Myelofibrosis
Conditions
Keywords
Primary myelofibrosis, PMF
Brief summary
The purpose of this study is to look at the effectiveness of giving patients who have been newly diagnosed with untreated early stage primary myelofibrosis (PMF) a study drug called PEGINTRON (also known as pegylated interferon alfa 2b). This intervention will be compared to the widely employed watch and wait (best supportive care) approach for early stage PMF, in which patients are followed closely and treatment initiated only if the disease progresses.
Detailed description
Subjects will be randomized into one of the study groups: one in which subjects get treated with PEGINTRON and the other in which subjects are closely followed and get best supportive care until disease progression (the presently accepted standard approach for early disease). Subjects on the observation arm will be carefully monitored for clinical or laboratory progression of disease during scheduled study visits. However, they will not be treated with an active drug like Interferon alfa or others such as Hydroxyurea, Revlimid, Thalidomide, Pomalidomide, and the newly approved JAK2 (Janus Kinase 2) inhibitor Ruxolitinib (Jakafi). If their disease progresses, they will be eligible for cross-over into the treatment arm with PEGINTRON. Subjects randomized to the treatment arm will receive PEGINTRON once weekly.
Interventions
DRUGPeginterferon alfa-2a
50 mcg subcutaneous injection once per week
Sponsors
Merck Sharp & Dohme LLC
Weill Medical College of Cornell University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
\- Patients must meet laboratory, and bone marrow histological criteria for primary myelofibrosis as defined by World Health Organization (WHO) diagnostic criteria as follows: WHO diagnostic criteria for PMF Proposed Criteria for PMF Major Criteria 1. Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or collagen fibrosis, or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by an increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (ie. prefibrotic cellular-phase disease) 2. Not meeting WHO criteria for Polycythemia Vera (PV), Chronic Myeloid Leukemia (CML), Myledysplastic Syndrome (MDS), or other myeloid neoplasm 3. Demonstration of JAK2617V\>F or other clonal marker (e.g. MPL515W\>L/K), or in the absence of a clonal marker, no evidence of bone marrow fibrosis due to underlying inflammatory or other neoplastic disease Minor Criteria 1. Leukoerythroblastosis 2. increase in serum Lactase Dehydrogenase (LDH) 3. Anemia 4. Palpable splenomegaly * Patients must have Low or Intermediate 1 stage of disease as defined by International Working Group (IWG) risk stratification of primary myelofibrosis in the dynamic international prognostic scoring system (DIPSS). In addition, they must show some active hematopoiesis with a cellularity of at least 15%, irrespective of the degree of reticulin and/or collagen fibrosis as defined by Manoharan criteria. * Patients should NOT have had prior therapy for primary myelofibrosis. This includes treatment with cytoreductive drugs (Hydroxyurea), immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), JAK2 inhibitors, or other therapies specifically for myelofibrosis. If they received these classes of drugs for indications other than PMF, treatment should be discontinued at least 6 weeks prior to randomization. * Eastern Cooperative Oncology Group (ECOG) performance status \< 2 * Patients must have normal organ and marrow function as defined below: * White blood cell (WBC) ≥ 3,000/microL * Absolute Neutrophil Count (ANC) ≥ 1,500/microL * Platelets ≥ 100,000//microL * Total bilirubin within normal limits * Aspartate aminotransferase - serum glutamic oxaloacetic transaminase (AST(SGOT)) and alanine aminotransferase - serum glutamic pyruvic transaminase (ALT(SGPT)) less than or equal to 2.5 X upper limit of normal * Creatinine Clearance ≥ 50 ml/min * The effects of peg-IFNα-2b on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. * Ability to understand and the willingness to sign a written informed consent document.
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy within 6 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 6 weeks earlier. * Patients with Intermediate 2 or High risk stage of disease as defined by International Working Group (IWG) risk stratification of primary myelofibrosis in the dynamic international prognostic scoring system (DIPSS) and/or bone marrow biopsy showing less than 15% cellularity in the presence +2 or more reticulin fibrosis (by Manoharan criteria), collagen fibrosis, or osteosclerosis. * Patients may not be receiving any other investigational agents. * History of allergic reactions attributed to compounds of similar chemical or biologic composition to peg-IFNα-2b * Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Improvement | One year | Clinical improvement (CI) Requires one of the following in the absence of both disease progression (as outlined below) and Complete Response (CR)/Partial Response (PR) assignment (CI response is validated only if it lasts for no fewer than 8 weeks) i. A minimum 20-g/L increase in hemoglobin level or becoming transfusion independent (applicable only for patients with baseline hemoglobin level of less than 100 g/L). ii. Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable. iii. A minimum 100% increase in platelet count and an absolute platelet count of at least 50 000 109/L (applicable only for patients with baseline platelet count below 50 109/L). iv. A minimum 100% increase in Absolute Neutrophil Count (ANC) and an ANC of at least 0.5 109/L (applicable only for patients with baseline absolute neutrophil count below 1 109/L). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | Week 21 | Progression free survival is the measure of subject survival in the absence of disease progression. Disease progression is defined as progression to the next higher International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Dynamic International Prognostic Scoring System (DIPSS) stage from diagnosis. The IWG-MRT DIPSS stratifies primary myelofibrosis (PMF) into four risk categories (low, intermediate 1, intermediate 2, and high risk), based on 5 clinical factors; Age\>65, Hemoglobin \<10gm/dL, white blood cell (WBC)\>25,000/uL, peripheral blasts\>1%, and constitutional symptoms. Progression free survival will be assessed at 21 weeks from time of study entry. |
| Overall Survival | Week 21 | Overall survival measures subject survival regardless of disease progression. Overall survival will be assessed at 21 weeks from time of study entry. |
Countries
United States
Participant flow
Pre-assignment details
Patients were randomized to either the treatment arm or the control arm of the study with a 2:1 allocation ratio. 8 patients were enrolled. No patients crossed over from observation to treatment.
Participants by arm
| Arm | Count |
|---|---|
| Treatment Arm Patients treated with 50mcg of peginterferon alfa-2b subcutaneously per week. | 5 |
| Observation Arm Patients who did not receive treatment and were observed only. | 3 |
| Total | 8 |
Baseline characteristics
| Characteristic | Treatment Arm | Observation Arm | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 1 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Continuous | 71.9 years STANDARD_DEVIATION 6.2 | 69.1 years STANDARD_DEVIATION 5.5 | 69.9 years STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 6 Participants |
| Region of Enrollment United States Emory University | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States Weill Cornell Medicine | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 3 |
| other Total, other adverse events | 1 / 5 | 0 / 3 |
| serious Total, serious adverse events | 2 / 5 | 0 / 3 |
Outcome results
Primary
Clinical Improvement
Clinical improvement (CI) Requires one of the following in the absence of both disease progression (as outlined below) and Complete Response (CR)/Partial Response (PR) assignment (CI response is validated only if it lasts for no fewer than 8 weeks) i. A minimum 20-g/L increase in hemoglobin level or becoming transfusion independent (applicable only for patients with baseline hemoglobin level of less than 100 g/L). ii. Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline or a spleen that is palpable at more than 5 cm at baseline becomes not palpable. iii. A minimum 100% increase in platelet count and an absolute platelet count of at least 50 000 109/L (applicable only for patients with baseline platelet count below 50 109/L). iv. A minimum 100% increase in Absolute Neutrophil Count (ANC) and an ANC of at least 0.5 109/L (applicable only for patients with baseline absolute neutrophil count below 1 109/L).
Time frame: One year
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Arm | Clinical Improvement | Achieved Clinical Improvement (CI) | 1 Participants |
| Treatment Arm | Clinical Improvement | Did not achieve Clinical Improvement (CI) | 2 Participants |
| Treatment Arm | Clinical Improvement | Not evaluable | 2 Participants |
| Observation Arm | Clinical Improvement | Achieved Clinical Improvement (CI) | 0 Participants |
| Observation Arm | Clinical Improvement | Did not achieve Clinical Improvement (CI) | 2 Participants |
| Observation Arm | Clinical Improvement | Not evaluable | 1 Participants |
Secondary
Overall Survival
Overall survival measures subject survival regardless of disease progression. Overall survival will be assessed at 21 weeks from time of study entry.
Time frame: Week 21
Population: Due to early termination of the trial, there is not enough data to evaluate overall survival.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Arm | Overall Survival | Not deceased | 4 Participants |
| Treatment Arm | Overall Survival | Deceased | 0 Participants |
| Observation Arm | Overall Survival | Not deceased | 3 Participants |
| Observation Arm | Overall Survival | Deceased | 0 Participants |
Secondary
Progression Free Survival
Progression free survival is the measure of subject survival in the absence of disease progression. Disease progression is defined as progression to the next higher International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Dynamic International Prognostic Scoring System (DIPSS) stage from diagnosis. The IWG-MRT DIPSS stratifies primary myelofibrosis (PMF) into four risk categories (low, intermediate 1, intermediate 2, and high risk), based on 5 clinical factors; Age\>65, Hemoglobin \<10gm/dL, white blood cell (WBC)\>25,000/uL, peripheral blasts\>1%, and constitutional symptoms. Progression free survival will be assessed at 21 weeks from time of study entry.
Time frame: Week 21
Population: Analysis population includes subjects who were evaluable at 21 weeks from time of study entry.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment Arm | Progression Free Survival | Disease did not progress | 2 Participants |
| Treatment Arm | Progression Free Survival | Disease progressed | 2 Participants |
| Observation Arm | Progression Free Survival | Disease did not progress | 3 Participants |
| Observation Arm | Progression Free Survival | Disease progressed | 0 Participants |