Elsevier

The Lancet Haematology

Volume 7, Issue 3, March 2020, Pages e196-e208
The Lancet Haematology

Articles
Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study

https://doi.org/10.1016/S2352-3026(19)30236-4Get rights and content

Summary

Background

The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment.

Methods

PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).

Findings

Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3–201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4–169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia).

Interpretation

In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea.

Funding

AOP Orphan Pharmaceuticals AG.

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.

References (35)

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A complete list of the PROUD-PV Study Group investigators is in the appendix

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