Leukemia, Myelodysplastic Syndromes
Conditions
Keywords
de novo myelodysplastic syndromes, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia, refractory cytopenia with multilineage dysplasia, chronic myelomonocytic leukemia, secondary myelodysplastic syndromes, childhood myelodysplastic syndromes
Brief summary
RATIONALE: Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing. Colony-stimulating factors, such as darbepoetin alfa and G-CSF, may increase the number of red blood cells and white blood cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Giving azacitidine together with darbepoetin alfa and G-CSF may be an effective treatment for myelodysplastic syndromes. PURPOSE: This clinical trial is studying how well giving azacitidine together with darbepoetin alfa and G-CSF works in treating patients with myelodysplastic syndromes.
Detailed description
OBJECTIVES: Primary * Determine the hematological response rate in patients with myelodysplastic syndromes treated with azacitidine, darbepoetin alfa, and filgrastim (G-CSF). Secondary * Determine the time to leukemia progression, survival, and changes in apoptotic index of bone marrow in patients treated with this regimen. OUTLINE: This is an open-label, nonrandomized study. * Initial therapy (courses 1 and 2): Patients receive azacitidine subcutaneously (SC) or intra-venous (IV) on days 1-5 (week 1) and darbepoetin alfa\* SC on day 8 (week 2). Treatment repeats every 28 days for 2 courses. Patients undergo bone marrow aspirate and biopsy to assess response. Patients with a major hematological improvement OR with grade 3-4 hematological toxicities during the first 2 courses of therapy AND/OR ≥ 50% reduction in bone marrow cellularity compared to baseline proceed to optimization therapy A. Patients not meeting any of the above criteria proceed to optimization therapy B. Patients with disease progression are removed from study. * Optimization therapy A (courses 3-8): Patients receive azacitidine SC or IV on days 1-5 (week 1), darbepoetin alfa\*\* SC on day 8 (week 2), and filgrastim (G-CSF) SC 3 times weekly in weeks 2-4. * Optimization therapy B (courses 3-8): Patients receive a higher dose of azacitidine on days 1-5 (week 1), darbepoetin alfa\*\* SC on day 8 (week 2), and G-CSF 3 times weekly in weeks 2-4. In both optimization therapy A and B, treatment repeats every 28 days for 6 courses. Patients with any degree of hematological improvement after initial therapy and optimization therapy proceed to maintenance therapy. * Maintenance therapy (course 9 and all subsequent courses): Patients receive azacitidine on days 1-5 (week 1). Only patients with anemia (hemoglobin \< 12 g/dL) and/or neutropenia (absolute neutrophil count \< 1,500/mm ³) at the start of any given course during maintenance therapy receive darbepoetin alfa\*\* SC beginning on day 8 (week 2) and continuing once every 21 days and G-CSF SC 3 times weekly beginning in week 2. Courses repeat every 28-56 days (determined by the treating physician) in the absence of disease progression or unacceptable toxicity. Bone marrow samples are obtained at baseline and after the completion of course 2 of study treatment for apoptosis analysis, flow cytometry, and gene expression profiles of p53 and p21 by immunohistochemistry. Peripheral blood samples are obtained periodically and analyzed for hemoglobin F quantitation. NOTE: \*Administered only if the patient is anemic (hemoglobin \< 12 g/dL). NOTE: \*\*Darbepoetin alfa is held if hemoglobin \> 12 g/dL on day 1 of a given cycle.
Interventions
DRUGAzacitadine and Hematopoietic Growth Factors
Combination of Azacitadine and Hematopoietic Growth Factors
Sponsors
National Cancer Institute (NCI)
Wake Forest University Health Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Diagnosis of myelodysplastic syndromes (MDS) * Bone marrow aspirate and biopsy with karyotyping performed within the past 8 weeks * Patients with chronic myelomonocytic leukemia (CMML), refractory anemia (RA), or refractory anemia with ringed sideroblasts (RARS) according to FAB classification OR RA, RARS, refractory anemia with multilineage dysplasia, or RARS with multilineage dysplasia according to WHO classification must meet ≥ 1 of the following criteria: * Symptomatic anemia requiring RBC transfusion for ≥ 3 months before study entry * Thrombocytopenia with ≥ 2 platelet counts \< 50,000/mm³ OR a significant hemorrhage requiring platelet transfusion * Neutropenia with an absolute neutrophil count \< 1,000/mm³ and an infection requiring IV antibiotics * No refractory anemia with excess blasts in transformation * No history of leukemia * No known primary or metastatic hepatic tumor PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * Life expectancy \> 2 months * AST and ALT ≤ 2 times upper limit of normal * Creatinine \< 2.0 mg/dL * Serum vitamin B12 normal * Serum and/or red cell folate levels normal * Ferritin ≥ 50 ng/mL * Copper \> 40 µg/dL * Not pregnant or nursing * Fertile patients must use effective contraception * Negative pregnancy test PRIOR CONCURRENT THERAPY: * No prior azacitidine or decitabine * No prior therapy for MDS * Supportive therapy within the past 28 days allowed * No other concurrent treatment for MDS (i.e., thalidomide, arsenic trioxide, cyclosporine, or melphalan) * No other concurrent hematopoietic growth factors, including epoetin alfa, filgrastim (G-CSF), sargramostim (GM-CSF), or interleukin-11 (oprelvekin)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Response | Approximately 112 days | Complete response is normalization of abnormal blood counts, and disappearance of signs of morphological changes in the bone marrow. If the previously present cytogenetic abnormalities are absent then it is referred also as a cytogenetic complete remission. |
| Rate of Major Hematological Improvement | Approximately 112 days | For patients with pretreatment hemoglobin less than 11 g/dL, greater than 2 g/dL increase in hemoglobin; for red cell transfusion-dependent patients, transfusion independence. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Minor Hematological Improvements | Approximately 112 days | For patients with pretreatment platelet count less than 100,000/mm3, a 50% or more increase in platelet count with a net increase greater than 10,000/mm3 but less than 30,000/mm3 |
| Time to Progression to Acute Myeloid Leukemia (Blast ≥ 20%) or Death | Approximately 12 months | Death during treatment or disease progression characterized by worsening of cytopenias, increase in the percentage of the blasts, reduction of hemoglobin concentration by at least 2 g/dl or transfusion dependence in the absence of another explanation, such as acute infection, gastrointestinal bleeding, hemolysis. |
| Overall Survival | Approximately 12 months | — |
| Change in Bone Marrow Apoptosis | Baseline and approximately 12 months | — |
| Expression of p53 and p21 | Approximately 12 months | — |
Countries
United States
Participant flow
Recruitment details
Three patients were enrolled between 09/14/06 and 01/07/2008. The study was closed for slow accrual on 09/02/2009.
Participants by arm
| Arm | Count |
|---|---|
| Azacitidine and Darbopoietin and G-CSF | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | all patient progressed before completion | 3 |
Baseline characteristics
| Characteristic | Azacitidine and Darbopoietin and G-CSF |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 69.407 years STANDARD_DEVIATION 3.691 |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 |
Outcome results
Primary
Number of Participants With Complete Response
Complete response is normalization of abnormal blood counts, and disappearance of signs of morphological changes in the bone marrow. If the previously present cytogenetic abnormalities are absent then it is referred also as a cytogenetic complete remission.
Time frame: Approximately 112 days
Population: There were a total of 3 patients accrued on this trial. All were eligible and evaluable for response and evaluable for toxicity, as per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine and Darbopoietin and G-CSF | Number of Participants With Complete Response | 0 Participants |
Primary
Rate of Major Hematological Improvement
For patients with pretreatment hemoglobin less than 11 g/dL, greater than 2 g/dL increase in hemoglobin; for red cell transfusion-dependent patients, transfusion independence.
Time frame: Approximately 112 days
Population: Because no patients completed therapy, no analysis was possible
Secondary
Change in Bone Marrow Apoptosis
Time frame: Baseline and approximately 12 months
Population: Because no patients completed therapy, no analysis was done
Secondary
Expression of p53 and p21
Time frame: Approximately 12 months
Population: Because no patients completed therapy, no analysis was possible
Secondary
Minor Hematological Improvements
For patients with pretreatment platelet count less than 100,000/mm3, a 50% or more increase in platelet count with a net increase greater than 10,000/mm3 but less than 30,000/mm3
Time frame: Approximately 112 days
Population: Because no patients completed therapy, no analysis was possible
Secondary
Overall Survival
Time frame: Approximately 12 months
Population: Because no patients completed therapy, and the protocol was closed early, analysis was not performed
Secondary
Time to Progression to Acute Myeloid Leukemia (Blast ≥ 20%) or Death
Death during treatment or disease progression characterized by worsening of cytopenias, increase in the percentage of the blasts, reduction of hemoglobin concentration by at least 2 g/dl or transfusion dependence in the absence of another explanation, such as acute infection, gastrointestinal bleeding, hemolysis.
Time frame: Approximately 12 months
Population: Because no patients completed therapy, no analysis was possible