Low-risk Essential Thrombocythemia Research Articles

Resveratrol and tetrahydroisoquinoline effects on neutrophil sensitivity to NETosis formation in low-risk essential thrombocythemia patients.

Recent studies scrutinize how NETosis (a unique cell death mechanism of neutrophil), impacts thrombosis patients with essential thrombocythemia (ET). This research evaluates the susceptibility of ET neutrophils to form NETs and tests two potential inhibitors, resveratrol (RSV) and tetrahydroisoquinoline (THIQ), in vitro. Platelet-rich plasma from low-risk ET patients was used, along with neutrophils from both patients and controls. NET formation assays, with or without RSV and THIQ treatment after LPS stimulation, were conducted in a CO2 incubator. Evaluation included flow cytometry and fluorescence microscopy for NET formation and ELISA for TNFα, IL8, and vWF:Ag levels in patient and control plasma. Neutrophils from ET patients released more NETs than controls, confirmed by flow cytometry and fluorescence microscopy. Additionally, patients had significantly higher plasma levels of IL8 and TNFα compared to controls, while RSV was more effective than THIQ in reducing NETosis rates in these patients. In ET patients, a platelet counts over 1 million indicates the need for preventive treatment against thrombotic events. Similarly, in this study, RSV and THIQ significantly reduced the rate of NETosis in ET patients with higher platelet counts, and this role was more prominent in the case of the second inhibitor (RSV).

Patient-reported outcomes of patients with myelofibrosis or essential thrombocythemia enrolled in the MOST study

The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) is an ongoing, noninterventional study assessing clinical characteristics and patient-reported outcomes (PROs) of patients with myelofibrosis (MF) or essential thrombocythemia (ET). This analysis assessed PROs at enrollment; symptom burden and quality of life (QoL), work productivity, and activity were assessed using validated questionnaires in patients with low- or intermediate-1-risk (age-alone) MF, or high- or low-risk ET (receiving ET-directed therapy) at enrollment. In MF and ET cohorts, fatigue had highest mean symptom score. Women had higher mean total symptom scores (TSS), mean symptom scores, and reduced QoL versus men. In patients with MF, mean TSS and symptom scores were similar between risk groups. Patients with low-risk ET had higher mean TSS and symptom scores than patients with high-risk ET. In conclusion, patients with lower risk MF and low- or high-risk ET experience significant symptom burden affecting QoL and ability to work.

MPN-186 Community Versus Academic Practice in Essential Thrombocythemia and Myelofibrosis: Differences in Clinical Characteristics, Diagnosis, Treatment Patterns, and Symptom Burden: Analysis of Data from the MOST Study.

Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) (NCT02953704) is an ongoing observational study in essential thrombocythemia (ET) or myelofibrosis (MF) patients enrolled in academic (AC) and community (CC) centers throughout the US. Examine baseline demographics, diagnosis, treatment patterns, and symptom burden in AC versus CC. Longitudinal, prospective, noninterventional. 24 AC; 82 CC. High-risk (≥60 years old and/or thromboembolic history) or low-risk ET (receiving ET-directed therapy, excluding aspirin); ≥18 years old, with low-risk or intermediate-1-risk (INT-1-risk) MF (age >65 years). ET cohort (n=1,182): AC (n=273 [17% low-risk; 83% high-risk]); CC (n=909 [12% low-risk; 88% high-risk]). For AC versus CC, mean age (63.7 vs. 69.2 y), race, ethnicity, education level, and employment status were significantly different (P<0.05); 72.0% of AC versus 60.5% of CC patients had >high school education; 43.2% versus 28.2% were employed. Significantly fewer AC patients were White (84.4% vs. 90.3%) and Hispanic/Latino (4.0% vs. 8.6%) (P<0.05). Of high-risk AC versus CC patients, 78.4% versus 81.5% received ET-directed monotherapy (hydroxyurea, 81.5% vs. 82.3%; interferon, 7.3% vs. 0.9%; anagrelide, 5.6% vs. 12.1%). Among low-risk AC versus CC patients, 95.7% versus 93.6% received ET-directed monotherapy (hydroxyurea, 59.1% vs. 84.5%; interferon, 31.8% vs. 1.0%; anagrelide, 2.3% vs. 11.7%). Significantly more AC versus CC patients had ≥1 ET-related, physician-reported symptom and leukopenia (P<0.05). MF cohort (n=203): AC (n=92 [50% low-risk; 50% INT-1-risk]); CC (n=111 [35% low-risk; 65% INT-1-risk]). For AC versus CC, mean age (65.4 vs. 68.5 y), ethnicity, and education level were significantly different; significantly fewer AC than CC patients were Hispanic/Latino (0% vs. 6.3%) (P<0.05). Of low-risk AC versus CC patients, 60.9% versus 53.8% received MF-directed monotherapy (hydroxyurea, 57.1% vs. 52.4%; interferon, 10.7% vs. 4.8%). Among INT-1-risk AC versus CC patients, 50.0% versus 59.7% received MF-directed monotherapy (hydroxyurea, 17.4% vs. 48.8%; interferon, 30.4% vs. 2.3%). Similar percentages of AC versus CC patients had ≥1 MF-related, physician-reported symptom. Real-world data demonstrate similar care between AC and CC. The clinical significance of key differences in demographics, disease features, and treatment history remains unclear. Understanding these will help improve disease management across sites. Older and minority populations in CC may represent a key population for clinical trial recruitment.

Low-risk polycythemia vera and essential thrombocythemia: management considerations and future directions.

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.

Community Versus Academic Practice in Essential Thrombocythemia and Myelofibrosis: Differences in Clinical Characteristics, Diagnosis, Treatment Patterns, and Symptom Burden (Analysis of Data from the MOST Study)

Community Versus Academic Practice in Essential Thrombocythemia and Myelofibrosis: Differences in Clinical Characteristics, Diagnosis, Treatment Patterns, and Symptom Burden (Analysis of Data from the MOST Study)

Management Issues and Controversies in Low-Risk Patients with Essential Thrombocythemia and Polycythemia Vera.

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. 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.

Disease and Clinical Characteristics of Patients With a Clinical Diagnosis of Essential Thrombocythemia Enrolled in the MOST Study

Few data exist regarding the disease and clinical characteristics of patients with essential thrombocythemia (ET) in the United States. The ongoing, multicenter, noninterventional, prospective, Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) was designed to collect data pertaining to the demographics, clinical management, and patient-reported outcomes in patients with myelofibrosis or ET in the United States (NCT02953704). This analysis examines the clinical characteristics of patients with clinical diagnoses of high-risk or low-risk ET receiving ET-directed therapy at enrollment. At data cutoff (June 17, 2019), 1207 of 1234 enrolled patients were eligible for this analysis (median age, 70 years; 65% female; 88% white); 917 patients (76%) had mutation testing results available. The median time from ET diagnosis to study enrollment was 4.2 years. The majority of patients (87%) had high-risk ET. Of 333 patients with a history of thrombotic events, 247 had at least 1 event classified as arterial and/or venous. Platelet count was above normal range in 54% of patients. Hypertension (56%) was the most common comorbidity. At enrollment, the majority of patients (low-risk ET, 94%; high-risk ET, 79%) were receiving ET-directed monotherapy. Additional prospective analyses from MOST will help to identify areas of unmet need.

Myeloproliferative neoplasms and pregnancy: Overview and practice recommendations.

Pregnancy in the context of myeloproliferative neoplasms (MPN) poses unique fetal and maternal challenges. Current literature in this regard mostly involves essential thrombocythemia (ET) and less so polycythemia vera (PV) or myelofibrosis. In ET, live birth rate is estimated at 70% with first trimester fetal loss (˜ 30%) as the major complication. Risk of pregnancy-associated complications is higher in PV, thus mandating a more aggressive treatment approach. Herein, we appraise the relevant literature, share our own experience and propose management recommendations. Aspirin therapy may offer protection against fetal loss; however the additive benefit of systemic anticoagulation or cytoreductive therapy, in the absence of high risk disease, is unclear. We recommend cytoreductive therapy in the form of interferon alpha in all high risk and select low-risk ET and PV patients with history of recurrent fetal loss, prominent splenomegaly or suboptimal hematocrit control with phlebotomy. In addition, all women with PV should maintain strict hematocrit control <45% with the aid of phlebotomy. Systemic anticoagulation with low molecular weight heparin is advised in patients with history of venous thrombosis. Further clarification awaits prospective clinical trials that implement risk adapted therapeutic interventions.

Clinical Characteristics and Treatment Patterns By Risk Stratification in Patients with Essential Thrombocythemia: An Analysis of the MOST Study

Clinical Characteristics and Treatment Patterns By Risk Stratification in Patients with Essential Thrombocythemia: An Analysis of the MOST Study

Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus and risk of leukemic or fibrotic transformation. Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR or MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily or twice-daily aspirin (81 mg), in the absence of contraindications. Very low risk ET might not require therapy while aspirin therapy is advised for low risk disease. Cytoreductive therapy is recommended for high-risk ET and PV, but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Controlled studies are needed to confirm the clinical outcome value of twice-daily vs once-daily aspirin dosing and the therapeutic role of pegylated interferons and direct oral anticoagulants.

Co-existence of myeloproliferative neoplasias and β-thalassemia with IVS-2-654 mutation—a case report

Thalassemia and myeloproliferative neoplasias (MPNs) are recognized as two separate diseases. Thalassemia is a hemolytic disease caused by abnormal goblin genes, which results in the deficiency of globin chains. MPNs are clonal hematopoietic stem cell diseases characterized by the proliferation of multiple myeloid lineages. The coexistence of thalassemia and myeloproliferative neoplasia are rarely reported. We herein describe a case of a 24-year-old woman, previously diagnosed as β-thalassemia, with a lifelong history of thrombocytosis. She was subsequently diagnosed as low-risk essential thrombocythemia (ET), one of the MPNs. The patient was treated with folic acid supplementation and Iron-chelating therapy, without aspirin or cytoreductive therapy. Up to date, no thrombotic events or disease-related bleeding are happening to the patient, who remains in good health. Furthermore, we found three novel genes mutations EP300, CUX1, and FGFR3 after next-generation sequencing. We presume that the mutations of these genes in β-thalassemia might have an impact on the happening of ET and therefore need further investigations.

3023 Mayo Clinic Patients With Myeloproliferative Neoplasms: Risk-Stratified Comparison of Survival and Outcomes Data Among Disease Subgroups

ObjectiveTo document the Mayo Clinic decades-long experience with myeloproliferative neoplasms (MPNs) and provide mature risk-stratified survival data and disease complication estimates. Patients and MethodsAll Mayo Clinic patients with World Health Organization–defined MPNs constituted the core study group and included those with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). ResultsA total of 3023 consecutive patients (median age, 62 years; range, 18-96 years) were considered: 665 PV, 1076 ET, and 1282 PMF. From October 27, 1967, through December 29, 2017, 1631 deaths (54%), 183 leukemic transformations (6%), 244 fibrotic progressions (14%), and 516 thrombotic events (17%) were recorded. Median overall survival (OS) was 18 years for ET, 15 years for PV, and 4.4 years for PMF (P<.05 for all intergroup comparisons). Inferior survival was documented in patients with ET diagnosed more recently (post-1990) (P<.001), whereas survival data were time independent in PV and PMF. After conventional risk stratification, OS in low-risk ET and low-risk PV were superimposed (P=.89) but each differed significantly from that of age- and sex-matched controls (P<.001). Leukemia-free survival was similar for ET and PV (P=.22) and significantly worse with PMF (P<.001). Compared with ET, PV was associated with higher risk of fibrotic progression (P<.001). Thrombosis risk after diagnosis was highest in PV and lowest in PMF (P=.002 for PV vs ET; P=.56 for ET vs PMF; and P=.001 for PV vs PMF). ConclusionThis study provides the most mature survival and outcomes data in MPNs and highlights MPN subgroup risk categorization as key in appraising disease natural history. The OS was only marginally better in ET compared with PV, and PV displayed a higher risk of thrombosis and fibrotic progression.

3,023 Mayo Clinic Patients with Myeloproliferative Neoplasms: Risk-Stratified Comparison of Survival and Outcomes Data Among Disease Subgroups

▪Background:While several population-based studies have reported on adverse outcomes and life expectancy in myeloproliferative neoplasms (MPN) (JCO. 2015;33:2288; AJH. 1999;61:10; Leukemia. 2013;27:1874; JCO. 2012;30:2995), large-scale studies reporting mature data have been rare and important questions remain unanswered. The current study documents the Mayo Clinic (MC) decades-long experience with over 3,000 consecutive MPN patients including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) with the majority of patients followed until death. Herein, we provide mature, and importantly, risk-stratified survival data and disease complication estimates.Methods:Study patients were recruited from MC, Rochester, MN, USA between 10/27/1967 and 12/29/2017. All MPN diagnoses and documentation of fibrotic/leukemic transformations were in accordance with the 2016 World Health Organization criteria (Blood. 2016;127:2391). Clinical and laboratory data were abstracted from medical records. Risk-stratification used conventional risk models considering age, leukocytes, and venous thrombosis for PV (Leukemia. 2013;27:1874), international prognostic score for ET (Blood. 2012;120:1197), and dynamic international prognostic scoring system for PMF (Blood. 2010;115:1703). Statistical analyses were based on parameters obtained at the time of referral to MC which, in the majority of cases, coincided with or was within 1 year of diagnosis. All patients were followed from diagnosis until death or date of last follow-up/contact. Recipients of allogeneic stem cell transplants were censored at the time of transplant. Standard statistical methods and time-to-event curves prepared using the Kaplan-Meier method were used to compare MPN subgroups. Survival data for low-risk ET/PV were compared with age- and sex-matched controls from Olmstead County, MN, USA. JMP® Pro 13.0.0 software (SAS Institute, Cary, NC, USA) was used for all analyses.Results:3,023 consecutive patients (median age 62 years, range 18-96; 51% males) were considered, including 89% diagnosed within the year: 665 PV, 1076 ET and 1282 PMF. Conventional risk stratification in 2925 evaluable patients revealed low, intermediate, and high-risk status in 26%, 29%, and 45% of PV and 30%, 42%, and 28% of ET patients, respectively, while PMF cases were attributed low (14%), intermediate-1 (38%) -2 (40%) and high (8%) risk (Table 1). After a median follow-up of 8.2 years for PV (range 0-39), 9.9 for ET (range 0-47), and 3.2 for PMF (range 0-31), 1631 (54%) deaths, 183 (6%) leukemic transformations, 244 (14%) fibrotic progressions, and 516 (17%) thrombotic events were recorded (Table 1).Median overall survival (OS) was 18 years for ET, 15 for PV and 4.4 for PMF (p<0.05 for all inter-group comparisons) (Figure 1A). Leukemia-free survival was similar for ET and PV (p=0.22) and significantly worse for PMF (p<0.001) (Figure 1B). PV, compared to ET, was associated with higher risk of fibrotic progression (p<0.001) (Figure 1C). Thrombosis risk after diagnosis was highest in PV and lowest in PMF (p=0.002 for PV vs ET; 0.56 for ET vs PMF; and 0.001 for PV vs PMF) (Figure 1D).Following risk stratification, median OS in low-risk ET (28 years) and low-risk PV (27 years) were superimposed (p=0.89) (Figure 2). Similarly, intermediate or high-risk PV and ET patients had comparable OS within each risk strata (p=0.23 and 0.11, respectively). Low-risk PMF survival was analogous to that of intermediate-risk PV (p=0.06). All other risk-stratified categories disclosed significantly different inter- and intra-group survival patterns (p<0.001) (Figure 2).Despite their categorization as favorable-risk disease, both low-risk ET and low-risk PV displayed excess mortality relative to age- and sex-matched controls with median survival of 26.7 and 28.1 years respectively, compared to the expected 37.5 and 39.2 years (p<0.001) (Figure 3).Conclusions:The current study provides large-scale and uniquely mature survival and outcomes data in MPN and highlights MPN subgroup risk categorization as cardinal in appraising disease natural history. Interestingly, OS was only marginally better in ET, compared to PV, while the latter clearly displayed a higher risk of thrombosis and fibrotic progression. Moreover, data disclosed shortened life expectancy relative to matched controls even in MPN with favorable risk attribution. [Display omitted] DisclosuresBusque:BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Paladin: Consultancy.

Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk‐stratification and management

Disease Overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR, or myeloproliferative leukemia mutations. In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. Survival: Median survivals are 14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET. Risk of thrombosis is higher in JAK2-mutated ET. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. Thrombosis Risk: In PV, 2 risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors); in ET, 4 risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). Risk-Adapted Therapy: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once- or twice-daily aspirin (81 mg), in the absence of contraindications. Very low-risk ET might not require therapy while aspirin therapy is advised for low-risk disease. Cytoreductive therapy is recommended for high-risk ET and PV but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs.

Polycythemia vera and essential thrombocythemia: 2017 update on diagnosis, risk-stratification, and management.

Polycythemia Vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms respectively characterized by erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. JAK2, CALR, and MPL mutations are the mutually exclusive "driver" mutations in ET with respective incidences of 55%, 25%, and 3%; approximately 17% are triple-negative. However, the same molecular markers might also be present in prefibrotic myelofibrosis, whose morphological distinction from ET is prognostically relevant. Median survivals are approximately 14 years for PV and 20 years for ET; the corresponding values for younger patients (age <60 years) are 24 and 33 years. Life-expectancy in ET is inferior to the control population. Driver mutational status has not been shown to affect survival in ET whereas the presence of JAK2/MPL mutations has been associated with higher risk of arterial thrombosis and that of MPL with higher risk of fibrotic progression. Risk factors for overall survival in both ET and PV include advanced age, leukocytosis and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Most recently, ASXL1, SRSF2, and IDH2 mutations have been associated with inferior overall, leukemia-free or fibrosis-free survival in PV; similarly adverse mutations in ET included SH2B3, SF3B1, U2AF1, TP53, IDH2, and EZH2. Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis. Accordingly, PV includes two risk categories: high-risk (age >60 years or thrombosis history) and low-risk (absence of both risk factors). In ET, risk stratification includes four categories: very low risk (age ≤60 years, no thrombosis history, JAK2/MPL un-mutated), low risk (age ≤60 years, no thrombosis history, JAK2/MPL mutated), intermediate risk (age >60 years, no thrombosis history, JAK2/MPL un-mutated), and high risk (thrombosis history or age >60 years with JAK2/MPL mutation). In addition, presence of extreme thrombocytosis (platelets >1000 × 10(9)/L) might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily aspirin (81 mg). In addition, high-risk patients with PV require cytoreductive therapy. Very low risk ET patients might not require any form of therapy while low-risk patients require at least once-daily aspirin therapy. Cytoreductive therapy is also recommended for high-risk ET patients but it is not mandatory for intermediate-risk patients. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We currently do not recommend treatment with ruxolutinib or other JAK2 inhibitors in PV or ET, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 92:95-108, 2017. © 2016 Wiley Periodicals, Inc.

Management of extreme thrombocytosis in myeloproliferative neoplasms: an international physician survey.

Extreme thrombocytosis (ExT) has been associated with an increased bleeding risk in myeloproliferative neoplasm (MPN) patients and is included in the high risk category in treatment guidelines. Treatment of patients with ExT has not been studied in prospective trials. To study physicians' approaches to ExT, we distributed a web based questionnaire with clinical case scenarios to 202 members of MPN working groups. Cases included low thrombotic risk essential thrombocythemia (ET) with either JAK2V617F or CALR mutation, polycythemia vera with ExT either with or without leukocytosis, an ET patient needing urgent orthopedic surgery, and a poorly controlled ET patient with acute cerebral venous sinus thrombosis. Responses were received from 90 physicians (45%) and were variable in most case scenarios. Country of practice had the most significant influence on physician response. The USA and Israel physicians responded similarly in most cases and differently to the Europe physicians. Treatment of asymptomatic JAK2V617F positive ET and target platelet count on cytoreduction were significantly influenced by physician years of experience. Responses were not influenced by the volume of MPN practice or by whether MPN was considered a major interest by the physician. Our results show a lack of consensus on how to manage MPN patients with ExT. Randomized controlled trials properly designed to address these questions are needed.

Fatal ischemic stroke following Tityus serrulatus scorpion sting in a patient with essential thrombocythemia

Context: Stroke following scorpion stings is rare. We report a fatal envenomation involving multiple, extensive brain infarcts in a patient with a previous diagnosis of essential thrombocythemia (ET) who was stung by Tityus serrulatus (T. serrulatus).Case details: A 44-year-old woman with a diagnosis of low-risk ET (platelets <1,000,000/mm3, age <60 years and no history of thrombosis; positive JAK2V617F mutation) was admitted to a local ED 1 h after being stung by T. serrulatus on the left foot. She developed signs of severe envenomation, including several episodes of profuse vomiting, pallor and confusion soon after the sting, followed by shock (BP: 90/60 to 60/40 mmHg) and was treated with scorpion antivenom, vasopressors and mechanical ventilation. A brain computed tomography (CT) scan (54-h poststing) revealed diffuse bilateral cerebellar hypodensity, with partial involvement of both occipital lobes and thalamus, obstructive hydrocephaly with signs of cerebrospinal fluid extravasation, and ascending transtentorial herniation, suggestive of bilateral ischemia involving the posterior cerebral circulation. External ventricular drainage resulted in no improvement and brain death was confirmed on day 10.Discussion: Several mechanisms have been proposed to explain stroke following scorpion stings, such as sympathetic stimulation, myocardial dysfunction, hypotension/shock, arrhythmias and coagulopathy. Ischemic stroke is one of the most serious complications of ET. The risk factors for thrombotic/ischemic events in patients with ET include age (≥60 years) and previous vascular events. Severe scorpion envenomation resulting in myocardial dysfunction and systemic inflammatory response syndrome may increase the overall risk of arterial thrombosis in this patient.

Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation.

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2(V617F) mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2(V617F)-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2(V617F)-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3-42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2(V617F)-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

A Study of the Role of Antiplatelet Therapy in the Prevention of Thrombosis in Patients with Calr-Mutated Low Risk Essential Thrombocythemia

▪Young patients (age < 60 years) with essential thrombocythemia (ET) and no history of thrombosis are considered at low risk of thrombosis and therefore managed on a conservative approach with antiplatelet therapy or even without any treatment. JAK2 V617F and CALR exon 9 mutations are the most frequent molecular alterations observed in ET, with CALR-positive ET being considered a distinct clinical entity due to its higher platelet counts and lower incidence of thrombosis as compared with JAK2 V617F-positive ET. There is some evidence supporting a role for antiplatelet therapy in JAK2 V7617F-positive neoplasms. However, the role of antiplatelet therapy in CALR-positive ET has not been studied.The aim of the present study was to assess the effect of antiplatelet therapy in the primary prevention of thrombosis in patients with CALR-positive ET without indication of cytoreductive therapy. For such purpose, 240 patients (107 males, 133 females) diagnosed with ET at a median age of 42 years (range 13-59) were included in a multicenter retrospective study. Initial treatment consisted of antiplatelet therapy (n=109) or careful observation (n=108), whereas 23 patients received cytoreduction since diagnosis and were excluded. During a median follow up of 8 years, 137 patients were started on cytoreductive therapy because of the following indications: age > 60 years (n=10), thrombosis (n=10), bleeding (n=2), microvascular symptoms (n=18), extreme thrombocytosis (n=89), and others (n=8). Median time free of cytoreductive therapy was 3.2 years. Thrombosis-free survival restricted to the time of cytoreductive therapy abstention was calculated using the Kaplan-Meier method. Variables attaining a significant level at the univariate analysis were included in a Cox proportional hazard model.During the period of abstention of cytoreductive therapy, a total of 10 thrombotic events and 8 major bleeding episodes were registered. The probability of thrombosis at 3 years was 5% in patients managed with careful observation and 1% in those receiving antiplatelet therapy (p = 0.2). At multivariate analysis, antiplatelet therapy did not result in a lower risk of thrombosis after correction for age, sex and presence of cardiovascular risk factors. Interaction studies did not identify any subgroup of patients that benefited from antiplatelet therapy in thrombosis prevention. Regarding major bleeding, patients receiving antiplatelet therapy experienced a higher rate than those managed on observation (3-year probability of major bleeding, 5.5% and 0%, respectively, p=0.05). At multivariate analysis, antiplatelet therapy was associated with a tendency towards and increased risk of major bleeding (HR: 7.7, 95%CI: 0.9-66.2, p=0.06) independently of platelet count at diagnosis, age and gender.In conclusion, CALR-mutated low-risk ET patients under cytoreductive therapy abstention may not obtain a clear benefit from antiplatelet therapy since the increase in the rate of bleeding may offset the reduction in the rate of thrombosis DisclosuresGarcía-Gutierrez:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Approach to special issues associated with myeloproliferative neoplasms

Myeloproliferative neoplasms are frequently complicated by thrombosis and bleeding. Therefore, not only their primary prevention, but also the management of special clinical issues is important. These issues include venous thromboembolic disorders such as splanchnic venous thromboembolism, as well as major bleeding, surgery, and pregnancy. As for the primary prevention of thrombosis, it has been proposed that low-risk essential thrombocythemia with newly reported risk factors (cardiovascular risks or JAK2V617F) might be included among the factors meriting prevention. As for management of the aforementioned special clinical issues, an expert consensus has been established, wherein the recommended treatment strategies are described. In Japan as well, clinical practice based on this consensus would be preferable.