Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)
Condition: High Risk Polycythemia Vera; High Risk Essential Thrombocythemia
MeSH terms: Polycythemia Vera; Polycythemia; Thrombocytosis; Thrombocythemia, Essential
Intervention: PEGASYS; Hydroxyurea; Aspirin
Intervention description: The subject will begin receiving the PEGASYS at a dose level of 45 micrograms weekly and gradually get increased to the maximum dose of 180 micrograms per week. The dose will be administered by prefilled syringes that will be injected subcutaneously. Subjects will receive therapy for up to 12 months.; Subjects will receive a 500mg tablet to be taken twice daily for up to 12 months of treatment.; Subject will be asked to take 81 to 100mg per day for the 12 months of the study treatment.
Intervention MeSH terms: Aspirin; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2a; Hydroxyurea
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 168.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Polycythemia vera; Essential thrombocythemia; Hydroxyurea; PEGASYS; Pegylated Interferon Alfa-2a

Summary:

      This research is looking at two conditions, Essential Thrombocythemia (ET) and Polycythemia
      Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes
      too many platelets and red blood cells to be made. Platelets are particles which circulate in
      the blood stream and normally prevent bleeding and bruising. Having too many platelets in the
      blood increases the risk of developing blood clots, which can result in life threatening
      events like heart attacks and strokes. When the number of red blood cells is increased in PV
      this will slow the speed of blood flow in the body and increases the risk of developing blood
      clots.

      The purpose of this study is to look at the effectiveness of giving participants who have
      been diagnosed with ET or PV one of two different study regimens over time. The study subject
      will be followed for their condition for about 5 years. The subject will be randomized into
      one of two study regimens, either Pegylated Interferon Alfa-2a (PEGASYS) or Aspirin and
      Hydroxyurea (also called Hydroxycarbamide). The subject must be newly diagnosed or already
      receiving treatment for either PV or ET. Each of the study drugs used in this study is
      already being used to treat subjects with ET or PV currently, but the investigators are
      unsure which study drug is better.
    

Eligibility criteria:

        Inclusion Criteria:

          -  A diagnosis of Essential Thrombocythemia (ET) or Polycythemia Vera (PV) shall be made
             in accordance with the WHO (2008)criteria (Swerdlow 2008) as shown below.

          -  Diagnosis < 5 years prior to entry.

          -  Polycythemia Vera (2 major criteria required)

               1. Hb >18.5g/dl (♂) or 16.5g/dl (♀) or HCT >99 percentile reference range or
                  Elevated red cell mass (>25% above mean predicted value) or Hb >17g/dl (♂) or
                  15g/dl (♀) if associated with a sustained rise from baseline with no apparent
                  cause (e.g. treated iron deficiency).

               2. Presence of JAK2V617F

                    -  If source documentation of diagnostic criterion #1 cannot be obtained, then
                       diagnosis can be made with (1) the addition of an erythropoietin level below
                       the reference range of normal AND (2) bone marrow biopsy showing
                       hypercellularity for age with trilineage (panmyelosis) with prominent
                       erythroid, granulocytic, and megakaryocytic proliferation.

          -  Essential Thrombocythemia (all 6 criteria required)

               1. Platelets count ≥ 450 x 10 to 9/L

               2. Megakaryocyte proliferation with large and mature morphology. No significant
                  increase or left shift of neutrophil granulopoiesis or erythropoiesis. Patients
                  may have up to and including 2+ marrow reticulin fibrosis (0, 1 or 2 on scale 0
                  -4).

               3. Not meeting WHO criteria for CML, PV, MDS, PMF or other myeloid neoplasm

               4. Demonstration of clonal cytogenetic marker or no evidence of reactive
                  thrombocytosis.

               5. Absence of a leukoerythroblastic blood picture.

               6. 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 MPN)
                       either after diagnosis or within 10 years before diagnosis and considered to
                       be disease related

                    -  Significant splenomegaly (> 5cm below the left costal margin on palpitation)
                       or symptomatic splenomegaly (splenic infarcts or requiring analgesia)

                    -  Platelets ≥ 1000 x 10 to 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 to 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

                  Other Inclusion criteria (Both Strata)

                    -  Diagnosed less than 5 years prior to entry on trial

                    -  Never treated with cytoreductive drugs except hydroxyurea for up to 3 months
                       maximum (phlebotomy, aspirin allowed, anagrelide allowed)

                    -  Age: ≥ 18 years (no upper limit)

                    -  Ability and willingness to comply with all study requirements

                    -  Signed informed consent to participate in this study.

                    -  Willing to participate in associated correlative science biomarker study

                    -  Serum creatinine ≤ 1.5 x upper limit of normal

                    -  ST and ALT ≤ 2 x upper limit of normal

                    -  No known PNH (paroxysmal nocturnal hemoglobinuria) clone

                    -  No concurrent hormonal oral contraceptive use

                  Exclusion Criteria:

                  (ANY of the following, both strata)

                    -  Known to meet the criteria for primary myelofibrosis (as opposed to ET) by
                       WHO 2008

                    -  Patients with a prior malignancy within the last 5 years (except for basal
                       or squamous cell carcinoma, or in situ cancer of the cervix)

                    -  Any contraindications to pegylated interferon or hydroxyurea

                    -  Presence of any life-threatening co-morbidity

                    -  History of active substance or alcohol abuse within the last year

                    -  Subjects who are pregnant, lactating or of reproductive potential and not
                       practicing an effective means of contraception

                    -  History of psychiatric disorder (e.g. depression) Subjects with a history of
                       mild depression may be considered for entry into this study, provided that a
                       pretreatment assessment of the subject's affective status supports that the
                       subject is clinically stable based on the investigator's normal practice for
                       such subject.

                    -  History of autoimmune disorder (e.g. hepatitis)

                    -  Hypersensitivity to interferon alfa

                    -  Hepatitis B or C infection (HBV), or untreated systemic infection

                    -  Known HIV disease

                    -  Evidence of severe retinopathy (e.g. 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

                    -  Neutrophil count <1.5 x 10 to 9/L

                    -  JAK2 exon 12 mutation: PV that lacks the JAK2V617F mutation but is
                       characterized by the exon 12 mutation.

                    -  Meets criteria for post PV or post ET-MF

                    -  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.

                    -  Previous exposure to any formulation of pegylated interferon

                    -  History of major organ transplantation

                    -  History of uncontrolled severe seizure disorder

                    -  Inability to give informed written consent

                    -  Total bilirubin >1.5 x ULN (patients that have an isolated indirect
                       bilirubin that causes total bilirubin to be elevated beyond 1.5 x ULN due to
                       documented Gilbert's syndrome or hemolysis may be included). No detectable
                       PNH (paroxysmal nocturnal hemoglobinuria) clone where tested