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

Blood, vol. 146, pp. 2032

Abstract

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.

Authors 13

1. Veronika Buxhofer‐Ausch

   Johannes Kepler University of Linz · Krankenhaus der Elisabethinen

   Affiliation as printed

   1Ordensklinikum Linz Elisabethinen, Department of Internal Medicine I with Hematology, Stem Cell Transplantation, Hemostaseology and Medical Oncology, Linz, Austria

   2Johannes Kepler University Linz, Medical Faculty, Linz, Austria

2. Andreas Reiter

   Heidelberg University · University Medical Centre Mannheim

   Affiliation as printed

   3University Hospital Mannheim, Heidelberg University, Mannheim, Germany

3. Ciprian Tomuleasa

   Iuliu Hațieganu University of Medicine and Pharmacy

   Affiliation as printed

   4Iuliu Hațieganu University of Medicine and Pharmacy, Department of Personalized Medicine and Rare Diseases, Medfuture Institute for Biomedical Research, Cluj-Napoca, Romania

4. Albert Woelfler

   University of Graz · Medical University of Graz

   Affiliation as printed

   5Medical University of Graz, Graz, Austria, Division of Hematology, Graz, Austria

5. Lino Lars Teichmann

   University Hospital Bonn

   Affiliation as printed

   6University Hospital Bonn, Bonn, Germany

6. Luminita Ocroteala
   Affiliation as printed

   7Filantropia Municipal Clinical Hospital, Craiova, Romania

7. Krauth Maria-Theresa

   Medical University of Vienna

   Affiliation as printed

   8Medical University of Vienna, Vienna, Austria

8. Stefanie Schlager
   Affiliation as printed

   9AOP Health, Vienna, Austria

9. Victoria G. Empson
   Affiliation as printed

   9AOP Health, Vienna, Austria

10. Christoph S. Klade
    Affiliation as printed

    9AOP Health, Vienna, Austria

11. Kurt Krejcy
    Affiliation as printed

    9AOP Health, Vienna, Austria

12. Heinz Gisslinger

    Medical University of Vienna

    Affiliation as printed

    8Medical University of Vienna, Vienna, Austria

13. Steffen Koschmieder Aachen Department of Hematology, Oncology Faculty of Medicine

    RWTH Aachen University

    Affiliation as printed

    10RWTH Aachen University, Department of Hematology, Oncology, Hemostaseology, and SCT, Faculty of Medicine, Aachen, Germany

    11Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Aachen, Germany