Management of polycythemia vera in the community oncology setting
Patients with the chronic myeloproliferative neoplasm polycythemia vera have shortened survival and often experience disease-related symptoms that negatively affect quality of life. Consequently, there is a demonstrable need for early diagnosis of polycythemia vera, followed by long-term, responsive, evidence-based disease management. The diagnostic and management landscape for polycythemia vera continues to improve, but gaps remain in diagnostic and treatment strategies. The diagnosis of polycythemia vera is based on World Health Organization criteria, and treatment goals for the condition include modifying the risk of cardiovascular and hemorrhagic events, reducing the risk of fibrotic and/or leukemic disease transformation, and alleviating polycythemia vera–related symptoms. The current treatment strategy for polycythemia vera is for all patients to receive aspirin and phlebotomy, with a hematocrit goal of <45%. Some patients may also benefit from cytoreductive therapy, typically with hydroxyurea. For those patients who become resistant to or intolerant of hydroxyurea, ruxolitinib is currently the only approved treatment option. This review provides community-based oncologists and other clinicians with an overview of current diagnostic and management strategies for polycythemia vera.
Accepted for publication April 28, 2017
Correspondence Michael R Grunwald, MD;
michael.grunwald@carolinashealthcare.org
Disclosures Dr Grunwald has served as a consultant, participated in advisory boards, and received research funding from Incyte Corp, the maker of ruxolitinib, a treatment option for polycythemia vera. Dr Scola has served on a speakers bureau for and is a stockholder of Incyte Corp. Dr Miller has served on advisory boards and speakers bureaus for, and received institutional research funding from, Incyte Corp and Novartis. Dr Onitilo has no conflicts to disclose. The authors received writing assistance from Complete Healthcare Communications, LLC, which was funded by Incyte Corp.
Citation JCSO 2017;15(4):e195-e203
©2017 Frontline Medical Communications
doi https://doi.org/10.12788/jcso.0349
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Polycythemia vera, classified as a myeloproliferative neoplasm (MPN) and characterized by uncontrolled, clonal, myeloid expansion with predominant erythrocytosis,1 affects about 100,000 individuals in the United States.2 It is a chronic and burdensome disease associated with shortened survival.3 Patients are at an increased risk of cardiovascular events, solid tumors, and transformation to myelofibrosis (MF) and/or acute myeloid leukemia (AML).4,5 Furthermore, patients generally have a reduced quality of life (QoL) stemming from prevalent and occasionally severe polycythemia vera–related signs and symptoms, including fatigue, pruritus, and splenomegaly.6 In general, the classical Philadelphia chromosome-negative MPNs are associated with driver mutations in the following three genes: Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL).7 Almost all patients with polycythemia vera have an activating mutation in the cytoplasmic signal transduction protein JAK2.4 Patients with essential thrombocythemia (ET) or MF can have mutations in JAK2, CALR, or MPL. However, CALR and MPL mutations are absent or exceedingly rare in patients with polycythemia vera.7 Diagnosis can be challenging and is currently based on 2016 World Health Organization (WHO) diagnostic criteria.1
Management strategies include the use of aspirin, phlebotomy, and cytoreductive therapy. Ruxolitinib is a newer treatment option available for patients with polycythemia vera who are either resistant to or intolerant of hydroxyurea8,9— a population that previously had few treatment options. It is important for community oncologists and other treating clinicians to understand current diagnostic strategy and management options based on established guidelines, recent clinical evidence, and regulatory updates.
Search and selection process for research sources
In September 2016, we searched PubMed for articles published since 2006 with polycythemia vera included in the abstract or title. The initial 1,730 publications were screened by eye to select 46 key articles that guide current management of polycythemia vera. Four studies published before 2006 were also included based on their continued relevance.
Epidemiology and pathophysiology
Based on a meta-analysis of patients from Europe and the United States, the annual incidence of polycythemia vera estimated to be between 0.7 and 2.6 per 100,000 people.10 The age-adjusted prevalence of polycythemia vera in the United States is about 45-57 per 100,000 people,2 however, the true prevalence might be considerably greater.
Patients with polycythemia vera are at increased risk of cardiovascular events, thrombosis, and death.3-5 Risk is highest among patients older than 60 years or with a history of thrombosis.11 Uncontrolled myeloproliferation has also been identified as a risk factor for cardiovascular mortality and thrombosis. This was demonstrated in the prospective Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial, which reported more cardiovascular events in patients with hematocrit levels of 45%-50%, compared with those whose hematocrit levels were <45%.12 In addition, retrospective data suggest leukocytosis is a potential risk factor for thromboembolic events and poor outcomes.13
Dysregulated JAK2 signaling is the principal driver of polycythemia vera pathophysiology. About 95% of patients with polycythemia vera will have an identifiable JAK2 V617F exon 14 mutation, with an additional 3%-5% demonstrating a JAK2 exon 12 mutation.4,14 Under physiologic conditions, JAK2 interacts with the STAT family of signal transduction proteins and serves as an important regulator of normal hematopoiesis.15 Mutated, constitutively activated JAK2 signaling promotes the various polycythemia vera disease manifestations, including excessive myeloproliferation, splenomegaly,15 and constitutional symptoms.14,16,17
Burden of disease for the individual
Mortality
Patients with polycythemia vera have an increased risk of mortality compared with an unaffected, age- and gender-matched cohort of the general population.3 A retrospective study of Medicare patients with polycythemia vera (mean age at diagnosis, 76.1 years) reported a median survival of 5.4 years, compared with 8.7 years for a matched cohort.3 A second retrospective study reported a median survival of 13.5 years (median age at diagnosis, 64 years; median follow-up time, 11.8 years).18
Leading causes of death for patients with polycythemia vera include cardiovascular and thrombotic events, the development of secondary solid tumors, and disease transformation to MF and/or AML. In the prospective European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study of 1,638 patients, 45% of deaths (74/164) resulted from cardiovascular causes (1.7 per 100 patient-years).5 Thirteen percent of deaths were related to either leukemic or myelofibrotic transformation, and 20% of deaths were attributed to secondary solid tumors.5 In a retrospective analysis of 1,545 patients with polycythemia vera followed for a median of 6.9 years after diagnosis, 347 had died, primarily from acute leukemia (10%), secondary malignancies (10%), and thrombotic events (9%).4 Arterial and venous thrombotic events occurred in 12% and 9% of patients, respectively, with disease transformation to MF and AML occurring in 9% and 3% of patients. Further support of an increased risk of secondary malignancies comes from a retrospective analysis of a large Swedish cancer registry (1958–2006) that found an increased risk of secondary endocrine, renal, and skin malignancies; MF; and leukemia among patients with polycythemia vera.19
