Chronic Myeloproliferative Disorders, Secondary Myelofibrosis
Conditions
Keywords
primary myelofibrosis, polycythemia vera, essential thrombocythemia, secondary myelofibrosis
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. PURPOSE: This phase II trial is studying how well azacitidine works in treating patients with myelofibrosis.
Detailed description
OBJECTIVES: Primary * Determine the efficacy of azacitidine in patients with myelofibrosis (MF) with myeloid metaplasia. * Evaluate the safety of azacitidine in these patients. Secondary * Evaluate pertinent biologic characteristics of MF before and during therapy with azacitidine. * Assess the effects of study treatment on constitutional symptoms in these patients. * Estimate time to event distributions for overall survival and progression. OUTLINE: Patients receive azacitidine subcutaneously once daily on days 1-5. Treatment repeats every 4 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed periodically for up to 3 years. PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.
Interventions
DRUGazacitidine
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed myelofibrosis with myeloid metaplasia (MMM), including any of the following subtypes: * Agnogenic myeloid metaplasia * Post-polycythemic myeloid metaplasia * Post-thrombocythemic myeloid metaplasia * Evaluable and symptomatic disease, defined as 1 of the following: * Anemia (hemoglobin \< 10 g/dL or erythrocyte transfusion-dependent, requiring 1 transfusion ≤ 8 weeks) * Treatment required\* for symptomatic palpable splenomegaly (palpable hepatomegaly is acceptable if previously splenectomized) NOTE: \*Subjective but painful enough to mandate intervention * Absence of t(9;22) by fluorescent in situ hybridization (FISH) or standard cytogenetics (by peripheral blood or marrow) \- Previous demonstration of a lack of this translocation (at any point) is sufficient * No advanced malignant hepatic tumors PATIENT CHARACTERISTICS: * ECOG performance status 0-2 * Absolute neutrophil count ≥ 1,000/mm³ * Platelet count ≥ 50,000/mm³ * Creatinine ≤ 2.0 mg/dL * Total bilirubin ≤ 2.0 mg/dL OR direct bilirubin ≤ 2.0 mg/dL if total bilirubin elevated (unless attributed to underlying disease) * AST and ALT ≤ 2 times upper limit of normal (unless clinically attributed to hepatic extramedullary hematopoiesis) * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No baseline peripheral or autonomic neuropathy ≥ grade 2 * No condition, including the presence of laboratory abnormalities, that would preclude study compliance * No hypersensitivity to mannitol or azacitidine * Not incarcerated in a municipality (i.e., county, state, or federal prison) PRIOR CONCURRENT THERAPY: * At least 14 days since prior chemotherapy, including interferon alfa, anagrelide, or other myelosuppressive agents * At least 14 days since prior systemic corticosteroids * At least 14 days since prior investigational agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Patients With Confirmed Response (Complete Remission or Partial Remission on 2 Consecutive Evaluation at Least 4 Weeks Apart) During the First 4 Months of Treatment | 4 months | Response Definitions: * Completion Remission (CR):complete resolution of disease-related symptoms, ultrasound-documented resolution of hepastosplenomegaly, normalization of the peripheral blood count, white cell differential, and smear, normalization of bone marrow histology including disappearance of fibrosis and osteosclerosis. Residual cytogenetic abnormalities are allowed. * Partial Remission (PR): a major response in any baseline applicable criteria (except constitutional symptoms) without progression in any other category. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From date of registration until death or 3 years after registration if patient is still alive | OS was defined as the time from registration to death due to any cause or time from registration to 3 years after registration if patient is still alive. |
| Time to Progression | up to 3 years | Time to progression was defined as the time from registration to progression of disease. Those who die without documentation of disease progression will be considered to have had disease progression at the time of their death unless documented evidence clearly indicates no progression has occured. |
| Number of Participants With Treatment Related Adverse Events | Every 4 weeks during treatment | Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE. Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE |
Countries
United States
Participant flow
Recruitment details
Ten patients were recruited from August 2006 to December 2007 at Mayo Clinic. This trial was permanently closed in December 2007 due to lack of accrual and it demonstrated too little clinical benefit.
Participants by arm
| Arm | Count |
|---|---|
| Azacitidine Azacitidine 75 mg/m\^2 subcutaneously | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Death | 1 |
| Overall Study | Patient Choice | 1 |
| Overall Study | Progression | 2 |
Baseline characteristics
| Characteristic | Azacitidine |
|---|---|
| Age Continuous | 72 years |
| Disease Post-essential Thrombocythemia Myelofibrosis | 1 participants |
| Disease Post-polycythemia Vera Myelofibrosis | 1 participants |
| Disease Primary Myelofibrosis | 8 participants |
| Lilie Score at Diagnosis (Myelofibrosis only) 0 (Low Risk) | 2 participants |
| Lilie Score at Diagnosis (Myelofibrosis only) 1 (Intermediate Risk) | 5 participants |
| Lilie Score at Diagnosis (Myelofibrosis only) 2 (High Risk) | 3 participants |
| Prior Therapy for Myelofibrosis No | 3 participants |
| Prior Therapy for Myelofibrosis Yes | 7 participants |
| Prior Thrombosis or Hemorrhage No | 10 participants |
| Prior Thrombosis or Hemorrhage Yes | 0 participants |
| Red Cell Transfusion-dependent No | 3 participants |
| Red Cell Transfusion-dependent Yes | 7 participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 4 / 10 |
Outcome results
Primary
Patients With Confirmed Response (Complete Remission or Partial Remission on 2 Consecutive Evaluation at Least 4 Weeks Apart) During the First 4 Months of Treatment
Response Definitions: * Completion Remission (CR):complete resolution of disease-related symptoms, ultrasound-documented resolution of hepastosplenomegaly, normalization of the peripheral blood count, white cell differential, and smear, normalization of bone marrow histology including disappearance of fibrosis and osteosclerosis. Residual cytogenetic abnormalities are allowed. * Partial Remission (PR): a major response in any baseline applicable criteria (except constitutional symptoms) without progression in any other category.
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azacitidine | Patients With Confirmed Response (Complete Remission or Partial Remission on 2 Consecutive Evaluation at Least 4 Weeks Apart) During the First 4 Months of Treatment | 0 participants |
Secondary
Number of Participants With Treatment Related Adverse Events
Adverse events (AE) that are classified as either possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE version 3.0). The maximum grade for each type of AE will be recorded for each patient. Grade refers to the severity of the AE. Grade 1: Mild AE, Grade 2: Moderate AE, Grade 3: Severe AE, Grade 4: Life-threatening or disabling AE, Grade 5: Death related AE
Time frame: Every 4 weeks during treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine | Number of Participants With Treatment Related Adverse Events | Grade 1-2 Hematologic | 1 Participants |
| Azacitidine | Number of Participants With Treatment Related Adverse Events | Grade 3-4 Hematologic | 8 Participants |
| Azacitidine | Number of Participants With Treatment Related Adverse Events | Grade 1-2 Non-hematologic | 23 Participants |
| Azacitidine | Number of Participants With Treatment Related Adverse Events | Grade 3-4 Non-hematologic | 0 Participants |
Secondary
Overall Survival (OS)
OS was defined as the time from registration to death due to any cause or time from registration to 3 years after registration if patient is still alive.
Time frame: From date of registration until death or 3 years after registration if patient is still alive
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine | Overall Survival (OS) | 16.9 months |
Secondary
Time to Progression
Time to progression was defined as the time from registration to progression of disease. Those who die without documentation of disease progression will be considered to have had disease progression at the time of their death unless documented evidence clearly indicates no progression has occured.
Time frame: up to 3 years
Population: Only 2 out of 10 patients had disease progression. One patient progressed at 0.5 months after registration and one patient progressed at 2.8 months after registration. Thus, median of time to progression and upper limit of 95% confidence interval are not attainable.