Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea in Polycythemia Vera (PV) and Essential Thrombocythemia (ET)

The Philadelphia chromosome negative myeloproliferative neoplasms (MPN) are a group of clonal
hematological malignancies that are characterized by a chronic course which can be punctuated
by a number of disease related events including thrombosis, hemorrhage, pruritis and leukemic
transformation. These disorders include Polycythemia Vera (PV), Essential Thrombocythemia
(ET) and Primary Myelofibrosis (PM). Recently an acquired somatic mutation in the
intracellular kinase, JAK2 (JAK2V617F) has been observed in 95% of patients with PV, 50% of
patients with ET and 50% of patients with primary myelofibrosis. At present the
chemotherapeutic agent hydroxyurea is the standard of care for high risk patients with PV.
Concern exists about prolonged use of this drug leading to leukemia and the inability of
hydroxyurea to eliminate the malignant clone.

Interferon (rIFN -2b), is a drug that appears to be non-leukemogenic, and may have a
preferential activity on the malignant clone in PV, as suggested by cytogenetic remissions
obtained in patients treated with rIFN -2b. Several investigators recently reported that
patients with PV treated with rIFN -2b had lower JAK2V617F allele burdens as compared to a
control group that included patients treated with phlebotomy, hydroxyurea, or anagrelide, or
who remained untreated. The results confirm the hypothesis that rIFN -2b preferentially
targets the malignant clone in PV and raises the possibility that the JAK2V617F allele
burden, and a reversion of clonal hematopoiesis monitored in females by expression of
X-chromosome polymorphic alleles maybe useful in monitoring minimal residual disease in PV
patients.

Pegylated Interferon Alfa-2a (PEGASYS) has been demonstrated in phase II trials of patients
with PV and ET to have clinical efficacy as measured by normalization of myeloproliferation,
lack of vascular events while on therapy, and a decrease in the JAK2V617F allele burden.
Overall the tolerability of the therapy was good, with each of these trials having a dropout
rate secondary to toxicity of less than 10% of those enrolled. Although dropout rates for
toxicity were low, that is not to say the therapy was without symptomatic toxicity, and
indeed a spectrum of toxicities might be encountered and need to be weighed in the analysis
of the net clinical benefit patients experience on a clinical trial with Pegylated Interferon
Alfa-2a.

A new MPN assessment form will be utilized in this study. This 19 item instrument includes a
previously validated 9 item brief fatigue inventory (BFI), symptoms related to splenomegaly,
inactivity, cough, night sweats, pruritus, bone pains, fevers, weight loss, and an overall
quality of life assessment. The instrument yields an independent result for each symptom
(fatigue is a composite score), as this methodology (of linear analog scale assessment
[LASA]) has proven very valid in the past. This instrument was validated prospectively (by
comparison to a panel of instruments each containing an aspect of the MPN-SAF) for
administration at a single time point.

This is a randomized trial between hydroxyurea and Pegylated Interferon Alfa-2a, it is an
open label clinical trial in two independent disease strata: (1) high risk polycythemia vera
and (2) high risk essential thrombocythemia.

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