Myelodysplastic Syndromes
Conditions
Keywords
previously treated myelodysplastic syndromes, refractory anemia with excess blasts, refractory anemia with ringed sideroblasts, refractory anemia, secondary myelodysplastic syndromes, de novo myelodysplastic syndromes
Brief summary
RATIONALE: Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. PURPOSE: This phase II trial is studying how well bortezomib works in treating patients with myelodysplastic syndromes.
Detailed description
OBJECTIVES: Primary * Determine the efficacy of bortezomib, in terms of reduced cytopenia, in patients with myelodysplastic syndromes. * Determine the safety and toxic effects of this drug in these patients. Secondary * Determine changes in marrow blast percentage or karyotypic profile in patients treated with this drug. OUTLINE: This is an open-label study. Patients receive bortezomib IV on days 1, 4, 8, and 11. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for 1 year. PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.
Interventions
DRUGbortezomib
Sponsors
University of Rochester
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
DISEASE CHARACTERISTICS: * Diagnosis of myelodysplastic syndromes (MDS) * Requires treatment or transfusion support for MDS, as indicated by 1 of the following: * Demonstrates transfusion or epoetin alfa dependence * Transfusion dependence is defined as requiring ≥ 2 units of packed RBCs within an 8-week period prior to study entry * Hemoglobin \< 11g/dL on 2 separate occasions 2 weeks apart * No iron, cyanocobalamin (vitamin B\_12), or folic acid deficiency or other causes of anemia * Must have 1 of the following FAB subtypes: * Refractory anemia * Refractory anemia with ringed sideroblasts * Refractory anemia with excess blasts * Secondary MDS (if ≥ 3 years since active primary cancer) * No chronic myelomonocytic leukemia * Not refractory to platelet transfusion support (i.e., inability to maintain platelet count \> 20,000/mm\^3 with transfusion) * No current acute myelogenous leukemia (e.g., \> 30% blasts) PATIENT CHARACTERISTICS: Performance status * Karnofsky 50-100% Life expectancy * At least 6 months Hematopoietic * See Disease Characteristics Hepatic * Bilirubin ≤ 2 mg/dL * AST and ALT \< 2 times upper limit of normal Renal * Creatinine clearance ≥ 30 mL/min Cardiovascular * No significant cardiovascular condition that would preclude study participation * No uncontrolled hypertension Pulmonary * No significant pulmonary condition that would preclude study participation Immunologic * No serious concurrent infection * Active infections must be adequately treated with antibiotics prior to study entry * No hypersensitivity to bortezomib, boron, or mannitol Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for up to 4 weeks after completion of study treatment * No peripheral neuropathy ≥ grade 2 * No uncontrolled seizure activity, as defined by no activity within the past year on stable anticonvulsant medications * No other malignancy within the past 3 years except adequately treated basal cell skin cancer or carcinoma in situ of the cervix * No endocrine, neurologic, or other systemic disease that would preclude study entry PRIOR CONCURRENT THERAPY: Biologic therapy * See Disease Characteristics * No prior allogeneic bone marrow transplantation * Concurrent transfusion support allowed * Concurrent epoetin alfa or darbepoetin alfa allowed if initiated before start of study therapy, dose is stable for ≥ 4 weeks, and dose is stable during study participation * No concurrent platelet growth factor support * No concurrent thalidomide Chemotherapy * No concurrent chemotherapy * No concurrent hydroxyurea Endocrine therapy * Concurrent corticosteroids for chronic autoimmune or inflammatory condition allowed if initiated before start of study therapy and maintained on a stable or decreasing dose Other * Recovered from all prior therapies * At least 4 weeks since prior MDS therapy, except epoetin alfa, darbepoetin alfa, filgrastim (G-CSF), pegfilgrastim (G-CSF), or transfusion support * At least 30 days since prior investigational agents * No prior bortezomib * No other concurrent investigational agents * No other concurrent therapy for MDS
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Number of Participants Who Experienced Cytopenias | 21 Days/course for up to 12 courses |
| Number of Participants Who Experienced an Adverse Event | For 21 days/course for up to 12 courses |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Percentage of Light Density Cells in Apoptosis | day 14 | The CD34+ fraction of light density marrow obtained from patients at baseline and while receiving bortezomib were assessed through measurement of Annexin V (assay obtained form R&D Systems) and by flow cytometry analysis. |
| Average Number of Colony Forming Unit-granulocyte-macrophages in Bone Marrow | day 14 | Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as \> 20 grouped cells. |
| Interleukin 6 Levels in Serum | day 14 | interleukin-6 levels were measured by enzyme-linked immunosorbant assay ELISA in serum from participants exposed to bortezomib. Levels were measured at Day 0 and Day 14 of cycle 1 of the clinical trial. |
| Average Number of Leukemia Forming Units in Bone Marrow | day 14 | Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as \> 20 grouped cells. |
| Average Number of Erthroid Burst Forming Units in Bone Marrow | day 14 | Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as \> 20 grouped cells. |
| Vascular Endothelial Growth Factor (VEGF) Levels in Serum | day 14 | VEGF levels were measured by ELISA (R&DSystems) in serum from participants exposed to bortezomib. Levels were measured at Day 0 and Day 14 of cycle 1 of the clinical trial. |
Countries
United States
Participant flow
Recruitment details
23 patients were screened for the study.
Pre-assignment details
15 patients did not meet study eligibility criteria.
Participants by arm
| Arm | Count |
|---|---|
| Bortezomib Bortezomib was given at a dose of 1.3 mg per meter squared on day 1, 4, 8, and 11 on a 21 day cycle. Up to 12 cycles were allowed. Response assessments were made after the 3rd, 6th and 12 cycles of therapy. | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Bortezomib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 69 years |
| Region of Enrollment United States | 8 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 5 / 8 |
| serious Total, serious adverse events | 2 / 8 |
Outcome results
Primary
Number of Participants Who Experienced an Adverse Event
Time frame: For 21 days/course for up to 12 courses
Population: patients enrolled to receive study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bortezomib | Number of Participants Who Experienced an Adverse Event | 6 participants |
Primary
Number of Participants Who Experienced Cytopenias
Time frame: 21 Days/course for up to 12 courses
Population: This data was not collected.
Secondary
Average Number of Colony Forming Unit-granulocyte-macrophages in Bone Marrow
Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as \> 20 grouped cells.
Time frame: day 14
Population: baseline marrow samples were available only 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bortezomib | Average Number of Colony Forming Unit-granulocyte-macrophages in Bone Marrow | pre bortezomib | 16.1 number of colonies per 50000 cell plated | Standard Deviation 12.8 |
| Bortezomib | Average Number of Colony Forming Unit-granulocyte-macrophages in Bone Marrow | post bortezomib | 28.6 number of colonies per 50000 cell plated | Standard Deviation 25.8 |
Secondary
Average Number of Erthroid Burst Forming Units in Bone Marrow
Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as \> 20 grouped cells.
Time frame: day 14
Population: analysis was performed on only four participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bortezomib | Average Number of Erthroid Burst Forming Units in Bone Marrow | pre bortezomib | 14.75 number of colonies per 50000 cell plated | Standard Deviation 14.98 |
| Bortezomib | Average Number of Erthroid Burst Forming Units in Bone Marrow | post bortezomib | 14.75 number of colonies per 50000 cell plated | Standard Deviation 25.51 |
Secondary
Average Number of Leukemia Forming Units in Bone Marrow
Colony forming unit-granulocyte-macrophage (CFU-GM) progenitors, erythroid burst forming units (BFU-E), and leukemia colony forming units (CFU-L) were measured at day 0 and day 14 of cycle 1. Five × 10(4) light density cell for granulocyte-macrophage colony forming unit (CFU-GM) or erythroid burst forming unit (BFU-E) assays were plated in 0.9% methylcellulose, 30% FCS, 2 mmol/L L-glutamine, 10-4 mol/L β-mercaptoethanol, and 1% BSA with 3U/ml human erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, and 50 ng/ml stem cell factor (SCF) (c-kit ligand). For leukemia colony forming units (CFU-Ls), the plating mixture was comparable with the exception that the cytokines utilized were 4 U/ml erythropoietin, 10 ng/ml GM-CSF, 10 ng/ml IL-3, 100 ng/ml c-kit ligand, and 100 ng/ml Flt3 ligand. The methylcellulose mixture and associated reagents were purchased from Stem Cell Technologies (Vancouver, BC). Colonies were scored at Day 14 and were defined as \> 20 grouped cells.
Time frame: day 14
Population: baseline bone marrow was only available on 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bortezomib | Average Number of Leukemia Forming Units in Bone Marrow | pre bortezomib | 27.65 number of colonies per 50000 cell plated | Standard Deviation 25.15 |
| Bortezomib | Average Number of Leukemia Forming Units in Bone Marrow | post bortezomib | 54.28 number of colonies per 50000 cell plated | Standard Deviation 59.16 |
Secondary
Average Percentage of Light Density Cells in Apoptosis
The CD34+ fraction of light density marrow obtained from patients at baseline and while receiving bortezomib were assessed through measurement of Annexin V (assay obtained form R&D Systems) and by flow cytometry analysis.
Time frame: day 14
Population: marrow samples were not available on all participants at baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bortezomib | Average Percentage of Light Density Cells in Apoptosis | pre bortezomib | 6.68 percentage of apoptotic cells | Standard Deviation 2.67 |
| Bortezomib | Average Percentage of Light Density Cells in Apoptosis | post bortezomib | 11.37 percentage of apoptotic cells | Standard Deviation 3.73 |
p-value: 0.05t-test, 2 sided
Secondary
Interleukin 6 Levels in Serum
interleukin-6 levels were measured by enzyme-linked immunosorbant assay ELISA in serum from participants exposed to bortezomib. Levels were measured at Day 0 and Day 14 of cycle 1 of the clinical trial.
Time frame: day 14
Population: data was only available on 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bortezomib | Interleukin 6 Levels in Serum | pre bortezomib | 6.8 pg/ml | Standard Deviation 1.7 |
| Bortezomib | Interleukin 6 Levels in Serum | post bortezomib | 8.6 pg/ml | Standard Deviation 3.3 |
p-value: <0.05t-test, 2 sided
Secondary
Vascular Endothelial Growth Factor (VEGF) Levels in Serum
VEGF levels were measured by ELISA (R&DSystems) in serum from participants exposed to bortezomib. Levels were measured at Day 0 and Day 14 of cycle 1 of the clinical trial.
Time frame: day 14
Population: data was only available on 5 participants
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bortezomib | Vascular Endothelial Growth Factor (VEGF) Levels in Serum | pre bortezomib | 402 pg/ml | Standard Deviation 105 |
| Bortezomib | Vascular Endothelial Growth Factor (VEGF) Levels in Serum | post bortezomib | 254 pg/ml | Standard Deviation 69 |
p-value: <0.05t-test, 2 sided