Erythropoietin (EPO)+/- Filgrastim (G-CSF) vs. Supportive Therapy Alone for Patients With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase III Evaluation of EPO With or Without G-CSF Versus Supportive Therapy Alone in the Treatment of Myelodysplastic Syndromes

Conditions
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Anemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Biological: Erythropoietin
* Biological: Filgrastim
* Procedure: Transfusion


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Supportive Care<br>Patients received red cell and platelet transfusions for symptoms or to maintain hematocrit at or above 25% by volume. Patients who required transfusion support for symptomatic anemia prior to entering the study and who developed an increase in their transfusion requirement of >= 50% shall cross over to the Erythropoietin treatment arm, after at least four months on the supportive therapy arm. | Procedure: Transfusion<br>* Red cell and platelet transfusions<br>|
| Experimental: Erythropoietin<br>Erythropoietin was administered at 150 units/kg subcutaneously every day. If patients stopped responding, they were subsequently treated with Erythropoietin (150 units/kg) and filgrastim and then Erythropoietin (300 units/kg) and filgrastim. | Biological: Erythropoietin<br>* Administered at 150 units/kg subcutaneously every day. Rotating sites should be used. The dose should be rounded off to the nearest 1000 U. The dose should be adjusted based on hematocrit.<br>* Other names: EPO;Biological: Filgrastim<br>* G-CSF should start at a dose of 1 mcg/kg per day or 2.5 mcg/kg three times a week subcutaneously. Rotating sites should be used The dose should be rounded off to the nearest 10 mcg.<br>* Other names: r-methHuG-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients Free of Transfusion at 4 Months | Whether a patient required transfusion or not at 4 months was recorded. | Assessed at 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Time from randomization to death from any cause. Patients alive at the time of analysis were censored at the date of last contact. | Assessed every 3 months for 2 years, every 6 months for 3 subsequent years, and annually thereafter | 
| Quality of Life- Total Functional Assessment of Cancer Therapy - General (FACT-G) Score at 4 Months | The FACT-G scale has 4 dimensions, including physical well-being, social/family well-being, emotional well-being, and functional well-being. The score for each subscale was added together to obtain the total FACT-G score that was evaluated on this study. The total FACT-G score ranges from 0 to 108 with higher scores reflecting better quality of life. It was administered at the time of study entry, every 4 months for the first year, and at the time patient went off treatment. Due to limited data after 4 months on treatment, the analysis was restricted to the four-month time point. | Assessed at 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anemia, refractory anemia, myelodysplastic syndromes, erythropoietin, filgrastim