Study Title:

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

ClinicalTrials.gov Identifier:

Sponsored By:

The Myeloproliferative Disorders Research Consortium

Participating Centers:

This is an international study that includes 40 medical centers in North America (19) and Europe (21).

Study Design:

Open label, randomized study comparing treatment with hydroxyurea with that of pegylated interferon alfa-2a in patients with high-risk polycythemia vera (PV) and high-risk essential thrombocythemia (ET). Patients will be treated for up to 12 months to achieve a complete response (CR) or a partial response (PR). Patients who achieve a CR or PR will be treated and followed for a maximum of four years.

  • Patients with high-risk PV are defined as having one of the following characteristics: age > 60 years; previously documented thrombosis; erythromelalgia or migraine either after diagnosis or within 10 years before diagnosis and considered to be disease-related; significant splenomegaly (i.e., > 5 cm below costal margin on palpation) or symptomatic splenomegaly (pain, early satiety); platelets > 1,000 x 109/L; or diabetes or hypertension requiring pharmacological therapy.

  • Patients with high-risk ET are defined as having one of the following characteristics: age > 60 years; platelet count > 1,500 x 109/L; previous thrombosis; previous hemorrhage related to ET; or diabetes or hypertension requiring pharmacological therapy.

Sample Size:

306 patients with high-risk PV and 306 patients with high-risk ET.

Rationale:

Although earlier investigations clearly demonstrated that interferon has activity in patients with PV and ET, more recent studies demonstrate that interferon could induce both hematologic remissions and cytogenetic responses based on quantitation of the mutant allele burden in patients with JAK2V617F-positive disease. In some JAK2V617F-positive patients, the abnormal allele was no longer detectable by sensitive PCR techniques, suggesting that the mutant clone can be eradicated by treatment with interferon. The pegylated interferon that will be used in this study may be better tolerated than previous formulations of the recombinant protein. While the primary objective is to compare the complete hematologic response rates for the two treatments, the study incorporates a number of interesting secondary objectives including the following:

  • To compare the impact of therapy on several key biomarkers of the disease (JAK2V617F allele burden, hematopoietic cell clonality in platelets and granulocytes in female patients, bone marrow histopathology, and cytogenetic abnormalities)

  • To estimate survival and incidence of development of myelodysplastic syndrome, myelofibrosis, or leukemic transformation after therapy

  • To estimate the 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 events)

Comment:

This is a timely translational study that incorporates relevant clinical endpoints with basic studies suggested by recent developments in the understanding of the pathobiology of myeloproliferative neoplasms. Substantive new information will certainly accrue from this comprehensive, well-designed study. A companion study titled "Single Arm Salvage Therapy With Pegylated Interferon Alfa-2a for Patients With High-Risk Polycythemia Vera or High-Risk Essential Thrombocythemia who are Either Hydroxyurea Resistant or Intolerant or have had Abdominal Vein Thrombosis" will be launched simultaneously and will have the same organizational structure as that of the randomized study. The enrollment goals for the non-randomized study are as follows: 84 patients with high-risk PV, 84 patients with high-risk ET, and up to 20 patients with splanchnic-vein thrombosis.