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Expert Review of Hematology Feb 2015Polycythemia vera (PV) is a chronic myeloproliferative neoplasm defined by erythrocytosis and often accompanied by leukocytosis and thrombocytosis. Current treatment... (Review)
Review
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm defined by erythrocytosis and often accompanied by leukocytosis and thrombocytosis. Current treatment options, including IFN-α and hydroxyurea, effectively manage PV in many patients. However, some high-risk patients, particularly those who become hydroxyurea-intolerant/resistant, may benefit from IFN-α or new treatment options. A better understanding of PV pathophysiology, including the role of the JAK/STAT pathway, has inspired the development of new therapies. Several JAK inhibitors directly target JAK/STAT pathway activation and have been evaluated in Phase II/III trials with promising results. Pegylated variants of IFN-α, which reduce dosing frequency and toxicity associated with recombinant IFN-α, have yielded favorable efficacy results in Phase II trials. Finally, histone deacetylase inhibitors have been developed to manage PV at the level of chromatin-regulated gene expression. The earliest Phase III results from these next-generation therapies are expected in 2014.
Topics: Humans; Polycythemia Vera
PubMed: 25353086
DOI: 10.1586/17474086.2015.972359 -
Blood Reviews Jul 2015Thrombotic and cardiovascular events are among the leading causes of death for patients with polycythemia vera (PV), and thrombosis history is a key criterion for... (Review)
Review
Thrombotic and cardiovascular events are among the leading causes of death for patients with polycythemia vera (PV), and thrombosis history is a key criterion for patient risk stratification and treatment strategy. Little is known, however, about mechanisms of thrombogenesis in patients with PV. This report provides an overview of thrombogenesis pathophysiology in patients with PV and elucidates the roles of conventional and nonconventional thrombotic risk factors. In addition to several conventional risk factors for thrombosis, clinical data have implicated increased hematocrit and red blood cell adhesiveness, activated platelets, leukocytosis, and elevated JAK2(V617F) allele burden in patients with PV. Furthermore, PV-related inflammation may exacerbate thrombogenesis through varied mechanisms, including endothelial damage, inhibition of natural anticoagulant pathways, and secretion of procoagulant factors. These findings suggest a direct link between myeloproliferation and thrombogenesis in PV, which is likely to provide new opportunities for targeted antithrombotic interventions aimed at decreasing PV-related morbidity and mortality.
Topics: Humans; Polycythemia Vera; Risk Factors; Thrombosis
PubMed: 25577686
DOI: 10.1016/j.blre.2014.12.002 -
Haematologica Feb 2008
Topics: Adolescent; Adult; Age Factors; Algorithms; Amino Acid Substitution; Child; Child, Preschool; Diagnosis, Differential; Female; GPI-Linked Proteins; Humans; Isoantigens; Janus Kinase 2; Male; Membrane Glycoproteins; Mutation, Missense; Polycythemia Vera; Receptors, Cell Surface; Receptors, Thrombopoietin; Thrombocythemia, Essential
PubMed: 18245648
DOI: 10.3324/haematol.12002 -
Expert Opinion on Investigational Drugs Jun 2020Polycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a mutation. Patients are at... (Comparative Study)
Comparative Study Review
INTRODUCTION
Polycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a mutation. Patients are at increased risk of thrombohemorrhagic events, and progression to myelofibrosis or acute leukemia. Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). Givinostat is a potent, class I/II histone deacetylase (HDAC) inhibitor that is in phase I/II clinical trials in PV. Givinostat was well tolerated and yielded promising clinico-hematological responses. A phase III study of givinostat versus hydroxyurea in high-risk PV patients is planned.
AREAS COVERED
We present an overview of PV, current treatment guidelines, and the putative mechanism(s) of action of givinostat. We discuss the preclinical and clinical studies of givinostat in PV and briefly review approved and investigational competitor compounds.
EXPERT OPINION
HDAC inhibitors have long been known to be active in PV, but chronic toxicities can be challenging. Givinostat, however, is active and well tolerated, and is entering a pivotal Phase III randomized trial. Givinostat offers the possibility of replacing hydroxyurea as the standard first-line cytoreductive choice for PV patients. This would completely change the current therapeutic paradigm and guidelines for PV management. Although surrogate clinical study endpoints may suffice for regulatory purposes, thrombosis reduction and prevention of disease progression remain most important to patients and clinicians.
Topics: Animals; Carbamates; Disease Progression; Histone Deacetylase Inhibitors; Humans; Hydroxyurea; Janus Kinase 2; Mutation; Polycythemia Vera
PubMed: 32693648
DOI: 10.1080/13543784.2020.1761323 -
The Journal of International Medical... Jan 2022Pulmonary embolism and splenic infarction are rare in patients with polycythemia vera. We herein describe a man in his early 60s whose main symptoms were chest...
Pulmonary embolism and splenic infarction are rare in patients with polycythemia vera. We herein describe a man in his early 60s whose main symptoms were chest tightness, cough, and sputum expectoration. Antibiotics, bronchodilators, and mucoactive agents did not improve his symptoms. Pulmonary artery computed tomography angiography showed pulmonary embolism, and abdominal computed tomography showed multiple hypodense foci in the spleen. Bone marrow aspiration cytology, biopsy, and genetic testing confirmed polycythemia vera. The patient's symptoms were relieved after treatment with hydroxyurea and rivaroxaban. This case emphasizes that although pulmonary embolism and splenic infarction are relatively rare in patients with polycythemia vera, the possibility of polycythemia vera should be considered in clinical practice.
Topics: Angiography; Humans; Male; Polycythemia Vera; Pulmonary Embolism; Splenic Infarction; Tomography, X-Ray Computed
PubMed: 35023386
DOI: 10.1177/03000605211072801 -
Haematologica Apr 2019Here we critically evaluate the role of elevated hematocrit as the principal determinant of thrombotic risk in polycythemia and erythrocytosis, defined by an expansion... (Review)
Review
Here we critically evaluate the role of elevated hematocrit as the principal determinant of thrombotic risk in polycythemia and erythrocytosis, defined by an expansion of red cell mass. Since red cell volume determination is no longer readily available, in clinical practice, polycythemia and erythrocytosis are defined by elevated hemoglobin and hematocrit. Thrombosis is common in Chuvash erythrocytosis and polycythemia vera. Although the increased thrombotic risk is assumed to be due to the elevated hematocrit and an associated increase in blood viscosity, thrombosis does not accompany most types of erythrocytosis. We review studies indicating that the occurrence of thrombosis in Chuvash erythrocytosis is independent of hematocrit, that the thrombotic risk is paradoxically increased by phlebotomy in Chuvash erythrocytosis, and that, when compared to chemotherapy, phlebotomy is associated with increased thrombotic risk in polycythemia vera. Inherited and environmental causes that lead to polycythemia and erythrocytosis are accompanied by diverse cellular changes that could directly affect thrombotic risk, irrespective of the elevated hematocrit. The pressing issue in these disorders is to define factors other than elevated hematocrit that determine thrombotic risk. Defining these predisposing factors in polycythemia and erythrocytosis should then lead to rational therapies and facilitate development of targeted interventions.
Topics: Hematocrit; Humans; Polycythemia; Polycythemia Vera; Risk Factors; Thrombosis
PubMed: 30872370
DOI: 10.3324/haematol.2018.210732 -
Journal of Cancer Research and Clinical... Jul 2023Despite comparatively favourable prognosis in polycythemia vera (PV) patients (pts), the overall survival is shorter compared to the age-matched general population. The...
INTRODUCTION
Despite comparatively favourable prognosis in polycythemia vera (PV) patients (pts), the overall survival is shorter compared to the age-matched general population. The aim of the study was to evaluate the impact of chosen laboratory and genetic factors on the individual disease outcome, i.e. risk of thrombosis, myelofibrosis/blastic transformation and death.
MATERIALS AND METHODS
The study group consisted of 151 pts and 57 healthy donors (HD).
RESULTS
JAK2V617F mutation was found in 96.7% (146/151) of the studied pts. JAK2 exon 12 mutations were identified in 2 individuals. The coexistence of JAK2V617F and JAK2 exon 12 mutation was confirmed in 2 other pts. In one case, neither JAK2V617F nor JAK2 exon 12 mutation was found. The presence of ten different non-driver mutations (ASXL1, SRSF2, U2AF1, IDH2) in eight of the analyzed pts (5.3%) was confirmed. The overall frequency of thrombotic events (TE) in the studied PV group was 23.8% (36/151). In patients with TE, median platelet count was lower than in pts without TE. Thrombotic risk did not depend on JAK2 rs12343867, TERT rs2736100, OBFC1 rs9420907 SNV, however, we found a novel strong tendency towards statistical significance between the CC genotype miR-146a rs2431697 and thrombosis. The disease progression to fibrotic phase was confirmed in 9% of the pts. Fibrotic transformation in PV pts was affected mainly by JAK2V617F variant allele frequency (VAF) and the presence of coexisting non-driver variants. The high JAK2V617F VAF and elevated white blood cell (WBC) count at the time of diagnosis were associated with an increased risk of death.
CONCLUSION
Therefore, in our opinion, complex, laboratory and genetic PV pts evaluation at the time of diagnosis should be incorporated into a new prognostic scoring system to more precisely define the PV prognosis and to optimize the therapeutic decision-making process.
Topics: Humans; Polycythemia Vera; Thrombosis; Janus Kinase 2; Mutation; Gene Frequency; Nucleotides
PubMed: 36242602
DOI: 10.1007/s00432-022-04327-0 -
Annals of Hematology Feb 2023Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to... (Randomized Controlled Trial)
Randomized Controlled Trial
Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.
Topics: Humans; Hydroxyurea; Medical Futility; Nitriles; Polycythemia Vera; Pyrimidines; Janus Kinases
PubMed: 36564535
DOI: 10.1007/s00277-022-05080-7 -
Blood Dec 2002
Review
Topics: Anemia; Apoptosis; Clone Cells; Disease Progression; Erythropoiesis; Erythropoietin; Female; Growth Substances; Hematologic Tests; Hematopoietic Stem Cells; Humans; Iron; Leukemia, Myeloid; Male; Myeloproliferative Disorders; Phlebotomy; Phosphorus Radioisotopes; Polycythemia Vera; Pregnancy; Pregnancy Complications, Hematologic; Receptors, Erythropoietin; Receptors, Growth Factor; Thrombocytosis; Thrombosis
PubMed: 12393615
DOI: 10.1182/blood-2001-12-0349 -
Hematology. American Society of... Dec 2017Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom... (Review)
Review
Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms that are characterized by thrombohemorrhagic complications, symptom burden, and impaired survival mainly due to thrombosis, progression to myelofibrosis, and transformation to acute leukemia. In this manuscript, we will review the most recent changes in diagnostic criteria, the improvements in risk stratification, and the "state of the art" in the daily management of these disorders. The role of conventional therapies and novel agents, interferon α and the JAK2 inhibitor ruxolitinib, is critically discussed based on the results of a few basic randomized clinical studies. Several unmet needs remain, above all, the lack of a curative approach that might overcome the still burdensome morbidity and mortality of these hematologic neoplasms, as well as the toxicities associated with therapeutic agents.
Topics: Humans; Interferon-alpha; Janus Kinase 2; Nitriles; Polycythemia Vera; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Risk Assessment; Thrombocythemia, Essential
PubMed: 29222296
DOI: 10.1182/asheducation-2017.1.480