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

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.

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.