Differentiation Therapy With Decitabine in Treating Patients With Myelodysplastic Syndrome

PRIMARY OBJECTIVES:

I. Demonstrate that differentiation therapy with DNMT1 depleting but non-DNA damaging doses
of decitabine is efficacious and can be administered weekly for > = 12 months. SECONDARY
OBJECTIVES: I. Assess safety of the regimen.

II. Retrospectively compare study and standard regimen clinical responses. III. Assess the
ability of a pharmacodynamic assay that measures DNMT1 depletion in peripheral blood white
blood cells to predict clinical responses to decitabine.

IV. Assess PCR for aberrant methylation signature as an early marker of relapse. V. Identify
biologic features of MDS that correlate with response to decitabine, thereby facilitating
future patient selection.

VI. In cases of relapse or resistance, assess the role of the enzyme CDA in altering
decitabine metabolism and preventing DNMT1 depletion.

OUTLINE:

INDUCTION PHASE: Patients receive decitabine subcutaneously (SC) twice weekly for 4 weeks or
thrice weekly until achieving bone marrow blasts < 5%.

MAINTENANCE PHASE: Patients then receive decitabine SC twice weekly for up to 52 weeks in the
absence of disease progression or unacceptable toxicity. After completion of study treatment,
patients are followed periodically.

Inclusion

- MDS classified by hematopathology review as WHO categories refractory anemia (RA) or
refractory cytopenia with multi-lineage dysplasia (RCMD) or refractory anemia with
ring sideroblasts (RARS) or refractory anemia with excess blasts (RAEB1 or RAEB2) or
chronic myelo-monocytic leukemia (CMML1 or CMML2)

- Symptomatic anemia OR thrombocytopenia with a platelet count of < 100 x 10^9/L OR
transfusion dependence for red-cells OR transfusion dependence for platelets OR
absolute neutrophil count < 1 x 10^9/L

Exclusion

- MDS of the WHO sub-types RA or RCMD with sole 5q- abnormality on cytogenetics unless
failed lenalidomide (Revlimid) therapy

- Previous treatment with decitabine

- Untreated erythropoietin deficiency defined as an erythropoietin level of < 200 IU/L
and erythropoietin replacement therapy for < 8 weeks (erythropoietin deficiency until
corrected)

- Uncontrolled infection

- Severe sepsis or septic shock

- Current pregnancy or breast feeding

- The patient is of childbearing age, and is unwilling to use contraception and has not
had a tubal ligation, hysterectomy, or vasectomy , or their partner is also unwilling
to use an acceptable method of contraception as determined by the investigator

- Not able to give informed consent

- Altered mental status or seizure disorder

- ALT > 300 IU; or albumin < 2.0 mg/dL

- Creatinine > 2.5 mg/dl and creatinine clearance < 60ml/min

- B12, folate, or iron deficient, until corrected

- NYHA class III/IV status

- ECOG performance status > 2

- HIV positive or history of seropositivity for HIV

- Transformation to acute leukemia ( >= 20% myelo-blasts in marrow aspirate)

- Any experimental agents other than the study drug decitabine