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Subclones homozygous for JAK2V617F are more common in polycythemia vera (PV) than essential thrombocythemia (ET), but their prevalence and significance remain unclear. The JAK2 mutation status of 6495 BFU-E, grown in low erythropoietin conditions, was determined in 77 patients with PV or ET. Homozygous-mutant colonies were common in patients with JAK2V617F-positive PV and were surprisingly prevalent in JAK2V617F-positive ET and JAK2 exon 12-mutated PV. Using microsatellite PCR to map loss-of-heterozygosity breakpoints within individual colonies, we demonstrate that recurrent acquisition of JAK2V617F homozygosity occurs frequently in both PV and ET. PV was distinguished from ET by expansion of a dominant homozygous subclone, the selective advantage of which is likely to reflect additional genetic or epigenetic lesions. Our results suggest a model in which development of a dominant JAK2V617F-homzygous subclone drives erythrocytosis in many PV patients, with alternative mechanisms operating in those with small or undetectable homozygous-mutant clones.

Physicians from nine European countries were asked to complete a survey, which was conducted in two waves (Wave II, October 2009; Wave III, May 2010), based on their current treatment practices for essential thrombocythemia (ET). The aim of the study was to gain insight into physicians' criteria for treatment initiation and reasons for switching from one therapy option to another. The majority of patients receiving first-line cytoreductive therapy for ET were treated with hydroxycarbamide (HC; 63 and 71% in Waves II and III, respectively), while the majority of patients on second-line therapy received anagrelide (51 and 60% in Waves II and III, respectively). Efficacy was the main factor cited for switching therapies (cited by 47 and 58% of physicians in Waves II and III, respectively). Further studies are needed to determine whether current practices used by physicians for the treatment of ET are consistent with consensus guidelines.

European experts were convened to develop a definition of response to treatment in polycythemia vera (PV) and essential thrombocythemia (ET). Clinicohematologic (CH), molecular, and histologic response categories were selected. In ET, CH complete response (CR) was: platelet count less than or equal to 400 x 10(9)/L, no disease-related symptoms, normal spleen size, and white blood cell count less than or equal to 10 x 10(9)/L. Platelet count less than or equal to 600 x 10(9)/L or a decrease greater than 50% was partial response (PR). In PV, CH-CR was: hematocrit less than 45% without phlebotomy, platelet count less than or equal to 400 x 10(9)/L, white blood cell count less than or equal to 10 x 10(9)/L, and no disease-related symptoms. A hematocrit less than 45% without phlebotomy or response in 3 or more of the other criteria was defined as PR. In both ET and in PV, molecular CR was a reduction of any molecular abnormality to undetectable levels. Molecular PR was defined as a reduction more than or equal to 50% in patients with less than 50% mutant allele burden, or a reduction more than or equal to 25% in patients with more than 50% mutant allele burden. Bone marrow histologic response in ET was judged on megakaryocyte hyperplasia while on cellularity and reticulin fibrosis in PV. The combined use of these response definitions should help standardize the design and reporting of clinical studies.

Two hundred and fifty hematologists and oncologists (50 each from France, Germany, Italy, Spain and the United Kingdom) participated in this survey to assess the current management of essential thrombocythemia (ET), with particular reference to the use of anagrelide. Data were collected between October 9 and November 2, 2006 on 2000 patients with ET. Thirty-eight per cent of patients had been tested for the Janus kinase 2 (JAK2) mutation (JAK2V617F), of whom 54% tested positive. JAK2V617F mutation status was not influenced by age, gender or cardiovascular risk. Overall, 297 patients (14.9%) were receiving anagrelide hydrochloride; 16.8% of these patients were aged 18-40 years, 43.1% aged 41-60 years and 40.1% aged over 60 years. Hydroxycarbamide, alone or in combination with aspirin, was the most commonly prescribed treatment in 136/191 (71.2%) patients prior to switching to anagrelide. In conclusion, this survey provides a useful insight into the epidemiology of ET and current prescribing patterns for anagrelide in Europe.

The frequency of cytogenetic abnormalities in the Philadelphia-negative myeloproliferative neoplasms (MPNs) varies from approximately 30% in primary myelofibrosis (PMF) to less than 5% in essential thrombocytosis (ET). The spectrum of aberrations is heterogeneous, ranging from gains and losses of genetic material to structural changes including unbalanced translocations. However, no specific abnormality has been identified to date. Nevertheless, such investigations can provide evidence of clonality and, as a result, cytogenetic findings have been included in the WHO diagnostic criteria for this group of diseases. The aim of the current review is to discuss the pathogenetic insight and prognostic information that standard, as well as molecular cytogenetic analysis has provided. A brief overview is given of the cytogenetic findings in the individual diseases, followed by a more detailed discussion of the possible pathogenetic consequences of specific abnormalities and their impact on prognosis.

The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 x 10(9)/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.

A widely accepted definition of resistance or intolerance to hydroxyurea (HU) in patients with essential thrombocythemia (ET) is lacking. An international working group (WG) was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET. To this aim, an analytic hierarchy process (AHP), a multiple-attribute decision-making technique, was used. The steps consisted of selecting the candidate criteria for defining resistance/intolerance; identifying the motivations that could influence the preference of the WG for any individual criterion; comparing the candidate criteria in a pair-wise manner; and grading them according their ability to fulfill the motivations. Every step in the model was derived by questionnaires or group discussion. The WG proposed that the definition of resistance/intolerance should require the fulfillment of at least one of the following criteria: platelet count greater than 600,000/micro l after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400,000/micro l and WBC less than 2500/micro l or Hb less than 10 g/dl at any dose of HU; presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU; HU-related fever.

Most patients with polycythemia vera and half with idiopathic myelofibrosis and essential thrombocythemia have an acquired V617F mutation in JAK2. Using sensitive polymerase chain reaction (PCR)-based methods, we genotyped 152 patients with idiopathic myelofibrosis to establish whether there were differences in presentation and outcome between those with and those without the mutation. Patients positive for V617F had higher neutrophil and white cell counts (P = .02) than did patients negative for V617F, but other diagnostic features were comparable between the 2 groups. Patients positive for V617F were less likely to require blood transfusion during follow-up (P = .03). Despite this, patients positive for V617F had poorer overall survival, even after correction for confounding factors (P = .01).

Background: We conducted a randomized comparison of hydroxyurea with anagrelide in the treatment of essential thrombocythemia., Methods: A total of 809 patients with essential thrombocythemia who were at high risk for vascular events received low-dose aspirin plus either anagrelide or hydroxyurea. The composite primary end point was the actuarial risk of arterial thrombosis (myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, or peripheral arterial thrombosis), venous thrombosis (deep-vein thrombosis, splanchnic-vein thrombosis, or pulmonary embolism), serious hemorrhage, or death from thrombotic or hemorrhagic causes., Results: After a median follow-up of 39 months, patients in the anagrelide group were significantly more likely than those in the hydroxyurea group to have reached the primary end point (odds ratio, 1.57; 95 percent confidence interval, 1.04 to 2.37; P=0.03). As compared with hydroxyurea plus aspirin, anagrelide plus aspirin was associated with increased rates of arterial thrombosis (P=0.004), serious hemorrhage (P=0.008), and transformation to myelofibrosis (P=0.01) but with a decreased rate of venous thromboembolism (P=0.006). Patients receiving anagrelide were more likely to withdraw from their assigned treatment (P<0.001). Equivalent long-term control of the platelet count was achieved in both groups., Conclusions: Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for patients with essential thrombocythemia at high risk for vascular events., (Copyright 2005 Massachusetts Medical Society.)