Azacitidine, Darbepoetin Alfa, and Erythropoietin and Filgastrim (G-CSF) in Treating Patients With Myelodysplastic Syndromes

OBJECTIVES:

Primary

- Determine the hematological response rate in patients with myelodysplastic syndromes
treated with azacitidine, darbepoetin alfa, and filgrastim (G-CSF).

Secondary

- Determine the time to leukemia progression, survival, and changes in apoptotic index of
bone marrow in patients treated with this regimen.

OUTLINE: This is an open-label, nonrandomized study.

- Initial therapy (courses 1 and 2): Patients receive azacitidine subcutaneously (SC) or
intra-venous (IV) on days 1-5 (week 1) and darbepoetin alfa* SC on day 8 (week 2).
Treatment repeats every 28 days for 2 courses.

Patients undergo bone marrow aspirate and biopsy to assess response. Patients with a major
hematological improvement OR with grade 3-4 hematological toxicities during the first 2
courses of therapy AND/OR ≥ 50% reduction in bone marrow cellularity compared to baseline
proceed to optimization therapy A. Patients not meeting any of the above criteria proceed to
optimization therapy B. Patients with disease progression are removed from study.

- Optimization therapy A (courses 3-8): Patients receive azacitidine SC or IV on days 1-5
(week 1), darbepoetin alfa** SC on day 8 (week 2), and filgrastim (G-CSF) SC 3 times
weekly in weeks 2-4.

- Optimization therapy B (courses 3-8): Patients receive a higher dose of azacitidine on
days 1-5 (week 1), darbepoetin alfa** SC on day 8 (week 2), and G-CSF 3 times weekly in
weeks 2-4.

In both optimization therapy A and B, treatment repeats every 28 days for 6 courses. Patients
with any degree of hematological improvement after initial therapy and optimization therapy
proceed to maintenance therapy.

- Maintenance therapy (course 9 and all subsequent courses): Patients receive azacitidine
on days 1-5 (week 1). Only patients with anemia (hemoglobin < 12 g/dL) and/or
neutropenia (absolute neutrophil count < 1,500/mm ³) at the start of any given course
during maintenance therapy receive darbepoetin alfa** SC beginning on day 8 (week 2) and
continuing once every 21 days and G-CSF SC 3 times weekly beginning in week 2.

Courses repeat every 28-56 days (determined by the treating physician) in the absence of
disease progression or unacceptable toxicity.

Bone marrow samples are obtained at baseline and after the completion of course 2 of study
treatment for apoptosis analysis, flow cytometry, and gene expression profiles of p53 and p21
by immunohistochemistry. Peripheral blood samples are obtained periodically and analyzed for
hemoglobin F quantitation.

NOTE: *Administered only if the patient is anemic (hemoglobin < 12 g/dL).

NOTE: **Darbepoetin alfa is held if hemoglobin > 12 g/dL on day 1 of a given cycle.

DISEASE CHARACTERISTICS:

- Diagnosis of myelodysplastic syndromes (MDS)

- Bone marrow aspirate and biopsy with karyotyping performed within the past 8
weeks

- Patients with chronic myelomonocytic leukemia (CMML), refractory anemia (RA), or
refractory anemia with ringed sideroblasts (RARS) according to FAB classification OR
RA, RARS, refractory anemia with multilineage dysplasia, or RARS with multilineage
dysplasia according to WHO classification must meet ≥ 1 of the following criteria:

- Symptomatic anemia requiring RBC transfusion for ≥ 3 months before study entry

- Thrombocytopenia with ≥ 2 platelet counts < 50,000/mm³ OR a significant
hemorrhage requiring platelet transfusion

- Neutropenia with an absolute neutrophil count < 1,000/mm³ and an infection
requiring IV antibiotics

- No refractory anemia with excess blasts in transformation

- No history of leukemia

- No known primary or metastatic hepatic tumor

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Life expectancy > 2 months

- AST and ALT ≤ 2 times upper limit of normal

- Creatinine < 2.0 mg/dL

- Serum vitamin B12 normal

- Serum and/or red cell folate levels normal

- Ferritin ≥ 50 ng/mL

- Copper > 40 µg/dL

- Not pregnant or nursing

- Fertile patients must use effective contraception

- Negative pregnancy test

PRIOR CONCURRENT THERAPY:

- No prior azacitidine or decitabine

- No prior therapy for MDS

- Supportive therapy within the past 28 days allowed

- No other concurrent treatment for MDS (i.e., thalidomide, arsenic trioxide,
cyclosporine, or melphalan)

- No other concurrent hematopoietic growth factors, including epoetin alfa, filgrastim
(G-CSF), sargramostim (GM-CSF), or interleukin-11 (oprelvekin)