Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo

Verger, Emmanuelle; Soret-Dulphy, Juliette; Maslah, Nabih; Roy, Lydia; Rey, Jérôme; Ghrieb, Zineb; Královics, Róbert; Gisslinger, Heinz; Grohmann-Izay, Barbara; Klade, Christoph; Chomienne, Christine; Giraudier, Stéphane; Cassinat, Bruno; Kiladjian, Jean‐Jacques

doi:10.1038/s41408-018-0133-0

Cited by 42 publications

(40 citation statements)

References 19 publications

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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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confidence: 99%

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

et al. 2020

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“…Interferon alfa has the capacity to selectively reduce the malignant JAK2 mutated stem cell clone content [59,60,61] was as effective as hydroxyurea after 12 months of treatment in terms of complete hematological responses (non-inferior vs. HU). However, in contrast to HU, the PEG-interferon 2b treatment continuation up 36 months was associated with higher response rates and with a higher proportion of patients with molecular response (a steady decrease in the mean absolute JAK2 V617F allele burden level by month 36 from 42.8% at baseline to 19.7%).…”

Section: Interferon In the Treatment Of Pvmentioning

confidence: 99%

Medical dilemmas – erythrocytosis

Lewandowski

2020

Acta Haematologica Polonica

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Erythrocytosis is defined not only by an increase in the erythrocyte count, hemoglobin concentration, and hematocrit value, but also by the occurrence of specific symptoms, the intensity and frequency of which depend on the character of the initial genetic lesion. Ischemic episodes and thrombotic complications caused by increased blood viscosity are frequently the first clinical manifestation of the disease. This paper represents the current level of knowledge about the pathogenesis of erythrocytosis and the diagnostic algorithms used to precisely define the type of the disease.

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“…Ropeginterferon alpha-2b (Ropeg) is a long-acting pegylated-IFNα-2b, recently shown to be safe and well tolerated in phase 1-2 studies in PV patients. Both hematological and molecular responses have been reported in a phase 2 trial [104]. The discovery of JAK2 V617F mutation and its role in constitutive activation of downstream signaling pathways and MPN pathogenesis triggered the search for specific JAK2 kinase inhibitors as potential targeted therapy.…”

Section: Pcd Resistance In Myeloid Proliferation Exploited In Single mentioning

confidence: 99%

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

Diaconu¹,

Gurban²,

Mambet³

et al. 2020

Programmed Cell Death

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BCR-ABL1-negative myeloproliferative neoplasms are classically represented by primary myelofibrosis, polycythemia vera, and essential thrombocythemia. These entities are stem cell-derived clonal disorders characterized by hematopoietic progenitor autonomy or hypersensitivity to cytokines, most of them presenting mutations in Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL). Deregulation of pro-and antiapoptotic genes is also claimed as an important mechanism involved in cell resistance to cell death and accumulation of myeloid cells in myeloproliferative neoplasms. Apoptosis, as one of the best-characterized types of programmed cell death, has a clear role in hematopoiesis control. However, the exact pathways affected in BCR-ABL1-negative myeloproliferative neoplasms have not yet been fully clarified. This chapter will explore the modifications affecting programmed cell death pathways involved in myeloid proliferation and how these alterations might be exploited in single or combined targeted therapeutic strategies.

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Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivo

Cited by 42 publications

References 19 publications

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

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

Medical dilemmas – erythrocytosis

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

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