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American Journal of Hematology Sep 2023Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis; other features include leukocytosis, thrombocytosis,... (Review)
Review
DISEASE OVERVIEW
Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis; other features include leukocytosis, thrombocytosis, splenomegaly, pruritus, constitutional symptoms, microcirculatory disturbances, and increased risk of thrombosis and progression into myelofibrosis (post-PV MF) or acute myeloid leukemia (AML).
DIAGNOSIS
A working diagnosis is considered in the presence of a JAK2 mutation associated with hemoglobin/hematocrit levels of >16.5 g/dL/49% in men or 16 g/dL/48% in women; morphologic confirmation by bone marrow examination is advised but not mandated.
CYTOGENETICS
Abnormal karyotype is seen in 15%-20% of patients with the most frequent sole abnormalities being +9 (5%), loss of chromosome Y (4%), +8 (3%), and 20q- (3%).
MUTATIONS
Over 50% of patients harbor DNA sequence variants/mutations other than JAK2, with the most frequent being TET2 (18%) and ASXL1 (15%). Prognostically adverse mutations include SRSF2, IDH2, RUNX1, and U2AF1, with a combined incidence of 5%-10%.
SURVIVAL AND PROGNOSIS
Median survival is ⁓15 years but exceeds 35 years for patients aged ≤40 years. Risk factors for survival include older age, leukocytosis, abnormal karyotype, and the presence of adverse mutations. Twenty-year risk for thrombosis, post-PV MF, or AML are ⁓26%, 16% and 4%, respectively.
RISK FACTORS FOR THROMBOSIS
Two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). Additional predictors for arterial thrombosis include cardiovascular risk factors and for venous thrombosis higher absolute neutrophil count and JAK2V617F allele burden.
TREATMENT
Current goal of therapy is to prevent thrombosis. Periodic phlebotomy, with a hematocrit target of <45%, combined with once- or twice-daily aspirin (81 mg) therapy, absent contraindications, is the backbone of treatment in all patients, regardless of risk category. Cytoreductive therapy is reserved for high-risk disease with first-line drugs of choice being hydroxyurea and pegylated interferon-α and second-line busulfan and ruxolitinib. In addition, systemic anticoagulation is advised in patients with venous thrombosis history.
ADDITIONAL TREATMENT CONSIDERATIONS
At the present time, we do not consider a drug-induced reduction in JAK2V617F allele burden, which is often incomplete and seen not only with peg-IFN but also with ruxolitinib and busulfan, as an indicator of disease-modifying activity, unless accompanied by cytogenetic and independently-verified morphologic remission. Accordingly, we do not use the specific parameter to influence treatment choices. The current review also includes specific treatment strategies in the context of pregnancy, splanchnic vein thrombosis, pruritus, perioperative care, and post-PV MF.
Topics: Male; Humans; Female; Polycythemia Vera; Busulfan; Thrombocythemia, Essential; Leukocytosis; Microcirculation; Thrombosis; Leukemia, Myeloid, Acute; Janus Kinase 2
PubMed: 37357958
DOI: 10.1002/ajh.27002 -
Leukemia Dec 2021Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be... (Review)
Review
Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or leukemic events, with respective 20-year rates of 26%, 16%, and 4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk, and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication, and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.
Topics: History, 19th Century; History, 20th Century; History, 21st Century; Humans; Polycythemia Vera
PubMed: 34480106
DOI: 10.1038/s41375-021-01401-3 -
American Family Physician Jun 2021Polycythemia vera is one of three stem-cell-derived myeloid malignancies commonly known as myeloproliferative neoplasms. It is characterized by erythrocytosis, often... (Review)
Review
Polycythemia vera is one of three stem-cell-derived myeloid malignancies commonly known as myeloproliferative neoplasms. It is characterized by erythrocytosis, often with associated leukocytosis and thrombocytosis. It has a significant negative impact on overall mortality and morbidity in the form of arterial and venous clots, symptoms of fatigue and pruritus, and conversion to leukemia and myelofibrosis. The World Health Organization's major diagnostic criteria include an elevated hemoglobin or hematocrit level, abnormal results on bone marrow biopsy, and presence of the Janus kinase 2 genetic mutation, which is present in approximately 98% of cases. The only minor criterion is a subnormal erythropoietin level, which helps differentiate polycythemia vera from common causes of secondary erythrocytosis such as smoking, sleep apnea, and testosterone use. First-line treatments, such as low-dose aspirin and goal-directed phlebotomy to a hematocrit level of less than 45% to reduce thrombotic events, improve quality of life and prolong survival. When indicated, cytoreductive therapy, primarily with hydroxyurea, can be added with consideration of second-line agents such as pegylated interferon-alfa, busulfan, and ruxolitinib, depending on the clinical scenario. Smoking cessation and cardiometabolic disease are modifiable risk factors that should be addressed to reduce the risk of thrombosis. Currently, no medications have been shown to cure the disease or to reduce the risk of conversion to leukemia and myelofibrosis.
Topics: Antineoplastic Agents; Fibrinolytic Agents; Genetic Markers; Humans; Hydroxyurea; Janus Kinase 2; Mutation; Phlebotomy; Polycythemia Vera
PubMed: 34060791
DOI: No ID Found -
Blood Reviews Jul 2020Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms characterized by increased rate of cardiovascular events, a varying burden of... (Review)
Review
Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms characterized by increased rate of cardiovascular events, a varying burden of symptoms, and an intrinsic risk of evolution to secondary forms of myelofibrosis and acute leukemia; however, survival is only modestly reduced in most instances. In the last few years, following the description of driver mutations in JAK2, MPL and CALR, the diagnostic criteria for PV and ET were revised, making the identification of very early stages feasible. Scores for identifying patients at different risk of thrombosis were refined, and they largely guide therapeutic decisions. Treatment is therefore mainly focused on reduction of thrombosis risk, control of myeloproliferation, improvement of symptomatic burden, and management of disease-associated complications. New drugs recently entered the clinical arena, with the promise to improve overall patients' management. However, evidence of a disease-modifying potential is largely missing and represents a still unmet clinical need.
Topics: Animals; Disease Management; Humans; Polycythemia Vera; Thrombocythemia, Essential; Thrombosis
PubMed: 32546373
DOI: 10.1016/j.blre.2020.100714 -
Journal of Clinical Oncology : Official... Jul 2023Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms.
PATIENTS AND METHODS
MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response.
RESULTS
One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; = .03). Serial analysis of V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] = .001, EFS = .001, overall survival = .01) and clearance of V617F stem/progenitor cells. 1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; = .003). The safety profile of ruxolitinib was as previously reported.
CONCLUSION
The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
Topics: Humans; Polycythemia Vera; Treatment Outcome; Hydroxyurea; Nitriles; Hemorrhage
PubMed: 37126762
DOI: 10.1200/JCO.22.01935 -
The Lancet. Haematology Apr 2022Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several... (Review)
Review
Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several randomised trials for the treatment of this disorder are now available, and both a new ropegylated formulation of interferon alfa-2b (ropeginterferon alfa-2b; 2018) and ruxolitinib (2015) have been approved in Europe. European LeukemiaNet (ELN) investigators have therefore deemed it appropriate to provide recommendations for the use of these drugs in clinical practice. An expert panel of 14 senior haematologists from ELN centres that had actively participated in previous ELN projects or relevant randomised trials, chaired by a member of the ELN Steering Committee, developed a list of clinical questions, and a methodologist established three patient, intervention, comparator, outcome (PICO) questions and systematically reviewed the evidence. Recommendations were approved by six Delphi consensus rounds and two virtual meetings (on Jan 26, 2021, and June 24, 2021). The expert panel recommended that patients with polycythaemia vera who are younger than 60 years and have not had previous thrombotic events should start cytoreductive drug therapy if at least one of the following criteria are fulfilled: strictly defined intolerance to phlebotomy, symptomatic progressive splenomegaly, persistent leukocytosis (>15 × 10 white blood cells per L), progressive leukocytosis (at least 100% increase if baseline count is <10 × 10 cells per L or at least 50% increase if baseline count is >10 × 10 cells per L), extreme thrombocytosis (>1500 × 10 platelets per L), inadequate haematocrit control requiring phlebotomies, persistently high cardiovascular risk, and persistently high symptom burden. Recombinant interferon alfa, either in the form of ropeginterferon alfa-2b or pegylated interferon alfa-2a, is the recommended cytoreductive treatment for these patients. The expert panel suggested that either interferon alfa or ruxolitinib should be considered for patients who are being treated with hydroxyurea but require a therapy change.
Topics: Cytoreduction Surgical Procedures; Humans; Hydroxyurea; Polycythemia Vera; Quality of Life; Splenomegaly
PubMed: 35358444
DOI: 10.1016/S2352-3026(22)00046-1 -
Blood Jul 2019Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a... (Review)
Review
Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a clonal hematopoietic stem cell (HSC) disorder, PV is a neoplasm but its driver mutations result in overproduction of morphologically and functionally normal blood cells. PV arises in an HSC but it can present initially as isolated erythrocytosis, leukocytosis, thrombocytosis, or any combination of these together with splenomegaly or myelofibrosis, and it can take years for a true panmyelopathy to appear. PV shares the same mutation as essential thrombocytosis and primary myelofibrosis, but erythrocytosis only occurs in PV. However, unlike secondary causes of erythrocytosis, in PV, the plasma volume is frequently expanded, masking the erythrocytosis and making diagnosis difficult if this essential fact is ignored. PV is not a monolithic disorder: female patients deregulate fewer genes and clinically behave differently than their male counterparts, while some PV patients are genetically predisposed to an aggressive clinical course. Nevertheless, based on what we have learned over the past century, most PV patients can lead long and productive lives. In this review, using clinical examples, I describe how I diagnose and manage PV in an evidence-based manner without relying on chemotherapy.
Topics: Adult; Aged, 80 and over; Biomarkers; Combined Modality Therapy; Disease Management; Disease Susceptibility; Evidence-Based Medicine; Female; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Polycythemia Vera; Treatment Outcome
PubMed: 31151982
DOI: 10.1182/blood.2018834044 -
The Lancet. Haematology Mar 2020The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients... (Comparative Study)
Comparative Study Randomized Controlled Trial
Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study.
BACKGROUND
The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment.
METHODS
PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 μg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing).
FINDINGS
Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3-201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4-169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia).
INTERPRETATION
In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea.
FUNDING
AOP Orphan Pharmaceuticals AG.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Equivalence Trials as Topic; Female; Follow-Up Studies; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Polycythemia Vera; Polyethylene Glycols; Prognosis; Recombinant Proteins
PubMed: 32014125
DOI: 10.1016/S2352-3026(19)30236-4 -
British Journal of Haematology Jan 2019
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Current Treatment Options in Oncology Mar 2018Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the ultimate phenotype of the JAK2 V1617F mutation, the MPN with the highest incidence of... (Review)
Review
Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the ultimate phenotype of the JAK2 V1617F mutation, the MPN with the highest incidence of thromboembolic complications, which usually occur early in the course of the disease, and the only MPN in which erythrocytosis occurs. The classical presentation of PV is characterized by erythrocytosis, leukocytosis, and thrombocytosis, often with splenomegaly and occasionally with myelofibrosis, but it can also present as isolated erythrocytosis with or without splenomegaly, isolated thrombocytosis or isolated leukocytosis, or any combination of these. When PV is present, the peripheral blood hematocrit (or hemoglobin) determination will not accurately represent the actual volume of red cells in the body, because in PV, in contrast to other disorders causing erythrocytosis, when the red cell mass increases, the plasma volume usually increases. In fact, unless the hematocrit is greater than 59%, true erythrocytosis cannot be distinguished from pseudoerythrocytosis due to plasma volume contraction. Usually, the presence of splenomegaly or leukocytosis or thrombocytosis establishes the diagnosis. However, when a patient presents with isolated thrombocytosis and a positive JAK2 V617F assay, particularly a young woman, the possibility of PV must always be considered because of plasma volume expansion. The WHO PV diagnostic guidelines are not helpful in this situation, since the hematocrit is invariably normal and a bone marrow examination will not distinguish ET from PV. Only a direct measurement of both the red cell mass and plasma volume can establish the correct diagnosis. In managing a PV patient, it is important to remember that PV is an indolent disorder in which life span is usually measured in decades, even when myelofibrosis is present, that chemotherapy is futile in eradicating the disease but does increase the incidence of acute leukemia and that hydroxyurea is not safe in this regard nor is it antithrombotic. Phlebotomy to a sex-specific normal hematocrit is the cornerstone of therapy and there now exist safe remedies for controlling leukocytosis, thrombocytosis, and extramedullary hematopoiesis and symptoms due to inflammatory cytokines when this is necessary.
Topics: Hematocrit; Humans; Janus Kinase 2; Leukocytosis; Polycythemia; Polycythemia Vera; Splenomegaly; Thrombocytosis; Thromboembolism
PubMed: 29516275
DOI: 10.1007/s11864-018-0529-x