Chronic Myelomonocytic Leukemia, de Novo Myelodysplastic Syndromes, Myelodysplastic Syndromes, Refractory Anemia, Refractory Anemia With Excess Blasts, Refractory Anemia With Ringed Sideroblasts, Refractory Cytopenia With Multilineage Dysplasia, Thrombocytopenia
Conditions
Keywords
previously treated myelodysplastic syndromes, secondary myelodysplastic syndromes
Brief summary
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.
Detailed description
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.
Interventions
OTHERflow cytometry
Correlative studies
OTHERDNA methylation analysis
Correlative studies
OTHERcytogenetic analysis
Correlative studies
DRUGdecitabine
Given subcutaneously
GENETICmicroarray analysis
Correlative studies
GENETICgene expression analysis
Correlative studies
OTHERpharmacological study
Correlative studies
GENETICpolymorphism analysis
Correlative studies
Sponsors
Case Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | Formal assessment at week 12 for study primary end-point (hematologic improvement). | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cytogenetic Response as Per IWG Criteria | at 12 months | 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). |
| Proportion of Patients With Pharmacodynamic Evidence of Drug Effect. | 6 weeks after treatment | 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. |
| Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria | up to 12 months of treatment | 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. |
| Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy. | 6 weeks after treatment | 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 |
| Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response | Baseline | Proportion of patients with particular genetic abnormalities, including DNA Methyltransferase 1 (DNMT1) depletion, detected by whole exome sequencing correlation with clinical response |
| Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. | 6 weeks after treatment | 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. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from medical clinic between July 2010 and September 2011.
Participants by arm
| Arm | Count |
|---|---|
| Arm I: Decitabine 0.2mg/kg INDUCTION PHASE: Patients receive decitabine subcutaneously (SQ) twice weekly for 4 weeks or thrice weekly until achieving bone marrow blasts \< 5%. MAINTENANCE PHASE: Patients then receive decitabine SQ twice weekly for up to 52 weeks in the absence of disease progression or unacceptable toxicity. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Physician Decision | 1 |
Baseline characteristics
| Characteristic | Arm I: Decitabine 0.2mg/kg |
|---|---|
| Age, Customized 40-49 years | 1 participants |
| Age, Customized 50-59 years | 1 participants |
| Age, Customized 60-69 years | 8 participants |
| Age, Customized 70-79 years | 9 participants |
| Age, Customized 80-89 years | 6 participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 25 |
| other Total, other adverse events | 0 / 0 |
| serious Total, serious adverse events | 15 / 25 |
Outcome results
Primary
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).
Population: All patients enrolled and that received any treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I: Decitabine 0.2mg/kg | Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | Hematologic Improvement | 7 participants |
| Arm I: Decitabine 0.2mg/kg | Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | Complete Remission | 4 participants |
| Arm I: Decitabine 0.2mg/kg | Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | Partial Remission | 0 participants |
| Arm I: Decitabine 0.2mg/kg | Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | Stable Disease | 9 participants |
| Arm I: Decitabine 0.2mg/kg | Number of Patients With Response as Defined by IWG (International Working Group) Criteria for Myelodysplasia | Disease Progression | 5 participants |
Secondary
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
Population: Patients that had cytogenetic abnormalities at baseline and were evaluable with follow-up metaphase karyotyping.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I: Decitabine 0.2mg/kg | Cytogenetic Response as Per IWG Criteria | no cytogenetic remission | 4 participants |
| Arm I: Decitabine 0.2mg/kg | Cytogenetic Response as Per IWG Criteria | complete cytogenetic remission | 5 participants |
| Arm I: Decitabine 0.2mg/kg | Cytogenetic Response as Per IWG Criteria | partial cytogenetic remission | 2 participants |
Secondary
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
Population: All patients that received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Decitabine 0.2mg/kg | Number of Patients That Experience > Grade 2 Non-hematologic Toxicity by National Cancer Institute (NCI)/Cancer Therapy Evaluation Program (CTEP) v4 Criteria | 16 participants |
Secondary
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
Population: Patients with chromosomal abnormalities which were evaluable for follow-up karyotyping
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I: Decitabine 0.2mg/kg | Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. | Complete cytogenetic remission | 5 participants |
| Arm I: Decitabine 0.2mg/kg | Proportion of Patients With Bone Marrow Evidence of Cytotoxicity. | Partial cytogenetic remission | 2 participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Decitabine 0.2mg/kg | Proportion of Patients With Bone Marrow Evidence of Terminal Differentiation Response to Therapy. | 11 participants |
Secondary
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Decitabine 0.2mg/kg | Proportion of Patients With Particular Genetic Abnormalities Detected by Whole Exome Sequencing Correlation With Clinical Response | 4 participants |
Secondary
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
Population: All subjects that had treatment with DNMT1 depletion.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I: Decitabine 0.2mg/kg | Proportion of Patients With Pharmacodynamic Evidence of Drug Effect. | 25 participants |