The ROP-ET trial, a multicenter, prospective, single-arm phase III study, is evaluating the efficacy and safety of ropeginterferon alfa-2b in patients with essential thrombocythemia (ET) who are intolerant, resistant, or ineligible for standard cytoreductive therapies. This trial aims to address the unmet need for effective treatments in this patient population.
The study, designed with a maximum duration of 36 months per patient, includes a 12-month period for primary analysis and an additional 24 months for long-term data collection. The primary endpoint focuses on the disease response rate at 12 months, defined by modified European LeukemiaNet (ELN) criteria. These criteria include durable peripheral blood count remission (platelets ≤ 400 × 109/L and white blood cells < 10 × 109/L), absence of hemorrhagic or thrombotic events and disease progression, durable improvement or non-progression in disease-related signs, and durable symptom improvement based on the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS).
Eligibility and Treatment
Eligible patients are those aged 18 or older diagnosed with ET according to WHO 2016 criteria, confirmed by a bone marrow biopsy within the past 5 years. These patients must require cytoreductive treatment but are intolerant, resistant, or ineligible for locally approved therapies like hydroxyurea (HU), anagrelide (ANA), busulfan (BUS), or pipobroman. Resistance or intolerance to HU is defined by modified ELN criteria, while resistance/intolerance to ANA, BUS, or pipobroman is based on non-responder status or treatment-related toxicities. Patients must also be interferon-treatment naive.
Ropeginterferon alfa-2b is administered subcutaneously every two weeks at a dose of 125 μg, with potential adjustments to 250 or 500 μg based on hematologic response after 3 or 6 months, respectively. The dosing frequency may be adjusted to every four weeks after 12 months at the investigator's discretion. Low-dose aspirin (75–100 mg/day) is permitted unless contraindicated.
Study Assessments and Outcomes
Patient visits are scheduled every two weeks for the first two months, then every 3 months until month 12, and every 6 months thereafter. Disease response assessments occur every 3 months in the first year and every 6 months in the subsequent two years. Quantitative measurements of JAK2, CALR, and MPL allelic burden are performed every 6 months by a central laboratory. Safety assessments include monitoring vital signs, clinical safety laboratory tests, physical examinations, ECG evaluation, ECOG performance status, ocular examination, and adverse events, graded according to CTCAE v.5.0.
Secondary endpoints include response rates at months 9, 18, 24, 30, and 36, changes in response rates over 12 months, thromboembolic and bleeding events, disease progression, quality of life (EQ-5D-5 L questionnaire), symptomatic improvement (MPN-SAF TSS), changes in inflammation markers and cytokines, and changes in JAK2, CALR, or MPL allelic burden. An exploratory sub-study will investigate the impact of ropeginterferon alfa-2b on neutrophil extracellular traps (NETs) and its association with thrombotic events.
Statistical Considerations
Based on previous studies, a response rate of at least 40% for ropeginterferon alfa-2b is anticipated. The study aims to enroll 117 patients to ensure 93 are evaluable for the primary endpoint assessment at 12 months, allowing for a level of precision of 10%. An interim analysis of the 12-month primary endpoint is planned after the last patient has reached month 12. Statistical analyses will be performed using SAS software, version 9.4 or higher.
