A Prospective Open-Label Pilot Trial of PS-341 (Bortezomib; VELCADE) for the Therapy of Symptomatic Advanced Myeloproliferative Disorders

Inclusion Criteria

DISEASE CHARACTERISTICS:

- Histologically confirmed advanced myeloproliferative disorder, including 1 of the
following subtypes:

- Myelofibrosis with myeloid metaplasia defined by the following criteria:

- Evaluable or symptomatic disease as evidenced by ≥ 1 of the following:

- Anemia, defined as hemoglobin < 10 g/dL OR erythrocyte-transfusion
dependence, defined as requiring 1 transfusion within the past 8 weeks

- Symptomatic palpable splenomegaly (palpable hepatomegaly is acceptable
if previously splenectomized) requiring treatment* NOTE: *Subjective
but painful enough to mandate intervention

- Chronic myelomonocytic leukemia (CMML) defined by the following criteria:

- Absence of an imatinib mesylate-sensitive molecular abnormality for CMML
(i.e., t[5;12], t[5;10], t[1;5], and t[5;7]) confirmed by fluorescent in
situ hybridization (FISH) or standard cytogenetic bone marrow analysis
within the past 18 months

- Symptomatic disease as evidenced by ≥ 1 of the following:

- Anemia, defined as hemoglobin < 10 g/dL OR erythrocyte-transfusion
dependence, defined as requiring 1 transfusion within the past 8 weeks

- Palpable splenomegaly (palpable hepatomegaly is acceptable if
previously splenectomized) requiring treatment* NOTE: *Subjective but
painful enough to mandate intervention

- Leukocytosis associated with ascites, serositis, pleural effusions,
vasculitis, or other overt manifestation

- Systemic mast cell disease defined by the following criteria:

- Absence of the FIP1LI-PDGFRA mutation as confirmed by FISH

- Evaluable and symptomatic disease requiring therapy, as evidenced by
involvement with organs other than skin (i.e., heart, bowel, peripheral
blood, liver/spleen, or marrow)

- Debilitating mast cell mediator symptoms not responsive to standard therapy
such as antihistamines

- Absence of t(9;22) translocation as confirmed by FISH or standard cytogenetic
peripheral blood or marrow analysis at any prior time point

PATIENT CHARACTERISTICS:

- ECOG performance status 0-2

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- Not incarcerated in a municipal, county, state, or federal prison

- Absolute neutrophil count ≥ 1,000/mm³

- Platelet count ≥ 75,000/mm³

- Creatinine ≤ 2.0 mg/dL

- Total or direct bilirubin ≤ 2.0 mg/dL

- AST and ALT ≤ 3 times upper limit of normal (unless clinically attributed to hepatic
extramedullary hematopoiesis)

- No baseline peripheral or autonomic neuropathy ≥ grade 2

- No other condition or laboratory abnormality that would place the patient at
unacceptable risk or confound the ability to interpret study data

- No hypersensitivity to boron, mannitol, or bortezomib

- No myocardial infarction within the past 6 months

- No New York Hospital Association class III-IV heart failure

- No uncontrolled angina

- No severe uncontrolled ventricular arrhythmia

- No evidence of acute ischemia or active conduction system abnormality by ECG

- ECG screening abnormalities must be documented as not medically relevant

- No other serious medical or psychiatric illness that would preclude study
participation

PRIOR CONCURRENT THERAPY:

- At least 14 days since prior chemotherapy (e.g., interferon alfa, anagrelide, or
other myelosuppressive agent) or any other experimental therapy

- At least 14 days since prior growth factors

- At least 14 days since prior systemic use of corticosteroids

- More than 14 days since prior investigational drugs

- Concurrent hydroxyurea allowed for ≤ 14 days during study therapy if clinically
indicated for extreme leukocytosis control