Anemia, Myelodysplastic Syndromes
Conditions
Keywords
anemia, refractory anemia, myelodysplastic syndromes, erythropoietin, filgrastim
Brief summary
RATIONALE: Erythropoietin and colony-stimulating factors such as filgrastim stimulate the production of blood cells. It is not yet known whether erythropoietin with or without filgrastim is more effective than standard blood transfusions in reducing the need for transfusions in patients who have anemia associated with myelodysplastic syndrome. PURPOSE: Randomized phase III trial to compare the effectiveness of erythropoietin with or without filgrastim with that of standard blood transfusions in reducing the need for transfusions in patients who have anemia associated with myelodysplastic syndrome.
Detailed description
OBJECTIVES: * Compare the benefit of erythropoietin vs standard transfusion support in reducing transfusion requirements in patients with myelodysplastic syndromes. * Compare the clinical response, disease progression, and survival in patients treated with these regimens. * Compare the toxicity of these regimens in these patients. * Evaluate whether adding filgrastim (G-CSF) or increasing the erythropoietin dose will reduce the transfusion requirement in patients who do not respond to erythropoietin alone. * To compare the benefit of erythropoietin versus supportive care alone on quality of life (QOL) in persons with myelodysplastic syndromes. OUTLINE: This is a randomized, controlled, multicenter, cross-over study. Patients are stratified according to morphologic subtype (refractory anemia \[RA\] vs RA with ringed sideroblasts vs RA with excess blasts), transfusion requirement (yes vs no), prior erythropoietin treatment (yes vs no), and erythropoietin level (at least 200 mU/mL vs less than 200 mU/mL). Patients are randomized to one of two treatment arms. * Arm I (standard transfusion support): Patients receive red cell and platelet transfusions for symptoms or to maintain hematocrit level of 25% or above. Patients undergo bone marrow aspirate and biopsy at 4 months and then every year until development of acute leukemia or completion of study. Patients with progressive disease may cross over to arm II after at least 4 months on study and up to 1 year from the time of randomization. Patients who cross over receive erythropoietin alone. * Arm II (Erythropoietin): Patients receive erythropoietin subcutaneously (SC) or intravenously (IV) daily. Patients undergo bone marrow aspirate and biopsy as in arm I. Treatment continues daily for a maximum of 1 year. Patients with stable or progressive disease at day 120 receive filgrastim (G-CSF) SC daily or 3 days a week and erythropoietin SC daily for up to 6 months. Patients with no response to G-CSF and lower-dose erythropoietin may proceed to a higher dose of erythropoietin. Quality of life is assessed at baseline, every 4 months during study, and at study completion. Patients are followed every 4 months for 2 years, every 6 months for 3 years, and then annually for 5 years. ACTUAL ACCRUAL: A total of 118 patients were accrued for this study.
Interventions
BIOLOGICALErythropoietin
Administered at 150 units/kg subcutaneously every day. Rotating sites should be used. The dose should be rounded off to the nearest 1000 U. The dose should be adjusted based on hematocrit.
BIOLOGICALFilgrastim
G-CSF should start at a dose of 1 mcg/kg per day or 2.5 mcg/kg three times a week subcutaneously. Rotating sites should be used The dose should be rounded off to the nearest 10 mcg.
PROCEDURETransfusion
Red cell and platelet transfusions
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 18 years of age * Diagnosis of a myelodysplastic syndrome * Refractory anemia (RA) * RA with ringed sideroblasts * RA with excess blasts (RAEB). RAEB patients must have a bone marrow blast count of less than 20% and less than 5% blast forms on peripheral blood * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 3 * Platelet count greater than 30,000/mm\^3 (without platelet transfusions) * Hematocrit less than 30% (pretransfusion) * Bilirubin less than 3 mg/dL * Blood urea nitrogen (BUN) less than 40 mg/dL or Creatinine less than 2.0 mg/dL * Prior epoetin alfa allowed provided dosage was less than 30,000 units per week for less than 1 month duration * At least 1 month since prior erythropoietin * At least 2 months since prior recombinant growth factor * At least 2 months since prior chemotherapy for other malignancy or autoimmune disease * At least 2 weeks since prior androgen or steroids for treatment of myelodysplastic syndromes
Exclusion criteria
* RAEB in transformation * Chronic myelomonocytic leukemia * Splenomegaly greater than 6 cm below the left costal margin or greater than 3 times normal size * Uncontrolled hypertension * Sensitivity to E. coli-derived proteins * Sensitivity to epoetin alfa or any of its components (e.g., human albumin) * Documented iron deficiency. If marrow iron stain is not available, the transferrin saturation must be greater than 20% or ferritin greater than 100 ng/dL * Active infection or bleeding * Other uncontrolled malignancy * Pregnant or nursing. Fertile patients must use effective contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients Free of Transfusion at 4 Months | Assessed at 4 months | Whether a patient required transfusion or not at 4 months was recorded. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Assessed every 3 months for 2 years, every 6 months for 3 subsequent years, and annually thereafter | Time from randomization to death from any cause. Patients alive at the time of analysis were censored at the date of last contact. |
| Quality of Life- Total Functional Assessment of Cancer Therapy - General (FACT-G) Score at 4 Months | Assessed at 4 months | The FACT-G scale has 4 dimensions, including physical well-being, social/family well-being, emotional well-being, and functional well-being. The score for each subscale was added together to obtain the total FACT-G score that was evaluated on this study. The total FACT-G score ranges from 0 to 108 with higher scores reflecting better quality of life. It was administered at the time of study entry, every 4 months for the first year, and at the time patient went off treatment. Due to limited data after 4 months on treatment, the analysis was restricted to the four-month time point. |
Countries
United States
Participant flow
Recruitment details
This study was activated on December 9, 1997, accrued its first patient on March 4, 1998, and closed on June 1, 2004. A total of 118 patients were enrolled (110 ECOG patients and 8 Canadian Leukemia Study Group \[CLSG\] patients).
Participants by arm
| Arm | Count |
|---|---|
| Supportive Care Patients received red cell and platelet transfusions for symptoms or to maintain hematocrit at or above 25% by volume. Patients who required transfusion support for symptomatic anemia prior to entering the study and who developed an increase in their transfusion requirement of \>= 50% shall cross over to the Erythropoietin treatment arm, after at least four months on the supportive therapy arm. | 57 |
| Erythropoietin Erythropoietin was administered at 150 units/kg subcutaneously every day. If patients stopped responding, they were subsequently treated with Erythropoietin (150 units/kg) and filgrastim and then Erythropoietin (300 units/kg) and filgrastim. | 53 |
| Total | 110 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Step 1 | Never started treatment | 1 | 0 |
| Step 1 | Reasons off treatment not documented | 60 | 57 |
| Step 2 (Cross Over) | Reasons off treatment not documented | 26 | 0 |
| Step 3 (EPO 150 Units/kg and G-CSF) | Never started treatment | 0 | 1 |
| Step 3 (EPO 150 Units/kg and G-CSF) | Off treatment reasons not documented | 12 | 19 |
| Step 4 (EPO 300 Units/kg and G-CSF) | Off treatment reasons not documented | 6 | 7 |
Baseline characteristics
| Characteristic | Total | Supportive Care | Erythropoietin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 93 Participants | 50 Participants | 43 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 7 Participants | 10 Participants |
| Sex: Female, Male Female | 41 Participants | 21 Participants | 20 Participants |
| Sex: Female, Male Male | 69 Participants | 36 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 8 / 56 | 28 / 53 | 13 / 26 | 18 / 31 | 8 / 13 |
| serious Total, serious adverse events | 0 / 56 | 16 / 53 | 7 / 26 | 6 / 31 | 1 / 13 |
Outcome results
Primary
Proportion of Patients Free of Transfusion at 4 Months
Whether a patient required transfusion or not at 4 months was recorded.
Time frame: Assessed at 4 months
Population: Only patients with transfusion data were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Supportive Care | Proportion of Patients Free of Transfusion at 4 Months | 0.459 Proportion of patients |
| Erythropoietin | Proportion of Patients Free of Transfusion at 4 Months | 0.714 Proportion of patients |
Secondary
Overall Survival
Time from randomization to death from any cause. Patients alive at the time of analysis were censored at the date of last contact.
Time frame: Assessed every 3 months for 2 years, every 6 months for 3 subsequent years, and annually thereafter
Population: All patients with complete data were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Supportive Care | Overall Survival | 31 Months |
| Erythropoietin | Overall Survival | 37 Months |
Secondary
Quality of Life- Total Functional Assessment of Cancer Therapy - General (FACT-G) Score at 4 Months
The FACT-G scale has 4 dimensions, including physical well-being, social/family well-being, emotional well-being, and functional well-being. The score for each subscale was added together to obtain the total FACT-G score that was evaluated on this study. The total FACT-G score ranges from 0 to 108 with higher scores reflecting better quality of life. It was administered at the time of study entry, every 4 months for the first year, and at the time patient went off treatment. Due to limited data after 4 months on treatment, the analysis was restricted to the four-month time point.
Time frame: Assessed at 4 months
Population: Only patients who completed quality of life assessment at 4 months were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Supportive Care | Quality of Life- Total Functional Assessment of Cancer Therapy - General (FACT-G) Score at 4 Months | 84.1 Scores on a scale | Standard Deviation 15.77 |
| Erythropoietin | Quality of Life- Total Functional Assessment of Cancer Therapy - General (FACT-G) Score at 4 Months | 84.33 Scores on a scale | Standard Deviation 14.75 |