ArticlesRopeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study
Introduction
Polycythaemia vera, as a subgroup of the myeloproliferative neoplasms, is characterised by uncontrolled malignant proliferation of haematopoietic cells leading to increased concentrations of red cells, often accompanied by elevated leucocyte and platelet counts.1, 2, 3 The oncogenic pathway in polycythaemia vera is driven by the Val617Phe mutation in the JAK2 gene present in about 95% of patients, which results in constitutive kinase activity promoting both haematopoietic cell proliferation and a proinflammatory state.3, 4, 5, 6, 7 The main clinical manifestations include pruritus, fatigue, and microcirculatory disturbances. Patients with polycythaemia vera are predisposed to thrombosis and disease progression to myelofibrosis or secondary leukaemia, which results in poor prognosis.1, 3 Besides phlebotomy and low dose aspirin, cytoreductive therapy improves symptoms and might prevent thromboembolic events.1, 2
Among cytoreductive agents used to treat polycythaemia vera, interferon alfa (IFNα) has been consistently reported to have a disease-modifying capacity by selectively decreasing the malignant stem cell pool and inducing durable molecular remissions in some patients.8, 9, 10, 11, 12, 13, 14, 15, 16 These properties suggest that IFNα might be of greatest benefit when used early in the course of the disease to inhibit the clonal evolution that underlies disease progression.13 Clinical and haematological efficacy of IFNα-based therapy in myeloproliferative neoplasms has been reported since the 1980s; however, toxicity and the need for frequent parenteral application of conventional formulations led to high proportions of patients discontinuing treatment.4, 9, 11, 17, 18, 19, 20, 21, 22, 23
Ropeginterferon alfa-2b is a monopegylated IFNα developed for treating myeloproliferative neoplasms. In contrast to other pegylated IFNα compounds, ropeginterferon alfa-2b consists of a single positional isomer resulting in an extended elimination half-life, enabling less frequent dosing (every other week, or monthly during maintenance therapy) and improved tolerability, supporting long-term patient compliance.19
After more than 30 years of clinical use of IFNα in myeloproliferative neoplasms, this phase 3 clinical programme in an early polycythaemia vera population (comprising the PROUD-PV study for the first year of treatment and its extension study CONTINUATION-PV for a further 2 years) provides, to our knowledge, the first, randomised, controlled, head-to-head comparison of an IFNα with hydroxyurea, the current standard first-line cytoreductive treatment.
Section snippets
Study design and participants
PROUD-PV and its extension study CONTINUATION-PV were multicentre, open-label, active-controlled, phase 3 trials done in 48 clinics in Europe (appendix pp 31–33). In PROUD-PV, patients were randomly assigned to receive either ropeginterferon alfa-2b or hydroxyurea for 12 months; cross-over was not permitted. The primary objective in PROUD-PV was originally to assess the superiority of ropeginterferon alfa-2b versus hydroxyurea regarding disease response. Before database lock or sponsor
Results
In PROUD-PV we recruited 306 patients from Sept 17, 2013 to March 13, 2015. In PROUD-PV, of 257 patients randomly assigned, 127 were allocated and received ropeginterferon alfa-2b and 130 were allocated to received hydroxyurea. Three patients in the hydroxyurea group withdrew consent after randomisation and finally 127 patients received treatment. A total of 21 (17%) of 127 in the ropeginterferon alfa-2b group and 16 (13%) of 127 patients in the hydroxyurea group prematurely discontinued the
Discussion
To our knowledge, the randomised, controlled PROUD-PV trial and its extension, CONTINUATION-PV, provide the first and largest comparison of an interferon versus hydroxyurea or best available treatment in polycythaemia vera, and were the basis of the European Commission's approval of ropeginterferon alfa-2b as a first-line treatment of polycythaemia vera. A smaller randomised, controlled, phase 3 trial comparing IFNα with hydroxyurea has been done in patients with polycythaemia vera or essential
Data sharing
Anonymised clinical study reports including all aggregated patient data, selected by-patient listings, study protocols, and the full statistical analysis plans will be shared indefinitely on completion of the mandatory disclosure process by the European Medicines Agency.
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