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Leukemia Dec 2021Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be... (Review)
Review
Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but its natural history might be interrupted by thrombotic, fibrotic, or leukemic events, with respective 20-year rates of 26%, 16%, and 4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk, and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication, and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.
Topics: History, 19th Century; History, 20th Century; History, 21st Century; Humans; Polycythemia Vera
PubMed: 34480106
DOI: 10.1038/s41375-021-01401-3 -
American Family Physician Jun 2021Polycythemia vera is one of three stem-cell-derived myeloid malignancies commonly known as myeloproliferative neoplasms. It is characterized by erythrocytosis, often... (Review)
Review
Polycythemia vera is one of three stem-cell-derived myeloid malignancies commonly known as myeloproliferative neoplasms. It is characterized by erythrocytosis, often with associated leukocytosis and thrombocytosis. It has a significant negative impact on overall mortality and morbidity in the form of arterial and venous clots, symptoms of fatigue and pruritus, and conversion to leukemia and myelofibrosis. The World Health Organization's major diagnostic criteria include an elevated hemoglobin or hematocrit level, abnormal results on bone marrow biopsy, and presence of the Janus kinase 2 genetic mutation, which is present in approximately 98% of cases. The only minor criterion is a subnormal erythropoietin level, which helps differentiate polycythemia vera from common causes of secondary erythrocytosis such as smoking, sleep apnea, and testosterone use. First-line treatments, such as low-dose aspirin and goal-directed phlebotomy to a hematocrit level of less than 45% to reduce thrombotic events, improve quality of life and prolong survival. When indicated, cytoreductive therapy, primarily with hydroxyurea, can be added with consideration of second-line agents such as pegylated interferon-alfa, busulfan, and ruxolitinib, depending on the clinical scenario. Smoking cessation and cardiometabolic disease are modifiable risk factors that should be addressed to reduce the risk of thrombosis. Currently, no medications have been shown to cure the disease or to reduce the risk of conversion to leukemia and myelofibrosis.
Topics: Antineoplastic Agents; Fibrinolytic Agents; Genetic Markers; Humans; Hydroxyurea; Janus Kinase 2; Mutation; Phlebotomy; Polycythemia Vera
PubMed: 34060791
DOI: No ID Found -
Blood Jul 2019Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a... (Review)
Review
Since its discovery, polycythemia vera (PV) has challenged clinicians responsible for its diagnosis and management and scientists investigating its pathogenesis. As a clonal hematopoietic stem cell (HSC) disorder, PV is a neoplasm but its driver mutations result in overproduction of morphologically and functionally normal blood cells. PV arises in an HSC but it can present initially as isolated erythrocytosis, leukocytosis, thrombocytosis, or any combination of these together with splenomegaly or myelofibrosis, and it can take years for a true panmyelopathy to appear. PV shares the same mutation as essential thrombocytosis and primary myelofibrosis, but erythrocytosis only occurs in PV. However, unlike secondary causes of erythrocytosis, in PV, the plasma volume is frequently expanded, masking the erythrocytosis and making diagnosis difficult if this essential fact is ignored. PV is not a monolithic disorder: female patients deregulate fewer genes and clinically behave differently than their male counterparts, while some PV patients are genetically predisposed to an aggressive clinical course. Nevertheless, based on what we have learned over the past century, most PV patients can lead long and productive lives. In this review, using clinical examples, I describe how I diagnose and manage PV in an evidence-based manner without relying on chemotherapy.
Topics: Adult; Aged, 80 and over; Biomarkers; Combined Modality Therapy; Disease Management; Disease Susceptibility; Evidence-Based Medicine; Female; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Polycythemia Vera; Treatment Outcome
PubMed: 31151982
DOI: 10.1182/blood.2018834044 -
Journal of Clinical Oncology : Official... Jul 2023Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV,... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms.
PATIENTS AND METHODS
MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response.
RESULTS
One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; = .03). Serial analysis of V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] = .001, EFS = .001, overall survival = .01) and clearance of V617F stem/progenitor cells. 1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; = .003). The safety profile of ruxolitinib was as previously reported.
CONCLUSION
The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.
Topics: Humans; Polycythemia Vera; Treatment Outcome; Hydroxyurea; Nitriles; Hemorrhage
PubMed: 37126762
DOI: 10.1200/JCO.22.01935 -
The New England Journal of Medicine Jan 2013Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Current treatment recommendations for patients with polycythemia vera call for maintaining a hematocrit of less than 45%, but this therapeutic strategy has not been tested in a randomized clinical trial.
METHODS
We randomly assigned 365 adults with JAK2-positive polycythemia vera who were being treated with phlebotomy, hydroxyurea, or both to receive either more intensive treatment (target hematocrit, <45%) (low-hematocrit group) or less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group). The primary composite end point was the time until death from cardiovascular causes or major thrombotic events. The secondary end points were cardiovascular events, cardiovascular hospitalizations, incidence of cancer, progression to myelofibrosis, myelodysplasia or leukemic transformation, and hemorrhage. An intention-to-treat analysis was performed.
RESULTS
After a median follow-up of 31 months, the primary end point was recorded in 5 of 182 patients in the low-hematocrit group (2.7%) and 18 of 183 patients in the high-hematocrit group (9.8%) (hazard ratio in the high-hematocrit group, 3.91; 95% confidence interval [CI], 1.45 to 10.53; P=0.007). The primary end point plus superficial-vein thrombosis occurred in 4.4% of patients in the low-hematocrit group, as compared with 10.9% in the high-hematocrit group (hazard ratio, 2.69; 95% CI, 1.19 to 6.12; P=0.02). Progression to myelofibrosis, myelodysplasia or leukemic transformation, and bleeding were observed in 6, 2, and 2 patients, respectively, in the low-hematocrit group, as compared with 2, 1, and 5 patients, respectively, in the high-hematocrit group. There was no significant between-group difference in the rate of adverse events.
CONCLUSIONS
In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%. (Funded by the Italian Medicines Agency and others; ClinicalTrials.gov number, NCT01645124, and EudraCT number, 2007-006694-91.).
Topics: Aged; Antineoplastic Agents; Cardiovascular Diseases; Combined Modality Therapy; Female; Follow-Up Studies; Hematocrit; Humans; Hydroxyurea; Janus Kinase 2; Male; Middle Aged; Phlebotomy; Polycythemia Vera; Thrombosis
PubMed: 23216616
DOI: 10.1056/NEJMoa1208500 -
British Journal of Haematology Jan 2019
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Leukemia Sep 2013Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health...
Under the auspices of an International Working Group, seven centers submitted diagnostic and follow-up information on 1545 patients with World Health Organization-defined polycythemia vera (PV). At diagnosis, median age was 61 years (51% females); thrombocytosis and venous thrombosis were more frequent in women and arterial thrombosis and abnormal karyotype in men. Considering patients from the center with the most mature follow-up information (n=337 with 44% of patients followed to death), median survival (14.1 years) was significantly worse than that of the age- and sex-matched US population (P<0.001). In multivariable analysis, survival for the entire study cohort (n=1545) was adversely affected by older age, leukocytosis, venous thrombosis and abnormal karyotype; a prognostic model that included the first three parameters delineated risk groups with median survivals of 10.9-27.8 years (hazard ratio (HR), 10.7; 95% confidence interval (CI): 7.7-15.0). Pruritus was identified as a favorable risk factor for survival. Cumulative hazard of leukemic transformation, with death as a competing risk, was 2.3% at 10 years and 5.5% at 15 years; risk factors included older age, abnormal karyotype and leukocytes ≥15 × 10(9)/l. Leukemic transformation was associated with treatment exposure to pipobroman or P32/chlorambucil. We found no association between leukemic transformation and hydroxyurea or busulfan use.
Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Cohort Studies; Disease Progression; Female; Humans; Incidence; Leukemia; Male; Middle Aged; Polycythemia Vera; Prognosis; ROC Curve; Young Adult
PubMed: 23739289
DOI: 10.1038/leu.2013.163 -
Nucleic Acids Research Jun 2023Normal erythropoiesis requires the precise regulation of gene expression patterns, and transcription cofactors play a vital role in this process. Deregulation of...
Normal erythropoiesis requires the precise regulation of gene expression patterns, and transcription cofactors play a vital role in this process. Deregulation of cofactors has emerged as a key mechanism contributing to erythroid disorders. Through gene expression profiling, we found HES6 as an abundant cofactor expressed at gene level during human erythropoiesis. HES6 physically interacted with GATA1 and influenced the interaction of GATA1 with FOG1. Knockdown of HES6 impaired human erythropoiesis by decreasing GATA1 expression. Chromatin immunoprecipitation and RNA sequencing revealed a rich set of HES6- and GATA1-co-regulated genes involved in erythroid-related pathways. We also discovered a positive feedback loop composed of HES6, GATA1 and STAT1 in the regulation of erythropoiesis. Notably, erythropoietin (EPO) stimulation led to up-regulation of these loop components. Increased expression levels of loop components were observed in CD34+ cells of polycythemia vera patients. Interference by either HES6 knockdown or inhibition of STAT1 activity suppressed proliferation of erythroid cells with the JAK2V617F mutation. We further explored the impact of HES6 on polycythemia vera phenotypes in mice. The identification of the HES6-GATA1 regulatory loop and its regulation by EPO provides novel insights into human erythropoiesis regulated by EPO/EPOR and a potential therapeutic target for the management of polycythemia vera.
Topics: Animals; Humans; Mice; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Erythroid Cells; Erythropoiesis; GATA1 Transcription Factor; Gene Expression Profiling; Polycythemia Vera; Repressor Proteins
PubMed: 36929421
DOI: 10.1093/nar/gkad167 -
British Journal of Haematology Jan 2019
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Leukemia Sep 2021Interferon-alpha (rIFNα) is the only disease-modifying treatment for polycythemia vera (PV), but whether or not it prolongs survival is unknown. This large single... (Clinical Trial)
Clinical Trial
Interferon-alpha (rIFNα) is the only disease-modifying treatment for polycythemia vera (PV), but whether or not it prolongs survival is unknown. This large single center retrospective study of 470 PV patients compares the myelofibrosis-free survival (MFS) and overall survival (OS) with rIFNα to two other primary treatments, hydroxyurea (HU) and phlebotomy-only (PHL-O). The median age at diagnosis was 54 years (range 20-94) and the median follow-up was 10 years (range 0-45). Two hundred and twenty-nine patients were women (49%) and 208 were high-risk (44%). The primary treatment was rIFNα in 93 (20%), HU in 189 (40%), PHL-O in 133 (28%) and other cytoreductive drugs in 55 (12%). The treatment groups differed by ELN risk score (p < 0.001). In low-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 84%, 65% and 55% respectively (p < 0.001) and 20-year OS was 100%, 85% and 80% respectively (p = 0.44). In high-risk patients, 20-year MFS for rIFNα, HU, and PHL-O was 89%, 41% and 36% respectively (p = 0.19) and 20-year OS was 66%, 40%, 14% respectively (p = 0.016). In multivariable analysis, longer time on rIFNα was associated with a lower risk of myelofibrosis (HR: 0.91, p < 0.001) and lower mortality (HR: 0.94, p = 0.012). In conclusion, this study supports treatment of PV with rIFNα to prevent myelofibrosis and potentially prolong survival.
Topics: Adult; Aged; Aged, 80 and over; Antiviral Agents; Female; Follow-Up Studies; Humans; Interferon-alpha; Male; Middle Aged; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Retrospective Studies; Survival Rate; Young Adult
PubMed: 33654206
DOI: 10.1038/s41375-021-01183-8