Long-term efficacy and safety of ropeginterferon alfa-2b under its hidat regimen for the treatment of polycythemia vera

Abstract Polycythemia vera (PV), a BCR::ABL1-negative myeloproliferative neoplasm characterized by erythrocytosis and commonly associated with the JAK2V617F mutation, remains incurable. Leukocytosis and JAK2V617F variant allele frequency (VAF) in peripheral blood cells correlate with thrombotic risk and disease progression. Durable complete molecular response (CMR), defined by undetectable JAK2V617FVAF, indicates clearance of disease-driving neoplastic cells and improved clinical outcomes. Ropeginterferon alfa-2b (ropeg), a mono-pegylated interferon, selectively inhibits neoplastic cell proliferation, reducing tumorigenicity and clonal expansion. One study to date has shown that a Higher Initial Dose (250 µg) and Accelerated Titration (HIDAT) regimen can lead to rapid complete hematologic and deep molecular remission. Here, we present 36-month follow-up data from this phase 2, multicenter, single-arm trial (N=49) evaluating the HIDAT regimen in hydroxyurea-intolerant PV patients. Forty-four patients entered the extension phase post-first-year treatment, with 43 completing 36 months of treatment. Despite dose reductions and extended intervals from biweekly to monthly dosing during stabilization, patients maintained high complete hematologic remission (CHR) rates: 75.0% (33/44) at Month 24; 84.1% (37/44) at Month 30, and 75.0% (33/44) at Month 36. Median JAK2V617F VAF significantly reduced from 61.2% (baseline) to 4.9% (at 36 months), with molecular responses observed in 86.0% (37/43) of patients, including 34.9% (15/43) achieving CMR. Event-free survival (EFS) was significantly higher in patients achieving CMR (3-year EFS 100%) compared to those without molecular response (3-year EFS 70%, p=0.035). There was no significant difference in EFS between patients achieving partial molecular response compared to those without molecular response. Furthermore, ropeg demonstrated a favorable safety profile, with no Grade 4 or higher adverse events (AEs) observed and grade 3 AEs occurring in only 9.1% of patients (4/44). The most common AEs included leukopenia and elevated transaminases. None of which resulted in significant clinical consequences. No patients developed disease progression to secondary myelofibrosis or acute myeloid leukemia on the study, and only one major thrombosis and two bleeding events occurred. In conclusion, long-term ropeg administration under an optimized HIDAT regimen effectively sustains CHRs, induces profound molecular responses, and exhibits favorable safety in hydroxyurea-intolerant PV patients. Achieving CMR correlated with improved EFS, highlighting its prognostic significance.