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

Gisslinger, Heinz; Klade, Christoph; Georgiev, Pencho; Krochmalczyk, Dorota; Gercheva-Kyuchukova, Liana; Egyed, Miklós; Rossiev, Viktor; Dulíček, Petr; Illés, Árpád; Pylypenko, Halyna; Sivcheva, Lylia; Mayer, Jiřı́; Yablokova, Vera; Krejcy, Kurt; Grohmann-Izay, Barbara; Hasselbalch, Hans Carl; Královics, Róbert; Kiladjian, Jean‐Jacques; Bauer, F.Samuel; Berbec, Nicoleta P.; Raebel, Carlos Besses; Borbényi, Zita; Bumbea, Horia; Buxhofer‐Ausch, Veronika; Całbecka, Małgorzata; Cayssials-Caylus, Emilie; Cazzola, Mario; Cerná, O; Cucuianu, Andrei; Dima, Delia; Forjan, Ernst; Gheorghita, Emanuil; Greil, Richard; Hatalova, Antónia; Hrubisko, M; Jakucs, János; Kaplan, Polina; Klymenko, Sergiy; Koschmieder, Steffen; Lazaroiu, Mihaela; Lysa, Tamila; Masliak, Zvenyslava; Masszi, Tamás; Mihaylov, Georgi; Myasnikov, Alexander; Platzbecker, Uwe; Puyade, Mathieu; Rey, Jérôme; Roy, Lydia; Schwarz, Jiřı́; Skotnicki, Aleksander B.; Sokolova, I. Ya.; Soroka-Wojtaszko, Maria; Starzak-Gwóźdź, Jolanta; Stoeva, Vera; Torregrosa-Diaz, José Miguel; Vallova, Anna; Volodicheva, Elena; Warzocha, Krzysztof; Willenbacher, Ella; Wolf, Dominik

doi:10.1016/s2352-3026(19)30236-4

Cited by 211 publications

(224 citation statements)

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“… 1 4 5 In addition to its ability to induce hematologic responses, IFNa has disease-modifying properties as shown by the high rate of reduction of the mutant JAK2 V617F allele burden. 6 7 8 9 10 11 In elderly patients with PV, however, a higher number of toxicity-related dose reductions or discontinuations and lower hematological response rates have been reported among IFNa-treated patients compared to HU. 12…”

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“…The full trial methodology of the PROUD-PV/CONTINUATION-PV phase III trials was previously published. 10 Briefly, eligible patients aged ≥18 years were diagnosed with PV according to the World Health Organization 2008 criteria. Patients with PV were randomly assigned 1:1 to receive either ropeginterferon (starting dose 50–100 μg) every two weeks or HU (starting dose 500 mg) daily.…”

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Ropeginterferon Alfa‐2b: Efficacy and Safety in Different Age Groups

et al. 2020

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Dear Editor, Interferon alpha (IFNa) and hydroxyurea (HU) are recommended for cytoreductive treatment of polycythaemia vera (PV), 1-3 a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by deregulated hematopoiesis driven by mutated constitutive-active JAK2. 1,4,5 In addition to its ability to induce hematologic responses, IFNa has disease-modifying properties as shown by the high rate of reduction of the mutant JAK2V617F allele burden. [6][7][8][9][10][11] In elderly patients with PV, however, a higher number of toxicity-related dose reductions or discontinuations and lower hematological response rates have been reported among IFNa-treated patients compared to HU. 12 Ropeginterferon (Besremi ® ) is a novel mono-pegylated IFNa-2b with reduced dosing frequency and improved tolerability compared to other pegylated IFNs, and is approved in Europe as first-line therapy for treatment of PV in patients of all ages. 10,13 Here we report the efficacy and safety after 24 months of ropeginterferon treatment compared to HU in the PROUD-PV/ CONTINUATION-PV phase III trials (EudraCT: 2012-005259-18; 2014-001357-17), analyzed post-hoc in two age cohorts (<60 years and ≥60 years) in PV patients aiming to evaluate the benefit-risk ratio of ropeginterferon therapy in the elderly.The full trial methodology of the PROUD-PV/CONTINUA-TION-PV phase III trials was previously published. 10 Briefly, eligible patients aged ≥18 years were diagnosed with PV according to the World Health Organization 2008 criteria. Patients with PV were randomly assigned 1:1 to receive either ropeginterferon (starting dose 50-100 mg) every two weeks or HU (starting dose 500 mg) daily. Patients provided written informed consent in accordance with the Declaration of Helsinki. Study protocols were approved by the institutional review board or independent ethics committees at each site.Efficacy assessment included the rate of complete hematological response (CHR, defined as hematocrit < 45% with no phlebotomy in the last three months, platelet count < 400 x 10 9 /L and leukocyte count < 10 x 10 9 /L), rate of CHR and symptom improvement (disease-related signs including clinically significant splenomegaly and PV-related symptoms), evolution of JAK2V617F allelic burden, and molecular response rate. Efficacy and safety were assessed in the age categories < 60 years and ≥60 years including all 171 patients who entered the CONTINUA-TION-PV study. An additional analysis of the age categories < 70 years and ≥70 years was conducted but is considered exploratory due to the small number of patients in the ≥70 year age group (9 in the ropeginterferon arm and 12 in the control treatment arm).Baseline characteristics were balanced between the treatment groups and indicated an early PV population. The median age was 58.0 years in the ropeginterferon arm and 59.0 years in the HU arm. In both treatment arms, patients aged ≥60 years

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Ropeginterferon Alfa‐2b: Efficacy and Safety in Different Age Groups

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“…Although IFNα targets JAK2 V617F hematopoietic progenitors, in patient or mouse models its long-term efficacy remains modest ( Austin et al, 2020 ; Gisslinger et al, 2020 ; Hasan et al, 2013 ; Kiladjian et al, 2006 ; Mullally et al, 2012 ). Several clinical and preclinical studies have attempted to improve IFNα efficacy, for example, through combinations with MDM2 or JAK2 inhibitors ( Austin et al, 2020 ; Lu et al, 2014 ; Mascarenhas et al, 2019 ).…”

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JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML

Dagher

Maslah

Edmond

et al. 2020

Journal of Experimental Medicine

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Interferon α (IFNα) is used to treat JAK2V617F-driven myeloproliferative neoplasms (MPNs) but rarely clears the disease. We investigated the IFNα mechanism of action focusing on PML, an interferon target and key senescence gene whose targeting by arsenic trioxide (ATO) drives eradication of acute promyelocytic leukemia. ATO sharply potentiated IFNα-induced growth suppression of JAK2V617F patient or mouse hematopoietic progenitors, which required PML and was associated with features of senescence. In a mouse MPN model, combining ATO with IFNα enhanced and accelerated responses, eradicating MPN in most mice by targeting disease-initiating cells. These results predict potent clinical efficacy of the IFNα+ATO combination in patients and identify PML as a major effector of therapy, even in malignancies with an intact PML gene.

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“…Because the culprit in these PIDs is the lack of type I interferon production, the application of recombinant IFN‐α or IFN‐β would be an alluring alternative in life‐threatening infections. Currently, treatment with pegylated interferon α2 is applied in patients with Behҫet's disease, chronic hepatitis B and C infections and myeloproliferative neoplasms 237‐239 . Pegylated interferon β‐1a can be effective in the management of multiple sclerosis 240 .…”

Section: Host‐directed Strategies In Immunological Loss‐of‐functionmentioning

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Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

Made

Hoischen

Netea

et al. 2020

Immunological Reviews

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In the last decade, the paradigm of primary immunodeficiencies (PIDs) as rare recessive familial diseases that lead to broad, severe, and early‐onset immunological defects has shifted toward collectively more common, but sporadic autosomal dominantly inherited isolated defects in the immune response. Patients with PIDs constitute a formidable area of research to study the genetics and the molecular mechanisms of complex immunological pathways. A significant subset of PIDs affect the innate immune response, which is a crucial initial host defense mechanism equipped with pattern‐recognition receptors. These receptors recognize pathogen‐ and damage‐associated molecular patterns in both the extracellular and intracellular space. In this review, we will focus on primary immunodeficiencies caused by genetic defects in cytosolic pattern‐recognition receptor pathways. We discuss these PIDs organized according to their mutational mechanisms and consequences for the innate host response. The advanced understanding of these pathways obtained by the study of PIDs creates the opportunity for the development of new host‐directed treatment strategies.

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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

Cited by 211 publications

References 37 publications

Ropeginterferon Alfa‐2b: Efficacy and Safety in Different Age Groups

Ropeginterferon Alfa‐2b: Efficacy and Safety in Different Age Groups

JAK2V617F myeloproliferative neoplasm eradication by a novel interferon/arsenic therapy involves PML

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

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