ROP-ET: A Prospective Phase III Trial Investigating the Efficacy and Safety of Ropeginterferon Alfa-2b in Essential Thrombocythemia Patients with Limited Treatment Options
Authors: Kiladjian Jean-Jacques , Ferrer Marin Francisca , Al-Ali Haifa Kathrin , Alvarez-Larran Alberto , Beggiato Eloise , Bieniaszewska Maria , Breccia Massimo , Buxhofer-Ausch Veronika , Cerna Olga , Crisan Ana Manuela , Danaila Catalin , De Stefano Valerio , Döhner Konstanze , Empson Victoria , Gora Tybor Joanna , Griesshammer Martin , Grosicki Sebastian , Guglielmelli Paola , García Gutiérrez Valentín , Heidel Florian , Illes Arpad , James Chloe , Koschmieder Steffen , Maria-Theresa Krauth , Krejcy Kurt , Lazaroiu Mihaela Cornelia , Mayer Jiri , Nagy Zsolt , Palandri Francesca , Pappa Vasiliki , Reiter Andreas , Sacha Tomasz , Schlager Stefanie , Schmidt Stefan Ulrich , Terpos Evangelos , Tomuleasa Ciprian , Torregrosa Diaz Jose Miguel , Unger Martin , Woelfler Albert , Xicoy Blanca , Klade Christoph 
Published: December 2024

Background and Significance:

Commonly used approved treatments for essential thrombocythemia (ET), such as hydroxyurea (HU) and anagrelide (ANA) aim to normalize hematological parameters and reduce the thrombotic risk, but do not control malignant mutation-carrying clones and hence have no impact on disease progression. In addition, a significant portion of patients with ET are unable to receive available therapies due to treatment failures, contraindications, or other safety concerns; as a result, these patients are left without approved treatment options.

Interferon-based therapies have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including ET. Ropeginterferon alfa-2b (BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval was approved in 2019 in Europe and in 2021 in the US for the treatment of polycythemia vera (PV). Ropeginterferon alfa-2b not only provides robust hematological efficacy but also induces a sustained molecular response by reducing the mutation burden, offering a unique potential for disease modification in PV.

In patients with ET, interferons are commonly used off-label with an observed overall response rate exceeding 80% and with ~60% of patients achieving complete hematologic remission (Bewersdorf et al 2021, Gu et al 2021, Stegelmann et al 2023). In addition, available evidence suggests a molecular response in up to 50% of patients (Gu et al 2021) and a significant improvement in myelofibrosis-free survival (Beauverd et al 2023), indicating that, much like in PV, interferons such as ropeginterferon alfa-2b hold promise as a treatment option for ET.

The ROP-ET trial (EudraCT2023-505160-12-00; NCT06514807) assesses the long-term safety and efficacy of ropeginterferon alfa-2b in ET patients with high need, i.e. patients, who are unable to adequately receive available approved cytoreductive therapies. The trial focusses on evaluating the capability of ropeginterferon alfa-2b to control abnormal hematologic parameters, disease-related symptoms and vascular risk, while controlling malignant clones, thereby potentially slowing the neoplastic progression of the disease.

Study Design and Methods:

This is an ongoing prospective, multicenter, single-arm phase III trial. Key eligibility criteria include age (≥ 18 years), diagnosis according to WHO 2016 and no prior exposure to interferon. Patients must be intolerant or resistant to, and/or ineligible for approved therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman. Ropeginterferon alfa-2b is administered as a subcutaneous injection every two weeks at a dose of 125 μg, with dose adjustments to 250 or 500 μg, if needed. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. During the 3-year trial, secondary endpoints include allele burden, disease-related symptoms, vascular events, disease progression, and the safety profile of ropeginterferon alfa-2b. This trial is designed to evaluate efficacy assuming a historical response rate of 40%. As an exploratory aspect, the study monitors inflammatory markers and cytokines (CRP, pentraxin 3, GRO-α, EGF, BLC, M-CSF, eotaxin-2, and TIMP-1), and most patients are participating in a sub-study focused on neutrophil extracellular traps (NETs) to investigate their association with thrombotic events and the treatment's impact.

The trial commenced recruitment in December 2023 and is currently recruiting in 36 sites in 10 countries in Europe. To date, 92 patients have been enrolled (41 men and 51 women). The plan is to enroll 117 patients in total; an interim analysis of the 12-month primary endpoint is planned to be performed in Q4 2025.