Is long-term administration of interferons in polycythaemia vera associated with risks?
Authors:
J. Suchopár 1; M. Doubek 2
Authors‘ workplace:
DrugAgency, Praha
1; Interní hematologická a onkologická klinika LF MU a FN Brno
2
Published in:
Transfuze Hematol. dnes,31, 2025, No. 3, p. 186-196.
Category:
Review/Educational Papers
doi:
https://doi.org/10.48095/cctahd2025prolekare.cz16
Overview
The treatment of polycythaemia vera and other myeloproliferative disorders with interferons is undergoing a renaissance, primarily for three reasons. Firstly, the duration of action has been extended through pegylation. Secondly, pegylation has improved local tolerance and reduced cytokine release. Thirdly, new and promising evidence has demonstrated efficacy with solid tolerability for pegylated interferons. Different pegylated interferons vary in both their chemical properties and the three-dimensional structure of their positional isomers. Notably, one pegylated interferon – ropeginterferon a2b – consists of a single molecule and lacks positional isomers. The isomers of pegylated interferons likely exhibit distinct biological activity, which may contribute to differences in tolerability and the incidence of adverse effects. Two of the largest adverse event databases, the US FAERS and the European EudraVigilance, consistently indicate that there are differences in the incidence and severity of adverse effects among pegylated interferons. Moreover, these differences are corroborated by the findings of controlled phase 2 and phase 3 clinical trials, which, among other outcomes, examined the incidence of early treatment discontinuation due to adverse effects. Based on the analysis of adverse effects and the results of controlled clinical trials, it can be concluded that, for the treatment of polycythaemia vera, ropeginterferon a2b exhibits significantly better tolerability compared with peginterferon a2a and peginterferon a2b across nearly all classes of adverse effects according to the MedDRA classification. Furthermore, a significantly lower proportion of patients undergoing ropeginterferon a2b therapy need to discontinue treatment prematurely due to adverse effects compared with those treated with peginterferon a2a or peginterferon a2b. For clinicians, information on treatment safety is just as crucial as information on clinical efficacy, as this knowledge enables the optimal selection of therapy for each patient.
Keywords:
adverse effects – polycythaemia vera – EudraVigilance – FAERS – severity of adverse effects – treatment discontinuation due to adverse effects – peginterferon 2a – peginterferon 2b – ropeginterferon 2b
Sources
1. Patel AB, Masarova L, Mesa RA, et al. Polycythemia vera: past, present and future. Leuk Lymphoma. 2024; 65 (11): 1552–1564.
2. Gilbert HS. Historical perspective on the treatment of essential thrombocythemia and polycythemia vera. Semin Hematol. 1999; 36 (Suppl 2): 19–22.
3. Radin AI, Kim HT, Grant, BW, et al. Phase II study of alpha2 interferon in the treatment of the chronic myeloproliferative disorders (E5487): a trial of the Eastern Cooperative Oncology Group. Cancer. 2003; 98 (1): 100–109.
4. Quintás-Cardama A, Kantarjan H, Mansouhri T, et al. Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009; 27 (32): 5418–5424.
5. Masarova L, Patel KP, Newbery KJ, et al. Pegylated interferon alfa-2a in patients with essential thrombocythaemia or polycythaemia vera: a post-hoc, median 83 month follow-up of an open-label, phase 2 trial. Lancet Haematol. 2017; 4 (4): e165–e175.
6. Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 2020; 7 (3): e196–e208.
7. Kiladjian J-J, Klade C, Georgiev P, et al. Long-term outcomes of polycythemia vera patients treated with ropeginterferon alfa-2b. Leukemia. 2022; 36 (5): 1408–1411.
8. Barbui T, Vannucchi A, DeStefano V, et al. Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial. Lancet Haematol. 2021; 8 (3): e175–e184.
9. Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-a vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022; 139 (19): 2931–2941.
10. Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib versus best available therapy for polycythemia vera intolerant or resistant to hydroxycarbamide in a randomized trial. J Clin Oncol. 2023; 41 (19): 3534–3544.
11. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2024. Accessed February 28, 2024. Dostupné z: https: //www.nccn.org/professionals/physician_gls/pdf/mpn.pdf
12. Knudsen TA, Skov V, Stevenson K, et al. Genomic profiling of a randomized trial of interferon-a vs hydroxyurea in MPN reveals mutation-specific responses. Blood Adv. 2022; 6 (7): 2107–2119.
13. Knudsen TA, Hansen DL, Ocias LF, et al. Final analysis of the Daliah Trial: a randomized phase III trial of interferon-a versus hydroxyurea in patients with MPN. 65th ASH Annual Meeting & Exposition. December 7-10, 2024, in San Diego, California. Abstract No 743.
14. Gisslinger H, Klade C, Georgiev P, et al. Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment. Leukemia. 2023; 37 (10): 2129–2132.
15. Samuelsson J, Hasselbach H, Bruserud O, et al. A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. Cancer. 2006; 106 (11): 2397–2405.
16. Yacoub A, Mascarenhas J, Kosiorek H, et al. Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea. Blood. 2019; 134 (18): 1498–1509.
17. Gisslinger H, Buxhofer-Ausch V, Thaler j, et al. Long-term efficacy and safety of ropeginterferon alfa-2b in patients with polycythemia vera — final phase I/II Peginvera study results. Blood. 2018; 132 (Suppl 1): 3030.
18. Edahiro Y, Ohishi K, Gotoh A, et al. Efficacy and safety of ropeginterferon alfa-2b in Japanese patients with polycythemia vera: an open-label, single-arm, phase 2 study. Int J Hematol. 2022; 116 (2): 215–227.
19. Barbui T, Carobbio A, De Stefano V, et al. Ropeginterferon phase 2 randomized study in low-risk polycythemia vera: 5-year drug survival and efficacy outcomes. Ann Hematol. 2024; 103 (2): 437–442.
20. Vachhani P, Mascarenhas J, Bose P, et al. Interferons in the treatment of myeloproliferative neoplasms. Ther Adv Hematol. 2024; 15 : 20406207241229588.
21. Illés Á, Pinczés LI, Egyad M. A pharmacokinetic evaluation of ropeginterferon alfa-2b in the treatment of polycythemia vera. Expert Opin Drug Metab Toxicol. 2021; 17 (1): 3–7.
22. Foser S, Schacher A, Weyer KA, et al. Isolation, structural characterization, and antiviral activity of positional isomers of monopegylated interferon alpha-2a (PEGASYS). Protein Expr Purif. 2003; 30 (1): 78–87.
23. Dhalluin C, Ross A, Huber W, et al. Structural, kinetic, and thermodynamic analysis of the binding of the 40 kDa PEG-interferon-alpha2a and its individual positional isomers to the extracellular domain of the receptor IFNAR2. Bioconjug Chem. 2005; 16 (3): 518–527.
24. Okikiolu J, Woodley C, Cadman-Davies L, et al. Real world experience with ropeginterferon alpha-2b (Besremi) in essential thrombocythaemia and polycythaemia vera following exposure to pegylated interferon alfa-2a (Pegasys). Leuk Res Rep. 2022; 19 : 100360.
25. Bang SY, Lee SE. A case report of ropeginterferon alfa-2b for polycythemia vera during pregnancy. Hematol Rep. 2023; 15 (1): 172–179.
26. Belohlavkova P. Treatment of polycythemia vera with ropeginterferon alfa 2b in a young woman with a successful pregnancy – case report. Onkol Rev. 2023; 10 (6): 485–489.
PODÍL AUTORŮ NA ZPRACOVÁNÍ ČLÁNKU
Josef Suchopár 50 %, Michael Doubek 50 %
PROHLÁŠENÍ O KONFLIKTU ZÁJMU
JS – advisory boards, přednášková činnost a výzkumné projekty od společností AbbVie, Amgen, AOP Orphan, AstraZeneca, IBSA, Merck, MSD, Novartis, Pfizer, sanofi-aventis, Stada, TEVA, Zentiva
MD – advisory boards a výzkumné projekty od společností AbbVie, AOP Orphan, AstraZeneca, Johnson and Johnson, Swixx
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Haematology Internal medicine Clinical oncologyArticle was published in
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