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.