PEG-interferon Alfa-2a in Treating Patients With High Risk Polycythemia Vera or High Risk Essential Thrombocythemia
The purpose of this study is to look at the effectiveness of giving patients who have been diagnosed with essential thrombocythemia (ET) and polycythemia vera (PV) a study drug regimen using aspirin (acetylsalicylic acid) and pegylated interferon alfa-2a (PEG-interferon alfa-2a) (instead of the standard treatment drug called hydroxyurea), for whom this drug may not be suitable. The drug may not be suitable either because it is not adequately controlling the number of blood cells or some specific side effects occur.
Inclusion Criteria
- A diagnosis of ET or PV shall be made in accordance with the World Health Organization (WHO) (2008) criteria as shown below (Values below are at the time of diagnosis, not study entry): * Polycythemia Vera (2 major criteria required) ** Hemoglobin (Hb) > 18.5g/dl (male) or 16.5g/dl (female) or ** Hematocrit (HCT) > 99 percentile reference range or ** Elevated red cell mass (> 25% above mean predicted value) or ** Hb > 17g/dl (male) or 15g/dl (female) if associated with a sustained rise from baseline with no apparent cause (e.g. treated iron deficiency) ** Presence of JAK2V617F * Essential Thrombocythemia (all 4 major criteria required) ** Platelets count >= 450 x 10^9/L ** Megakaryocyte proliferation with large and mature morphology; no significant increase or left shift of neutrophil granulopoiesis or erythropoiesis ** Not meeting WHO criteria for chronic myelogenous leukemia (CML), PV, myelodysplastic syndromes (MDS) or other myeloid neoplasms ** Demonstration of JAK2V617F, clonal cytogenetic marker or no evidence of reactive thrombocytosis ** May participate in study without presence of JAK2V617F
- Patients must have high risk disease as defined below: * High risk PV ANY ONE of the following: ** Age > 60 years ** Previous documented thrombosis, erythromelalgia or migraine (severe, recurrent, requiring medications, and felt to be secondary to the myeloproliferative neoplasm [MPN]) either after diagnosis or within 10 years before diagnosis and considered to be disease related ** Significant (i.e. > 5 cm below costal margin on palpation) or symptomatic (splenic infarcts or requiring analgesia) ** Platelets > 1000 x 10^9/L ** Diabetes or hypertension requiring pharmacological therapy for > 6 months * High risk ET ANY ONE of the following: ** Age > 60 years ** Platelet count > 1500 x 10^9/L ** Previous documented thrombosis, erythromelalgia or migraine headaches (severe, recurrent, requiring medications, and felt to be secondary to the MPN) either after diagnosis or within 10 years before diagnosis and considered to be disease related ** Previous hemorrhage related to ET ** Diabetes or hypertension requiring pharmacological therapy for > 6 months
- In addition patients must EITHER be intolerant or resistant to hydroxyurea according to previously modified established criteria as follows: * Any ONE of the following: ** Platelet count > 600 x 10^9/L after 3 months of at least 2g/day of hydroxyurea or maximally tolerated dose (MTD) of hydroxyurea (2.5 g/day in patients with a body weight greater than 80 kg) ** White blood cell (WBC) < 2.5 x 10^9/L or Hgb < 11g/dl at any dose of hydroxyurea not to exceed 2g/day (for a period of at least 2 months) ** Progressive splenomegaly or hepatomegaly (> 5cm from initiation of hydroxyurea) or the appearance of new splenomegaly or hepatomegaly while on maximum tolerated dose (MTD) of hydroxyurea ** Not achieving a Hct < 45% in order to eliminate the need for supplemental phlebotomies after 3 months of at least 2g/day MTD of hydroxyurea ** Not achieving a WBC of < 10 x 10^9/L after 3 months of at least 2g/day MTD of hydroxyurea ** Having a platelet count < 100 x 10^9/L on hydroxyurea at any dose without eliminating the need for supplemental phlebotomy or having progressive splenomegaly as defined above ** Development of a major thrombotic episode (cerebral vascular accident [CVA], myocardial infarction, severe migraines requiring medication, abdominal vein thrombosis, deep vein thrombosis) while being treated with maximal tolerated doses of hydroxyurea ** Presence of leg ulcers or other unacceptable hydroxyurea-related-nonhematological toxicities, such as unacceptable mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis or fever at any dose of hydroxyurea * OR have Splanchnic Vein Thrombosis (SVT) (includes Budd-Chiari, abdominal vein thrombosis, portal vein thrombosis, splenic vein thrombosis); for these patients the following additional inclusion/exclusion criteria apply: ** > 3 months since onset of SVT ** SVT treated with oral anticoagulants but no aspirin ** Liver enzymes not > 2 times the normal value ** Absence of encephalopathy, refractory or infected ascites, esophageal varicose of grade > 1 at time of trial entry ** Bone marrow biopsy confirmed diagnosis of PV or ET ** JAK2-V617F present ** These patients may have a normal blood count at trial entry
- Able and willing to comply with study criteria
- Signed and informed consent to participant in this study
- Willing to participate in associated correlative science biomarker study
- Serum creatinine =< 1.5 x upper limit of normal
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2 x upper limit of normal
- Total bilirubin within normal limits
Exclusion Criteria
- Patients cannot have any other form of chemotherapy for their MPN (other than hydroxyurea); specifically prior interferon or JAK2 inhibitors are prohibited
- Presence of any life-threatening co-morbidity
- History of active substance or alcohol abuse within the last year
- Any contraindications to pegylated or non-pegylated interferon
- Subjects who have a positive pregnancy test, are pregnant, lactating or have reproductive potential and not practicing an effective means of contraception
- History of psychiatric disorder (e.g. depression; suicidal ideation; psychosis)
- History of autoimmune disorder (e.g. hepatitis; idiopathic thrombocytopenic purpura [ITP]; scleroderma; severe psoriasis affecting > 10% of the body, rheumatoid arthritis requiring more than intermittent nonsteroidal anti-inflammatory drugs [NSAID] for management)
- Hypersensitivity to interferon-alpha (IFN-alpha)
- Hepatitis B virus (HBV) or untreated systemic infection
- Known human immunodeficiency virus (HIV) disease
- Evidence of severe retinopathy (e.g. cytomegalovirus [CMV] retinitis, macular degeneration) or clinically relevant ophthalmological disorder (e.g. due to diabetes mellitus or hypertension)
- History or other evidence of decompensated liver disease
- History or other evidence of chronic pulmonary disease associated with functional limitation
- Thyroid dysfunction not adequately controlled
- Any investigational drug < 6 weeks prior to the first dose of study drug or not recovered from effects of prior investigational agent
- Presence of JAK2 exon 12 mutation
- Patients should not meet criteria for post PV or post ET-myelofibrosis (MF)
- No previous exposure to any formulation of interferon
- Subjects with any other medical condition, which in the opinion of the investigator would compromise the results of the study by deleterious effects of treatment
- History of major organ transplantation
- History of uncontrolled severe seizure disorder
- Inability to give informed written consent
- Serum creatinine > 1.5 x upper limit of normal
- AST and ALT > 2 x upper limit of normal
- Total bilirubin >= 1.5 mg/ml
- No detectable PNH (paroxysmal nocturnal hemoglobinuria) clone where tested
- Concurrent hormonal contraceptive use
Additional locations may be listed on ClinicalTrials.gov for NCT01259817.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. To evaluate the ability of Pegylated Interferon Alfa-2a to achieve Complete Response or Partial Response (by LeukemiaNet Criteria) in patients with either high risk polycythemia vera or high risk essential thrombocythemia resistant or intolerant of hydroxyurea (stratified by disease group).
SECONDARY OBJECTIVES:
I. To evaluate the toxicity, safety and tolerability of Pegylated Interferon Alfa-2a therapy in the study populations.
II. To measure the impact of Pegylated Interferon Alfa-2a on key biomarkers of the disease(s) –including janus kinase 2 V617F mutation (JAK2V617F), hematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities.
III. To evaluate specific pre-defined toxicity and tolerance of Pegylated Interferon Alfa-2a and validate the utility of sequential structured symptom assessment package of patient reported outcome instruments.
IV. To estimate survival, and incidence of development of myelodysplastic disorders, myelofibrosis, or leukemic transformation after Pegylated Interferon Alfa-2a.
V. To estimate observed incidence of major cardiovascular events (defined as cardiovascular death, myocardial infarction, stroke, transient ischemic attack, pulmonary embolism, Budd Chiari syndrome, deep vein thrombosis, and any other clinically relevant thrombotic event) after therapy Pegylated Interferon Alfa-2a.
OUTLINE: This is a dose escalation study.
Patients receive PEG-interferon alfa-2a subcutaneously (SC) once per week. Patients entering with concurrent hydroxyurea discontinue treatment with hydroxyurea prior to course 3. Treatment repeats every month for up to 15 months in the absence of disease progression or unacceptable toxicity. Patients achieving complete response (CR) or partial response (PR) may continue to receive treatment for up to 48 months.
After completion of study treatment, patients are followed up every 4 weeks for 6 months and then every 3 months for 2 years.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMount Sinai Hospital
Principal InvestigatorLewis R. Silverman
- Primary IDMPD-RC 111
- Secondary IDsNCI-2012-00268, 111
- ClinicalTrials.gov IDNCT01259817