Search

Interferon alpha (IFN-α) is a fascinating molecule with many biological properties yet to be fully understood. Among these properties, several have demonstrated usefulness for targeting malignant cells, including hematopoietic cells from patients with myeloproliferative neoplasms. Indeed, IFN-α has been used for decades across all myeloproliferative neoplasms, but only recently a new form, ropegIFN-α2b, was approved to treat patients with polycythemia vera. Many phase 2 and more recently phase 3 studies have demonstrated IFN-α's promise in treating patients with essential thrombocythemia and early-stage myelofibrosis. In addition, although not approved in that situation, IFN-α is the only cytoreductive therapy that can be used during pregnancy. Today, IFN-α is a key medicine for polycythemia vera and essential thrombocythemia, while its place in the management of myelofibrosis must be better defined. The advantages of IFN therapy include a well-known safety profile, high rates of clinical and molecular responses, and a unique ability to deeply reduce the mutant allele burden of most of the driver mutations causing myeloproliferative neoplasms. Recent preliminary data from prospective studies suggest that molecular responses may be correlated with prolonged event-free survival, raising the hope that IFN therapy may ultimately alter the natural history of many diseases., (Copyright © 2024 by The American Society of Hematology.)

We report the first large-scale retrospective cohort study on adolescent and young adult (AYA) polycythemia vera (PV) and essential thrombocythemia (ET) in Japan, a subgroup analysis using Japanese multicenter registry data (JSH-MPN-R18). This study included patients with PV (n = 31) or ET (n = 141) aged 20 to 39 years at the initial visit. Hemorrhage-free survival (HFS) was better in AYA ET than in non-AYA ET (5-year HFS: 100% vs. 88.6%, p < 0.01), which might be attributed to differences in antithrombotic treatment rates between AYA and non-AYA patients. Although thrombosis-free survival did not differ statistically, the percentage of venous thrombotic events (TEs) among total TEs was higher in AYA compared to non-AYA PV and ET in Japan (26.0% vs. 6.0%, p < 0.01), but much lower than figures reported in European or US cohorts. Cytoreductive therapy (CRT) was administered to 25.8% of AYA patients with PV and 43.3% of AYA patients with ET, and the reason was usually unrelated to high risk of thrombosis. These results could be used to develop a more appropriate strategy for managing PV and ET in the Japanese AYA population., Competing Interests: Declarations. Conflict of interest: YS reports honoraria from PharmaEssentia Japan K.K., Novartis Pharmaceutical, and research funds under contract from Incyte Biosciences Japan and Toyo Kohan K.K. KN reports research funds from Takeda Pharmaceutical internationals. KO reports research funds under contract from PharmaEssentia Japan K.K. and Abbvie Inc. TI reports honoraria from Novartis Pharmaceutical, Sanofi, and Takeda Pharmaceutical, and honoraria and grants from Abbvie Inc. and Bristol-Myers Squibb. AG reports grants from Eisai Co. Ltd., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Shinyaku Co. Ltd., Chugai Pharmaceutical Co. Ltd., MSD K.K., Otsuka Pharmaceutical Co. Ltd., Sumitomo Pharma Co. Ltd., Bayer Yakuhin Ltd., Daiichi Sankyo Co. Ltd., Nihon Pharmaceutical Co. Ltd. and honoraria from Novartis Pharma K.K., Alexion Pharmaceuticals Inc., Eisai Co. Ltd., Ono Pharmaceutical Co. Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Nippon Shinyaku Co. Ltd., Chugai Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co. Ltd., Daiichi Sankyo Co. Ltd., Nihon Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Janssen Pharmaceutical K.K., Pfizer Japan Inc., Sanofi K.K., and PharmaEssentia Japan K.K. MN reports research funds from Veritas Corporation and honoraria to her spouse from Amgen Inc., Astellas Pharma, AstraZeneca plc., Bristol-Myers Squibb, Daiichi Sankyo, Janssen Pharmaceutical K.K., Meiji Seika Pharma Co. Ltd., Nippon Shinyaku, Novartis Pharmaceutical, Ono Pharmaceutical, Otsuka Pharmaceutical, Sumitomo Pharma, and Takeda Pharmaceutical. FK reports grants from Takeda Pharmaceutical, Janssen Pharmaceutical K.K., Chugai Pharmaceutical, AstraZeneca K.K., AbbVie GK, Kissei Pharmaceutical, and Sanofi K.K. KK reports honoraria from Novartis Pharmaceutical, Takeda Pharmaceutical, and PharmaEssentia Japan. HW reports grants from Chugai Pharmaceutical, Kyowa Kirin, Ono Pharmaceutical, and Takeda Pharmaceutical. KU reports research funds under contract from Astellas, Aperis, Celgene, Daichi Sankyo, MSD, Pfizer, and Yakult; honoraria under contract from Alnylam Japan and SOBI; and honoraria and research funds under contract from Novartis, Abbvie, Alexion, Amgen, Asahi Kasei Pharma, AstraZeneca, Bristol-Myers Squibb, Chugai, Eisai, Incyte, Kyowa-Kirin, Meiji Seika Pharma, Nippon-Shinyaku, Ohara, Ono, Otsuka, PharmaEssentia, Sanofi, Takeda, and Janssen. TM reports honoraria from Pfizer, Novartis Pharmaceutical, Takeda Pharmaceutical, and PharmaEssentia Japan, and research funds under contract from Asahi Kasei Pharma, Chugai Pharmaceutical, Kyowa Kirin, Eisai Pharmaceutical, JCR Pharmaceuticals, Abbvie Inc., Sumitomo Pharma, CSL Behring, Japan Blood Products Organization, and Otsuka Pharmaceutical. KS reports honoraria from Bristol-Myers Squibb, Celgene, Novartis Pharmaceutical, and Takeda Pharmaceutical; research funds under contract from PharmaEssentia Japan K.K.; and grants from Abbvie Inc., Astellas Pharma, Chugai Pharmaceutical, Kyowa Kirin, and MSD. AT reports honoraria from Takeda Pharmaceutical, research funds under contract from Kyowa Kirin, Novartis Pharmaceutical, Ono Pharmaceutical, Perseus Proteomics Inc., Pfizer, and Taiho Pharmaceutical and honoraria and research funds under contract from Chugai Pharmaceutical. YE reports research funds under contract from Meiji Seika Pharma and an endowed chair funded by PharmaEssentia Japan K.K. YH reports honoraria from Takeda Pharmaceutical and Novartis Pharmaceutical, and an endowed chair funded by PharmaEssentia Japan K.K. KA reports honoraria from Celgene and Novartis Pharmaceutical, grants from Asahi Kasei Pharma, Mochida, MSD, Mundi Pharma, Nippon Shinyaku Pharmaceutical, Ono Pharmaceutical, Shionogi, Sanofi, Sumitomo Dainippon Pharma, Taiho Pharmaceutical, Toyama Chemical, Shin Nippon Biomedical Laboratories, Yakult Honsha, and Takeda Pharmaceutical; honoraria and research funds under contract from Bristol-Myers Squibb and Janssen Pharmaceutical; honoraria and grants from Abbvie Inc., Chugai Pharmaceutical, and Eisai Pharmaceutical; research funds under contract and grants from Daiichi Sankyo and Otsuka Pharmaceutical, honoraria, research funds under contract; and grants from Astellas Pharma and Kyowa Kirin. IM received speakers bureau fees from Pfizer Japan Inc., Ono Pharmaceutical Co. Ltd., Novartis Pharma K.K., Chugai Pharmaceutical Co. Ltd., AbbVie G.K., Janssen Pharmaceutical K.K., Bristol-Myers Squibb K.K. (Celgene K.K.), AstraZeneca K.K., and Otsuka Pharmaceutical Co. Ltd. and received research funding from Chugai Pharmaceutical Co. Ltd., Kyowa Kirin Co. Ltd., Sumitomo Pharma Co. Ltd., Nippon Shinyaku Co. Ltd., Eisai Co. Ltd., Asahi Kasei Pharma Corp., AbbVie G.K., Taiho Pharmaceutical Co. Ltd., and received consultancy fees from Otsuka Pharmaceutical Co. Ltd. KT reports honoraria from Novartis Pharmaceutical and MSD; grants from Astellas Pharma, Chugai Pharmaceutical, and Otsuka Pharmaceutical; and honoraria and grants from Kyowa Kirin. NK has received a salary from PharmaEssentia Japan, where he is a board member; reports honoraria from Abbvie Inc., Celgene, and Japan Tobacco Inc.; research funds under contract from FUJIFILM Wako Chemicals, Fuso-pharm, Meiji Seika Pharma, Perseus Proteomics Inc., and Pfizer, grants from Bristol-Myers Squibb, Chugai Pharmaceutical, Kyowa Kirin, and Sumitomo Dainippon Pharma; honoraria and grants from Novartis Pharmaceutical and Otsuka Pharmaceutical; and honoraria, research funds under contract, and an endowed chair funded by PharmaEssentia Japan K.K. The other authors declare no competing interests., (© 2024. Japanese Society of Hematology.)

There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of JAK2 -mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.

Polycythemia vera (PV) is a myeloproliferative tumor with low incidence and complex symptoms, affecting patients' quality of life and shortening their life span. Since the beginning of the 21st century, there has been an update but a need for uniform consensus regarding diagnosing and treating PV. With the continued interest of researchers in this field, a bibliometric study of PV is necessary. This paper aims to analyze articles on PV through bibliometric software to provide collaborative information and new ideas for researchers in this field. We collected PV-related publications in the Web of Science Core Collection database from 2000 to 2023. The included literature was analyzed using Citespace (6.2.R2), VOSviewer (1.6.19), and Bibliometrix. The study included country/region, institution, authors, journals, keywords, and references, and a visual knowledge network diagram was constructed. Microsoft Excel 2013 was also used for statistical analysis. A total of 1,093 articles were eventually included. The number of PV-related publications has steadily increased from 2000 to the present, with great potential for future growth. The US and US institutions have contributed more to this field, with the US ranking first in the number of publications, total citations, and centrality. Alessandro M. Vannucchi is the most published author. Tefferi, Ayalew is the most cited author. And BLOOD has the most publications, topping the list of the eleven high-productivity core source journals. The most cited article was "Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders" (Baxter, EJ, 2005). By examining the keywords, we found that the diagnosis and typing of true erythrocytosis, the use of ruxolitinib, and the tyrosine kinase JAK2 are the research hotspots in the field; genetic and molecular research in the field of true erythrocytosis is a cutting-edge topic in the field; and risk factors for true erythrocytosis is a cutting-edge hotspot issue in the field. The fruitful research in this century has laid the foundation for developing the field of PV. The information in this article will provide researchers with current hotspots and future potential in the discipline, helping the field achieve more extraordinary breakthroughs. Currently, research should focus on increasing global multicenter collaborative research in diagnosis and treatment to develop scientifically recognized diagnostic and treatment protocols and new clinical drug research. Our proposed model of global innovation collaboration will provide strong support for future research., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Woven coronary artery (WCA) is a rare and underdiagnosed congenital anomaly that involves multiple thin and tortuous epicardial arterial conduits reassembling distally into a single lumen. Recanalized thrombus may present as woven-like coronary arteries, appearing similar to WCA on angiographic images., Case Presentation: A 58-year-old female patient with intermittent chest pain for 5 years and polycythaemia vera (PV) for 8 years. The left anterior descending artery was presented like WCA on coronary angiography and finally confirmed as recanalized thrombus by optical coherence tomography(OCT), which might have been caused by PV. Given the patient's high thrombotic risk of PV and thrombotic changes in the left circumflex artery (LCX), we ultimately chose a conservative treatment without stenting., Conclusions: OCT would be needed for the diagnosis and differential diagnosis of woven-like coronary arteries. And physicians should take an appropriate treatment in a personalized way in patients with PV., (© 2024. The Author(s).)

Although polycythemia vera (PV) is a chronic and incurable disease, effective management can allow most patients to maintain functional lives with near-normal life expectancy. However, there remain several inter-related factors that contribute to many ongoing challenges associated with the management of PV, which this review aims to explore. First, as a disease hallmarked by constitutive activation of the JAK/STAT pathway, PV is often accompanied by inflammatory symptoms that negatively impact quality of life. Next, patients often require recurrent therapeutic phlebotomies to maintain their hematocrit below the 45% threshold that has been associated with a decreased risk of thrombotic events. The need to closely monitor hematocrit and perform conditional therapeutic phlebotomies ties patients to the healthcare system, thereby limiting their autonomy. Furthermore, many patients describe therapeutic phlebotomies as burdensome and the procedure is often poorly tolerated, further contributing to quality-of-life decline. Phlebotomy needs can be reduced by utilizing cytoreductive therapy; however, standard first-line cytoreductive options (i.e., hydroxyurea and interferon) have not been shown to significantly improve symptom burden. Collectively, current PV management, while reducing thrombotic risk, often has a negative impact on patient quality of life. As researchers continue to advance towards the goal of developing a disease-modifying therapy for patients with PV, pursuit of nearer-term opportunities to shift the current treatment paradigm towards improving symptoms without compromising quality of life is also warranted, for example, by reducing or eliminating the frequent use of phlebotomy., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: JAK2-mutated polycythaemia vera (PV) is associated with reduced survival because of thrombotic events and haematological disease transformation. Therapeutic venesection has traditionally been used to lower haematocrit, but the technique of erythrocytapheresis has emerged over the last decade., Aim: To compare erythrocytapheresis with venesection as treatment for PV by assessing medical efficacy and financial viability., Methods: One hundred sixteen patients with PV who received red cell depletion therapy at Barwon Health between 2014 and 2021 were identified. The haematocrit drop after each session, interval between treatment times and number of sessions required to achieve a haematocrit <0.45 were compared with an independent t test. Thrombosis rates were compared with Pearson's chi-squared test. Cost-funding analysis was done by assessing the Weighted Inlier Equivalent Separation and National Weighted Activity Unit funding models., Results: Patients treated with erythrocytapheresis achieved a greater haematocrit drop each treatment session (0.075 vs 0.03, P < 0.01), required fewer sessions to achieve a haematocrit <0.45 (1 vs 4, P < 0.01) and experienced fewer thrombotic complications (8.7% vs 32.1%, P = 0.02) than those treated with venesection. Cost-funding analysis demonstrated that erythrocytapheresis was more financially viable with a surplus of AU$297 per session compared to a deficit of AU$176 with venesection. Even if funding for venesection is increased, the cost of erythrocytapheresis may be mitigated by a lower number of procedures required per year (3.8 vs 5.3, P < 0.01)., Conclusions: Erythrocytapheresis is more efficacious than venesection for the treatment of PV and is accompanied by rapid reductions in haematocrit and reduced thrombotic complications., (© 2023 Royal Australasian College of Physicians.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Treatment selection for patients with polycythemia vera (PV) is based on patient age and history of thrombosis. The standard treatment is low-dose aspirin and phlebotomy for low-risk PV, with cytoreductive therapy added for high-risk PV. Thrombotic events and disease progression due to PV clone expansion affect the prognosis of PV. Although phlebotomy is effective in controlling hematocrit level, it has no effect on disease progression or PV-related symptoms. In Western countries, interferon (IFN) has been used as a cytoreductive therapy for PV. Long-term IFN therapy has been shown to result in sustained hematologic remission and molecular responses. Ropeginterferon-α-2b (ropeg-IFN), which is administered every two weeks, has recently become available. Clinical trials in patients with PV have shown that ropeg-IFN treatment is safe and efficacious, reducing JAK2V617F allele burden. Ropeg-IFN could ultimately affect long-term hematologic remission and molecular response in younger patients with low-risk PV, and may even offer a cure.

Classical myeloproliferative neoplasms (MPN), also known as Ph - MPN, includes polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Secondary myelofibrosis (sMF) and secondary acute myeloid leukemia (sAML) are important disease progressions of MPN. After MPN disease progression, hematopoietic stem cells undergo new clonal evolution, leading to drug resistance, poor treatment effect and poor survival of patients. In recent years, the exploration of the mechanism of disease progression and the precise diagnosis and treatment of MPN have attracted much attention. This article summarizes the research status of MPN disease progression, including the pathogenesis, risk stratification, and precision treatment, in order to provide reference for exploring new diagnosis and treatment methods of MPN disease progression.

Objectives: This Japanese cross-sectional survey evaluated the symptoms, daily living activities, and treatment needs of patients with polycythemia vera (PV), as perceived by patients themselves and their physicians., Methods: The study was conducted at 112 centers (March to July 2022) and included PV patients aged ≥20 years ( n  = 265) and their attending physicians ( n  = 151). The patient and physician questionnaires included 34 and 29 questions, respectively, to assess daily living, PV symptoms, treatment goals, and physician-patient communication., Results: Concerning daily living (primary endpoint), work (13.2%), leisure activities (11.3%), and family life (9.6%) were most affected by PV symptoms. Patients aged <60 years more frequently reported an impact on daily living than patients aged ≥60 years. Some patients (30%) reported anxiety about their future condition. The most common symptoms were pruritus (13.6%) and fatigue (10.9%). Pruritus was ranked as the first treatment need for patients, while physicians ranked it fourth. Concerning treatment goals, physicians prioritized thrombosis/vascular event prevention, while patients prioritized delaying PV progression. Physicians were less satisfied with physician-patient communication than patients., Conclusions: Patients' daily living was largely affected by PV symptoms. There are differences in physician and patient perceptions of symptoms, daily living, and treatment needs in Japan., Trial Registration: UMIN Japan identifier: UMIN000047047.

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., (© 2023 by The American Society of Hematology.)

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by aberrant myeloid lineage hematopoiesis with excessive red blood cell and pro-inflammatory cytokine production. Patients with PV present with a range of thrombotic and hemorrhagic symptoms that affect quality of life and reduce overall survival expectancy. Thrombotic events, transformation into acute myeloid leukemia, and myelofibrosis are largely responsible for the observed mortality. Treatment of PV is thus primarily focused on symptom control and survival extension through the prevention of thrombosis and leukemic transformation. Patients with PV frequently experience thrombotic events and have elevated cardiovascular risk, including hypertension, dyslipidemias, obesity, and smoking, all of which negatively affect survival. To reduce the risk of thrombotic complications, PV therapy should aim to normalize hemoglobin, hematocrit, and leukocytosis and, in addition, identify and modify cardiovascular risk factors. Herein, we review what is currently known about the associated cardiovascular risk and propose strategies for diagnosing and managing patients with PV., Competing Interests: G.B. has been on the advisory board, and been a speaker for Novartis, Janssen, BMS-Celgene M.M. has received consultancy fees from Gilead srl. E.B. has been a speaker for Novartis, Alexion and Incyte. A.M. has taken part in an advisory board for Amgen. D.R. has been advisor for Blueprint Medicines and has received travel grants from Novartis. The authors report no other conflicts of interest in this work., (© 2023 Benevolo et al.)

Introduction: Erythrocytapheresis, an apheresis treatment which selectively removes red blood cells, is an alternative to therapeutic phlebotomy, over which it has several advantages. Actually there is a high degree of variability in the use of this treatment. This prompted SIdEM (Italian Society of Hemapheresis and Cell Manipulation) to conduct a survey on the use of erythrocytapheresis in the Italian Transfusion Services. The purpose is to monitor this activity in the treatment of Polycythemia Vera (pv), secondary erythrocytosis and hemochromatosis., Materials and Methods: A data collection file was sent to the SIdEM regional delegates who, in turn, involved the Transfusion Centers in the areas they cover. The data collected were processed on a Microsoft Excel spreadsheet., Results: 75 centers from 14 Italian regions responded to the Survey: 36 centers (48 %) use erythrocytapheresis (35 centers perform therapeutic apheresis and 1 center only donor apheresis), 39 centers (52 %) do not (15 centers perform therapeutic apheresis, 18 centers only donor apheresis and 6 centers do not perform either therapeutic apheresis or donor apheresis). Although most centers have a substantially uniform attitude concerning the indications for which erythrocytapheresis is used, the survey shows that there are still differences more evident in the treatment of secondary erythrocytosis than in the treatment of pv or hemochromatosis., Conclusions: This survey has been useful to document the current Italian reality and to raise awareness about the need for improvement in optimizing and standardizing the use of a therapy with a great potential to exploit properly., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Exercise therapy during cancer treatment reduces symptom burden and improves quality of life (QoL). Polycythemia vera (PV) is a myeloproliferative neoplasia associated with good overall survival (up to decades) but a significant symptom burden, including thromboembolic events and dysesthesias. There are no specific exercise recommendations for patients with PV. Thus, we aimed to determine the exercise preferences of patients with PV and to derive specific recommendations based on the most commonly reported symptoms., Methods: This multicenter survey included patients with PV ≥18 years old. Demographic, clinical, and disease burden data were collected. The severity of selected symptoms was assessed using the adapted Myeloproliferative Neoplasms Symptom Assessment Form: 0 (absent), 1-30 (mild), 31-70 (moderate), or 71-100 (severe). The patients' information needs about physical activity (PA) and exercise preferences were recorded depending on their motivation and analyzed with regard to demographic aspects., Results: The sample comprised 182 patients (68% female, 61 ± 12 years). The prevalence of moderate-to-severe symptoms was 60% for fatigue, 44% for concentration problems, and 35% for bone/muscle pain. Other commonly reported symptoms included skin reactions (49%), splenomegaly (35%), and increased bleeding tendency (28%). Overall, 67% of respondents requested more information regarding PA. Patients with PV preferred individual training (79%) located outdoors (79%) or at home (56%). Regarding the amount of training, sports-inactive patients preferred a frequency of 1-2 times/week and session durations of 15-45 min, whereas sports-active patients preferred 3-4 times/week and 30-60 min (p < 0.001). Higher sport-inactiveness was observed in patients with lower educational level compared to patients with higher educational level (69% vs. 50%, p = 0.021). For beginners, combined resistance-endurance (circuit) training two times/week, which can be performed outdoors or at home, should be recommended. In the case of splenomegaly or bleeding symptoms, exercises with a low injury risk should be chosen., Conclusion: PA is important for patients with PV; therefore, counseling should be integrated into the treatment plan. Specifically, patients with low educational level should be addressed. Prospective studies are warranted to evaluate the effects of the novel exercise recommendations., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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., (© 2023 Wiley Periodicals LLC.)

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.

Disease Overview: JAK2 unmutated or non-polycythemia vera (PV) erythrocytosis encompasses a heterogenous spectrum of hereditary and acquired entities., Diagnosis: Foremost in the evaluation of erythrocytosis is the exclusion of PV through JAK2 (inclusive of exons 12-15) mutation screening. Initial assessment should also include gathering of previous records on hematocrit (Hct) and hemoglobin (Hgb) levels, in order to streamline the diagnostic process by first distinguishing longstanding from acquired erythrocytosis; subsequent subcategorization is facilitated by serum erythropoietin (Epo) measurement, germline mutation screening, and review of historical data, including comorbid conditions and medication list. Hereditary erythrocytosis constitutes the main culprit in the context of longstanding erythrocytosis, especially when associated with a positive family history. In this regard, a subnormal serum Epo level suggests EPO receptor mutation. Otherwise, considerations include those associated with decreased (high oxygen affinity Hgb variants, 2,3-bisphosphoglycerate deficiency, PIEZO1 mutations, methemoglobinemia) or normal oxygen tension at 50% Hgb saturation (P50). The latter include germline oxygen sensing pathway (HIF2A-PHD2-VHL) and other rare mutations. Acquired erythrocytosis commonly results from central (e.g., cardiopulmonary disease, high-altitude habitat) or peripheral (e.g., renal artery stenosis) hypoxia. Other noteworthy conditions associated with acquired erythrocytosis include Epo-producing tumors (e.g., renal cell carcinoma, cerebral hemangioblastoma) and drugs (e.g., testosterone, erythropoiesis stimulating agents, sodium-glucose cotransporter-2 inhibitors). Idiopathic erythrocytosis is an ill-defined terminology that presumes the existence of an increased Hgb/Hct level without an identifiable etiology. Such classification often lacks accounting for normal outliers and is marred by truncated diagnostic evaluation., Management: Current consensus treatment guidelines are not supported by hard evidence and their value is further undermined by limited phenotypic characterization and unfounded concerns for thrombosis. We are of the opinion that cytoreductive therapy and indiscriminate use of phlebotomy should be avoided in the treatment of non-clonal erythrocytosis. However, it is reasonable to consider therapeutic phlebotomy if one were to demonstrate value in symptom control, with frequency determined by symptoms rather than Hct level. In addition, cardiovascular risk optimization and low dose aspirin is often advised., Future Directions: Advances in molecular hematology might result in better characterization of "idiopathic erythrocytosis" and expansion of the repertoire for germline mutations in hereditary erythrocytosis. Prospective controlled studies are needed to clarify potential pathology from JAK2 unmutated erythrocytosis, as well as to document the therapeutic value of phlebotomy., (© 2023 Wiley Periodicals LLC.)

Introduction: Significant advances have been made in the diagnosis and management of patients with polycythemia vera (PV) over the past two decades, but a few important issues remain, either overlooked or controversial., Areas Covered: We discuss making an accurate diagnosis of PV with careful interpretation of hematocrit values, red cell count, and red cell mass when available, and bone marrow histomorphology to distinguish PV from other JAK2 V617F myeloproliferative neoplasms (MPNs). We cover aspects of initial PV treatment with phlebotomy (PHL), its drawbacks in the long term, and alternative strategies. We comprehensively discuss cytoreductive therapy using interferon-alpha or hydroxyurea, with emphasis on patient selection, treatment goals, clinical endpoints, biomarkers and, most importantly, event-free and overall survival., Expert Opinion: A bone marrow biopsy in PV is essential for diagnosis and baseline histomorphology. Both hematocrit and red cell counts should be controlled with both phlebotomy (PHL) and cytoreductive agents. PHL alone is often inadequate in the long term, and cytoreduction is needed for most. Interferon is our preferred first-line agent due to improved survival outcomes. Short-term biomarkers predictive of long-term outcomes are needed to guide optimal therapy and development of new treatments.

Polycythemia vera (PV) is a subtype of myeloproliferative neoplasms (MPN), with the highest incidence. Thromboembolism is the most common complication of PV, which has significant effects on the quality of life and survival of patients. To standardize the diagnosis, treatment and prevention strategies of thromboembolism associated with PV, the Myelodysplastic Syndrome/Myeloproliferative Neoplasms (MDS/MPN) Association affiliated to Chinese Medicine Education Association has reached the following consensus based on available proofs from evidence-based medicine after repeated considerations. The consensus covers risk stratification, diagnosis and treatment of PV, multidisciplinary management of PV thromboembolism, and patient follow-up, thereby providing the reference for the standardized diagnosis, treatment and management of thromboembolism for Chinese PV patients.

Objectives: Therapeutic phlebotomy allows for a controlled and gradual decrease in red cell mass leading to improved blood flow and symptomatic relief in polycythaemia. The present study was aimed to determine the impact of serial fixed volume and fixed interval therapeutic phlebotomy protocol on the laboratory and clinical parameters in patients of polycythaemia., Material and Methods: This prospective longitudinal study was conducted over 18 months. The desired haematocrit for polycythemia vera and secondary polycythemia was 45% and 52% respectively. A fixed volume of 350 ml phlebotomy was performed every-three days till the achievement of desired haematocrit. Complete blood count was performed before and after each procedure and iron studies were done at the time of enrolment and after the achievement of desired haematocrit. Post-procedure symptomatic relief was assessed by a 10-point visual analogue scale (VAS)., Results: Of the 29 patients enrolled in the study, 3 patients were lost to follow up and data of 26 patients was analyzed. Mean Hb declined from 17.84 ± 1.88 gdL -1 to 14.67 ± 1.14 gdL -1 (p < 0.001) and mean haematocrit decreased from a baseline of 57.11 ± 5.47% to 46.27 ± 3.763% (p < 0.001) upon achievement of desired haematocrit. There was a significant decline in serum iron from the baseline of 132.85 ± 94.136 μg dL -1 to 69.41 ± 58.643 μg dL -1 at desired haematocrit. A significant change in VAS score of almost all clinical parameters was observed. Post phlebotomy hematocrit correlated negatively with the number of procedures (p = 0.015)., Conclusion: Our protocol yielded rapid and marked improvement in patients of primary and secondary polycythemia with minimal adverse events and significant amelioration of clinical parameters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Société française de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Polycythemia vera (PV) is an acquired clonal hematopoietic stem cell disorder characterized by the overproduction of red blood cells. It has long been underlined that there are differences in treatment patterns in routine practice. Therapeutic strategies have also expanded, and in recent years the JAK1/JAK2 inhibitor ruxolitinib has emerged as a second-line therapeutic option in patients who are intolerant to or resistant to hydroxyurea. Determining the impact of changes on practice patterns is of interest, especially for aspects that lack detailed guidance for management., Methods: To gain insights into treatment patterns by clinicians treating patients with PV in Italy, we carried out a survey of 60 hematologists and transfusion specialists. The questions covered: treatment of low-risk patients, definition of significant leukocytosis, splenomegaly and excessive phlebotomies, resistance/intolerance to hydroxyurea, use of ruxolitinib, cytoreductive therapy, and vaccines., Results: In general, the results of the survey indicate that there is a large heterogeneity in management of patients with PV across these areas., Conclusions: While helping to provide greater understanding of treatment patterns for patients with PV in Italy, our survey highlights the need for additional clinical studies to obtain more precise guidance for the routine care of patients with PV., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Polycythemia vera (PV) is a Philadelphia-negative myeloproliferative neoplasm characterized by excessive myeloid cells production, mostly secondary to mutations in the Janus kinase 2 (JAK2) gene. PV natural history might be burdened by thrombotic events (TEs) and evolution into post-PV myelofibrosis (PPV-MF) or blast phase (BP). To date, no treatment strategies have been shown to have disease modifying effects, so therapy is directed at preventing TEs. All patients require phlebotomies (PHLs) to keep hematocrit below 45% and once-daily low dose aspirin (if not contraindicated). Apart from patients at "high risk" because of age over 60 years or a thrombosis history, cytoreductive therapies (CT) should be given to patients with relevant signs of myeloproliferation or intolerance to PHLs. Approved choices both for first and second line CT are hydroxyurea (HU) and pegylated forms of interferon (peg-IFN), the latter probably being better for young patients, and subjects without critical and recent vascular events or massive splenomegaly. The JAK1/2 inhibitor ruxolitinib is the treatment of choice in case of resistance/intolerance to HU, with proved efficacy in terms of thrombotic prevention. Data are too preliminary to consider CT for "low risk" PV cases, but ropeg-IFN is being studied in this setting with a short follow-up. A careful monitoring for signs of evolution into PPV-MF is fundamental for optimizing patient management., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Polycythemia vera (PV) is a frequent myeloproliferative disease resulting in excessive red blood cells, white blood cells, and platelets rarely identified in military populations. Increased blood viscosity and platelets can lead to fatal myocardial infarction and stroke. Historically, regimented phlebotomy managed this condition, but modern medicinal advances now are utilized. These immunosuppressive medications are generally incompatible with active-duty service and can lead to medical discharge. Phlebotomy therefore is critical for readiness and health; however, this can be challenging in resource-limited environments, necessitating effective improvisation. We describe an active-duty Soldier with PV symptoms consisting of substernal chest pressure, bilateral lower extremity paresthesias, and persistent pruritic neck rash. He had an elevated hematocrit (Hct) of 47%, necessitating phlebotomy and posing a challenge to his primary care team. The local emergency medicine team employed blood collection bags from whole blood (WB) transfusion kits, including proven volume estimation methods, to routinely draw one unit of blood and effectively manage this condition. This is the first reported case in military literature of PV managed with improvised field resources and techniques., (2022.)

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., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background:  The management of myeloproliferative neoplasms (MPNs) is based on the reduction of thrombotic risk. The incidence, impact, and risk factors of bleedings have been less studied., Methods:  All patients with polycythemia vera ( n =339) or essential thrombocythemia ( n =528) treated in our center are included in OBENE (Observatoire BrEstois des NEoplasies myéloprolifératives) cohort (NCT02897297). Major bleeding (MB) and clinically relevant nonmajor bleeding (CRNMB) occurring after diagnosis were included, except after leukemic transformation., Results:  With a median follow-up of 8.3 years, incidence of hemorrhages was 1.85% patient/year, with an incidence of MB of 0.95% patient/year. The 10-year bleeding-free survival was 89%. The most frequent locations were digestive tract, "mouth, nose and throat," and muscular hematoma. The case fatality rate of MB was 25%. The proportion of potentially avoidable postoperative bleeding was remarkable (17.6%). In multivariable analysis, eight risk factors of bleeding were identified: leukocytes >20 G/L at diagnosis (hazard ratio [HR]=5.13, 95% confidence interval [CI]: 1.77-14.86), secondary hemopathies (HR=2.99, 95% CI: 1.27-7.04), aspirin use at diagnosis (HR=2.11, 95% CI: 1.24-3.6), platelet count >1,000 G/L at diagnosis (HR=1.93, 95% CI: 1.11-3.36), history of hemorrhage (HR=1.82, 95% CI: 1.03-3.24), secondary cancers (HR=1.71, 95% CI: 1.01-2.89), atrial fibrillation (HR=1.66, 95% CI: 1.01-2.72), and male sex (HR=1.54, 95% CI: 1.02-2.33). The occurrence of a CRNMB increased the risk of a secondary MB (odds ratio=6.13, 95% CI: 2.86-12.6, p <0.00001). Most patients taking hydroxyurea displayed a nonmacrocytic median corpuscular value in the months preceding bleeding (51.4%)., Discussion:  The morbidity and mortality of bleedings in MPN should not be underestimated, and patients with platelet count >1,000 G/L and/or leukocytes >20 G/L, and possibly patients who suffered from a CRNMB could benefit from cytoreduction to reducing bleeding risk. Postoperative bleedings represent a substantial proportion of bleeding and could be better prevented., Competing Interests: None declared., (Thieme. All rights reserved.)

Purpose of Review: Philadelphia-negative myeloproliferative neoplasms (MPNs) include polycythemia vera (PV), essential thrombocythemia (ET), prefibrotic (pre-), and overt-primary myelofibrosis (primary MF, PMF). PV and ET could evolve into secondary MF (SMF), whose early diagnosis relies on monitoring signs of possible progression. All MPNs have a risk of blast phase (BP), that is associated with a very dismal outcome. Overall survival (OS) is different among MPNs, and disease-specific prognostic scores should be applied for a correct clinical management. In this review, an overview of current prognostic scores in MPNs will be provided., Recent Findings: The biological complexity of MPNs and its role on the trajectory of disease outcome have led to the design of integrated prognostic models that are nowadays of common use in PMF patients. As for PV and ET, splicing gene mutations could have a detrimental role, but with the limit of the not routinary recommended application of extensive molecular analysis in these diseases. SMF is recognized as a distinct entity compared to PMF, and OS estimates should be calculated by the MYSEC-PM (Myelofibrosis SECondary-prognostic model). Both in PMF and SMF, decisions as selection of patients potentially candidates to allogenic stem cell transplant or that could benefit from an early shift from standard treatment are based not only on conventional prognostic scores, but also on multivariable algorithms. The expanding landscape of risk prediction for OS, evolution to BP, and SMF progression from PV/ET informs personalized approach to the management of patients affected by MPNs., (© 2022. The Author(s).)

Purpose: Patients with polycythemia vera (PV) show an elevated incidence of thromboembolic complications and decreased survival when compared to age-matched healthy individuals. Hypercellularity as indicated by elevated hematocrit, pathophysiological changes induced by the JAK2 driver mutation and cardiovascular risk factors contribute to the increased incidence of thromboembolic events. Higher age and a history of thromboembolic events define a high-risk population of PV patients. Depending on the individual risk profile, phlebotomy or pharmacologic cytoreduction is recommended in combination with low-dose acetylsalicylic acid. Stringent cytoreduction is required for effective risk reduction. However, in recent reports, the rate of thromboembolic complications in PV patients under cytoreductive therapy appears still elevated compared to healthy individuals. This study reports on a chart review to assess for cytoreductive therapy of 1440 PV patients in real life., Methods: Forty-two eligible hematologists/oncologists in private practice treating patients with MPN were recruited to participate in a paper-pencil-based survey conducted between January 2019 and March 2020 in Germany. Physicians were asked to report primary documented data obtained from patient charts. Descriptive analyses were conducted to assess for patient characteristics, treatment modalities, risk factors and thromboembolic complications., Results: Data were collected from the patient charts of 1440 individuals diagnosed with PV. The patient population was older than those reported in multicenter trials with a median age of 72.2 years at the time of reporting and 63.5 years at diagnosis. Age was the main factor accounting for high-risk status with 84.7% of patients being above the age of 60 followed by thromboembolic complications reported in 21.3% of patients. The use of pharmacologic cytoreduction was highly variable between participating centers with an average of 60.7% and a range of 10.1-100%. Hydroxyurea was the most frequently used drug followed by ruxolitinib, while interferons were reported for a minority of patients. For 35.4% of patients a persistent need for phlebotomy in addition to cytoreductive treatment was reported. Although presence of high-risk criteria and insufficient disease control were reported as main triggers to initiate pharmacologic cytoreduction, 28.1% had elevated hematocrit values (> 45%) and 38.6% showed persistence of elevated leukocyte count (> 10 9/l ) while on cytoreductive treatment. In contrast, physician-reported symptom burden was lower than published in clinical trials and patient-reported outcomes. The rate of patients experiencing thromboembolic complications was 32.2% at any time and 14.3% after diagnosis with most patients receiving acetylsalicylic acid and 10.8% remaining on oral anticoagulants or heparin., Conclusions: Cytoreductive treatment of high-risk PV in real life is highly variable regarding indication for cytoreduction and definition of therapy resistance. This study highlights the need for (i) improved risk stratification for thromboembolic events, (ii) consequent indication of pharmacologic cytoreduction in high-risk PV and (iii) attention to signs of therapy resistance that can trigger an earlier and stringent switch to second line agents., (© 2021. The Author(s).)

Background: Polycythemia vera (PV) is one of the most common chronic myeloproliferative neoplasms, yet, little data is available on the epidemiology of PV in Spain and the costs of its management. This study aimed to evaluate the hospital incidence and mortality rate of PV in Spain, and to estimate hospital medical costs., Methods: Hospital admission records of patients with PV registered between 2005 and 2019 were obtained from a Spanish hospital discharge database and analyzed in a retrospective multicenter study., Results: Admission files of 490 patients were reviewed. Median age was 74 years; patients presented numerous conditions associated to age, namely hypertension, diabetes or anemia. Hospital mortality rate was associated to pulmonary heart disease, respiratory conditions and kidney disease. Most of the files analyzed corresponded to inpatient admissions; hospital incidence decreased over the study period in patients over 60 years. Median admission cost was €5580, increasing in patients deceased during the hospitalization. Admission cost increased significantly between 2006 and 2011., Conclusions: This study provides an evaluation of hospital management and costs of PV in Spain. Future studies should focus on the revision of disease management in the country and measuring total medical costs, which could be higher than global estimations.

Polycythemia vera (PV) is characterized by clonal proliferation of a hematopoietic stem cell leading to erythrocytosis. Patients with PV have significantly higher morbidity and mortality compared to the general population due to increased risk of thrombosis, hemorrhage, and well-characterized microvascular and constitutional symptoms. There is also a propensity to transform to myelofibrosis and to an aggressive form of acute leukemia, further increasing morbidity and mortality. Current management is aimed at reducing the risk of thromboembolic events and improving symptom burden; however, none of the existing therapies have proven the ability to deplete the underlying malignant clone, or definitively reduce the risk of disease, progression leaving a large area of unmet need. In this review, we highlight the pathophysiology of PV, current management and limitations therein. We propose highly debated clinical practices that require further investigation. We conclude by discussing therapies in development and how these may fill unmet needs and be incorporated into the future PV treatment paradigm., Competing Interests: Declaration of competing interest JW reports no conflicts of interest. DT receives contracted research funding paid to his institution from Astellas Pharmaceuticals and consulting fees from AbbVie., (Copyright © 2022. Published by Elsevier Ltd.)

Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm driven by the JAK2 V617F (or rarely exon 12) mutation. Its natural history can extend over a few decades, and therefore treatment planning is predicated on continual reassessment of traditional risk features (age, prior thrombosis) to evaluate the need for cytoreduction besides foundational therapy with low-dose aspirin and stringent phlebotomy. Shorter- and longer-term patient goals should be considered in light of several variables such as comorbid conditions (especially cardiovascular risk factors), disease symptoms, and the risk-benefit profile of available drugs. While hydroxyurea has been the pro forma choice of cytoreduction for many practitioners over the last half-century, the more recent regulatory approvals of ruxolitinib and ropeginterferon-alfa-2b, based on phase 3 randomized trials, highlight an expanding portfolio of active drugs. Obtaining high-level evidence for short-term clinical trial endpoints such as hematocrit control, symptom burden/quality of life, splenomegaly, and JAK2 V617F allele burden lies within the timeline of most studies. However, in many cases, it may not be possible to adequately power trials to capture significant differences in the typically low event rates of thrombosis as well as longer-horizon endpoints such as evolution to myelofibrosis and acute myeloid leukemia and survival. This Perspective highlights the challenges of addressing these data gaps and outstanding questions in the emerging treatment landscape of PV., (© 2022 by The American Society of Hematology.)

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., Competing Interests: PD Dr. Michael Westhoff hat Vortragshonorare der Firmen Actelion und Janssens erhalten. Dr. Ursula Kreppein und Dr. Patric Litterst haben keine Interessenskonflikte., (Thieme. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: This work aims to describe the proportion of patients with polycythemia vera (PV) or essential thrombocythemia (ET) and thrombosis prior to the diagnosis who had erythrocytosis or thrombocytosis prior to the thrombosis., Patients and Methods: This is a retrospective review of 63 patients with PV and 130 with ET., Results: In regard to PV, we found prior erythrocytosis in 7 (11.1%) of the 17 cases (27%) with thrombosis prior to diagnosis. In ET, we found prior thrombocytosis in 10 (7.7%) of the 25 cases (19.2%) with thrombosis prior to diagnosis. The median time between the laboratory finding and thrombosis was 8.2 months and 11.8 months for PV and TE, respectively. In both entities, patients with thrombosis prior to diagnosis had significantly lower survival., Conclusion: A significant proportion of patients with thrombosis prior to the diagnosis of PV and ET present with erythrocytosis or thrombocytosis prior to the episode of thrombosis. This could allow for anticipating diagnosis and treatment., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Medicina Interna (SEMI). All rights reserved.)

Objectives: Polycythaemia vera (PV) is a condition that may potentially put patients undergoing cardiac surgery at an increased risk of bleeding and thrombosis; however, there is currently a paucity of literature regarding the management of these patients. We aim to examine the literature in this systematic review to indicate the interventions that may be considered to minimise complications., Methods: We conducted a literature search using keywords and MeSH terms to identify articles discussing PV and cardiac surgery. The studies were identified and qualitatively analysed using the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol., Results: In total, 10 case reports representing 11 patients were identified for this systematic review and were included in qualitative analysis. 63.6% of patients had preoperative intermittent phlebotomy, and the majority of patients received postoperative therapy that involved one antiplatelet agent and one anticoagulant. Generous perioperative fluid management, phlebotomy, preservation of core body temperature, early extubation, monitoring of myocardial ischaemia, infarction and vascular events, intense chest physiotherapy and patient mobilisation are important to consider to reduce the risk of complications arising from surgery., Conclusion: These considerations should be systematically discussed in a multidisciplinary team, where the acute surgical need can be balanced appropriately against the risk of haemorrhage and thrombosis., (Copyright © 2021 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Classical BCR-ABL-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematologic malignancies, including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), as well as post-PV-MF and post-ET-MF. Progression to more symptomatic disease, such as overt MF or acute leukemia, represents one of the major causes of morbidity and mortality. There are clinically evident but also subclinical types of MPN progression. Clinically evident progression includes evolution from ET to PV, ET to post-ET-MF, PV to post-PV-MF, or pre-PMF to overt PMF, and transformation of any of these subtypes to myelodysplastic neoplasms or acute leukemia. Thrombosis, major hemorrhage, severe infections, or increasing symptom burden (e.g., pruritus, night sweats) may herald progression. Subclinical types of progression may include increases in the extent of bone marrow fibrosis, increases of driver gene mutational allele burden, and clonal evolution. The underlying causes of MPN progression are diverse and can be attributed to genetic alterations and chronic inflammation. Particularly, bystander mutations in genes encoding epigenetic regulators or splicing factors were associated with progression. Finally, comorbidities such as systemic inflammation, cardiovascular diseases, and organ fibrosis may augment the risk of progression. The aim of this review was to discuss types and mechanisms of MPN progression and how their knowledge might improve risk stratification and therapeutic intervention. In view of these aspects, we discuss the potential benefits of early diagnosis using molecular and functional imaging and exploitable therapeutic strategies that may prevent progression, but also highlight current challenges and methodological pitfalls.

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., (© 2021. The Author(s).)

Purpose of Review: Essential thrombocythemia (ET) and polycythemia vera (PV) are the most common myeloproliferative neoplasms (MPNs). Treatment of ET and PV is based on the risk for subsequent thrombosis. High-risk patients, defined as older than 60, JAK2 V617F-positive patients, or patients with a history of prior thrombosis, merit cytoreduction to control blood counts, whereas a watchful waiting paradigm is utilized in low-risk patients. However, low-risk patients have a host of other specific management issues that arise during their disease course. This review will discuss the most common management issues specific to the care of low-risk patients, including anti-platelet therapy dosing, pregnancy, and indications for early cytoreduction., Recent Findings: Although low-dose aspirin is well established in PV, its indications and dosing regimens are less clear in ET. Recent evidence has supported twice daily low-dose aspirin in ET and observation alone in very low-risk ET patients. Pregnancy is not contraindicated in MPNs, and we recommend aspirin throughout pregnancy with consideration for prophylactic postpartum anticoagulation. High phlebotomy needs, symptom burden, and extreme thrombocytosis are common reasons for initiation of cytoreduction in low-risk patients, although we typically do not start cytoreduction for an isolated high platelet count alone. Recent data has also demonstrated a potential disease-modifying effect of interferons in MPNs, with some experts now advocating the early use of interferon in low-risk patients, although more mature data is needed before practice guidelines change. We evaluate the literature to inform clinical decision-making regarding these controversies, including most recent data that has challenged the "watchful waiting" paradigm. Our discussion provides guidance on common clinical scenarios seen in low-risk ET and PV patients, who face a myriad of complex management decisions in their care., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In 816 patients with 2016 World Health Organization-defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post-PV myelofibrosis (PPV-MF) and survival. Patients were subgrouped according to CCI = 0 (58.1%, no comorbidities) or CCI ≥ 1 (41.9%) and according to normal/underweight (BMI < 25, 54.5%) or overweight/obesity (BMI ≥ 25, 45.5%) at PV diagnosis. BMI was available for 529 patients. Patients with CCI ≥ 1 were older and more frequently presented cardiovascular risk factors compared to patients with CCI = 0 (p < 0.001), while overweight/obese patients were more frequently males (p < 0.001). Cumulative incidence of thromboses with death as competing risk was 13.3% at 10 years. Multivariable analysis with death as competing risk showed that previous thromboses (subdistribution hazard ratio [SHR]: 2.1, p = 0.01) and hypertension (SHR: 1.77, p = 0.04) were significantly associated with a higher thrombotic risk, while BMI ≥ 25 lost statistical significance (SHR: 1.69, p = 0.05) and CCI ≥ 1 was excluded after evaluation of goodness of fit. After a median follow-up of 6.1 years, progression to PPV-MF occurred in 44 patients, and 75 patients died. BMI ≥ 25 was associated with a lower probability of progression to PPV-MF (SHR: 0.38, CI95%: 0.15-0.94, p = 0.04) and better survival (hazard ratio [HR]: 0.42, CI95%: 0.18-0.97, p = 0.04). CCI ≥ 1 did not affect progression to PPV-MF (p = 0.44) or survival (p = 0.71).  The evaluation of CCI and BMI may improve the prognostic definition of PV. In patients with hypertension an accurate evaluation of thrombotic risk is warranted., (© 2021 John Wiley & Sons Ltd.)

Polycythaemia vera is a challenging disease to study given its low prevalence and prolonged time-to-event for important clinical endpoints such as thrombosis, progression, and mortality. Although researchers in this space often rise to meet these challenges, there is considerable room for improvement in the analysis of retrospective data, the development of risk-stratification tools, and the design of randomised controlled trials. In this Viewpoint, we review the evidence behind the contemporary approach to risk stratification and treatment of polycythaemia vera. Frameworks for using data more efficiently, constructing more nuanced prognostic models, and overcoming challenges in clinical trial design are discussed., Competing Interests: Declaration of interests JM receives grants or contracts from Inycte, Novartis, Geron, PharmaEssentia, Kartos, CTI BioPharma, Bristol Myers Squibb, Roche, Merck, and Forbius, and consulting honoraria from Incyte, Novartis, Geron, PharmaEssentia, Kartos, CTI BioPharma, Constellation, Bristol Myers Squibb, Roche, AbbVie, and Sierra Oncology. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Pregnancies in women with polycythemia vera (PV) are associated with an increased risk of PV-related maternal complications and often result in miscarriage. Recommendations for the management of PV pregnancies are mainly based on studies with a small number of patients. A correlation between pregnancy outcome and postpartum course has been reported for essential thrombocythemia, but corresponding data for PV are lacking so far., Methods: In 41 PV pregnancies, the pregnancy outcome, the use of PV-specific therapies (ie, acetylsalicylic acid, low-molecular weight heparin and/or interferon-alpha), and the postpartum PV course were investigated., Results: A live birth rate of 51.2% (21/41 pregnancies) was observed. 43.9% of pregnancies ended in spontaneous abortion and 4.9% in stillbirth. A significantly increased live birth rate occurred in pregnancies with PV-specific therapies compared to standard antenatal care (69.0% vs. 8.3%; P < .0019). The use of PV-specific therapy significantly increased the number of maternal hemorrhages (P = .021) without increasing the risk of fetal complications. During the median postpartum follow-up period of 1.2 years (range 0.1-13.7), complicated postpartum PV occurred significantly more often after miscarriages (P = .035)., Conclusions: According to our analysis, PV-specific therapy improved the live birth rate. Significantly more complicated postpartum PV courses were observed after miscarriages., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Polycythaemia vera is one of several classical myeloproliferative neoplasms that may occur in a juvenile onset or late-onset adult forms. It is linked to specific genetic mutations that cause a deleterious elevation in the patient's red cell mass. The discourse on genetics includes an exposé on the molecular biology of the disease and how a shared JAK2 V617F mutation can co-exist among three distinct neoplasms. Concepts of genetics and immunology help define the origin and behaviour of the disease: the tracking of allele burdens of mutations (genetic dosage), the timing or order of acquired mutations, the import of bystander mutations and the onco-inflammatory response; all theories are invoked to explain the progression of disease severity and potential transformational leukaemia. The World Health Organization's diagnostic criteria are accessed to focus on the subtleties of the Hb laboratories and sifting through the challenging listing of differential diagnoses that mimic PV, and our report includes an overview of manual and automated phlebotomy (erythrocytapheresis) procedures, enumerating their clinical indications, significance of temporary phlebotomy resistance and optimizing safety/ efficacy, quality and cost. Stratification of low and high-risk disease distinguishes when to commence chemo-cytoreductive therapy in the high-risk patient to prevent thrombotic complications. Drug resistance is circumvented by artfully switching drugs or using novel drug designs., (© 2021 International Society of Blood Transfusion.)

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.

Myeloproliferative neoplasms include essential thrombocythemia, polycythemia vera, and myelofibrosis. They are characterized by abnormal myeloid proliferation. Patients suffer from debilitating constitutional symptoms and splenomegaly. There have been advances in understanding the impact on quality of life in myeloproliferative neoplasms. Owing to the chronicity of these diseases, symptoms are considered in response criteria for clinical trials. This review wills cover how quality of life is measured in patients with myeloproliferative neoplasm. We review the impact of treatment options, including JAK inhibitors, allogeneic stem cell transplantation, and medications in development. We discuss nonpharmacologic methods of improving symptoms and quality of life., Competing Interests: Disclosure Authors have nothing to disclose., (Copyright © 2020 Elsevier Inc. All rights reserved.)