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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 -
Expert Opinion on Pharmacotherapy 2023Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or... (Review)
Review
INTRODUCTION
Polycythemia vera (PV) is driven by mutations in JAK2 kinase and subsequent JAK/STAT activation, presentation can range from an asymptomatic state to micro or macrovascular events. Characteristic aquagenic pruritus and fatigue can have a substantial impact on quality of life. Over time, a minority will transform into more aggressive conditions such as post-PV myelofibrosis or acute myeloid leukemia. The JAK1 and 2 inhibitor Ruxolitinib has been approved for the treatment of PV after the failure of first-line therapies. Other JAK inhibitors have not been extensively tested in PV.
AREAS COVERED
In this article, we describe how PV is diagnosed and conventional treatments before moving to cover the status of JAK inhibitors as a therapeutic option for this disease and other novel therapies following a literature review.
EXPERT OPINION
Ruxolitinib when used for PV delivers control of blood counts and reduces disease-related symptoms. Recent data have also suggested that treatment with Ruxolitinib can improve event-free survival and may be associated with disease modification. Adverse effects of Ruxolitinib such as the increased risk of infection and squamous cell skin cancers, most likely to be linked to immunosuppression and prior lines of therapies, require careful consideration.
Topics: Humans; Polycythemia Vera; Janus Kinase Inhibitors; Quality of Life; Pyrazoles; Nitriles; Janus Kinase 2
PubMed: 37343285
DOI: 10.1080/14656566.2023.2228688 -
The American Journal of the Medical... Jan 2022Polycythemia vera (PV) is a common type of Philadelphia chromosome-negative chronic myeloproliferative disorder. PV-associated kidney disease is rarely reported and...
BACKGROUND
Polycythemia vera (PV) is a common type of Philadelphia chromosome-negative chronic myeloproliferative disorder. PV-associated kidney disease is rarely reported and remains poorly understood. It has been observed that chronic kidney disease could be a risk factor for poor prognosis in PV.
METHODS
We retrospectively analyzed the clinicopathological features of renal presentations in eight patients with confirmed PV-associated kidney disease.
RESULTS
The eight patients were 6 males and 2 females, with a mean age of 46.4 ± 16.8 years. Six patients had a history of PV, with a duration range 0.5-16 years. The other two patients were newly diagnosed with PV simultaneously with glomerular disease. Seven patients conducted a JAK2 V617F mutation test, with a positive result in five. Proteinuria and renal dysfunction were the patients' main complaints, with only one having nephrotic syndrome and three having microscopic hematuria. The level of proteinuria ranged from 0.52-10.96 g/day. Three patients had advanced chronic kidney disease (CKD), two in stage 3b and one in stage 4, but only one patient had anemia. Three patients had monoclonal immunoglobulinemia, one patient with immunoglobulin (Ig) G kappa plus light chain lambda, one patient with IgG kappa, and one patient with IgG lambda. Five patients underwent a renal biopsy. The pathological diagnosis was IgA nephropathy in three, non-IgA mesangial proliferative glomerulopathy in one, and glomerular hypertrophy with ischemic renal injury in one patient. Glomerular ischemia, ischemic shrinkage, focal segmental sclerosis, and glomerulomegaly were common pathological features. Glomerular crescents and endocapillary proliferation were also observed. All patients were administered hydroxyurea, and seven were administered renin-angiotensin system inhibitors. During follow-up, one patient with uncontrolled PV developed secondary myelofibrosis and died, three patients were lost to follow-up, and four patients remained alive with CKD.
CONCLUSIONS
Patients with untreated or uncontrolled PV could have massive proteinuria and advanced CKD, pathologically showing ischemic, sclerosing glomerular lesions with hypercellurity, glomerular crescents and endocapillary proliferation. IgA nephropathy was most commonly diagnosed. These findings deserve attention because early screening and effective control of PV may benefit the long-term kidney prognosis.
Topics: Adult; Female; Glomerulonephritis, IGA; Humans; Immunoglobulin G; Kidney; Male; Middle Aged; Polycythemia Vera; Proteinuria; Renal Insufficiency, Chronic; Retrospective Studies
PubMed: 34687616
DOI: 10.1016/j.amjms.2021.10.009 -
Pneumologie (Stuttgart, Germany) May 2022Chronic myeloproliferative diseases are rare causes of PH class 5 according to Nice classification 2018. The present case reports show different courses, on the one...
INTRODUCTION
Chronic myeloproliferative diseases are rare causes of PH class 5 according to Nice classification 2018. The present case reports show different courses, on the one hand with a primary manifestation of a PH and subsequently a PV, on the other hand with the development of a PH in the context of a PV.
CASE REPORTS
1) At first contact, a 75-year-old female patient who complained progressive dyspnea and had evidence of stress-PH in the right heart catheter. During the course she developed a resting PH of up to 70 mmHg systolic despite initial monotherapy and subsequent dual therapy for PH. After 5 years she had the diagnosis of polycythemia vera, treated with hydroxycarbamide and subsequent phlebotomies. In the further course increasing cardiac decompensation and death. 2) 74-year-old female patient at the time of diagnosis of chronic megakaryocytic-granulocytic myelosis. After 7 years, evidence of polycythemia vera (V617F mutation in the JAK2 gene), a monoclonal gammopathy. In the case of splenomegaly, irradiation of the spleen was carried out and, after 1 year, therapy with ruxolitinib was started. After another 2 years, with increasing dyspnea, pulmonary hypertension (CTEPH) with a PA-mean of 43 mmHg and a PVR of 4.5 WE were detected. With anticoagulation and riociguat therapy exercise capacity and PA pressures were only temporarily improved. Within 1 year restrictive ventilation, hypoxemia, heart failure (EF 45 %) with leading right heart decompensation and cardiorenal syndrome developed. Dialysis showed only short-term recompensation, and the patient died.
DISCUSSION
The case reports are characterized by a combination of PV and PH, with different temporal sequence, as well as only a low influence of PH-specific therapy, with subsequent progressive cardiac decompensation. Thus, they reflect the different etiologies, clinical manifestations, and the low therapeutic influence of PH in myeloproliferative disorders. The value of PH-specific therapy remains unclear, especially in view of different pathomechanisms in the genesis of PH.
CONCLUSION
Patients with myeloproliferative diseases require screening for PH. In the course of PH, myeloproliferative disease can unmask or develop. The therapeutic influence on PH is limited.
Topics: Aged; Dyspnea; Female; Humans; Hypertension, Pulmonary; Mutation; Myeloproliferative Disorders; Polycythemia Vera
PubMed: 35381612
DOI: 10.1055/a-1775-6424 -
Leukemia Oct 2022Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential...
Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events.
Topics: Humans; Hydroxyurea; Janus Kinase Inhibitors; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential; Thrombosis
PubMed: 36042316
DOI: 10.1038/s41375-022-01673-3 -
Physiology International Sep 2023The classical myeloproliferative neoplasms are divided into chronic myeloid leukemia, and the Philadelphia negative polycythemia vera, essential thrombocythemia and... (Review)
Review
The classical myeloproliferative neoplasms are divided into chronic myeloid leukemia, and the Philadelphia negative polycythemia vera, essential thrombocythemia and primary myelofibrosis. These are heterogenous diseases, originating from the clonal proliferation of myeloid stem cells, resulting in increased mature cell numbers in one or more myeloid lineages. The most commonly seen mutations in the Philadelphia negative myeloproliferative neoplasms include those in Janus kinase, myeloproliferative leukemia protein and the calreticulin genes. Philadelphia negative myeloproliferative neoplasms occur infrequently, with a combined annual incidence of 2.58 per 100,000. There are many overlapping symptoms of Philadelphia negative MPNs, such as fatigue, night sweats, hepatosplenomegaly and circulatory symptoms due to increased cell numbers. Total Symptom Score of the MPN Symptom Assessment Form is used to assess symptom burden on patients. The most worrisome complications are thrombo-hemorrhagic events, and risk stratification is especially important as treatment of disease is based on their category. Phlebotomy and aspirin are the mainstay of treatment in low-risk polycythemia vera and essential thrombocythemia patients, whereas high-risk disease calls for additional cytoreduction, usually with hydroxyurea.
Topics: Humans; Polycythemia Vera; Thrombocythemia, Essential; Hydroxyurea; Aspirin; Mutation
PubMed: 37651280
DOI: 10.1556/2060.2023.00261 -
Annals of Hematology Jan 2024There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we...
There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.
Topics: Humans; Aged; Polycythemia Vera; Thrombocythemia, Essential; Primary Myelofibrosis; Prospective Studies
PubMed: 37946031
DOI: 10.1007/s00277-023-05528-4 -
Hematology/oncology Clinics of North... Apr 2021Consensus guidelines have helped to standardize the care of patients with essential thrombocythemia and polycythemia vera, focusing on reducing the risk of thrombosis,... (Review)
Review
Consensus guidelines have helped to standardize the care of patients with essential thrombocythemia and polycythemia vera, focusing on reducing the risk of thrombosis, mitigating symptoms, and avoiding therapies that may accelerate disease progression. However, many unmet needs still exist ranging from the roll of antiplatelet therapy in ET to medications that reduce disease progression. Retrospective studies suggest an improvement in myelofibrosis-free survival for treatment with interferons; new agents are looking to also enact disease modification.
Topics: Disease Progression; Humans; Polycythemia Vera; Primary Myelofibrosis; Retrospective Studies; Thrombocythemia, Essential
PubMed: 33641870
DOI: 10.1016/j.hoc.2021.01.003 -
Vnitrni Lekarstvi 2018Polycythemia vera is a chronic myeloproliferative neoplasm characterized by hematopoietic stem cell-derived clonal myeloproliferation resulting in erythrocytosis,...
Polycythemia vera is a chronic myeloproliferative neoplasm characterized by hematopoietic stem cell-derived clonal myeloproliferation resulting in erythrocytosis, leukocytosis and thrombocytosis. Survival is reduced compared with general population. Main reasons of death include thrombohemorrhagic complications, fibrotic progression and leuk-aemic transformation. Presence of Janus kinase (JAK2) gene mutations is a diagnostic marker and standard dia-gnostic criterion. World Health Organization 2016 diagnostic criteria focusing on hemoglobin levels, hematocrit, red cell mass and bone marrow morphology are mandatory. Therapeutic approach depends on stratification of patients according age and personal risk of thrombosis. Low-risk patients are treated first line with low-dose aspirin and phlebo-tomy. Cytoreduction is indicated in high-risk patients. Interferon-α has demonstrated efficacy in many clinical trials. Its pegylated form is well tolerated, enabling less frequent administration than standard interferon. Therefore it is therapy of choice based on Central European Myeloproliferative Neoplasm Organisation recommendation. Ropeginterferon α-2b has been shown to be more efficacious than hydroxyurea. Hydroxyurea is suspected of leukemogenic potential. JAK1/JAK2 inhibitor ruxolitinib is approved for hydroxyurea resistant/intolerant patients. Key words: diagnosis - polycythemia vera - therapy.
Topics: Aspirin; Enzyme Inhibitors; Humans; Hydroxyurea; Platelet Aggregation Inhibitors; Polycythemia Vera; Thrombocytosis; Thrombosis
PubMed: 30590943
DOI: No ID Found -
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