Azacitidine in Treating Patients With Myelofibrosis

Phase II Study of Azacitidine in Myelofibrosis

RATIONALE: Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing.

PURPOSE: This phase II trial is studying how well azacitidine works in treating patients with myelofibrosis.

OBJECTIVES:

Primary

• Determine the efficacy of azacitidine in patients with myelofibrosis (MF) with myeloid metaplasia.
• Evaluate the safety of azacitidine in these patients. Secondary
• Evaluate pertinent biologic characteristics of MF before and during therapy with azacitidine.
• Assess the effects of study treatment on constitutional symptoms in these patients.
• Estimate time to event distributions for overall survival and progression. OUTLINE: Patients receive azacitidine subcutaneously once daily on days 1-5. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 3 years.

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically confirmed myelofibrosis with myeloid metaplasia (MMM), including any of the following subtypes:

  • Agnogenic myeloid metaplasia
  • Post-polycythemic myeloid metaplasia
  • Post-thrombocythemic myeloid metaplasia

• Evaluable and symptomatic disease, defined as 1 of the following:

  • Anemia (hemoglobin < 10 g/dL or erythrocyte transfusion-dependent, requiring 1 transfusion ≤ 8 weeks)
  • Treatment required* for symptomatic palpable splenomegaly (palpable hepatomegaly is acceptable if previously splenectomized) NOTE: *Subjective but painful enough to mandate intervention

• Absence of t(9;22) by fluorescent in situ hybridization (FISH) or standard cytogenetics (by peripheral blood or marrow)

  - Previous demonstration of a lack of this translocation (at any point) is sufficient

• No advanced malignant hepatic tumors

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 50,000/mm³
• Creatinine ≤ 2.0 mg/dL
• Total bilirubin ≤ 2.0 mg/dL OR direct bilirubin ≤ 2.0 mg/dL if total bilirubin elevated (unless attributed to underlying disease)
• AST and ALT ≤ 2 times upper limit of normal (unless clinically attributed to hepatic extramedullary hematopoiesis)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No baseline peripheral or autonomic neuropathy ≥ grade 2
• No condition, including the presence of laboratory abnormalities, that would preclude study compliance
• No hypersensitivity to mannitol or azacitidine
• Not incarcerated in a municipality (i.e., county, state, or federal prison)

PRIOR CONCURRENT THERAPY:

• At least 14 days since prior chemotherapy, including interferon alfa, anagrelide, or other myelosuppressive agents
• At least 14 days since prior systemic corticosteroids
• At least 14 days since prior investigational agents