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

Condition(s) targeted: Chronic Myeloproliferative Disorders; Secondary Myelofibrosis

Intervention: cyclophosphamide (Drug); prednisone (Drug); thalidomide (Drug); antiangiogenesis therapy (Procedure); biopsy (Procedure); chemotherapy (Procedure); diagnostic procedure (Procedure); immunohistochemistry staining method (Procedure); laboratory biomarker analysis (Procedure); steroid therapy (Procedure)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: Mayo Clinic

Official(s) and/or principal investigator(s):
Ruben A. Mesa, MD, Study Chair, Affiliation: Mayo Clinic
Ayalew Tefferi, MD, Affiliation: Mayo Clinic

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.

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

Study design: Treatment, Open Label

Primary outcome: Confirmed response, defined as a complete or partial response in ≥ 1 of 3 response categories (i.e., anemia, thrombocytopenia, or splenomegaly or hepatomegaly)

Secondary outcome:

Constitutional symptom status and bone marrow morphology

Overall survival

Progression-free survival

Time to progression

Duration of response

Toxicity as measured by NCI CTC v 2.0

Detailed description: 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

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

Clinical trial summary from the National Cancer Institute's PDQ® database

Starting date: October 2004
Last updated: December 25, 2007