RATIONALE: Decitabine may help myelodysplastic cells become more like normal stem cells. PURPOSE: This clinical trial studies 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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
25
Correlative studies
Correlative studies
Correlative studies
Given subcutaneously
Correlative studies
Correlative studies
Correlative studies
Correlative studies
Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
Cleveland Clinic Taussig Cancer Institute, Case Comprehensive Cancer Center
Cleveland, Ohio, United States
Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia
Complete Response (CR) include less than 5% marrow blasts without evidence of dysplasia and normalization of peripheral blood counts, including a hemoglobin level of 110 g/L or more, a neutrophil count of 1.5 × 109/L or more, and a platelet count of 100 × 109/L or more. For PR, patients must demonstrate all CR criteria if abnormal before treatment except that marrow blasts should decrease by 50% or more compared with pretreatment levels, or patients may demonstrate a less-advanced MDS disease category than prior to treatment. Stable disease (SD) is defined by failure to achieve at least a partial response but no evidence of progression. Disease progression (DP) includes at least 50% decrease from maximum remission in granulocytes or platelets, reduction in hemoglobin by greater than or equal to 2g/dL, or transfusion dependence. Hematologic improvement (HI) includes hemoglobin increase by at least 1.5g/dL, reduction in transfusions, increase of platelets, increase of neutrophil count
Time frame: Formal assessment at week 12 for study primary end-point (hematologic improvement).
Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria
Incidence of treatment-emergent adverse events (AEs) will be presented in tables that include causality, seriousness, severity/grade, and whether the AE resulted in death or discontinuation of treatment, Laboratory data will be summarized in tables that show changes from pre-treatment values and frequencies of abnormal values. Descriptive statistics will also be provided.
Time frame: up to 12 months of treatment
Cytogenetic Response as Per IWG Criteria
Described as the number of patients with a major cytogenetic response (refers to disappearance of a cytogenetic abnormality) or a minor cytogenetic response (50% or more reduction of abnormal metaphases).
Time frame: at 12 months
Proportion of Patients With Pharmacodynamic Evidence of Drug Effect.
Evidence of pharmacodynamic effect will be correlated with clinical response criteria. The pharmacodynamic effect of treatment is defined as the number of participants that had depletion DNMT1 with minimal DNA damage and cytotoxicity.
Time frame: 6 weeks after treatment
Proportion of Patients With Bone Marrow Evidence of Cytotoxicity.
Cytotoxicity is the ability to destroy cells. This will be measured by taking bone marrow samples and measuring the damage to cells. The level of cell destruction will be correlated with clinical response criteria.
Time frame: 6 weeks after treatment
Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy.
Number of participants who, after therapy, had more of the differentiated types of blood (red cells, platelets, and white cells) compared to abnormal bone marrow cells than before therapy
Time frame: 6 weeks after treatment
Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response
Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response
Time frame: Baseline
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