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Review Polycythaemia Vera Optimising the Use of Ruxolitinib in Inadequately Controlled Polycythaemia Vera Jean-Jacques Kiladjian, 1 Yvonne Francis 2 and Juliette Soret 1 1. APHP, Hopital Saint-Louis, Centre d’Investigation Clinique, INSERM CIC 1427, Paris, France; 2. Haematology Clinical Nurse Specialist, Guy’s Hospital, London, UK P olycythaemia vera (PV) is an uncommon chronic myeloproliferative neoplasm characterised by increased red-cell mass. The condition is currently managed by phlebotomy and/or palliative cytoreductive therapy, most commonly using hydroxyurea (HU). However, around 25% of patients have an inadequate response and/or unacceptable adverse effects; furthermore, patients with resistance to HU appear to have shorter survival than other patients with PV. Recently, a second-line treatment has become available. Ruxolitinib, an oral inhibitor of the Janus kinase (JAK) 1 and JAK 2 tyrosine kinases, has recently received regulatory approval for the treatment of patients with PV who are resistant to or intolerant of HU. This treatment offers the potential to significantly reduce phlebotomy requirements and improve the symptom burden. However, in order to determine which patients will benefit most from ruxolitinib, it is necessary to identify those who are inadequate responders to HU, a definition that is not currently consensual in the literature. Five patient groups, for whom ruxolitinib may be a beneficial second-line treatment option, have been proposed. These comprise patients who are at high risk and retain a high symptom burden after HU, require frequent phlebotomy, have an elevated leukocyte count, are intolerant to HU or interferon, or have palpable splenomegaly. Keywords Myeloproliferative neoplasm, polycythaemia vera, ruxolitinib Disclosure: Jean-Jaques Kiladjian has received institutional research funding from Novartis and AOP Orphan and particpated on advisory boards for Novartis, Shire and AOP Orphan. Yvonne Francis and Juliette Soret have nothing to disclose in relation to this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Acknowledgements: Medical writing support was provided by Katrina Mountfort, for Touch Medical Media, UK, supported by Novartis. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 13 September 2016 Accepted: 11 October 2016 Citation: European Oncology & Haematology, 2016;12(2):81–6 Corresponding Author: Jean-Jaques Kiladjian, APHP, Hopital Saint-Louis, Centre d’Investigation Clinique, INSERM CIC 142, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10, France. E: jean-jacques.kiladjian@aphp.fr Support: The publication of this article was supported by Novartis. The views and opinions expressed are those of the authors and do not necessarily reflect those of Novartis. The authors provided Novartis with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion. Polycythaemia vera (PV) is a chronic myeloproliferative neoplasm characterised by unregulated proliferation of red blood cells, and sometimes leukocytes and platelets in the absence of a recognisable physiological stimulus. 1–4 Increased red blood cell mass leads to hyperviscosity of the blood and increased risk of thrombosis. In addition, patients may have a high symptom burden that includes intractable pruritus, fatigue and altered quality of life (QoL). 5,6 If inadequately controlled, the condition can lead to serious complications including increased risk of cardiovascular events, together with the development of splenomegaly as the disease progresses. 1 The disease progresses slowly and is associated with a reduced life expectancy; 3 the median survival of PV patients is 14.1 years, 7 and is lower in patients who are resistant or intolerant to hydroxyurea (HU), as well as patients at high risk of thrombosis. In addition, PV may transform into acute myelogenous leukaemia (AML) in up to 15% of patients every 10 years 7,9 or myelofibrosis (MF) in up to 10% of patients every 10 years. 10–12 PV is an uncommon but not so rare condition: its annual incidence is approximately 2.8 per 100,000 population of men and approximately 1.3 per 100,000 population of women. The prevalence of PV is approximately 22 cases per 100,000 people. 3 The median age at presentation is in the sixth decade but one third of patients with PV are under 50 years of age. 13 Despite advances in the treatment of PV, the symptom burden is often underestimated by physicians and is poorly managed, resulting in impaired QoL, 14 restricted participation in social events and physical activity. 6 Most therapies in PV appropriately aim to reduce thrombotic risk, which is the first cause of mortality and morbidity in the short term, but do not address PV symptoms. Recently, the Janus kinase (JAK) inhibitor ruxolitinib was approved for patients with PV who are intolerant to or resistant of HU, the most widely used first-line therapy for high-risk patients with PV. However, ruxolitinib is not commonly used in clinical practice 15 and there is a need to identify patients who will derive the most benefit from this therapy and to define inadequately controlled PV. This article aims to examine what constitutes inadequate control in PV and explores current treatment strategies. Current strategies for the management of polycythaemia vera The primary aim of present PV therapy is not to eliminate disease, but to reduce the incidence of thrombotic events while minimising the risk of haematological transformation to AML or MF. 16 Patients with PV are therefore treated according to their risk for thrombosis: patients aged <60 years and with no history of thrombosis are considered low risk while those age >60 years and/ or with history of thrombosis are high risk (see Table 1). 17–19 Some centres will also treat according TOU CH MED ICA L MEDIA 81