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

Recurrent Adult Acute Myeloid Leukemia Clinical Trial

Official title:

A Multi-center Phase III Study Comparing Myeloablative to Nonmyeloablative Transplant Conditioning in Patients With Myelodysplastic Syndrome or Acute Myelogenous Leukemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00322101
• Other study ID #: 1992.00
• Secondary ID: NCI-2010-00737P0
• Status: Completed
• Phase: Phase 3
• First received: May 2, 2006
• Last updated: October 23, 2014
• Start date: January 2006
• Est. completion date: October 2014

Study information

• Verified date: October 2014
• Source: Fred Hutchinson Cancer Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: October 2014
• Est. primary completion date: April 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 65 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• 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
• Down Syndrome
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndrome With Isolated Del(5q)
• Myelodysplastic Syndromes
• Myelodysplastic-Myeloproliferative Diseases
• Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
• Myeloproliferative Disorders
• Neoplasm Metastasis
• Preleukemia
• Previously Treated Myelodysplastic Syndromes
• Recurrent Adult Acute Myeloid Leukemia
• Recurrent Childhood Acute Myeloid Leukemia
• Secondary Acute Myeloid Leukemia
• Secondary Myelodysplastic Syndromes
• Syndrome

Intervention

Radiation:
• total-body irradiation
Radiation

Procedure:
• allogeneic hematopoietic stem cell transplantation
Undergo allogeneic transplantation

Drug:
• cyclophosphamide
Given IV
• mycophenolate mofetil
Given orally
• busulfan
Given IV or orally
• cyclosporine
Given IV or orally
• fludarabine phosphate
Given IV

Procedure:
• peripheral blood stem cell transplantation
Undergo transplantation
• nonmyeloablative allogeneic hematopoietic stem cell transplantation
Undergo allogeneic transplantation

Other:
• laboratory biomarker analysis
Correlative studies

Genetic:
• cytogenetic analysis
Correlative studies

Other:
• flow cytometry
Correlative studies

Genetic:
• fluorescence in situ hybridization
Correlative studies

Other:
• pharmacological study
Correlative studies

Genetic:
• polymorphism analysis
Correlative studies

Drug:
• tacrolimus
Given IV or orally
• methotrexate
Given IV

Locations

Country	Name	City	State
Germany	Technical University Dresden	Dresden	Saxony
United States	Emory University	Altanta	Georgia
United States	HealthOne Presbyterian St. Lukes Medical Center	Denver	Colorado
United States	Medical College Wisconsin	Milwaukee	Wisconsin
United States	Weill Cornell University	New York	New York
United States	University of Utah	Salt Lake City	Utah
United States	Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium	Seattle	Washington
United States	Veterans Administration Center-Seattle	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Research Center	National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival		At 2 years	No
Secondary	Progression-free Survival	IWG criteria was used to determine disease progression	After stem cell infusion to date of last follow up.	Yes
Secondary	Non-relapse Mortality		At 100 days	Yes
Secondary	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%.	After stem cell infusion to day 28	Yes
Secondary	Incidence of Disease Progression/Relapse	Disease progression/relapse was defined by IWG criteria	After stem cell infusion to date of last follow up.	No
Secondary	Incidence and Severity of Acute and Chronic Graft-vs-host Disease		After transplantation	Yes