Ropeginterferon alfa-2b in essential thrombocythemia of all risk levels ineligible for standard cytoreduction: 12-month primary endpoint analysis from the ROP-ET phase 3 study

Abstract Introduction Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by elevated platelet counts, risk of vascular events and disease progression to myelofibrosis or acute leukemia. Most available therapies primarily focus on reducing platelet counts without any demonstrated impact on disease progression. Moreover, these treatments are often limited by intolerance, resistance or contraindications, leaving a substantial proportion of patients without satisfactory therapeutic options. Ropeginterferon alfa-2b (BESREMi®), a mono-pegylated, next-generation interferon alfa, approved globally for polycythemia vera with the potential to modify disease course, is being studied to address this unmet need. Methods This fully recruited, ongoing, phase 3, prospective, multicenter, single-arm study (ROP-ET; NCT06514807) enrolled adults with ET according to WHO 2016 criteria requiring cytoreduction, who were intolerant or resistant and/or ineligible for all locally approved cytoreductive therapies including hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman (PB). A single-arm design was selected due to lack of an ethically acceptable comparator. Ropeginterferon alfa-2b is administered subcutaneously every two weeks starting at 125μg, with dose escalation to 250μg and 500μg if needed to achieve hematologic response. The primary endpoint is a composite durable hematologic and clinical response after 12 months based on modified European LeukemiaNet (ELN) criteria, including peripheral blood count remission, absence of thrombotic/hemorrhagic events and disease progression, and symptom improvement measured by the MPN-SAF Total Symptom Score (MPN-SAF TSS). The sample size was determined to ensure at least 93 evaluable patients for 12-month primary analysis (10% precision), with target enrollment of at least 117 to account for 20% dropout. The observed 12-month response rate will be statistically compared to a historical efficacy of 40%. Secondary endpoints include molecular response, quality of life, safety, and long-term outcomes. The total study duration is three years. Results A total of 132 ET patients received ropeginterferon alfa-2b. The study population had a median age of 56.5 years (range 22-87), included 58.3% females, and the median time from diagnosis was 3.3 years (range 0-25). Baseline median platelet count was 579 ×109/L (range 201-1958) and median white blood cell count was 7.3 ×109/L (range 3.2-20.5). At baseline, splenomegaly was present in 25.8% of patients and median MPN-SAF TSS was 8.0 (range 0-66). Driver mutations were distributed as follows: JAK2 (59.8%), CALR (27.9%), and MPL (1.6%). Risk stratification per revised IPSET-thrombosis criteria identified 43.8% patients as high, 13.8% as intermediate, 22.3% as low and 20% as very low risk. Of 132 patients 110 (83.3%) had prior cytoreductive therapy with either HU (32.6%), ANA (13.6%), HU and ANA (36.4%), or HU and PB (0.8%) but none received BUS. Among pre-treated patients, 107 (97.3%) patients were cytoreductive treatment resistant and/or intolerant with intolerance being most prominent (77.2% and 78.8% among HU and ANA pre-treated patients, respectively). All patients were interferon-naïve per inclusion criteria; 22 (16.7%) patients had not received any other cytoreductive therapy and were ineligible for all locally approved cytoreductive agents for ET. As of data cut-off (median exposure 301 days) treatment-emergent adverse events led to discontinuation in only 4 (3%) patients. The last patient 12-month visit will occur in Q3 2025 and primary endpoint results will be presented at the meeting. Conclusions Our study highlights the unmet need among ET patients of all risk levels for additional therapeutic options, since all patients enrolled required cytoreduction but were unable to receive locally approved agents. Aside reduction of thrombotic risk, ET patients, in particular younger individuals, have a significant lifetime risk of disease progression, requiring a disease modifying therapy. In this last-line population, treatment with ropeginterferon alfa-2b was well tolerated, with few discontinuations due to adverse events. The planned primary endpoint analysis will provide data on the efficacy of ropeginterferon alfa-2b in this underserved population.