Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia
Conditions
Brief summary
This phase II trial is studying how well decitabine works in treating patients with previously untreated acute myeloid leukemia. Drugs used in chemotherapy, such as decitabine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing
Detailed description
PRIMARY OBJECTIVES: I. Determine the rate of complete remission (CR) in patients with previously untreated acute myeloid leukemia treated with decitabine. SECONDARY OBJECTIVES: I. Determine the rate of overall survival at 1 year in patients treated with this drug. II. Determine the overall response rate (CR, incomplete CR, and partial remission) in patients treated with this drug. III. Correlate the biological activity of decitabine with clinical endpoints and maximum concentration of plasma decitabine. IV. Correlate intracellular concentration of decitabine with global DNA methylation, other biological endpoints, and clinical response. OUTLINE: Patients receive decitabine IV over 1 hour on days 1-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo bone marrow aspiration and blood sample collection periodically for pharmacological and correlative studies. Samples are analyzed for gene expression, methylation of gene promoters, fetal hemoglobin (HgF), DNMT1 protein expression, maximum concentration of plasma decitabine, and global DNA methylation. Samples are analyzed by RT-PCR, Bio-COBRA, matrix-assisted laser desorption ionization time-of-flight mass spectrometry, SDS-PAGE (polyacrylamide gel electrophoresis), immunoblotting, and LC-MS/MS. After completion of study treatment, patients are followed for at least 30 days.
Interventions
DRUGdecitabine
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
OTHERpharmacological study
Correlative studies
OTHERhigh performance liquid chromatography
Correlative studies
GENETICmicroarray analysis
Correlative studies
GENETICRNA analysis
Correlative studies
OTHERmass spectrometry
Correlative studies
GENETICDNA methylation analysis
Correlative studies
Correlative studies
Sponsors
National Cancer Institute (NCI)
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
* Histologically or cytologically confirmed acute myeloid leukemia (AML) meeting 1 of the following criteria: * At least 60 years of age and not a candidate for or refused standard induction treatment * Poor risk cytogenetics * AML following antecedent hematologic disorder * Therapy-related AML * Secondary AML * No granulocytic sarcoma as sole site of disease * No active CNS disease or CNS relapse * ECOG performance status 0-2 * Life expectancy \> 6 months * Total bilirubin \< 2.0 mg/dL * Creatinine \< 2.0 mg/dL * AST and ALT \< 2.5 times upper limit of normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No NYHA class III or IV congestive heart failure * No uncontrolled infection * No history of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine that are not easily managed * No other uncontrolled illness including, but not limited to, any of the following: * Symptomatic congestive heart failure * Unstable angina pectoris * Serious cardiac arrhythmia * Psychiatric illness or social situations that would preclude compliance with study requirements * No active second malignancy involving the blood or marrow or likely to progress and require therapy in the next 6 months * No prior therapy for AML except emergency leukapheresis or hydroxyurea for leukocytosis * No prior azacitidine or decitabine * No prior cytarabine or other conventional chemotherapy agents for antecedent hematologic disorders * Prior myeloid growth factors, recombinant erythropoietin, thalidomide, or lenalidomide allowed * No concurrent palliative radiotherapy * No other concurrent investigational agents * No other concurrent direct anti-leukemia therapy * No concurrent combination antiretroviral therapy for HIV-positive patients
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Complete Remission | Up to 24 weeks | Per International Working Group criteria: Morphologic complete remission (CRm): Defined as morphologic leukemia-free state, including \<5% blasts in BM aspirate with marrow spicules and a count of \> 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC \> 1000/uL, platelet count \> 100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia \<1000/uL or thrombocytopenia \<100,000/ul. Complete Remission Rate (CRm + CRi) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Measurement of DNA Methylation in Peripheral Blood or Bone Marrow Cells | From baseline to up to day 28 of course 1 | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. |
| Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells | Pre treatment | Expression studies were conducted using quantitative RT PCR. Expression of DNMT were normalized to the internal control to the ABL and levels of miR-29 to RNA U44. |
| Measurement of HbF in Peripheral Blood or Marrow Cells | From baseline to up to days 28 of course 2 | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. |
| Measurement of Gene Expression in Peripheral Blood or Bone Marrow | From baseline to up to day 28 of course 1 | Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Decitabine Decitabine 20mg/m2/day IV over 1 hour, days 1-10, repeat cycle every 28 days | 55 |
| Total | 55 |
Baseline characteristics
| Characteristic | Decitabine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 49 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 55 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 55 Participants |
| Region of Enrollment Canada | 1 patients |
| Region of Enrollment United States | 54 patients |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 53 / 53 |
| serious Total, serious adverse events | 0 / 53 |
Outcome results
Primary
Rate of Complete Remission
Per International Working Group criteria: Morphologic complete remission (CRm): Defined as morphologic leukemia-free state, including \<5% blasts in BM aspirate with marrow spicules and a count of \> 200 nucleated cells and no blasts with Auer rods, no persistent extramedullary disease, ANC \> 1000/uL, platelet count \> 100,000/uL. Patient must be independent of transfusions for a minimum of 1 week before each marrow assessment. Morphologic complete remission with incomplete blood count recovery (CRi): Defined as CR with the exception of neutropenia \<1000/uL or thrombocytopenia \<100,000/ul. Complete Remission Rate (CRm + CRi)
Time frame: Up to 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Decitabine | Rate of Complete Remission | 25 patients |
Secondary
Measurement of DNA Methylation in Peripheral Blood or Bone Marrow Cells
Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.
Time frame: From baseline to up to day 28 of course 1
Population: Data was not collected and analyzed
Secondary
Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells
Expression studies were conducted using quantitative RT PCR. Expression of DNMT were normalized to the internal control to the ABL and levels of miR-29 to RNA U44.
Time frame: Pre treatment
Population: Only pre treatment samples available for testing for 23 patients
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Decitabine | Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells | Expression levels of MiR-29b | 0.0056394 delta delta CT values |
| Decitabine | Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells | Expression levels of DNMT3a | 0.000196066 delta delta CT values |
| Non Responder | Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells | Expression levels of MiR-29b | 0.0024305 delta delta CT values |
| Non Responder | Measurement of DNMT Protein in Peripheral Blood or Bone Marrow Cells | Expression levels of DNMT3a | 0.000341819 delta delta CT values |
Comparison: Expression levels of miR-29b in pre treatment marrow samples from responding or non responding patients were compared using Wilcoxon rank sum testsp-value: 0.02Wilcoxon (Mann-Whitney)
Comparison: Expression levels of DNMT3a in pre treatment marrow samples from responding or non responding patients were compared using Wilcoxon rank sum testsp-value: 0.06Wilcoxon (Mann-Whitney)
Secondary
Measurement of Gene Expression in Peripheral Blood or Bone Marrow
Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.
Time frame: From baseline to up to day 28 of course 1
Population: Data was not collected and analyzed for this trial
Secondary
Measurement of HbF in Peripheral Blood or Marrow Cells
Standard paired statistical tests, parametric and nonparametric, will be used to baseline with treatment values. With data collected serially over time, repeated measures analysis of variance will be used to analyze data.
Time frame: From baseline to up to days 28 of course 2
Population: Data was not collected and analyzed for this trial