Clinical trial NCT00003138: Erythropoietin (EPO)+/- Filgrastim (G-CSF) vs. Supportive Therapy Alone for Patients With Myelodysplastic Syndromes
Official title: Phase III Evaluation of EPO With or Without G-CSF Versus Supportive Therapy Alone in the Treatment of Myelodysplastic Syndromes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Anemia
Myelodysplastic Syndromes
Keywords: anemia
refractory anemia
myelodysplastic syndromes
erythropoietin
filgrastim
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-01-27
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Erythropoietin and colony-stimulating factors such as filgrastim stimulate the production of blood cells. It is not yet known whether erythropoietin with or without filgrastim is more effective than standard blood transfusions in reducing the need for transfusions in patients who have anemia associated with myelodysplastic syndrome.

PURPOSE: Randomized phase III trial to compare the effectiveness of erythropoietin with or without filgrastim with that of standard blood transfusions in reducing the need for transfusions in patients who have anemia associated with myelodysplastic syndrome.

Detailed description: OBJECTIVES:

* Compare the benefit of erythropoietin vs standard transfusion support in reducing transfusion requirements in patients with myelodysplastic syndromes.
* Compare the clinical response, disease progression, and survival in patients treated with these regimens.
* Compare the toxicity of these regimens in these patients.
* Evaluate whether adding filgrastim (G-CSF) or increasing the erythropoietin dose will reduce the transfusion requirement in patients who do not respond to erythropoietin alone.
* To compare the benefit of erythropoietin versus supportive care alone on quality of life (QOL) in persons with myelodysplastic syndromes.

OUTLINE: This is a randomized, controlled, multicenter, cross-over study. Patients are stratified according to morphologic subtype (refractory anemia \[RA\] vs RA with ringed sideroblasts vs RA with excess blasts), transfusion requirement (yes vs no), prior erythropoietin treatment (yes vs no), and erythropoietin level (at least 200 mU/mL vs less than 200 mU/mL). Patients are randomized to one of two treatment arms.

* Arm I (standard transfusion support): Patients receive red cell and platelet transfusions for symptoms or to maintain hematocrit level of 25% or above. Patients undergo bone marrow aspirate and biopsy at 4 months and then every year until development of acute leukemia or completion of study. Patients with progressive disease may cross over to arm II after at least 4 months on study and up to 1 year from the time of randomization. Patients who cross over receive erythropoietin alone.
* Arm II (Erythropoietin): Patients receive erythropoietin subcutaneously (SC) or intravenously (IV) daily. Patients undergo bone marrow aspirate and biopsy as in arm I. Treatment continues daily for a maximum of 1 year.

Patients with stable or progressive disease at day 120 receive filgrastim (G-CSF) SC daily or 3 days a week and erythropoietin SC daily for up to 6 months. Patients with no response to G-CSF and lower-dose erythropoietin may proceed to a higher dose of erythropoietin.

Quality of life is assessed at baseline, every 4 months during study, and at study completion.

Patients are followed every 4 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

ACTUAL ACCRUAL: A total of 118 patients were accrued for this study.

Eligibility criteria: Inclusion Criteria:

* At least 18 years of age
* Diagnosis of a myelodysplastic syndrome
* Refractory anemia (RA)
* RA with ringed sideroblasts
* RA with excess blasts (RAEB). RAEB patients must have a bone marrow blast count of less than 20% and less than 5% blast forms on peripheral blood
* Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 3
* Platelet count greater than 30,000/mm\^3 (without platelet transfusions)
* Hematocrit less than 30% (pretransfusion)
* Bilirubin less than 3 mg/dL
* Blood urea nitrogen (BUN) less than 40 mg/dL or Creatinine less than 2.0 mg/dL
* Prior epoetin alfa allowed provided dosage was less than 30,000 units per week for less than 1 month duration
* At least 1 month since prior erythropoietin
* At least 2 months since prior recombinant growth factor
* At least 2 months since prior chemotherapy for other malignancy or autoimmune disease
* At least 2 weeks since prior androgen or steroids for treatment of myelodysplastic syndromes

Exclusion Criteria:

* RAEB in transformation
* Chronic myelomonocytic leukemia
* Splenomegaly greater than 6 cm below the left costal margin or greater than 3 times normal size
* Uncontrolled hypertension
* Sensitivity to E. coli-derived proteins
* Sensitivity to epoetin alfa or any of its components (e.g., human albumin)
* Documented iron deficiency. If marrow iron stain is not available, the transferrin saturation must be greater than 20% or ferritin greater than 100 ng/dL
* Active infection or bleeding
* Other uncontrolled malignancy
* Pregnant or nursing. Fertile patients must use effective contraception.

Primary outcomes:
measure: Proportion of Patients Free of Transfusion at 4 Months
timeFrame: Assessed at 4 months
Secondary outcomes:
measure: Overall Survival
timeFrame: Assessed every 3 months for 2 years, every 6 months for 3 subsequent years, and annually thereafter
measure: Quality of Life- Total Functional Assessment of Cancer Therapy - General (FACT-G) Score at 4 Months
timeFrame: Assessed at 4 months
Other outcomes:
Locations:
city: Denver
country: United States
facility: CCOP - Colorado Cancer Research Program, Incorporated
state: Colorado
city: Chicago
country: United States
facility: Veterans Affairs Medical Center - Lakeside Chicago
state: Illinois
city: Chicago
country: United States
facility: Robert H. Lurie Comprehensive Cancer Center at Northwestern University
state: Illinois
city: Peoria
country: United States
facility: CCOP - Illinois Oncology Research Association
state: Illinois
city: Urbana
country: United States
facility: CCOP - Carle Cancer Center
state: Illinois
city: Cedar Rapids
country: United States
facility: CCOP - Cedar Rapids Oncology Project
state: Iowa
city: Des Moines
country: United States
facility: CCOP - Iowa Oncology Research Association
state: Iowa
city: New Orleans
country: United States
facility: MBCCOP - LSU Health Sciences Center
state: Louisiana
city: Boston
country: United States
facility: Tufts - New England Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: CCOP - Michigan Cancer Research Consortium
state: Michigan
city: Kalamazoo
country: United States
facility: CCOP - Kalamazoo
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Saint Louis Park
country: United States
facility: CCOP - Metro-Minnesota
state: Minnesota
city: Omaha
country: United States
facility: CCOP - Missouri Valley Cancer Consortium
state: Nebraska
city: Las Vegas
country: United States
facility: CCOP - Southern Nevada Cancer Research Foundation
state: Nevada
city: East Orange
country: United States
facility: Veterans Affairs Medical Center - East Orange
state: New Jersey
city: Hackensack
country: United States
facility: CCOP - Northern New Jersey
state: New Jersey
city: New Brunswick
country: United States
facility: Cancer Institute of New Jersey
state: New Jersey
city: New York
country: United States
facility: NYU School of Medicine's Kaplan Comprehensive Cancer Center
state: New York
city: Fargo
country: United States
facility: CCOP - Merit Care Hospital
state: North Dakota
city: Cleveland
country: United States
facility: MetroHealth's Cancer Care Center at MetroHealth Medical Center
state: Ohio
city: Columbus
country: United States
facility: CCOP - Columbus
state: Ohio
city: Danville
country: United States
facility: CCOP - Geisinger Clinic and Medical Center
state: Pennsylvania
city: Sioux Falls
country: United States
facility: CCOP - Sioux Community Cancer Consortium
state: South Dakota
city: Temple
country: United States
facility: CCOP - Scott and White Hospital
state: Texas
city: Green Bay
country: United States
facility: CCOP - St. Vincent Hospital Cancer Center, Green Bay
state: Wisconsin
city: Marshfield
country: United States
facility: CCOP - Marshfield Clinic Research Foundation
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin Cancer Center
state: Wisconsin
Study officials:
affiliation: Beth Israel Deaconess Medical Center
name: Kenneth B. Miller, MD
role: STUDY_CHAIR
References:
citation: Cherry AM, Brockman SR, Paternoster SF, Hicks GA, Neuberg D, Higgins RR, Bennett JM, Greenberg PL, Miller K, Tallman MS, Rowe J, Dewald GW. Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an Eastern Cooperative Oncology Group (ECOG) study. Leuk Res. 2003 Dec;27(12):1085-90. doi: 10.1016/s0145-2126(03)00104-8.
citation: Greenberg PL, Sun Z, Miller KB, Bennett JM, Tallman MS, Dewald G, Paietta E, van der Jagt R, Houston J, Thomas ML, Cella D, Rowe JM. Treatment of myelodysplastic syndrome patients with erythropoietin with or without granulocyte colony-stimulating factor: results of a prospective randomized phase 3 trial by the Eastern Cooperative Oncology Group (E1996). Blood. 2009 Sep 17;114(12):2393-400. doi: 10.1182/blood-2009-03-211797. Epub 2009 Jun 29.
citation: Miller KB, Kim HT, Greenberg P, et al.: Phase III prospective randomized trial of EPO with or without G-CSF versus supportive therapy alone in the treatment of myelodysplastic syndromes (MDS): results of the ECOG- CLSG trial (E1996). [Abstract] Blood 104 (11): A-70, 2004.