Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial

Barbui, Tiziano; Vannucchi, Alessandro M.; Stefano, Valerio De; Masciulli, Arianna; Carobbio, Alessandra; Ferrari, Alberto; Ghirardi, Arianna; Rossi, Elena; Ciceri, Fabio; Bonifacio, Massimiliano; Iurlo, Alessandra; Palandri, Francesca; Benevolo, Giulia; Pane, Fabrizio; Ricco, Alessandra; Carli, Giuseppe; Caramella, Marianna; Rapezzi, Davide; Musolino, Caterina; Siragusa, Sergio; Rumi, Elisa; Patriarca, Andrea; Cascavilla, Nicola; Mora, Barbara; Cacciola, Emma; Mannarelli, Carmela; Loscocco, Giuseppe Gaetano; Guglielmelli, Paola; Betti, Silvia; Lunghi, Francesca; Scaffidi, Luigi; Bucelli, Cristina; Vianelli, Nicola; Bellini, Marta; Finazzi, Maria Chiara; Tognoni, Gianni; Rambaldi, Alessandro

doi:10.1016/s2352-3026(20)30373-2

Cited by 93 publications

(59 citation statements)

References 22 publications

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“…In this perspective, neither the "watch and wait strategy" in low-risk ET and PV patients nor treatment with HU seem rational. Instead, treatment with IFN might be highly relevant since it both normalizes elevated cell counts and importantly induces sustained normal cell counts, [47][48][49][50][51][52][53][54][55][56][57][58] which may even be maintained months and even years after the discontinuation of long-term treatment (>5 years) in some patients. 49 This is in sharp contrast to cell count kinetics after discontinuation of HU, which is followed by a recurrence of elevated cell counts after a few days off HU treatment.…”

Section: Discussionmentioning

confidence: 99%

Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Dam

Pedersen

Knudsen

et al. 2021

European J of Haematology

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Background: Hydroxyurea (HU) treatment of patients with essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF) (MPNs) normalizes elevated blood cell counts within weeks in the large majority of patients.Studies on the impact of HU upon the kinetics of the JAK2V617F allele burden, leukocyte, and platelet counts over time are scarce.Purpose: Using data-driven analysis as a novel tool to model the kinetics of the JAK2V617F allele burden and blood cell counts over time during treatment with HU. Material and methods:Using serial measurements of JAK2V617F and correlation analysis of routine hematological values (the Hb-concentration, leukocyte count, platelet count, and lactic dehydrogenase), we present a detailed description and analysis of the kinetics of the JAK2V617F, leukocyte, and platelet counts and lactic dehydrogenase in 27 patients (PV = 18; ET = 7; PMF = 2), who were followed in the Danish randomized trial (DALIAH). To further analyze the JAK2V617F kinetics, we use a machine learning clustering algorithm to group the response patterns.Results: Response patterns were highly heterogeneous, with clustering resulting in 3 groups and 3 outliers. In the large majority of patients, HU treatment was initially associated with a modest decline in the JAK2V617F allele burden in concert with a decline in leukocyte and platelet counts. However, HU did not induce a sustained and continuous decrease in the JAK2V617F allele burden. Conclusion:Using data-driven analysis of the JAK2V617F allele burden, leukocyte, and platelet kinetics during treatment with HU, we have shown that HU does not induce a sustained decrease in the JAK2V617F allele burden and neither induces sustained normalization of elevated cell counts in MPN patients. Our results may explain why MPN patients during treatment with HU still have a substantially increased risk of thrombosis.

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Section: Discussionmentioning

confidence: 99%

Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Dam

Pedersen

Knudsen

et al. 2021

European J of Haematology

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“…Also noteworthy is the recent European Medicine Agency (EMA) approval of Ropeginterferon alpha-2b (Besremi ® ) for the treatment of adult patients with polycythaemia vera [ 201 ] as a result of the PROUD, CONTINUATION-PV [ 202 ] and Low-PV clinical trials [ 203 ]. Besremi ® can be used as first-line treatment but may also offer an alternative for HU- and/or ruxolitinib-resistant or -intolerant patients.…”

Section: Treatmentmentioning

confidence: 99%

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

Stuckey

Gómez‐Casares

2021

IJMS

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Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as well as some very rare cases of familial hereditary MPN caused by inherited germline mutations. Patients with PV often progress to fibrosis or acute myeloid leukaemia, both associated with very poor clinical outcome. Moreover, thrombosis and major bleeding are the principal causes of morbidity and mortality. As a result of increasingly available and economical next-generation sequencing technologies, mutational studies have revealed the prognostic relevance of a few somatic mutations in terms of thrombotic risk and risk of transformation, helping to improve the risk stratification of patients with PV. Finally, knowledge of the molecular basis of PV has helped identify targets for directed therapy. The constitutive activation of the tyrosine kinase JAK2 is targeted by ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor for PV patients who are resistant or intolerant to cytoreductive treatment with hydroxyurea. Other molecular mechanisms have also been revealed, and numerous agents are in various stages of development. Here, we will provide an update of the recent published literature on how molecular testing can improve the diagnosis and prognosis of patients with PV and present recent advances that may have prognostic value in the near future.

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“…The present study showed that no patient achieved a CMR after 12 months of Peg-IFN-a-2b therapy, which may be due to the gradual realization of molecular responses over time, with a median time to response of 24 months according to previous studies (15). Recently, interim analysis of a multicentre, randomised phase 2 clinical trial on low-risk patients with PV provided evidence that Peg-IFN-a-2b in addition to phlebotomy and low-dose aspirin is superior to phlebotomy and low-dose aspirin alone in keeping low-risk patients with PV on haematocrit target (26). This evidence is sufficient to support the fact that MPNs therapy, especially for low-risk patients, can not be limited to conventional therapy, and Peg-IFN should be actively promoted.…”

Section: Discussionmentioning

confidence: 90%

Pegylated Interferon Alpha-2b in Patients With Polycythemia Vera and Essential Thrombocythemia in the Real World

et al. 2021

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Several clinical trials have shown promising efficacy of pegylated interferon (Peg-IFN) in the first- and second-line polycythemia vera (PV) and essential thrombocythemia (ET). However, the efficacy and safety of Peg-IFN in the real world have rarely been reported. Hence, we conducted a prospective, single-center, single-arm, open exploratory study, which aimed to explore the hematologic response, molecular response, safety, and tolerability of patients with PV and ET treated with Peg-IFN in the real world. This study included newly diagnosed or previously treated patients with PV and ET, aged 18 years or older, admitted to the Department of Hematology of the First Affiliated Hospital of Soochow University from November 2017 to October 2019. The results revealed that complete hematological response (CHR) was achieved in 66.7% of patients with PV and 76.2% of patients with ET, and the molecular response was obtained in 38.5% of patients with PV and 50% of patients with ET after 48 weeks of Peg-IFN treatment. Peg-IFN is safe, effective and well tolerated in most patients. In the entire cohort, 4 patients (9.1%) discontinued treatment due to drug-related toxicity. In conclusion, Peg-IFN is a promising strategy in myeloproliferative neoplasms (MPNs), and Peg-IFN alone or in combination with other drugs should be further explored to reduce treatment-related toxicity and improve tolerability.

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Ropeginterferon alfa-2b versus phlebotomy in low-risk patients with polycythaemia vera (Low-PV study): a multicentre, randomised phase 2 trial

Cited by 93 publications

References 22 publications

Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Data‐driven analysis of the kinetics of the JAK2V617F allele burden and blood cell counts during hydroxyurea treatment of patients with polycythemia vera, essential thrombocythemia, and primary myelofibrosis

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

Pegylated Interferon Alpha-2b in Patients With Polycythemia Vera and Essential Thrombocythemia in the Real World

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