Title: CRUK/11/048: MPD RC 112: Randomized Phase III Trial of Pegylated Interferon Alfa-2a (PEGASYS) versus Hydroxyurea Therapy in the Treatment of High Risk JAK2V617F positive Polycythemia Vera and High Risk JAK2V617F positive Essential Thrombocythemia
Funder: Cancer Research UK

Abstract: Background The myeloproliferative disorders (MPDs) polycythaemia vera (PV) and essential thrombocythaemia (ET) are chronic haematological malignancies associated with increased risk of thrombosis, haemorrhage and leukaemic transformation. Recently, an acquired mutation in JAK2 has been described in 95% of patients with PV and 50% with ET. JAK2 Despite these advances in understanding the molecular pathogenesis of MPDs, management remains empiric, based on normalising blood counts with non-specific cytoreduction. The optimal management for high risk PV and ET patients remains unclear but the current standard therapy for both conditions is hydroxyurea (or hydroxycabamide). The ability of pegylated-interferon alfa-2a (PEGASYS) to produce both a clinical and haematological response will be evaluated, in addition to, its ability to reduce JAK2V617F levels. The results of this trial both with the therapeutic agent and the use of JAK2V617F levels to monitor treatment response, may lead to a paradigm shift in MPD treatment. Aims & Objectives To evaluate pegylated interferon alfa-2a (PEGASYS) versus hydroxyurea (standard therapy) in the Treatment of JAK2 positive High Risk Polycythemia Vera and High Risk Essential Thrombocythaemia by comparing the rates of complete response using LeukemiaNet criteria. To compare the toxicity, safety and tolerability of therapy To compare the haematologic partial response rates on therapy by LeukemiaNet criteria [1]. To compare specific pre-defined toxicity and tolerance of therapy and validate the utility of sequential structured symptom assessment package of patient reported outcome instruments. To compare the impact of these therapies upon key biomarkers of the disease(s) – JAK2-V617F, haematopoietic cell clonality in platelets and granulocytes in females, bone marrow histopathology, and cytogenetic abnormalities. To estimate overall survival and the incidence of the development of myelodysplastic syndrome, myelofibrosis, or leukaemic transformation after therapy. To estimate 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. Methods Patients will receive subcutaneous pegylated interferon alfa-2a or oral hydroxyurea for 12 months (with 3 months confirmation) to achieve a Complete Response or Partial Response. Dosage is dependent on achievement of therapeutic target and toxicity. This phase 3 trial will inform the management of high risk PV and ET in the future and demonstrate if pegylated interferon alfa-2a treatment with reduction of JAK2V617F levels is superior to reduction of blood counts with hydroxyurea. It will thus dictate the management options for these patients in the future.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CANCER AND NEOPLASMS