-
Blood Nov 2023Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with...
Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease.
Topics: Humans; Polycythemia Vera; Primary Myelofibrosis; Thrombocytosis; Hydroxyurea; Thrombosis; Interferon-alpha; Leukemia, Myeloid, Acute; Janus Kinase 2
PubMed: 37729609
DOI: 10.1182/blood.2023021503 -
Annals of Hematology May 2022Thrombotic events are a distinctive feature of the myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and essential thrombocythemia (ET). Patients with these... (Review)
Review
Thrombotic events are a distinctive feature of the myeloproliferative neoplasms (MPNs) polycythemia vera (PV) and essential thrombocythemia (ET). Patients with these MPNs may also experience a poor quality of life secondary to symptom burden, as well as progression of disease to acute leukemia or myelofibrosis. Over the years, various risk stratification methods have evolved in order to attempt to predict thrombotic risk, which is the largest contributor of morbidity and mortality in these patients. More than half of PV and ET patients are low- or intermediate-risk disease status at the time of diagnosis. While therapeutic development is presently focused on high-risk patients, there is a paucity of therapies, outside of aspirin and therapeutic phlebotomy, which can reduce the thrombotic risk or delay disease progression in low-risk patients. In this review, we first describe the various complications that patients with PV and ET experience, and then detail our evolving understanding of risk stratification in these diseases. We then highlight the available evidence on the management of low-risk PV and ET and include a description of novel therapies currently under investigation in this space. We conclude with recommendations for future directions to advance our understanding and improve the treatment of low-risk PV and ET.
Topics: Aspirin; Humans; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Quality of Life; Thrombocythemia, Essential; Thrombosis
PubMed: 35344066
DOI: 10.1007/s00277-022-04826-7 -
International Journal of Laboratory... Jun 2023Myeloproliferative neoplasms (MPN) are a group of clonal haematological malignancies first described by Dameshek in 1957. The Philadelphia-negative MPN that will be... (Review)
Review
Myeloproliferative neoplasms (MPN) are a group of clonal haematological malignancies first described by Dameshek in 1957. The Philadelphia-negative MPN that will be described are polycythaemia vera (PV), essential thrombocythaemia (ET), pre-fibrotic myelofibrosis and primary myelofibrosis (PMF). The blood and bone marrow morphology are essential in diagnosis, for WHO classification, establishing a baseline, monitoring response to treatment and identifying changes that may indicate disease progression. The blood film changes may be in any of the cellular elements. The key bone marrow features are architecture and cellularity, relative complement of individual cell types, reticulin content and bony structure. Megakaryocytes are the most abnormal cell and key to classification, as their number, location, size and cytology are all disease-defining. Reticulin content and grade are integral to assignment of the diagnosis of myelofibrosis. Even with careful assessment of all these features, not all cases fit neatly into the diagnostic entities; there is frequent overlap reflecting the biological disease continuum rather than distinct entities. Notwithstanding this, an accurate morphologic diagnosis in MPN is crucial due to the significant differences in prognosis between different subtypes and the availability of different therapies in the era of novel agents. The distinction between "reactive" and MPN is also not always straightforward and caution needs to be exercised given the prevalence of "triple negative" MPN. Here we describe the morphology of MPN including comments on changes with disease evolution and with treatment.
Topics: Humans; Primary Myelofibrosis; Reticulin; Myeloproliferative Disorders; Bone Marrow; Polycythemia Vera
PubMed: 37211431
DOI: 10.1111/ijlh.14086 -
Blood Cancer Journal Jan 2018Recently reported mature survival data have confirmed the favorable prognosis in polycythemia vera (PV), with an estimated median survival of 24 years, in patients... (Review)
Review
Recently reported mature survival data have confirmed the favorable prognosis in polycythemia vera (PV), with an estimated median survival of 24 years, in patients younger than age 60 years old. Currently available drugs for PV have not been shown to prolong survival or alter the natural history of the disease and are instead indicated primarily for prevention of thrombosis. Unfortunately, study endpoints that are being utilized in currently ongoing clinical trials in PV do not necessarily target clinically or biologically relevant outcomes, such as thrombosis, survival, or morphologic remission, and are instead focused on components of disease palliation. Even more discouraging has been the lack of critical appraisal from "opinion leaders", on the added value of newly approved drugs. Keeping these issues in mind, at present, we continue to advocate conservative management in low-risk PV (phlebotomy combined with once- or twice-daily aspirin therapy) and include cytoreductive therapy in "high-risk" patients; in the latter regard, our first, second, and third line drugs of choice are hydroxyurea, pegylated interferon-α and busulfan, respectively. In addition, it is reasonable to consider JAK2 inhibitor therapy, in the presence of protracted pruritus or markedly enlarged splenomegaly shown to be refractory to the aforementioned drugs.
Topics: Aged; Aged, 80 and over; Algorithms; Female; Humans; Male; Middle Aged; Polycythemia Vera
PubMed: 29321547
DOI: 10.1038/s41408-017-0042-7 -
Clinical Lymphoma, Myeloma & Leukemia Aug 2016Polycythemia vera and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms associated with thrombotic or hemorrhagic complications, and increased risk... (Review)
Review
Polycythemia vera and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms associated with thrombotic or hemorrhagic complications, and increased risk of transformation to myelofibrosis and acute myeloid leukemia. The main goal of therapy is aimed at preventing vascular events that are the leading cause of morbidity and mortality in these patients. Accordingly, risk stratification is the basis for deciding when to treat a patient with cytoreductive therapy. The European LeukemiaNet has developed a series of management recommendations for front-line and second-line therapy to provide the optimal treatment for the individual patient. There is still controversy about the efficacy and safety of several modalities of cytoreductive treatment in the long-term for both diseases and in the use of antiplatelet therapy in ET. The presence of JAK2V617F and CALR mutations in patients with ET has been related to different thrombotic risks, and this will probably lead to different therapeutic approaches in the near future. On the other hand, the near normal life expectancy of these patients makes a careful analysis of the benefits and risks associated with treatment essential. This review provides our current management strategy of patients with polycythemia vera and ET.
Topics: Antineoplastic Agents; Cell Transformation, Neoplastic; Clinical Decision-Making; Combined Modality Therapy; Disease Management; Disease Progression; Drug Resistance; Humans; Platelet Aggregation Inhibitors; Polycythemia Vera; Protein Kinase Inhibitors; Risk Assessment; Risk Factors; Thrombocythemia, Essential; Thrombosis
PubMed: 27521307
DOI: 10.1016/j.clml.2016.02.029 -
Turkish Journal of Medical Sciences Aug 2018Very important developments related to polycythemia vera (PV) have occurred during the last two decades. The discovery of Janus kinase (JAK) 2 mutations has changed both... (Review)
Review
Very important developments related to polycythemia vera (PV) have occurred during the last two decades. The discovery of Janus kinase (JAK) 2 mutations has changed both the diagnosis and clinical management of PV. Currently JAK2 molecular testing is essential in the diagnostic work-up and JAK2 mutation positivity is a major diagnostic criterion. The discovery of JAK2 mutations suggested that abnormal JAK-STAT signaling was a pivotal feature in the pathogenesis of Philadelphia-negative myeloproliferative neoplasms. This idea led to the development of JAK inhibitors. Currently ruxolitinib, a JAK1/JAK2 inhibitor, is also approved for PV patients with hydroxyurea resistance or intolerance. International collaborations have made it possible to describe disease characteristics and evolution better. Presently it is possible to quantify the symptomatic burden of the disease and to estimate prognosis. In spite of these developments, management of PV still largely depends on estimation of thromboembolic risk and trying to decrease the risk with or without cytoreductive medications. Different approaches have been proposed by international disease experts for the diagnosis, thromboembolic risk estimation, and drug selection. This paper aims to review clinical aspects of PV and propose a management algorithm. The authors also point to still unresolved questions and unmet needs in diagnosis and management.
Topics: Disease Management; Disease Progression; Humans; Janus Kinase 2; Mutation; Polycythemia Vera; Prognosis
PubMed: 30114348
DOI: 10.3906/sag-1806-43 -
Current Opinion in Hematology Mar 2016Management of polycythemia vera and essential thrombocythemia requires understanding of the key concepts regarding diagnosis, risk stratification, and management. (Review)
Review
PURPOSE OF REVIEW
Management of polycythemia vera and essential thrombocythemia requires understanding of the key concepts regarding diagnosis, risk stratification, and management.
RECENT FINDINGS
Essential thrombocythemia and polycythemia vera are among the Philadelphia chromosome negative myeloproliferative neoplasms. They are characterized by overproduction of blood cells and their complications include thrombosis, hemorrhage, and progression to myelofibrosis or acute myeloid leukemia (AML). Management of essential thrombocythemia/polycythemia vera requires recognition of the risk factors for thrombosis and hemorrhage. Risk stratification allows the clinician to make a treatment plan that may include antiplatelet therapy with aspirin alone or in combination with therapeutic phlebotomy in the case of polycythemia vera, or cytoreductive therapy for high-risk patients with either essential thrombocythemia or polycythemia vera. Hydroxyurea remains first-line therapy for high-risk patients with essential thrombocythemia/polycythemia vera, whereas second-line options include anagrelide, pegylated-IFNα-2a, and the JAK1/2 inhibitor ruxolitinib. The current evaluation of pegylated-IFNα-2a in global phase II and III studies will provide clarity to the potential long-term benefit and risks associated with this biologic in patients with essential thrombocythemia/polycythemia vera. Novel therapeutics aimed at prevention of disease progression to myelofibrosis/AML are the focus of current clinical trials.
SUMMARY
Risk stratification of patients with essential thrombocythemia/polycythemia vera by age and/or history of thrombosis provides the basis of risk adapted therapeutic intervention. Aggressive control of modifiable cardiovascular risk factors, the use of antiplatelet agents, control of the hematocrit less than 45% in polycythemia vera, and cytoreductive therapy in high-risk essential thrombocythemia/polycythemia vera patients is the focus of management. The exact role of IFN-α remains undefined and under active investigation, and the recent approval of ruxolitinib provides patients with polycythemia vera a second-line option.
Topics: Combined Modality Therapy; Disease Management; Disease Progression; Humans; Polycythemia Vera; Risk; Thrombocythemia, Essential; Treatment Outcome
PubMed: 26717193
DOI: 10.1097/MOH.0000000000000216 -
Expert Review of Hematology Oct 2020Polycythemia vera is a myeloproliferative neoplasm characterized by an increased red blood cell mass, risk of thromboembolic events, and of transformation into secondary... (Review)
Review
INTRODUCTION
Polycythemia vera is a myeloproliferative neoplasm characterized by an increased red blood cell mass, risk of thromboembolic events, and of transformation into secondary myelofibrosis and acute leukemia. The goal of treatment is to reduce the risk of fatal cardiovascular events reducing the hematocrit level with phlebotomies and low-dose aspirin. In high-risk patients (age >60 years or previous thromboembolic events) cytoreductive therapy is indicated. In this setting, resistance and/or intolerance is common.
AREAS COVERED
Authors searched Medline, Embase, archives from the EHA and the ASH annual congresses from 2014 onward about ruxolitinib treatment in PV patients. Two trials (RESPONSE and RESPONSE2) have documented the efficacy and safety of ruxolitinib. The drug is able to persistently control the hematocrit level and symptoms (due to increased cytokine levels, increased viscosity, and increased splenomegaly), to reduce WBC counts and the rate of thromboembolic events, to increase the quality of life.
EXPERT OPINION
Although ruxolitinib has entered into the clinical practice, the real-life incidence of resistant/intolerant patients, the long-term safety, and the activity on thromboembolic events (associated or not to a reduction of the molecular burden) remains to be conclusively determined. More information extrapolated by registries are required to shed light on the missing information.
Topics: Clinical Trials as Topic; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Humans; Janus Kinase 2; Janus Kinase Inhibitors; Molecular Targeted Therapy; Mutation; Nitriles; Polycythemia Vera; Prognosis; Pyrazoles; Pyrimidines; Treatment Outcome
PubMed: 32873088
DOI: 10.1080/17474086.2020.1816819 -
Expert Opinion on Therapeutic Targets Jul 2020Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN). PV is characterized by erythrocytosis, leukocytosis, thrombocytosis, increased hematocrit,... (Review)
Review
INTRODUCTION
Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN). PV is characterized by erythrocytosis, leukocytosis, thrombocytosis, increased hematocrit, and hemoglobin in the peripheral blood. Splenomegaly and myelofibrosis often occur in PV patients. Almost all PV patients harbor a mutation in the gene, mainly represented by the point mutation.
AREAS COVERED
This article examines the recent and available models of PV and moreover, it offers insights on emerging biomarkers and therapeutic targets. The evidence from mouse models, resembling a PV-like phenotype generated by different technical approaches, is discussed. The authors searched PubMed, books, and clinicaltrials.gov for original and review articles and drugs development status including the terms Myeloproliferative Neoplasms, Polycythemia Vera, erythrocytosis, hematocrit, splenomegaly, bone marrow fibrosis, , Hematopoietic Stem Cells, MPN cytoreductive therapy, JAK2 inhibitor, histone deacetylase inhibitor, PV-like phenotype, BMT, transgenic mouse, physiologic promoter.
EXPERT OPINION
Preclinical models of PV are valuable tools for enabling an understanding of the pathophysiology and the molecular mechanisms of the disease. These models provide new biological insights on the contribution of concomitant mutations and the efficacy of novel drugs in a 'more faithful' setting. This may facilitate an enhanced understanding of pathogenetic mechanisms and targeted therapy.
Topics: Animals; Disease Models, Animal; Drug Development; Humans; Janus Kinase 2; Mice; Molecular Targeted Therapy; Point Mutation; Polycythemia Vera; Primary Myelofibrosis; Splenomegaly
PubMed: 32366208
DOI: 10.1080/14728222.2020.1762176 -
Annals of Hematology Jan 2021In recent times, there has been a growing interest in understanding the impact of gender on disease biology and clinical outcomes in Philadelphia-negative chronic... (Review)
Review
In recent times, there has been a growing interest in understanding the impact of gender on disease biology and clinical outcomes in Philadelphia-negative chronic myeloproliferative neoplasms. Among those, polycythemia vera (PV) is characterized by increased thrombotic risk, systemic symptoms, and overall reduced survival. Here, we aim to summarize data on whether and to what extent female sex can affect PV biology and outcome. To this end, we will discuss the latest acquisitions in terms of pathogenesis, diagnosis, epidemiology, clinical presentation and symptoms burden, thrombotic risk and related treatment strategies, and prognosis in female patients affected by PV.
Topics: Female; Hemoglobins; Humans; Janus Kinase 2; Male; Polycythemia Vera; Sex Characteristics
PubMed: 33006021
DOI: 10.1007/s00277-020-04287-w