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Concept: Polycythemia vera

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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 .).

Concepts: Epidemiology, Clinical trial, Blood, Function, Randomized controlled trial, Hematology, Clinical research, Polycythemia vera

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Marchioli et al.(1) report in the Journal that a hematocrit target of less than 45% for therapeutic phlebotomy reduces the risk of thrombosis in patients with polycythemia vera. In the genomic era, readers may question attention given to a measurement as mundane as the hematocrit, but this study resolves a half-century of debate about the role of phlebotomy in polycythemia vera and has ramifications for diagnosis and management. Polycythemia vera is a unique myeloproliferative disorder in which there is overproduction of morphologically normal erythrocytes, granulocytes, and platelets, a phenotype that is caused by a mutation (V617F) in JAK2, encoding . . .

Concepts: Blood, Red blood cell, Hematology, Hematocrit, Polycythemia vera

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Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden.

Concepts: Disease, Medical terms, Symptom, Hematology, Symptomatic treatment, Medical sign, Polycythemia vera, Resistance during World War II

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Ruxolitinib, a Janus kinase (JAK) 1 and 2 inhibitor, was shown to have a clinical benefit in patients with polycythemia vera in a phase 2 study. We conducted a phase 3 open-label study to evaluate the efficacy and safety of ruxolitinib versus standard therapy in patients with polycythemia vera who had an inadequate response to or had unacceptable side effects from hydroxyurea.

Concepts: Clinical trial, Effectiveness, Employee benefit, Polycythemia vera, Hydroxycarbamide

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Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase II trial of ruxolitinib (JAK1/2 inhibitor) vs Best Available Therapy (BAT) in ET and polycythemia vera (PV) patients resistant or intolerant to HC. Here findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 & 52 patients randomized to receive ruxolitinib or BAT respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P=.40). At 2 years rates of thrombosis, hemorrhage and transformation were not significantly different, however some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were two complete molecular responses (CMR) and one partial molecular response (PMR) in CALR positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in one CMR patient, presumably due to the emergence of a different clone raising questions about the relevance of CMR in ET patients. Grade 3&4 anemia occurred in 19% & 0% of ruxolitinib vs 0% (both grades) BAT arm, grade 3&4 thrombocytopenia in 5.2% & 1.7% of ruxolitinib vs 0% (both grades) of BAT treated patients. Rates of discontinuation or treatment switching did not differ between the two trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET.

Concepts: Clinical trial, Blood, Grade, Randomized controlled trial, Blood disorders, Myelofibrosis, Polycythemia vera, Hydroxycarbamide

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The classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), consisting of polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a heterogeneous group of neoplasms that harbor driver mutations in the JAK2, CALR, and MPL genes. The detection of these mutations has been incorporated into the recent World Health Organization (WHO) diagnostic criteria for MPN. Given a pressing clinical need to screen for these mutations in a routine diagnostic setting, a targeted next-generation sequencing (NGS) assay for the detection of MPN-associated mutations located in JAK2 exon 14, JAK2 exon 12, CALR exon 9, and MPL exon 10 was developed to provide a single platform alternative to reflexive, stepwise diagnostic algorithms.

Concepts: DNA, Diagnosis, Greek loanwords, World Health Organization, Myeloproliferative disease, Myelofibrosis, Essential thrombocytosis, Polycythemia vera

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Recently reported mature survival data have confirmed the favorable prognosis in polycythemia vera (PV), with an estimated median survival of 24 years, in patients younger than age 60 years old. Currently available drugs for PV have not been shown to prolong survival or alter the natural history of the disease and are instead indicated primarily for prevention of thrombosis. Unfortunately, study endpoints that are being utilized in currently ongoing clinical trials in PV do not necessarily target clinically or biologically relevant outcomes, such as thrombosis, survival, or morphologic remission, and are instead focused on components of disease palliation. Even more discouraging has been the lack of critical appraisal from “opinion leaders”, on the added value of newly approved drugs. Keeping these issues in mind, at present, we continue to advocate conservative management in low-risk PV (phlebotomy combined with once- or twice-daily aspirin therapy) and include cytoreductive therapy in “high-risk” patients; in the latter regard, our first, second, and third line drugs of choice are hydroxyurea, pegylated interferon-α and busulfan, respectively. In addition, it is reasonable to consider JAK2 inhibitor therapy, in the presence of protracted pruritus or markedly enlarged splenomegaly shown to be refractory to the aforementioned drugs.

Concepts: Present, Medicine, Epidemiology, Value added, Hematology, Clinical research, Polycythemia vera, Hydroxycarbamide

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Current drug therapy for myeloproliferative neoplasms, including essential thrombocythemia (ET) and polycythemia vera (PV), is neither curative nor has it been shown to prolong survival. Fortunately, prognosis in ET and PV is relatively good, with median survivals in younger patients estimated at 33 and 24 years, respectively. Therefore, when it comes to treatment in ET or PV, less is more and one should avoid exposing patients to new drugs that have not been shown to be disease-modifying, and whose long-term consequences are suspect (e.g., ruxolitinib). Furthermore, the main indication for treatment in ET and PV is to prevent thrombosis and, in that regard, none of the newer drugs have been shown to be superior to the time-tested older drugs (e.g., hydroxyurea). We currently consider three major risk factors for thrombosis (history of thrombosis, JAK2/MPL mutations, and advanced age), in order to group ET patients into four risk categories: “very low risk” (absence of all three risk factors); “low risk” (presence of JAK2/MPL mutations); “intermediate-risk” (presence of advanced age); and “high-risk” (presence of thrombosis history or presence of both JAK2/MPL mutations and advanced age). Herein, we provide a point-of-care treatment algorithm that is risk-adapted and based on evidence and decades of experience.

Concepts: Pharmacology, Drug, Illness, Hematology, Myeloproliferative disease, Myelofibrosis, Polycythemia vera, Hydroxycarbamide

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Patients with polycythemia vera (PV) are at increased risk of thromboembolic events (TEs), which are key contributors to reduced overall survival compared with the age- and sex-matched general population. In addition to aspirin and phlebotomy to maintain hematocrit level < 45%, many patients receive cytoreduction with hydroxyurea (HU), which is associated with improved survival and may reduce the risk of cardiovascular events and TEs. However, 1 in 4 patients become resistant to or intolerant of HU. In the general population, prophylaxis and treatment following arterial and venous thromboses are associated with increased health care resource utilization and costs.

Concepts: Health care, Health care provider, Blood, Myocardial infarction, Heart, Blood vessel, Hematocrit, Polycythemia vera

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The current survey aimed to gather pre-defined disease parameters and treatment strategies to characterize the polycythaemia vera (PV) patient population in Belgium METHODS: Cross-sectional data from PV patients, seen at least once between May 2014 and May 2015 at 10 sites in Belgium, were collected in aggregated form and analysed descriptively and quantitatively RESULTS: Data from 343 PV patients were collected. Of these, 174 (50.7%) were male and 256 (74.6%) were ≥60 years of age. Ninety-two (26.8%) had a prior history of thrombotic events. Considerable proportions of patients had increased haematological parameters (haematocrit >45% [31.2%], leukocytes >10x109 /L [33.3%], and platelet >400x109 /L [38.2%]). Most patients had non-palpable spleen (284, 87.7%) and no phlebotomies during the past 6 months (197, 57.4%). Low dose aspirin was given as thrombosis prophylaxis in 249 (72.6%) patients, while 232 (67.6%) received hydroxyurea as cytoreductive treatment. Forty-one patients (12.0%) were reported as resistant and/or intolerant to hydroxyurea. Seventeen patients (5.0%) received ruxolitinib in the context of clinical trials.

Concepts: Blood, Red blood cell, Platelet, Hematology, Spleen, Blood doping, Polycythemia, Polycythemia vera