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British Journal of Haematology Jan 2019
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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 -
Leukemia Sep 2021Interferon-alpha (rIFNα) is the only disease-modifying treatment for polycythemia vera (PV), but whether or not it prolongs survival is unknown. This large single... (Clinical Trial)
Clinical Trial
Interferon-alpha (rIFNα) is the only disease-modifying treatment for polycythemia vera (PV), but whether or not it prolongs survival is unknown. This large single center retrospective study of 470 PV patients compares the myelofibrosis-free survival (MFS) and overall survival (OS) with rIFNα to two other primary treatments, hydroxyurea (HU) and phlebotomy-only (PHL-O). The median age at diagnosis was 54 years (range 20-94) and the median follow-up was 10 years (range 0-45). Two hundred and twenty-nine patients were women (49%) and 208 were high-risk (44%). The primary treatment was rIFNα in 93 (20%), HU in 189 (40%), PHL-O in 133 (28%) and other cytoreductive drugs in 55 (12%). The treatment groups differed by ELN risk score (p < 0.001). In low-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 84%, 65% and 55% respectively (p < 0.001) and 20-year OS was 100%, 85% and 80% respectively (p = 0.44). In high-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 89%, 41% and 36% respectively (p = 0.19) and 20-year OS was 66%, 40%, 14% respectively (p = 0.016). In multivariable analysis, longer time on rIFNα was associated with a lower risk of myelofibrosis (HR: 0.91, p < 0.001) and lower mortality (HR: 0.94, p = 0.012). In conclusion, this study supports treatment of PV with rIFNα to prevent myelofibrosis and potentially prolong survival.
Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Female; Follow-Up Studies; Humans; Interferon-alpha; Male; Middle Aged; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Retrospective Studies; Survival Rate; Young Adult
PubMed: 33654206
DOI: 10.1038/s41375-021-01183-8 -
Leukemia Oct 2018Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease.... (Review)
Review
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm. Virtually all PV patients are iron deficient at presentation and/or during the course of their disease. The co-existence of iron deficiency and polycythemia presents a physiological disconnect. Hepcidin, the master regulator of iron metabolism, is regulated by circulating iron levels, erythroblast secretion of erythroferrone, and inflammation. Both decreased circulating iron and increased erythroferrone levels, which occur as a consequence of erythroid hyperplasia in PV, are anticipated to suppress hepcidin and enable recovery from iron deficiency. Inflammation which accompanies PV is likely to counteract hepcidin suppression, but the relatively low serum ferritin levels observed suggest that inflammation is not a major contributor to the dysregulated iron metabolism. Furthermore, potential defects in iron absorption, aberrant hypoxia sensing and signaling, and frequency of bleeding to account for iron deficiency in PV patients have not been fully elucidated. Insufficiently suppressed hepcidin given the degree of iron deficiency in PV patients strongly suggests that disordered iron metabolism is an important component of the pathobiology of PV. Normalization of hematocrit levels using therapeutic phlebotomy is the most common approach for reducing the incidence of thrombotic complications, a therapy which exacerbates iron deficiency, contributing to a variety of non-hematological symptoms. The use of cytoreductive therapy in high-risk PV patients frequently works more effectively to reverse PV-associated symptoms in iron-deficient relative to iron-replete patients. Lastly, differences in iron-related parameters between PV patients and mice with JAK2 V617F and JAK2 exon 12 mutations suggest that specific regions in JAK2 may influence iron metabolism by nuanced changes of erythropoietin receptor signaling. In this review, we comprehensively discuss the clinical consequences of iron deficiency in PV, provide a framework for understanding the potential dysregulation of iron metabolism, and present a rationale for additional therapeutic options for iron-deficient PV patients.
Topics: Anemia, Iron-Deficiency; Animals; Humans; Iron; Myeloproliferative Disorders; Polycythemia Vera; Signal Transduction; Thrombosis
PubMed: 30042411
DOI: 10.1038/s41375-018-0207-9 -
Oncology 2017Patients with polycythemia vera (PV) experience shortened survival, increased risk of thromboembolic and hemorrhagic events, and burdensome symptoms. For all patients... (Review)
Review
Patients with polycythemia vera (PV) experience shortened survival, increased risk of thromboembolic and hemorrhagic events, and burdensome symptoms. For all patients with PV, treatment with aspirin and hematocrit control with phlebotomy are recommended. In addition, patients with high-risk status or poor hematocrit control benefit from cytoreductive therapy with hydroxyurea, although approximately 1 in 4 patients develops resistance or intolerance. For patients who are resistant to or intolerant of hydroxyurea, studies have shown that ruxolitinib, a Janus kinase 1/2 inhibitor, provides hematocrit control, reduces spleen size, normalizes blood counts, and improves PV-related symptoms. For many patients, PV is managed in a community health setting, and it is important that community hematologists, oncologists, and internists are familiar with the contemporary management of PV to improve patient outcomes, including management for patients who present with unique health-care needs. This review provides an overview of current treatment options for patients with PV and discusses challenging circumstances encountered by community providers in the management of PV, including symptom assessment, identification of hydroxyurea resistance/intolerance, pregnancy, elective surgeries, concomitant immunosuppressants, and managing patients in areas with limited access to specialized hematologic care.
Topics: Community Health Centers; Drug Resistance, Neoplasm; Elective Surgical Procedures; Female; Hematocrit; Humans; Hydroxyurea; Immunosuppressive Agents; Interferon-alpha; Nitriles; Polycythemia Vera; Polyethylene Glycols; Pregnancy; Pyrazoles; Pyrimidines; Recombinant Proteins
PubMed: 28095380
DOI: 10.1159/000454953 -
Annals of Hematology Jun 2015Patients with polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic... (Review)
Review
Patients with polycythemia vera (PV), a myeloproliferative neoplasm characterized by an elevated red blood cell mass, are at high risk of vascular and thrombotic complications and have reduced quality of life due to a substantial symptom burden that includes pruritus, fatigue, constitutional symptoms, microvascular disturbances, and bleeding. Conventional therapeutic options aim at reducing vascular and thrombotic risk, with low-dose aspirin and phlebotomy as first-line recommendations for patients at low risk of thrombotic events and cytoreductive therapy (usually hydroxyurea or interferon alpha) recommended for high-risk patients. However, long-term effective and well-tolerated treatments are still lacking. The discovery of mutations in Janus kinase 2 (JAK2) as the underlying molecular basis of PV has led to the development of several targeted therapies, including JAK inhibitors, and results from the first phase 3 clinical trial with a JAK inhibitor in PV are now available. Here, we review the current treatment landscape in PV, as well as therapies currently in development.
Topics: Animals; Aspirin; Forecasting; Humans; Interferon-alpha; Janus Kinase 2; Phlebotomy; Polycythemia Vera; Treatment Outcome
PubMed: 25832853
DOI: 10.1007/s00277-015-2357-4 -
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 Medicine & Research Mar 2020World Health Organization (WHO) 2017 diagnostic criteria for hemoglobin levels in polycythemia vera (PV) were lowered from 185 g/L to 165 g/L for men and from 165 g/L to... (Clinical Trial)
Clinical Trial
BACKGROUND
World Health Organization (WHO) 2017 diagnostic criteria for hemoglobin levels in polycythemia vera (PV) were lowered from 185 g/L to 165 g/L for men and from 165 g/L to 160 g/L for women, but these cutoffs were not designed for screening.
OBJECTIVES
The primary aim of this study was to assess the value of laboratory and clinical parameters in deciding whether to further pursue a diagnosis of PV. A secondary aim was to explore the diagnostic utility of bone marrow morphology.
METHODS
We evaluated clinical and laboratory parameters that may be useful when considering further diagnostic work-up, emphasizing PV vs. secondary erythrocytosis (SE). We classified 200 patients with JAK2 V617F testing using WHO criteria.
RESULTS
Patients with myeloproliferative neoplasms (MPN) were rarely under age 40 and uncommonly obese (BMI ≥ 30 kg/m). Current smoking history favored SE, and these patients rarely had a platelet count ≥ 450 × 10/uL. Laboratory parameters suggesting greater PV likelihood were: RBC > 6.8 × 10 for men or > 5.9 × 10 for women; low erythropoietin; and low MCV or low ferritin. Bone marrow morphology (available in 111 cases) was generally more cellular in PV vs. SE and assessed disease progression.
CONCLUSIONS
Readily accessible clinical and laboratory data can assist in considering a PV workup, and a possible diagnostic algorithm is presented. These preliminary findings warrant larger studies to develop a more formal PV-risk scoring system with optimal cutoffs and weighting.
Topics: Adolescent; Adult; Aged; Amino Acid Substitution; Female; Hemoglobins; Humans; Janus Kinase 2; Male; Middle Aged; Mutation, Missense; Platelet Count; Polycythemia Vera
PubMed: 31582417
DOI: 10.3121/cmr.2019.1483 -
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 -
American Journal of Hematology Jul 2017Monocytosis (absolute monocyte count, AMC ≥ 1 × 10 /L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the...
Monocytosis (absolute monocyte count, AMC ≥ 1 × 10 /L) might accompany a spectrum of myeloid neoplasms, other than chronic myelomonocytic leukemia (CMML). In the current study, we examined the prevalence, laboratory and molecular correlates, and prognostic relevance of monocytosis in polycythemia vera (PV). Among 267 consecutive patients with World Health Organization (WHO)-defined PV, 55 (21%) patients displayed an AMC of ≥1 × 10 /L and 18 (7%) an AMC of ≥1.5 × 10 /L. In general, PV patients with monocytosis were significantly older and displayed higher frequencies of leukocytosis (81% vs. 50% at AMC ≥1 × 10 /L) and TET2/SRSF2 mutations (57%/29% vs. 19%/1% at AMC ≥ 1.5 × 10 /L). In univariate analysis, AMC ≥1.5 × 10 /L adversely affected overall (OS; P = .004; HR 2.6, 95% CI 1.4-4.8) and myelofibrosis-free (MFFS; P = .02; HR 4.4, 95% CI 1.3-15.1) survival; during multivariable analysis, significance was borderline sustained for OS (P = .05) and MFFS (P = .06). Other independent risk factors for OS included unfavorable karyotype (P = .02, HR 3.39, 95% CI 1.17-9.79), older age (P < .0001, HR 3.34 95% CI 1.97-5.65), and leukocytosis ≥15 × 10 /L (P = .004, HR 2.04, 95% CI 1.26-3.29). In conclusion, in the current study, we encountered a higher than expected prevalence of monocytosis in patients with PV and the mutation profile and age distribution of PV patients with monocytosis is akin to those of patients with CMML and might partly contribute to their worse prognosis.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; DNA Mutational Analysis; Female; Humans; Kaplan-Meier Estimate; Karyotyping; Leukocyte Count; Leukocytosis; Male; Middle Aged; Monocytes; Mutation; Phenotype; Polycythemia Vera; Prognosis; Young Adult
PubMed: 28370365
DOI: 10.1002/ajh.24740