECTIVES: I. Determine whether the conditioning intensity affects outcomes after HCT in patients with MDS or AML who have < 5% marrow myeloblasts at the time of HCT. OUTLINE: Patients are randomized to 1 of 2 treatment arms. Arm I (Nonmyeloablative regimen): 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. Arm II (Myeloablative regimen): 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. Treatment in both arms continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up periodically.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
25 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm I (Nonmyeloablative regimen)
Arm Type
Experimental
Arm Description
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.
Arm Title
Arm II (Myeloablative regimen)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Radiation
Intervention Name(s)
total-body irradiation
Other Intervention Name(s)
TBI
Intervention Description
Radiation
Intervention Type
Procedure
Intervention Name(s)
allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic transplantation
Intervention Type
Drug
Intervention Name(s)
cyclophosphamide
Other Intervention Name(s)
CPM, CTX, Cytoxan, Endoxan, Endoxana
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
mycophenolate mofetil
Other Intervention Name(s)
Cellcept, MMF
Intervention Description
Given orally
Intervention Type
Drug
Intervention Name(s)
busulfan
Other Intervention Name(s)
BSF, BU, Misulfan, Mitosan, Myeloleukon
Intervention Description
Given IV or orally
Intervention Type
Drug
Intervention Name(s)
cyclosporine
Other Intervention Name(s)
ciclosporin, cyclosporin, cyclosporin A, CYSP, Sandimmune
Intervention Description
Given IV or orally
Intervention Type
Drug
Intervention Name(s)
fludarabine phosphate
Other Intervention Name(s)
2-F-ara-AMP, Beneflur, Fludara
Intervention Description
Given IV
Intervention Type
Procedure
Intervention Name(s)
peripheral blood stem cell transplantation
Other Intervention Name(s)
PBPC transplantation, PBSC transplantation, peripheral blood progenitor cell transplantation, transplantation, peripheral blood stem cell
Intervention Description
Undergo transplantation
Intervention Type
Procedure
Intervention Name(s)
nonmyeloablative allogeneic hematopoietic stem cell transplantation
Intervention Description
Undergo allogeneic transplantation
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
cytogenetic analysis
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
flow cytometry
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
fluorescence in situ hybridization
Other Intervention Name(s)
fluorescence in situ hybridization (FISH)
Intervention Description
Correlative studies
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Intervention Type
Genetic
Intervention Name(s)
polymorphism analysis
Intervention Description
Correlative studies
Intervention Type
Drug
Intervention Name(s)
tacrolimus
Other Intervention Name(s)
FK 506, Prograf
Intervention Description
Given IV or orally
Intervention Type
Drug
Intervention Name(s)
methotrexate
Other Intervention Name(s)
amethopterin, Folex, methylaminopterin, Mexate, MTX
Intervention Description
Given IV
Primary Outcome Measure Information:
Title
Overall Survival
Time Frame
At 2 years
Secondary Outcome Measure Information:
Title
Progression-free Survival
Description
IWG criteria was used to determine disease progression
Time Frame
After stem cell infusion to date of last follow up.
Title
Non-relapse Mortality
Time Frame
At 100 days
Title
Donor Cell Engraftment
Description
Chimerism analysis was performed in patients who recieved nonmyeloablative tranplsnat. In this group the definition of engraftment was a CD3 count greater than 50%. In the myeloablative group, engraftment was defined as an absolute neutrophil count greater than 50%.
Time Frame
After stem cell infusion to day 28
Title
Incidence of Disease Progression/Relapse
Description
Disease progression/relapse was defined by IWG criteria
Time Frame
After stem cell infusion to date of last follow up.
Title
Incidence and Severity of Acute and Chronic Graft-vs-host Disease
Time Frame
After transplantation

10. Eligibility

Sex
All
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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: A positive anti-donor cytotoxic crossmatch or flow cytometric assay is an absolute donor exclusion at FHCRC/SCCA 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) Exclusion Criteria: 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 Patients with systemic, uncontrolled infections Active CNS disease as identified by positive CSF cytospin DONOR: Identical twin DONOR: Age < 12 years DONOR: Pregnancy DONOR: HIV seropositivity DONOR: Inability to achieve adequate venous access DONOR: Known adverse reaction to G-CSF
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bart Scott
Organizational Affiliation
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Official's Role
Principal Investigator
Facility Information:
Facility Name
HealthOne Presbyterian St. Lukes Medical Center
City
Denver
State/Province
Colorado
Country
United States
Facility Name
Emory University
City
Altanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Weill Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States
Facility Name
University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Facility Name
Veterans Administration Center-Seattle
City
Seattle
State/Province
Washington
ZIP/Postal Code
98108
Country
United States
Facility Name
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States
Facility Name
Medical College Wisconsin
City
Milwaukee
State/Province
Wisconsin
Country
United States
Facility Name
Technical University Dresden
City
Dresden
State/Province
Saxony
ZIP/Postal Code
01307
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

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

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