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

Phase 3
18 Years
Open (Enrolling)
High Risk Polycythemia Vera, High Risk Essential Thrombocythemia

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Trial Information

Randomized Trial of Pegylated Interferon Alfa-2a Versus Hydroxyurea Therapy in the Treatment of High Risk Polycythemia Vera (PV) and High Risk 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

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. Values
below are at the time of diagnosis, not study entry.

- Diagnosis < 3 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

- Essential Thrombocythemia (all 6 criteria required)

1. Platelets count ≥ 450 x 10 to 9/L

2. Megakaryocyte proliferation with large and mature morphology. No or little
granulocyte or erythroid proliferation. 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 over myeloid neoplasm

4. Demonstration of clonal cytogenetic marker or no evidence for a reactive

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 (i.e. > 5cm below costal margin on palpation) or symptomatic
(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 (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 3 years prior to entry on trial

- Never treated with cytoreductive drugs except hydroxyurea for up to 3
months maximum (phlebotomy, aspirin 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

- Total Bilirubin within normal limits

- 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

- 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)

- History of autoimmune disorder (e.g. hepatitis)

- Hypersensitivity to IFN-α

- 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

- Splanchnic vein thrombosis (includes Budd-Chiari, portal vein, splenic and
mesenteric thrombosis)

- 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

- Neutrophil count <1.5 x 10 to 9/L

- JAK2 exon 12 mutation

- Patients cannot meet criteria for post PV or post ET-MF (see appendix B)

- 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.

- No 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

- Serum creatinine < 1.5 x upper limit of normal

- AST and ALT < 2 x upper limit of normal

- Total Bilirubin within normal limits

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To compare hematologic response rates in patients randomized to treatment with Pegylated Interferon Alfa-2a vs Hydroxyurea in two strata of patients with high risk polycythemia vera (PV) or high risk essential thrombocythemia (ET).

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Ronald Hoffman, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Mount Sinai School of Medicine


United States: Food and Drug Administration

Study ID:

GCO 09-1300-00002



Start Date:

September 2011

Completion Date:

December 2014

Related Keywords:

  • High Risk Polycythemia Vera
  • High Risk Essential Thrombocythemia
  • Polycythemia vera
  • Essential thrombocythemia
  • Hydroxyurea
  • Pegylated Interferon Alfa-2a
  • Polycythemia
  • Polycythemia Vera
  • Thrombocythemia, Essential
  • Thrombocytosis



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