Ropeginterferon alfa-2b in 248 patients with polycythemia vera: Results from the italian cohort of a prospective, non-interventional, post-authorization study (ROPEG-PV)

Abstract Introduction: Ropeginterferon alfa-2b (Ropeg) was approved in Europe (2019) and in the US (2021) for treating polycythemia vera (PV), regardless of risk category or prior treatments. Despite its broad indication, real-world access in Europe varies due to national reimbursement policies. In Italy, use is restricted to patients intolerant to hydroxyurea (HU), women of childbearing who intend to become pregnant, and individuals with a history of skin cancer. As a result, the drug is mainly prescribed to subgroups potentially underrepresented in clinical trials, making real-life treatment patterns and outcomes poorly characterized. Aim: The ROPEG-PV study NCT06506084 evaluates the safety, effectiveness, and prescribing patterns in PV patients under different national reimbursement frameworks. Methods: ROPEG-PV is a prospective, non-interventional post-marketing study of adult PV patients treated with ropeginterferon alfa-2b. Initiated in 2022 with IRB approval and ELN endorsement, the study will conclude in 2028. This report presents data from the first cohort enrolled across 28 Italian centers. Results: Among 248 patients with JAK2 V617F or exon 12-mutation (VAF 38% to 59%), 238 started the treatment; 10 of them are in screening. Median follow-up was 12 months. A. Patient Characteristics: (i) HU-intolerant patients (N=152) Mostly male (66%), median age 60, 20% had splenomegaly. Most were high-risk (59%), primarily due to age. Prior history also included non-melanoma skin cancer (9%) and solid/lymphoid cancers (5%). At screening, treatments included HU (95%), phlebotomy (PHL) (72%), antiplatelets (83%), and anticoagulants (16%). Non-hematologic intolerance (80%) was common, with muco-cutaneous (41%) and gastrointestinal symptoms (33%) most frequent. (ii) Patients with prior skin cancer (N=45) Predominantly male (78%), median age 74, splenomegaly in 27%, with a median disease duration of 8.4 years, and mostly at high-risk (89%). Prior treatments included HU (82%), PHL (71%), and ruxolitinib (18%). The most common cancers were: squamous cell carcinoma and basalioma. Melanoma was reported in 4 cases. (iii) Women planning pregnancy (N=41) At presentation, median age 43 (IQR 38–48), 32% mild splenomegaly, and 100% ECOG 0. Prior obstetric complications in 23%, and 49% no prior live birth. Most had received PHL (71%) and antiplatelets (83%), while only 27% HU. One patient started Ropeg at 23 weeks of pregnancy via egg donation. B. Treatment Outcomes: (i) Hematologic response: Among 171 patients treated ≥6 months, 64% underwent any dose escalation up to max 500 µg every 2 weeks (median dose 200 µg) and 36% remained on a fixed dose (median 100 µg). Hematologic response rates improved steadily, from 16% at screening to 52% at 24 months. Phlebotomy need declined from 68% at baseline to 33% at last follow-up, indicating effective improvement of hematological control over time. (ii) Disease complications: Thrombotic events (n=4) occurred after a median of 9 months (2 strokes, 1 DVT, 1 SVT). Eight patients progressed (5 to myelofibrosis, 3 with splenomegaly) after a median of 8.4 months. Three solid tumors (genitourinary/testicular) occurred early (median 1.8 months), and three patients died (1 malignancy, 1 renal failure, 1 stroke). (iii) Adverse events (AEs) and drug discontinuation: A total of 56 AEs were reported, most commonly thyroid disorders (18%), skin reactions (11%), and liver enzyme elevations (9%). Infections, depressive symptoms, and cardiovascular events were also observed. Four grade 3–5 AEs: pericarditis, maculopathy, depressive symptoms. SAEs were rare (5%) and no severe infections or skin toxicities were observed. Cumulative rates of discontinuation reached 24%/33% at 12/24 months, respectively. The escalated-dose group experienced more moderate-to-severe AEs compared to the fixed-dose group. Discussion: This post-marketing study provides valuable real-world insight into Ropeg use in a cohort of individual with PV. Despite challenges, such as a 33% discontinuation rate at 24 months and a 3% rate of disease complications (thrombosis, disease evolution, second cancer and death), the study also highlights encouraging outcomes. Hematologic response rates improved substantially, even in difficult-to-treat subgroups. Future analyses with larger cohorts will be essential to confirm these benefits and to identify patients most likely to respond enabling more personalized drug dosing and optimized long-term care.