Final results from a prospective, multicenter, non-interventional study (BESREMi-PASS) on the safety of ropeginterferon alfa-2b in 229 patients with polycythemia vera

Abstract Introduction Ropeginterferon alfa-2b (ropeg), a next-generation mono-pegylated interferon (IFN) demonstrated a favorable safety and tolerability profile in phase 3 trials for treatment of polycythemia vera (PV). Hepatotoxicity is an important class effect of alfa IFN. This post-authorization study evaluated the hepatotoxicity risk and overall safety of ropeg in a real-world PV cohort. Methods This phase 4, prospective, non-interventional safety study was conducted in Austria (8 sites), Germany (20 sites), and Romania (6 sites). Ropeg-naïve PV patients aged ≥18 years who gave informed consent and had no relevant contraindications were eligible to receive ropeg during routine clinical care. The primary endpoint was the incidence of hepatotoxicity defined as: (1) Significant elevations in ALT (alanine amino transferase), AST (aspartate amino transferase), and/or GGT (gamma-glutamine transferase), defined as ≥3× upper limit of normal [ULN]) and/or total bilirubin (>2× ULN) and (2) Treatment-emergent hepatobiliary adverse drug reactions (ADRs) in the first 6 months of treatment. Additional endpoints included patient characteristics, incidence of cardiovascular events over the entire 18-month observation period, and all treatment-emergent adverse events. Results A total of 229 PV patients were enrolled and treated; 42.4% were female. Age and time since diagnosis varied considerably (age: median 58.0 years, range 23-91; time since diagnosis: median 0.9 years, range 0-30). At baseline, 58.5% of patients presented with PV-related symptoms, 17.0% had pre-existing liver disease and 56.3% of patients were classified as high risk for thromboembolic events; 25.3% already had experienced such an event. Cardiovascular disease was present in 61.1% and cardiovascular risk factors in 60.3% of patients at baseline. Prior cytoreduction was documented in 38.4% of patients, with a median of 1.0 (range 1-4) previous therapies. Ropeg was administered at a median starting dose of 100 µg/2 weeks. Dose individualization resulted in a median 2-weekly dose of 200 µg (IQR: 125-250) at 18 months. Regarding the primary endpoint, in the first 6 months, significant elevations in liver parameters were reported in 32 patients (14.0%; incidence rate per 100 patient-years [IR/100 PY]: 45.21 [95% CI: 33.45–59.77]; no hepatobiliary ADRs occurred in this period. Excluding patients with a significant elevation of liver parameters at baseline, 9.1% had significant elevations (IR/100 PY: 30.20 [95% CI: 20.37, 43.11]). Over the entire 18-month period, a lower incidence of significant elevations in liver parameters was observed (IR/100 PY: 30.83 [95% CI: 24.91, 37.72], or 23.24 [17.94, 29.62] excluding patients with significant elevations at baseline). One hepatobiliary ADR (grade 2 hepatic cirrhosis) occurred. Hepatotoxicity led to dose reduction, interruption or discontinuation in 2.6%, 3.5% and 1.3% of patients, respectively. Elevated liver parameters were more common among patients with pre-existing liver disease (37.2% vs 8.4% in those without pre-existing disease; p<0.0001). Thromboembolic events occurred in 11 patients (4.8%) during the entire study, all of whom had pre-existing cardiovascular disease and/or significant cardiovascular risk factors. One was a major adverse cardiovascular event (acute myocardial infarction) in a patient with a medical history of three prior major thromboembolic events. No new safety concerns emerged. Aside from liver enzyme elevations, the most common ADRs included fatigue (19.7%), pruritus (14.8%), and headache (6.6%), which may be difficult to distinguish from PV-related symptoms. Notably, typical IFN-related toxicity such as flu-like illness, autoimmune thyroiditis and depression were rare (3.1%, 1.7% and <1%, respectively).Prophylaxis with NSAIDs was uncommon (≤3%). A total of 13 (5.7%) patients discontinued treatment due to ADRs in the first 6 months and 15 (6.6%) thereafter. Conclusion This study underscores the heterogeneity of PV patient characteristics in clinical practice. Despite pre-existing liver disease in 17% of patients, hepatoxicity on ropeg occurred at a low overall rate, consistent with registration trials and prescribing information. In contrast to trial populations, substantial co-morbidity was observed, with more cardiovascular events in patients with history of cardiovascular risk. Our prospective investigation of a large PV cohort confirms the safety of ropeginterferon alfa-2b in a real-world setting.