Decitabine in Treating Patients With Myelofibrosis

PRIMARY OBJECTIVES:

I. To determine response rate (complete and partial responses and hematological improvement)
to decitabine in patients with myelofibrosis.

II. To determine the safety of decitabine in patients with myelofibrosis.

SECONDARY OBJECTIVES:

I. To determine the effects of decitabine on specific epigenetic changes including
methylation status of specific target genes and gene re-expression.

II. To determine the effect of decitabine on hemoglobin F levels and on the absolute numbers
of circulating cluster of differentiation (CD) 34+ progenitor cells and to investigate the
potential utility of these markers as a surrogate for biologic activity of decitabine in
myeloid metaplasia with myelofibrosis (MMM).

OUTLINE:

Patients receive decitabine subcutaneously (SC) on days 1-5 and 8-12. Treatment repeats every
42 days in the absence of disease progression or unacceptable toxicity.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed myeloid metaplasia with
myelofibrosis (this includes all subtypes - chronic idiopathic myelofibrosis or
angiogenic myeloid metaplasia, post thrombocythemic and post polycythemic
myelofibrosis); patients must have anemia (hemoglobin < 11 g/dL) or palpable
splenomegaly (measured in cm from costal margin - to be eligible); patients with
palpable splenomegaly must have spleen size documented ultrasonographically as well;
they must also meet standard diagnostic criteria for MMM

- Patients with morphologic evidence of advanced phases of the disease including
accelerated (10-19% blasts) phase or with evidence of evolution to acute leukemia (>=
20% blasts) are also eligible for this study

- The Italian Diagnostic Criteria for MMM

- Necessary criteria

- Diffuse bone marrow fibrosis

- Absence of the Philadelphia chromosome or BCR-ABL rearrangement in
peripheral blood cells

- Optional criteria

- Splenomegaly of any grade

- Anisopoikilocytosis with tear drop erythrocytes

- Presence of circulating immature myeloid cells

- Presence of circulating erythroblasts

- Presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone
marrow sections

- Myeloid metaplasia

- Diagnosis of MMM is acceptable if the following combinations are present

- The two necessary criteria plus any other two optional criteria when
splenomegaly is present OR

- The two necessary criteria plus any other four optional criteria when
splenomegaly is absent

- Patients may have had prior chemotherapy or radiation therapy including splenic
irradiation; prior therapy with erythropoietin, granulocyte-colony stimulating factor
(GCSF), other growth factors or androgenic steroids is also permitted; there is no
limit to the number of prior regimens received; at least 4 weeks must have elapsed
since prior chemo or radiation therapy; at least 2 weeks must have elapsed since
growth factor (erythropoietin, GCSF, granulocyte-macrophage colony-stimulating factor
[GM-CSF]) or other therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

- Total bilirubin =< 2mg/dL

- In patients with associated hemolytic anemia; total bilirubin > 2mg/dL is
permissible as long as this is as a result of predominantly unconjugated
hyperbilirubinemia; such patients may be enrolled only after discussion with the
study chair

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal unless due to disease

- Serum creatinine =< 2mg/dL

- Patients must not be pregnant or nursing; women of child- bearing potential and men
must agree to use an effective contraceptive method; should a woman become pregnant or
suspect she is pregnant while participating in this study, she should inform her
treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Prior therapy with decitabine

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients with known central nervous system (CNS) disease should be excluded from this
clinical trial

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to decitabine

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with decitabine

- Human immunodeficiency virus (HIV)-positive patients receiving combination
anti-retroviral therapy are excluded from the study