Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

AOP Health Vienna Austria

Centre d'Investigations Cliniques AP HP Hôpital Saint Louis Paris 75010 France

Centre Léon Bérard Lyon France

CIC 1427 Inserm Université Paris Cité 75010 Paris France

Clinic for Hematology Hemostasis Oncology and Stem Cell Transplantation Hannover Medical School Hannover Germany

Clinic of Internal Hematology University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Clinical Hematology Regional Institute of Oncology Iasi Romania

Department of Clinical Therapeutics School of Medicine National and Kapodistrian University of Athens Athens Greece

Department of Hematology Careggi University Hospital Florence Italy

Department of Hematology Hospital Clínic of Barcelona Barcelona Spain

Department of Hematology Jagiellonian University Hospital Kraków Poland

Department of Hematology Medical University of Lodz Lodz Poland

Department of Hematology Policlinica de Diagnostic Rapid Brasov Brasov Romania

Department of Hematooncology Copernicus Memorial Hospital Lodz Poland

Department of Internal Medicine 1 Clinical Department of Hematology and Hemostaseology Medical University of Vienna Vienna Austria

Department of Internal Medicine 1 for Hematology with Stem Cell Transplantation Hemostaseology and Medical Oncology Ordensklinikum Linz Elisabethinen Johannes Kepler University Linz Linz Austria

Department of Internal Medicine 3 University Hospital Ulm Ulm Germany

Department of Internal Medicine 5 Medical University Innsbruck Innsbruck Austria

Department of Internal Medicine and Hematology Division of Hematology Semmelweis University Budapest Hungary

Department of Internal Medicine Clinical Divison of Hematology Medical University Graz Graz Austria

Department of Oncology and Hematology Ruhr University Bochum Johannes Wesling Hospital Minden Minden Germany

Department of Translational and Precision Medicine Sapienza University of Rome Rome Italy

Faculty of Medicine Department of Hematology Oncology Hemostaseology and Stem Cell Transplantation RWTH Aachen University Aachen Germany

Faculty of Medicine Department of Internal Medicine Division of Hematology University of Debrecen Debrecen Hungary

Fondazione Policlinico Gemelli IRCCS Section of Hematology Catholic University Rome Italy

Fundeni Clinical Institute Center for Hematology and Bone Marrow Transplantation București Romania

Hospital Universitario Ramón y Cajal Madrid Madrid Spain

Institut Català d' Oncologia Hospital Germans Trias i Pujol Josep Carreras Leukemia Research Institute Universitat Autònoma de Barcelona Barcelona Spain

Ion Chiricuta Institute of Oncology Hematology Department and Medfuture Research Center for Advanced Medicine Iuliu Hatieganu University of Medicine and Pharmacy Cluj Napoca Romania

IRCCS Azienda Ospedaliero Universitaria di Bologna and Istituto di Ematologia Seràgnoli Bologna Italy

Laboratory of Hematology Bordeaux University Hospital Bordeaux France

Medical Clinic 3 Hematology and Internistic Oncology University Hospital Mannheim Mannheim Germany

Medical Faculty Johannes Kepler University Linz Linz Austria

Medical University of Gdańsk Gdańsk Poland

Medical University of Silesia Katowice Poland

Morales Meseguer University General Hospital Regional Center of Blood Donation CIBERER UCAM IMIB Murcia Murcia Spain

Universidad de Alcalá Madrid Spain

University Bordeaux INSERM BMC U1034 F 33600 Pessac France

University General Hospital Attikon Athens Greece

University Hospital Brno Department of Internal Medicine Hematology and Oncology Masaryk University Brno Czech Republic

University Hospital City of Health and Science of Turin Hospital Molinette Complex Structure of Hematology Torino Italy

University Hospital Halle Krukenberg Cancer Center Halle Halle Germany

Zobrazit více v PubMed

Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112(8):3065–3072. doi: 10.1182/blood-2008-03-143537. PubMed DOI

Masarova L, Patel KP, Newberry 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. doi: 10.1016/S2352-3026(17)30030-3. PubMed DOI PMC

Knudsen TA, Hansen DL, Ocias LF, et al. Long-term efficacy and safety of recombinant interferon alpha-2 vs. hydroxyurea in polycythemia vera: preliminary results from the three-year analysis of the Daliah Trial - a randomized controlled phase III clinical trial. Blood. 2018;132(no Suppl 1):pp580. doi: 10.1182/blood-2018-99-111255. DOI

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. doi: 10.1182/blood.2019000428. PubMed DOI PMC

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. doi: 10.1016/S2352-3026(19)30236-4. PubMed DOI

Mascarenhas J, Kosiorek HE, Prchal JT, et al. A randomized phase 3 trial of interferon-alpha vs hydroxyurea in polycythemia vera and essential thrombocythemia. Blood. 2022;139(19):2931–2941. doi: 10.1182/blood.2021012743. PubMed DOI PMC

Barbui T, Vannucchi AM, De Stefano V et al (2023) Ropeginterferon versus standard therapy for low-risk patients with polycythemia vera. NEJM Evid 2(6). 10.1056/EVIDoa2200335 PubMed

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 doi: 10.1038/s41375-023-02008-6. PubMed DOI PMC

Kiladjian JJ, Klade C, Georgiev P, et al. Long-term outcomes of polycythemia vera patients treated with ropeginterferon Alfa-2b. Leukemia. 2022;36(5):1408–1411. doi: 10.1038/s41375-022-01528-x. PubMed DOI PMC

Hasselbalch HC, Holmstrom MO. Perspectives on interferon-alpha in the treatment of polycythemia vera and related myeloproliferative neoplasms: minimal residual disease and cure? Semin Immunopathol. 2019;41(1):5–19. doi: 10.1007/s00281-018-0700-2. PubMed DOI PMC

Abu-Zeinah G, Silver RT, Abu-Zeinah K, et al. Normal life expectancy for polycythemia vera (PV) patients is possible. Leukemia. 2021;36(2):569–572. doi: 10.1038/s41375-021-01447-3. PubMed DOI

How J, Garcia JS, Mullally A. Biology and therapeutic targeting of molecular mechanisms in MPNs. Blood. 2023;141(16):1922–1933. doi: 10.1182/blood.2022017416. PubMed DOI PMC

Verger E, Soret-Dulphy J, Maslah N, et al. Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo. Blood Cancer J. 2018;8(10):94. doi: 10.1038/s41408-018-0133-0. PubMed DOI PMC

How J, Hobbs G. Interferons as the first choice of cytoreduction in essential thrombocythemia and polycythemia vera. J Natl Compr Canc Netw. 2022;20(9):1063–1068. doi: 10.6004/jnccn.2022.7026. PubMed DOI

Godfrey AL, Green AC, Harrison CN. Essential thrombocythemia: challenges in clinical practice and future prospects. Blood. 2023;141(16):1943–1953. doi: 10.1182/blood.2022017625. PubMed DOI

Masarova L, Verstovsek S. Emerging drugs for essential thrombocythemia. Expert Opin Emerg Drugs. 2019;24(2):93–105. doi: 10.1080/14728214.2019.1615437. PubMed DOI

Birgegard G, Besses C, Griesshammer M, et al. Treatment of essential thrombocythemia in Europe: a prospective long-term observational study of 3649 high-risk patients in the evaluation of anagrelide efficacy and long-term safety study. Haematologica. 2018;103(1):51–60. doi: 10.3324/haematol.2017.174672. PubMed DOI PMC

Gisslinger H, Gotic M, Holowiecki J, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood. 2013;121(10):1720–1728. doi: 10.1182/blood-2012-07-443770. PubMed DOI PMC

Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia treatment algorithm 2018. Blood Cancer J. 2018;8(1):2. doi: 10.1038/s41408-017-0041-8. PubMed DOI PMC

Alvarez-Larran A, Martinez-Aviles L, Hernandez-Boluda JC, et al. Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea. Ann Hematol. 2014;93(12):2037–2043. doi: 10.1007/s00277-014-2152-7. PubMed DOI

Hernandez-Boluda JC, Alvarez-Larran A, Gomez M, et al. Clinical evaluation of the European LeukaemiaNet criteria for clinicohaematological response and resistance/intolerance to hydroxycarbamide in essential thrombocythaemia. Br J Haematol. 2011;152(1):81–88. doi: 10.1111/j.1365-2141.2010.08430.x. PubMed DOI

Birgegard G. The use of anagrelide in myeloproliferative neoplasms, with focus on essential thrombocythemia. Curr Hematol Malig Rep. 2016;11(5):348–355. doi: 10.1007/s11899-016-0335-0. PubMed DOI PMC

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405. doi: 10.1182/blood-2016-03-643544. PubMed DOI

Barosi G, Besses C, Birgegard G, et al. A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group. Leukemia. 2007;21(2):277–280. doi: 10.1038/sj.leu.2404473. PubMed DOI

Barosi G, Mesa R, Finazzi G, et al. Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus project. Blood. 2013;121(23):4778–4781. doi: 10.1182/blood-2013-01-478891. PubMed DOI PMC

Stegelmann F, Teichmann LL, Heidel FH, et al. Clinicohematologic and molecular response of essential thrombocythemia patients treated with pegylated interferon-alpha: a multi-center study of the German Study Group-Myeloproliferative Neoplasms (GSG-MPN) Leukemia. 2023;37(4):924–928. doi: 10.1038/s41375-023-01837-9. PubMed DOI PMC

ICH Harmonised Tripartite Guideline (1999) Statistical principles for clinical trials, international conference on harmonisation E9 Expert Working Group Stat Med 18(15):1905–1942. https://www.ncbi.nlm.nih.gov/pubmed/10532877 PubMed

Gilreath JA, Tashi T, Kim SJ, et al. Compassionate use of ropeginterferon-alfa-2b/P1101 for treatment of high risk polycythemia vera and essential thrombocythemia patients previously controlled on pegylated interferon-alfa-2a/Pegasys®. Blood. 2018;132(Supplement 1):5459–5459. doi: 10.1182/blood-2018-99-116852. DOI

How J, Hobbs G. Real-world experience of ropeginterferon in myeloproliferative neoplasm patients. Blood. 2022;140(Supplement 1):12284–12285. doi: 10.1182/blood-2022-157076. DOI

Huang CE, Wu YY, Hsu CC, et al. Real-world experience with ropeginterferon-alpha 2b (Besremi) in philadelphia-negative myeloproliferative neoplasms. J Formos Med Assoc. 2021;120(2):863–873. doi: 10.1016/j.jfma.2020.08.021. PubMed DOI

Novak W, Annamária C, Crazzolara R, et al. Severe complications in JAK2 V617F positive pediatric patients with myeloproliferative neoplasms. Hemasphere. 2022;6(Suppl):936–937. doi: 10.1097/01.HS9.0000852292.38263.b8. DOI

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. 2023;19:100360. doi: 10.1016/j.lrr.2022.100360. PubMed DOI PMC

Podstavková N, Weinbergerová B, Procházková J, et al. Current experience with ropeginterferon Alfa-2b in Ph negative myeloproliferative neoplasm at the Department of Internal Medicine – Haematology and Oncology in Brno. Transfuze Hematol Dnes. 2022;28(4):1–6. doi: 10.48095/cctahd2022prolekare.cz15. DOI

Tashi T, Reeves BN, Kim SJ, et al. Real-world experience of ropeginterferon-alfa treatment of PV and ET - Two centers experience. Blood. 2023;142(Supplement 1):6397. doi: 10.1182/blood-2023-191268. DOI

Barbui T, Tefferi A, Vannucchi AM, et al. Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia. 2018;32(5):1057–1069. doi: 10.1038/s41375-018-0077-1. PubMed DOI PMC

Alvarez-Larran A, Sant’Antonio E, Harrison C, et al. Unmet clinical needs in the management of CALR-mutated essential thrombocythaemia: a consensus-based proposal from the European LeukemiaNet. Lancet Haematol. 2021;8(9):e658–e665. doi: 10.1016/S2352-3026(21)00204-0. PubMed DOI

Mesa RA, Jamieson C, Bhatia R, et al. NCCN guidelines insights: Myeloproliferative neoplasms, version 2.2018. J Natl Compr Canc Netw. 2017;15(10):1193–1207. doi: 10.6004/jnccn.2017.0157. PubMed DOI

Bewersdorf JP, Giri S, Wang R, et al. Interferon alpha therapy in essential thrombocythemia and polycythemia vera-a systematic review and meta-analysis. Leukemia. 2021;35(6):1643–1660. doi: 10.1038/s41375-020-01020-4. PubMed DOI PMC

Gu W, Yang R, Xiao Z, et al. Clinical outcomes of interferon therapy for polycythemia vera and essential thrombocythemia: a systematic review and meta-analysis. Int J Hematol. 2021;114(3):342–354. doi: 10.1007/s12185-021-03171-1. PubMed DOI

Beauverd Y, Ianotto J-C, Thaw KH et al (2023) Impact of cytoreductive drugs upon outcomes in a contemporary cohort of adolescent and young adults with essential thrombocythemia and polycythemia vera. Retrieved from https://ash.confex.com/ash/2023/webprogram/Paper185108.html. Accessed 27 Nov 2023

Alvarado Y, Cortes J, Verstovsek S, et al. Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia. Cancer Chemother Pharmacol. 2003;51(1):81–86. doi: 10.1007/s00280-002-0533-4. PubMed DOI

Langer C, Lengfelder E, Thiele J, et al. Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study. Haematologica. 2005;90(10):1333–1338. PubMed

Verger E, Cassinat B, Chauveau A, et al. Clinical and molecular response to interferon-alpha therapy in essential thrombocythemia patients with CALR mutations. Blood. 2015;126(24):2585–2591. doi: 10.1182/blood-2015-07-659060. PubMed DOI

Gowin K, Thapaliya P, Samuelson J, et al. Experience with pegylated interferon alpha-2a in advanced myeloproliferative neoplasms in an international cohort of 118 patients. Haematologica. 2012;97(10):1570–1573. doi: 10.3324/haematol.2011.061390. PubMed DOI PMC

Gowin K, Jain T, Kosiorek H, et al. Pegylated interferon alpha – 2a is clinically effective and tolerable in myeloproliferative neoplasm patients treated off clinical trial. Leuk Res. 2017;54:73–77. doi: 10.1016/j.leukres.2017.01.006. PubMed DOI

Jabbour E, Kantarjian H, Cortes J, et al. PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study. Cancer. 2007;110(9):2012–2018. doi: 10.1002/cncr.23018. PubMed DOI

Samuelsson J, Hasselbalch 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. doi: 10.1002/cncr.21900. PubMed DOI

Verstovsek S, Komatsu N, Gill H, et al. SURPASS-ET: phase III study of ropeginterferon alfa-2b versus anagrelide as second-line therapy in essential thrombocythemia. Future Oncol. 2022;18(27):2999–3009. doi: 10.2217/fon-2022-0596. PubMed DOI

Masarova L, Mascarenhas J, Qin A, et al. EXCEED-ET: a single-arm multicenter study to assess the efficacy, safety, and tolerability of ropeginterferon alfa-2b-njft (P1101) in north American adults with essential thrombocythemia. J Clin Oncol. 2023;41(16):TPS7088–TPS7088. doi: 10.1200/JCO.2023.41.16_suppl.TPS7088. DOI

Gisslinger H, Zagrijtschuk O, Buxhofer-Ausch V, et al. Ropeginterferon alfa-2b, a novel IFNalpha-2b, induces high response rates with low toxicity in patients with polycythemia vera. Blood. 2015;126(15):1762–1769. doi: 10.1182/blood-2015-04-637280. PubMed DOI PMC

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. doi: 10.1007/s12185-022-03341-9. PubMed DOI

Ferrer-Marin F, Arroyo AB, Bellosillo B, et al. miR-146a rs2431697 identifies myeloproliferative neoplasm patients with higher secondary myelofibrosis progression risk. Leukemia. 2020;34(10):2648–2659. doi: 10.1038/s41375-020-0767-3. PubMed DOI

Hasselbalch HC, Bjorn ME. MPNs as inflammatory diseases: the evidence, consequences, and perspectives. Mediators Inflamm. 2015;2015:102476. doi: 10.1155/2015/102476. PubMed DOI PMC

Morales ML, Ferrer-Marin F (2023) Deepening our understanding of the factors affecting landscape of myeloproliferative neoplasms: what do we know about them? Cancers (Basel) 15(4). 10.3390/cancers15041348 PubMed PMC

Guy A, Favre S, Labrouche-Colomer S, et al. High circulating levels of MPO-DNA are associated with thrombosis in patients with MPN. Leukemia. 2019;33(10):2544–2548. doi: 10.1038/s41375-019-0500-2. PubMed DOI

Schmidt S, Daniliants D, Hiller E, et al. Increased levels of NETosis in myeloproliferative neoplasms are not linked to thrombotic events. Blood Adv. 2021;5(18):3515–3527. doi: 10.1182/bloodadvances.2020004061. PubMed DOI PMC

Ferrer-Marin F, Cuenca-Zamora EJ, Guijarro-Carrillo PJ et al (2021) Emerging role of neutrophils in the thrombosis of chronic myeloproliferative neoplasms. Int J Mol Sci 22(3). 10.3390/ijms22031143 PubMed PMC

Marin Oyarzun CP, Carestia A, Lev PR, et al. Neutrophil extracellular trap formation and circulating nucleosomes in patients with chronic myeloproliferative neoplasms. Sci Rep. 2016;6:38738. doi: 10.1038/srep38738. PubMed DOI PMC

Wolach O, Sellar RS, Martinod K et al (2018) Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci Transl Med 10(436). 10.1126/scitranslmed.aan8292 PubMed PMC