Thalidomide, Prednisone, and Cyclophosphamide in Treating Patients With Myelofibrosis and Myeloid Metaplasia

Phase II Study of the Combination of Low-Dose Thalidomide, Prednisone, and Oral Cyclophosphamide ("TPC") in the Therapy of Myelofibrosis With Myeloid Metaplasia (MMM)

RATIONALE: Giving thalidomide together with prednisone and cyclophosphamide may lessen symptoms caused by myelofibrosis and myeloid metaplasia.

PURPOSE: This phase II trial is studying the side effects and how well giving thalidomide together with prednisone and cyclophosphamide works in treating patients with myelofibrosis and myeloid metaplasia.

OBJECTIVES:

Primary

• Determine the benefit of thalidomide, prednisone, and cyclophosphamide in alleviating disease-associated anemia, thrombocytopenia, and/or splenomegaly in patients with myelofibrosis with myeloid metaplasia (MMM).
• Determine the benefit of this regimen in palliating four hypercatabolic constitutional symptoms (i.e., weight loss, fatigue, drenching night sweats, and unexplained fevers) in these patients.
• Determine the toxicity profile of this regimen in these patients.

Secondary

• Determine the effect of this regimen on leukocyte count.
• Determine the effect of this regimen on bone marrow histology, including microvessel density and reticulin fibrosis.
• Determine the effect of this regimen on intramedullary and urinary markers of angiogenesis.
• Determine the effect of this regimen on circulating myeloid progenitor cells by quantifying CD34+ cells.

OUTLINE: Patients receive oral thalidomide, oral prednisone, and oral cyclophosphamide (TPC) once daily on days 1-28. Treatment repeats every 28 days for 3 courses. After 3 courses (3 months) of treatment, patients who respond to TPC therapy may receive oral thalidomide alone once daily for up to 3 months in the absence of disease progression or unacceptable toxicity.

Patients undergo bone marrow aspirate and biopsy prior to study entry, 6 months after starting therapy, and then every 6 months for up to 3 years. Samples are analyzed by microvessel density/angiogenesis studies (i.e., CD34 immunohistochemical and vascular endothelium-specific staining) to determine the effect of therapy on markers of bone marrow angiogenesis.

After completion of study therapy, patients are followed every 6 months for up to 3 years.

PROJECTED ACCRUAL: A total of 22 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

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

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

• Must have 1 of the following MMM-related conditions:

  • Anemia, defined as hemoglobin < 10 g/dL

    • Iron deficiency must be excluded as cause

  • Thrombocytopenia, defined as platelet count < 100,000/mm³

  • Palpable hepatomegaly or splenomegaly

• No evidence of myelofibrosis-associated conditions in the bone marrow, including any of the following:

  • Metastatic carcinoma
  • Lymphoma
  • Myelodysplasia
  • Hairy cell leukemia
  • Mast cell disease
  • Acute leukemia (including M7 type)
  • Acute myelofibrosis

• No chromosomal translocation t(9:22) or bcr-abl as determined by bone marrow chromosome analysis or peripheral blood fluorescent in situ hybridization (FISH) analysis

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3

• Absolute neutrophil count ≥ 750/mm³

• Bilirubin ≤ 2 times upper limit of normal (ULN), unless elevation due to MMM

• AST ≤ 5 times ULN, unless elevation due to MMM

• Creatinine ≤ 2.5 mg/dL

• No uncontrolled infection, including tuberculosis

  • No known history of positive purified protein derivative (PPD) untreated by isoniazid therapy

    • Positive PPD with normal chest X-ray and completion of full-course isoniazid therapy allowed

• No federal medical center inmates or other incarcerated patients

• No peripheral neuropathy ≥ grade 2

• No comorbid condition in which the use of study therapy is felt to be potentially harmful

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use 2 forms of effective contraception

PRIOR CONCURRENT THERAPY:

• No chemotherapy (e.g., hydroxyurea, myelosuppressive therapy) within the past 14 days
• Prior splenectomy for MMM allowed
• No concurrent hematopoietic growth factors