High-risk Essential Thrombocythemia Patients Research Articles

The Approach to Thrombosis Prevention across the Spectrum of Philadelphia-Negative Classic Myeloproliferative Neoplasms

Patients with myeloproliferative neoplasm (MPN) are potentially facing diminished life expectancy and decreased quality of life, due to thromboembolic and hemorrhagic complications, progression to myelofibrosis or acute leukemia with ensuing signs of hematopoietic insufficiency, and disturbing symptoms such as pruritus, night sweats, and bone pain. In patients with essential thrombocythemia (ET) or polycythemia vera (PV), current guidelines recommend both primary and secondary measures to prevent thrombosis. These include acetylsalicylic acid (ASA) for patients with intermediate- or high-risk ET and all patients with PV, unless they have contraindications for ASA use, and phlebotomy for all PV patients. A target hematocrit level below 45% is demonstrated to be associated with decreased cardiovascular events in PV. In addition, cytoreductive therapy is shown to reduce the rate of thrombotic complications in high-risk ET and high-risk PV patients. In patients with prefibrotic primary myelofibrosis (pre-PMF), similar measures are recommended as in those with ET. Patients with overt PMF may be at increased risk of bleeding and thus require a more individualized approach to thrombosis prevention. This review summarizes the thrombotic risk factors and primary and secondary preventive measures against thrombosis in MPN.

The Impact of Hydroxyurea on Survival and Risk of Thrombosis Among Older Patients with Essential Thrombocythemia

Introduction: Patients with essential thrombocythemia (ET) are at greater than 20% risk for thrombotic complications. They are categorized into high- and low-risk groups based on the presence of advanced age (> 60 years) and / or thrombosis history. One of the main goals of ET treatment is thrombosis prevention. Use of hydroxyurea (HU) among high-risk ET patients improves rate of thrombosis and is the frontline guideline-recommended therapy for older patients. Little is known about HU impact on the survival and thrombosis in the real-world setting.Methods: Using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database, we identified patients diagnosed with ET (International Classification of Diseases for Oncology, 3rd edition, code 9962) from 2007-2011. Patients were required to: 1) be aged 66-99 years; 2) have continuous enrollment in Medicare Parts A and B from one year before diagnosis to death or the end of study (12/31/2012); and 3) have continuous Part D six months before diagnosis to the end of follow-up to capture HU use. HU users were restricted to those who had more than two HU prescription claims. HU coverage was calculated as the percentage of days from diagnosis to the end of follow-up covered by HU prescriptions. Thrombotic events were defined as first occurrence of venous thrombosis, arterial thrombosis, or sudden death after diagnosis. Predictors of receiving HU were evaluated using multivariate logistic regression models. Multivariable Cox proportional hazard regression models were utilized to assess the impact of HU on survival and thrombotic events, controlling for patient age at diagnosis, sex, race, Part D low income subsidy (a proxy marker for lower socioeconomic status), influenza vaccination 12 months prior to diagnosis (an indicator for health care access), disability status (a claims-based proxy for poor performance status), modified Elixhauser comorbidity score (the original comorbidity score excluding cardiovascular conditions), and pre-existing cardiovascular conditions. HU was treated as a time-dependent variable in the Cox model.Results: A total of 654 high-risk ET patients with a mean age of 79.0 (standard deviation =7.4) years were included in the study, of which 67.9% were women and 85.5% were white. The median duration of follow-up was 2.5 years. In this large sample of older patients, only 59.2% of the patients received HU after ET diagnosis. Results of multivariate logistic regression models showed that patients with comorbidities (p<.01), with pre-existing cardiovascular conditions (p=.05), or disabled (p<.01) were less likely to receive HU. At the end of follow-up, 26.6% (n=103) HU users and 58.8% (n=157) non-users died. The median survival for HU non-users was 2.53 years, while it was not reached for HU users (log-rank test, p<.01, Figure 1). In the multivariate Cox model, HU usage after diagnosis was associated with a significantly lower risk of death (hazard ratio [HR]=0.42, 95% confidence interval [CI]: 0.32-0.54, p<.01). Every 10% increase of HU coverage was associated with a 16% decreased risk of death (HR=0.84, 95% CI: 0.81-0.88, p<.01). A total of 235 (35.9%) patients had thrombotic events after diagnosis, including 180 arterial thromboses, 54 venous thromboses and 1 sudden death. Thrombotic events occurred in 25.3% (n=85) HU users and nearly half of the HU non-users (47.2%, n=150). The median time to develop thrombosis was not reached for HU users and was significantly longer than for HU non-users (2.12 years, log-rank test, p<.01, Figure 2). In the multivariate model, compared with non-users, HU users had a significantly lower risk of thrombotic events (HR=0.51, 95% CI: 0.38-0.68, p<.01). Every 10% increase of HU coverage was associated with a 13% lower risk of thrombotic events (HR=0.87, 95% CI: 0.84-0.91, p<.01). Sensitivity analyses, which only included patients who survived more than 6 months, showed similar association between use of HU, improved survival and decreased incidence of thrombotic events.Conclusions: To our knowledge, this is the first study to evaluate association between HU and survival among high risk ET patients. Use of HU was associated not only with improved overall survival but also with reduced incidence of thrombotic events in older ET patients. HU was underutilized in the studied high risk ET population, including patients with pre-existing cardiovascular conditions who need the drug the most. [Display omitted] DisclosuresPodoltsev:Incyte: Consultancy; CTI biopharma/Baxalta: Consultancy; Alexion: Consultancy; Ariad: Consultancy. Zeidan:Otsuka: Consultancy; AbbVie, Otsuka, Pfizer, Gilead, Celgene, Ariad, Incyte: Consultancy, Honoraria; Takeda: Speakers Bureau. Huntington:Celgene: Consultancy, Other: Travel; Janssen: Consultancy; Pharmacyclics: Honoraria. Ma:Incyte Corp.: Consultancy.

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.

Cardiovascular Safety of Anagrelide Hydrochloride versus Hydroxyurea in Essential Thrombocythaemia

Essential thrombocythaemia (ET) is a rare myeloproliferative neoplasm. This multicentre, Phase 3b, randomised, open-label, non-inferiority study investigated the cardiac safety, efficacy and tolerability of first-line treatment with anagrelide or hydroxyurea in high-risk ET patients for up to 3 years. Eligible patients aged ≥ 18 years with a diagnosis of high-risk ET confirmed by bone marrow biopsy within 6 months of randomisation received anagrelide (n = 75) or hydroxyurea (n = 74), administered twice daily. Treatment dose for either compound was titrated to the lowest dose needed to achieve a response. Planned primary outcome measures were change in left ventricular ejection fraction from baseline over time and platelet count at Month 6. Planned secondary outcome measures were platelet count change from baseline at Months 3 and 36; percentage of patients with complete or partial response; time to complete or partial response; number of patients with thrombohaemorrhagic events; and changes in white blood cell count or red blood cell count over time. Neither treatment altered cardiac function. There were no significant differences in adverse events between treatment groups, and no reports of malignant transformation. The incidence of disease-related thrombotic or haemorrhagic events was numerically higher in anagrelide-treated patients. Both treatments controlled platelet counts at 6 months, with the majority of patients experiencing complete or partial responses. In conclusion, these results suggest that long-term treatment with anagrelide is not associated with adverse effects on cardiac function. This is one of the few studies using left ventricular ejection fraction assessment and central biopsy reading to confirm the diagnosis of ET.Trial registration number: Clinicaltrials.gov NCT00202644

Direct Oral Anticoagulant Use and Outcomes in Patients with High and Intermediate Risk BCR-ABL-Negative Myeloproliferative Neoplasms

Background: Patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) are prone to thrombohemorrhagic complications. Vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) are considered standard treatments for venous or arterial thromboses in BCR-ABL-negative MPN patients. However, there is little information regarding the safety and efficacy of direct oral anticoagulants (DOACs) in this population. Our primary aim was to determine the prevalence and outcomes of DOAC use in BCR-ABL-negative MPN patients at our institution. Methods: We performed a single-center, retrospective cohort study of all active BCR-ABL-negative MPN patients in the UCSF Hematology Clinic between January 2017 and March 2019. Patients were identified by ICD-10 codes and chart abstraction. Problem and medication lists were reviewed for appropriate diagnoses and medications. Provider notes were reviewed for anticoagulation indication, treatment course, and hemorrhagic or thrombotic complications. Descriptive statistics were used to summarize the data. Results: Of 299 patients with BCR-ABL-negative MPNs, 42 were treated with anticoagulation during our abstraction period. Of the 42 patients, 22 (52%) were treated with DOACs, 17 (41%) with warfarin, and 3 (7%) with LWMH. Of the 22 patients on DOACs, the median age was 74 (range 39-94) with a female to male ratio of 1.2:1. Of those on DOACs, the most common diagnosis was essential thrombocythemia (ET) (n=9; 41%), followed by primary myelofibrosis (MF) and post-ET or post-PV myelofibrosis (n=7; 32%), polycythemia vera (PV) (n=5; 22%), and MPN-Unclassifiable (n=1; 5%). All ET and PV patients (except 1 ET) were high-risk by IPSET-thrombosis and clinical criteria, and all primary myelofibrosis and post-ET or post-PV myelofibrosis patients were intermediate-2 by DIPSS-plus. Most patients were JAK2 V617F positive (n=19; 86%), with the remainder positive for CALR type 2 (n=2; 9%) and type 1 (n=1; 5%). Almost all ET and PV patients were concurrently treated with hydroxyurea (12/14; 86%) and 1 out of 5 PV patients was also treated with phlebotomy. Roughly one-third of patients (n=8; 36%) remained on aspirin while on a DOAC. Of the 22 patients, 15 (68%) were prescribed DOACs for thrombosis treatment and prophylaxis. The primary indications were pulmonary embolus (PE) (n=5), deep venous thrombosis (DVT) (n=4), splanchnic thrombosis (SVT) (n=3), organ ischemia (n=2), and cerebral sinus thrombosis (CVT) (n=1). The remaining 7 patients were on DOACs for atrial fibrillation, although two had histories of prior thrombotic events (PE and stroke). Nine (41%) of the patients on DOACs had a history of more than one significant venous or arterial thrombotic event. Most were on long-term anticoagulation with a median DOAC prescription of 26 months (range 4 to 62). Nineteen patients (86%) remained on a DOAC at their last provider visit, with two having completed treatments for provoked PEs and one discontinued for thrombocytopenia. DOACs prescribed for thrombosis indications included apixaban (n=8), rivaroxaban (n=5), and dabigatran (n=2). Of the 22 patients on DOACs, none experienced significant thrombotic events and one patient had a hemorrhagic event shortly before establishing care at our institution; a post-PV MF patient on dabigatran for a splanchnic thrombosis had an upper gastrointestinal bleed and required reversal with idarucizumab. Of the patients on warfarin and LWMH, there were 4 significant thrombohemorrhagic events: 1 bleeding and 3 clotting. The bleeding event happened in a high risk ET patient on warfarin plus aspirin for a splanchnic vein thrombosis (INR 2.2). Three clotting events occurred in high risk ET and PV patients on warfarin. One was concurrently diagnosed with a DVT, PE, and arterial thrombus (INR 2.1), and the other two were diagnosed with portal vein thromboses (INRs of 1.8 and 2.2). None were taking hydroxyurea or aspirin at time of their recurrent thrombosis. Conclusions: DOACs were used more frequently than warfarin or LWMH in our high and intermediate risk BCR-ABL-negative MPN patients with no clotting events but one notable hemorrhagic event. Future research regarding the safety and efficacy of DOAC use in BCR-ABL-negative MPNs, including randomized controlled trials, should be considered. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Logan:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; TeneoBio: Consultancy; Kadmon: Research Funding; Pharmacyclics: Research Funding; Abbvie: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kiadis: Consultancy; Kite: Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; Mirati Therapeutics: Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Spectrum: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding. Smith:Revolution Medicines: Research Funding; Astellas Pharma: Research Funding; fujiFilm: Research Funding; Abbvie: Research Funding.

Compassionate Use of Ropeginterferon-Alfa-2b/P1101 for Treatment of High Risk Polycythemia Vera and Essential Thrombocythemia Patients Previously Controlled on Pegylated Interferon-Alfa-2a/Pegasys®

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms (MPN) associated with morbidity and mortality resulting from thrombosis or transformation to myelofibrosis and/or secondary acute leukemia. The acquired somatic mutation JAK2V617Fhas been observed in 98% of PV patients, and around 50% of ET patients. Interferon is known to be an effective treatment for chronic MPNs, but unlike hydroxyurea (HU, Hydrea®), it has been shown to target the malignant clone by decreasing JAK2V617Fallelic burden, and in some patients restoring polyclonal hematopoiesis. (Liu et al, Blood. 2003;101:3294-3301). The covalent binding of polyethylene glycol to the interferon molecule, through pegylation, prolongs the half-life by lowering the clearance of interferon, thereby extending the duration of its therapeutic effects, permitting less frequent administration and fewer side-effects. Currently, there are two commercially available pegylated interferons in the U.S., peginterferon alfa-2b (PEG-Intron®, Merck) and peginterferon alfa-2a (Pegasys®, PEG, Roche), both with heterogeneous pegylation with multiple pegylation sites. Ropeginterferon-alfa 2b/P1101 (ROPEG) is a novel longer acting mono-pegylated recombinant proline-interferon alfa-2b which has shown good efficacy in PV and has successfully completed a phase III trial in PV patients comparing it against HU (PROUD-PV study) in Europe (ASH2016 Abstract;Blood. 2016;128:475).Earlier, we had enrolled 53 high risk PV and ET patients to the Myeloproliferative Disorders Research Consortium (MPD-RC) trials #111 (refractory to HU) and #112 (randomized to HU vs PEG)(www.clinicaltrials.gov; NCT01259856 and NCT01259817). After the completion of these trials, PEG was no longer supplied by the study and not adequately covered by insurance for many of our patients. Therefore, ROPEG was procured under an FDA-approved expanded access program and used as a substitute for those controlled on PEG, and these patients are being transitioned from PEG to ROPEG according to the dosing strategy shown in Table 1.Seven patients have been switched onto ROPEG as of writing this abstract (Table 2). After a mean follow-up of roughly 8 weeks (range: 2 - 10 weeks), all have maintained response to therapy and none have had a thrombotic event or new or increased interferon-related side effects thus far. Patient 002 experienced elevated AST/ALT while on PEG, which normalized after four q2 week doses of ROPEG (8 weeks of therapy). Patients 003 and 004 who had persistent fatigue on PEG, saw significant improvement of their symptoms after switching to ROPEG. In patient 005 who has ET, bone marrow cytogenetics at entry to PEG had a paracentric inversion of the long arm of chromosome 3, namely 3q21.3q26.2 (RPN1/MECOM, inv3; diagnostic of AML per WHO criteria), in 16/20 (80%) metaphases. Over the 4 ensuing years while on PEG, this cytogenetic abnormality progressively decreased. FISH assay was set up 2 years ago wherein 86/200 cells (46%) were positive with lowest achieved level of 36/200 cells (18%) without any evidence of emerging AML. Upon transition to ROPEG (2 fortnightly injections of 50 mcg), this response was maintained (23/200 cells scored (11.5%). Of the 3 patients who were JAK2V617Fpositive, one patient (patient 003) showed a decrease in the JAK2V617Fallelic burden (37% to 18%) after two months of ROPEG despite decreasing the dose to 50 mcg (from 100 mcg) 2 weeks after the first injection, while the other two patients had no statistically significant change in their JAK2V617Fallelic burden. Clonality will be followed in female subjects to see if clonal hematopoiesis is suppressed and normalizes with long-term administration of ROPEG.Our early experience suggests ROPEG is a safe and effective alternative to PEG permitting less frequent administration for patients with high risk PV and ET. Notable observations include normalization of hepatic transaminases previously induced by PEG, maintenance or even suppression of one highly deleterious cytogenetic abnormality, maintenance of ET & PV remission, and amelioration of interferon side-effects with lower equivalent doses. In the future, we intend to increase the pool of patients by designing a protocol for newly diagnosed high risk ET and PV with randomization to HU versus ROPEG. DisclosuresNo relevant conflicts of interest to declare.

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: 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.

Unmet Needs for Symptom Control in Essential Thrombocythemia with Front Line Therapy

Background:Thrombotic and hemorrhagic complications are commonly encountered in uncontrolled essential thrombocythemia (ET). Both anagrelide and hydroxyurea (HU) have proven efficacious in cytoreduction as well as reducing these events and remain first line therapy for most high-risk ET patients. Independent of their role in risk-reduction, little is known about how these therapies impact patient symptomatology or quality of life. In this study, we compared the clinical and symptomatic profiles of ET patients receiving HU or anagrelide against patients with no previous experience with these agents.Methods:Data was assessed from a prospectively collected international database of ET patients in which demographics, disease features, and ET symptoms utilizing the myeloproliferative neoplasm symptom assessment form (MPN-SAF; Scherber et al, 2011). The MPN-SAF includes the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Total symptom score (TSS) was computed based on symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. ET risk scores were calculated using the IPSET scoring algorithm (Passamonti 2012). Thrombocytopenia was defined as a platelet count <100 x 10(9)/L, anemia was defined as hemoglobin<10 g/dL and leukopenia was defined as a white blood cell count <4.0 x 10(9)/L. Associations between the MPN-SAF individual symptoms were investigated using chi-square test for categorical data and ANOVA F-test for continuous variables.ResultsHydroxyurea vs. HU NaiveA total of 402 ET patients with active HU use were compared to 392 ET patients with no history of HU use. Patients using HU were older (63.5 years vs. 52.3 years, p<0.001) and had a greater concentration of both high risk (24.9% vs. 11.4%, p=0.001) and intermediate risk (53.9% vs 38.4%, p<0.001) patients. They also had a higher rate of prior thrombosis (29.8% vs 11.3%, p<0.001) and leukopenia (10.1% vs. 3.0%, p<0.001). No differences were noted between gender, a history of prior hemorrhage, red blood cell transfusion requirements, or the presence of anemia/thrombocytopenia. In comparing symptom profiles, no significant differences were noted between TSS or individual symptoms with the exception of slightly more severe cough in HU patients (1.5 vs. 1.1, p=0.02, Figure 1).Anagrelide vs. Anagrelide NaiveA total of 49 ET patients with active anagrelide use were compared to 794 ET patients with no history of anagrelide use. Patients using anagrelide had a longer mean disease duration (8.1 years vs. 5.8 years) and were more anemic (9.1% vs. 1.2%, p<0.001). No differences were noted between age, gender, risk scores, the presence of leukopenia/thrombocytopenia, a history of prior thrombosis or hemorrhage complications or red blood cell transfusion requirements. Additionally, there were no significant differences between TSS or individual symptom items (Figure 1).HU vs. AnagrelideA total of 402 patients currently using HU were compared to 39 patients currently using anagrelide. Overall, HU users were slightly older (63.5 years vs. 55.1 years, p<0.001) with a greater population of patients meeting high risk criteria (24.9% vs. 2.8%, p=0.002) and having a history of prior thrombosis (29.8% vs. 12.8%, p=0.02). Patients receiving anagrelide had a slightly longer disease duration (8.2 years vs. 6.0 years, p=0.0446). In comparing symptom profiles, no differences were noted in TSS or individual symptom items between cohorts.DiscussionIn this retrospective analysis, it does not appear cytoreduction with either HU and/or anagrelide has a significant impact on ET symptom burden despite reducing vascular events. Importantly, the higher risk scores in HU patients did not translate directly into greater patient symptomatology supporting previous studies demonstrating a poor association between these two items. Prospective trials measuring ET symptom change, in the setting of randomized trials will better quantify impact of cytoreduction on symptom burden as well as quantify impact of newer agents such as interferon or jak inhibition. [Display omitted] DisclosuresKiladjian:Incyte Corporation: Consultancy; Novartis: Other: Travel grant; Research Funding paid to institution (Hôpital Saint-Louis et Université Paris Diderot); Novartis: Consultancy. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Barbui:Novartis: Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding. te Boekhorst:Novartis: Consultancy; CTI Biopharma: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Speakers Bureau; Novartis: Other: Research Funding paid to institution (University of Florence), Research Funding; Baxalta: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis. Research- incyte, Gilead, cti, Genentech, promedior, NS Pharma: Consultancy.

Long-Term Interferon-α Treatment in Essential Thrombocythemia

▪Background: Essential thrombocythemia (ET) is a chronic myeloid stem cell disorder characterized by an uncontrolled production of platelets. Common complications are recurring thrombotic events and/or haemorrhage. Although ET is in general associated with good prognosis, prognostically adverse events such as fibrotic or leukemic transformation occur at an increasing risk in patients with long disease duration. Since interferon-α (IFN-α) harbors the potential of inducing molecular remission in approximately 20% of ET patients as demonstrated by JAK2 V617F, the drug may prolong the natural course of the disease. Therefore, in particular younger ET patients are likely to benefit from long-term IFN-α treatment.Since data on long-term effects of IFN-α treatment are scarce, we here report on safety, efficacy, and molecular markers from ET high-risk patients being treated with IFN-α at our institution for up to 21 years.Results: Within 12 months (Jan 2014 - Dec 2014), 73 ET patients at the median age of 61 years (range 31-97) presented for regular follow-up at our out-patient clinic. All patients have given informed consent for data evaluation according to the Declaration of Helsinki. Eighty-one percent (59/73) were high-risk characterized by the presence of ≥1 of the following risk factors: i) age >60 years, ii) previous thrombosis, or iii) platelet count >1.500/nL. All high-risk patients received cytoreductive therapy: Hydroxyurea (HU) was the most frequent drug administered at last follow-up (27/59, 46%), followed by IFN-α (18/59, 30%), anagrelide (11/59, 19%), or HU plus anagrelide (3/59, 5%). At the time of data evaluation, no ET patient was treated with an approved or experimental drug within a clinical study. Of the 59 high-risk patients, a total number of 27 patients (46%) were currently (n=18) or previously (n=9) treated with IFN-α (conventional IFN-α, n=3; pegylated IFN-α, n=24). Median age of the total IFN-α cohort was 54 years (range 40-85). Main reasons for IFN-α initiation in these patients were previous thrombosis (n=16, 59%) and high platelet count (n=7, 26%), followed by age >60 years (n=4, 15%). Interestingly, one third of patients (9/27) received IFN-α as a long-term therapy for 10-21 years. IFN-α was discontinued in the 9 previously treated patients after a median treatment time of 71 months (range 1-206). Main reasons for discontinuation were depression/fatigue (n=3), arthralgia (n=2), diarrhea/nausea (n=2), lack of response (n=1), or myocardial infarction (n=1). Of note, the myocardial infarction represented a thromboembolic event and occurred in complete hematologic remission under long-term treatment with IFN-α (206 months). No further vascular events were recorded under IFN-α therapy. Given a total observation time of 211 patient years, the vascular complication rate in our IFN-α cohort is 0.13 per patient and year. Furthermore, no disease progression to secondary myelofibrosis or acute myeloid leukemia occurred during the whole observation period. Since JAK2 V617F had been identified in the year 2005, peripheral blood from all ET patients presenting at our out-patient clinic was preserved. In approximately one half of the 27 patients, IFN-α treatment was initiated before (n=14, 52%) or after (n=13, 48%) the year 2005. Mutation testing in the earliest samples available from each patient revealed mutation frequencies of JAK2 V617F, MPL W515L, and CALR of 52% (14/27), 0% (0/27), and 30% (8/27) in the total IFN-α population. Interestingly, patients under long-term treatment with IFN-α (10-21 years) were either triple-negative (n=3) or CALR mutated (n=6) at the sensitivity limit of DNA-based fragment analysis (~1%). Serial quantification of the JAK2 V617F allele burden before and under IFN-α could be performed in 10 patients and showed a decrease from 10.5% (5-27%) to 2.9% (0.1-22%) at the last follow-up (p = .004).Conclusions: We conclude from our data that long-term treatment with IFN-α for 10 years or more is feasible in approximately one third of high-risk ET patients. In our patients receiving IFN-α, vascular complications were restricted to a single event in an observation time of 211 patient years, whereas no disease progressions to secondary myelofibrosis or acute myeloid leukemia occurred. Controlled clinical trials are warranted to prove the long-term benefit of IFN-α treatment in high-risk ET. DisclosuresOff Label Use: Interferon-alpha is used and recommended for decades in therapy of essential thrombocythemia although randomized clinical trials leading to approval of the drug are lacking.. Schlenk:Pfizer: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Arog: Honoraria, Research Funding; Boehringer-Ingelheim: Honoraria; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.

Abstract 387: Ischemic Stroke Following Discontinuation of Antiplatelet Therapy in Essential Thrombocythemia: A Case Report

Introduction: Essential thrombocythemia (ET) is a rare cause of ischemic stroke. Low-dose aspirin is currently recommended for the prevention of thrombotic events in ET. However, the benefit is controversial. Herein, we report a case of ischemic stroke induced by ET following discontinuation of antiplatelet therapy. Case presentation: An 87- year-old African American male brought to ER with one episode of black stool (Guaiac positive). He had history of peripheral vascular disease, deep venous thrombosis, coronary artery disease, type 2 diabetes, and a stroke that happened 6 years ago. He had been on oral aspirin 81mg and clopidogrel 75mg daily which were discontinued after admission. Laboratory studies showed significantly elevated platelet count of 640 x 10^9/L on admission. Two days later, he developed one episode of transient slurred speech and right side body weakness. At that time, his platelet count was 736 x 10^9/L. Five days later he developed slurred speech, difficulty swallowing and right side hemiplegia. MRI brain demonstrated acute infarct in left basal ganglia and posterior limb of the left internal capsule. Platelet count was 859 x 10^9/L which continued to increase to over 1000 x 10^9/L after the stroke. Diagnosis of ET was confirmed with the detection of JAK2 V617F mutation in peripheral blood sample. Thrombolysis was not initiated due to new gastrointestinal bleeding although no source was identified with endoscopic study, but aspirin and clopidogrel were resumed, and hydroxyurea was added. Physical therapy was started. Discussion: Thrombotic complications are major causes of morbidity and mortality in ET likely due to persistently enhanced platelet activation. Low-dose aspirin is currently recommended in ET patients. However, no randomized trials have directly assessed the efficacy and safety of low-dose aspirin or other antiplatelet drugs for primary prophylaxis of thrombotic complications in ET, and only a non-significant risk reduction was reported for secondary prophylaxis of arterial thrombosis with antiplatelet drugs in ET. The case described here indicates that antiplatelet therapy is important in high risk ET patients, and caution should be exercised when discontinuing antiplatelet drugs in these patients.

Cytoreduction plus low‐dose aspirin versus cytoreduction alone as primary prophylaxis of thrombosis in patients with high‐risk essential thrombocythaemia: an observational study

The effectiveness of low-dose aspirin in the primary prevention of thrombosis in patients with high-risk essential thrombocythaemia (ET) treated with cytoreductive drugs is not well established. The risk-benefit balance of low-dose aspirin plus cytoreductive therapy compared with cytoreduction alone was retrospectively analysed in 247 patients with high-risk ET without prior thrombosis. Follow-up was 763 and 685 person-years for cytoreduction plus low-dose aspirin and cytoreduction alone, respectively. The rate of thrombosis was not significantly reduced in patients on cytoreduction plus aspirin (14·4 events per 1000 person-years) when compared with those on cytoreduction alone (24·8 events per 1000 person-years; P=0·2). However, in the subgroup of patients older than 60years, the addition of low-dose aspirin was associated with a significantly lower rate of thrombosis (8·6 vs. 29·2 thrombosis per 1000 person-years for combined treatment and cytoreduction alone, respectively, P=0·02). The rate of major bleeding was significantly higher with combined therapy than with cytoreduction alone both in the whole series (14·4 vs. 1·4 haemorrhagic events per 1000 person-years, respectively, P=0·006) and in the subgroup of patients older than 60years. In conclusion, low-dose aspirin benefits high-risk ET patients older than 60years receiving cytoreductive therapy as primary prophylaxis of thrombosis.

Front-line therapy in polycythemia vera and essential thrombocythemia

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

Cardiac surgery in a patient with essential thrombocythemia: a case report.

Patients with essential thrombocythemia (ET) are at increased risk of developing arterial thrombosis. We report a case of a 36-year-man with unstable angina in the presence of occlusion of two coronary arteries with insufficient collateral perfusion. We also found essential thrombocythemia in this patient. The patient underwent coronary artery bypass grafting (CABG). Ten days before surgery, the aspirin was replaced by a prophylactic dose of low-molecular-weight heparin. Postoperative follow-up was complicated by pulmonary embolisms and a cardiac tamponade. We conclude that ET is a risk factor for coronary heart disease that should be treated with aspirin. If a patient needs CABG, aspirin should be continued because of the high risk of thromboembolic events in the high-risk ET patients. (Neth Heart J 2010;18:378-80.).

Final Results of the ANAHYDRET-Study: Non-Inferiority of Anagrelide Compared to Hydroxyurea in Newly Diagnosed WHO-Essential Thrombocythemia Patients

Background: Both anagrelide and hydroxyurea effectively lower platelet counts in essential thrombocythemia (ET) and other thrombocythemic myeloproliferative neoplasms. Anagrelide has a selective inhibitory effect on megakaryopoiesis and platelet production in contrast to hydroxyurea, which is a nonspecific, myelosuppressive compound inhibiting megakaryopoiesis as well as granulopoieses and erythropiesis. Based on the superiority of hydroxyurea+aspirin over anagrelide+aspirin in ET patients in the PT1-trial, guidelines for cytoreductive therapy favor hydroxyurea as first line therapy for ET. However, the diagnosis of ET in the PT1-trial was made according to the PVSG cassification and it remains questionable if these recommendations can be applied to ET patients diagnosed according to the WHO classification.Patients and methods: In this prospective randomized single blind international multicenter phase III study efficacy and tolerability of anagrelide and hydroxyurea monotherapies were compared in high risk ET patients diagnosed according to the WHO classification. The study was designed as a non-inferiority trial as the limited number of treatment naïve ET patients available and the expected low number of ET related events following treatment with a cytoreductive therapy would not have allowed the conduct of a conventional superiority trial. After informed consent 258 treatment naïve, high risk patients with ET were randomized to receive either anagrelide (n=122) or hydroxyurea (136). The patients characteristics were equally distributed within both arms with a median age of 58,1 years, range 19–90 years; 46 male, 76 female in the anagrelide arm vs. a median age of 56,4 years, range 22– 83 years, 47 male, 89 female in the hydroxyurea arm. Anagrelide (Thromboreductin) was started with a dose of 1mg/day and hydroxyurea was initiated using a dose of 1500mg/day.Results: A central blinded pathologic review of 236 bone marrow biopsies revealed a high reproducibility of the ET diagnosis by applying the WHO classification: 194 (82.2%) of patients were classified as ET, 16 patients (6,8%) were reclassified as PMF-0 and 16 patients (6,8%) were considered to be early PVs with an ET-like clinical phenotype. Confirmatory proof of non-inferiority was achieved after a mean observation time of 2,1 years (comprising 539 patient years) based on predefined equivalence criteria for platelet counts, course of hemoglobin levels and white cell count during therapy, and for the rate of ET related events. In the anagrelide arm 75,4% of the patients received a complete response of platelet counts (<450×109/l) compared to 81,7% in the hydroxyurea arm. Neutrophile counts remained unchanged in the anagrelide arm but were significantly reduced by hydroxyurea. No significant differences were observed for the rates of major and minor clinical complications in the anagrelide group (4,29%, and 16,8%, resp.) compared to hydroxyurea (4,25%, and 12,8%, resp.). During the whole study period 11 major ET related complications occurred in the anagrelide group (5 arterial events, 2 venous thrombotic complications and 4 bleedings) and 12 major events were seen in the hydroxyurea arm (5 arterial events, 5 venous thrombositic events and 2 bleedings). 43 minor ET related events occurred in the anagrelide arm as compared to 36 such events in the hydroxyurea arm. Adverse drug reactions or poor response were reasons for discontinuations of the study drug in 19 patients treated with anagrelide and in 10 patients treated with hydroxyurea. Transformations to myelofibrosis were not reported during the whole study period. The JAK2 mutation status was evaluated in 189 patients with 101 JAK2 positive (53,4%) and 88 (46,6%) JAK2 negative patients. The impact of this mutation on thrombotic events in both arms will be presented at the meeting.Conclusion: The final analysis of the study provides evidence for non-inferiority of anagrelide compared to hydroxyurea in the treatment of ET diagnosed according to the WHO classification. Therefore it can be speculated that in these cases a thromboreductive therapy represented by anagrelide may be sufficient in order to prevent thrombotic complications whereas in other thrombocythemic MPN patients a cytoreductive treatment (e.g. with hydroxyurea) may be necessary.

Similar Rate of Thrombosis in Essential Thrombocythemia and Polycythemia Vera Patients after Stratification for JAK2 V617F Allele Burden.

Patients with Essential Thrombocythemia (ET) can be categorized as either JAK2 V617F mutated (V617F+) or wild type (V617F−). Mutated patients display multiple features resembling Polycythemia Vera (PV), with significantly higher hemoglobin level and neutrophil counts, lower platelet count, more pronounced bone marrow erythropoiesis and granulopoiesis and higher tendency to transform in PV. Presence of the mutation and/or allele burden has been variably associated with the rate of vascular complications in ET and PV, but a direct comparison between the two disorders under this respect has not been performed. To tackle this issue, we compared the rate of major thrombosis in 867 ET patients (57% were JAK2 V617F+) with that in 415 PV patients (all V617F+). The median follow-up was 4.9 (0 – 39) and 3.8 (0 – 26) years in ET and PV, respectively. High risk ET patients (age ≥ 60 years and/or previous thrombosis) received Hydroxyurea whereas the vast majority of low-risk remained untreated. PV patients were treated according to the current risk-stratified recommendations. Thrombotic episodes were recorded over time and calculated as rates % per patient/year (pt/yr). After adjusting for age, the thrombosis-free survival curves of JAK2 V617F+ and V617F− ET patients were superimposable until 10 years after the diagnosis, then they diverged so that the actuarial probability of major thrombosis in mutated ET patients reached that of PV (48% vs 55%, test for trend p=0.05). We found that JAK2 V617F+ allele burden measured by real-time quantitative PCR influenced these rates in a comparable way in both ET and PV. Actually, in JAK2 wild type ET (n=376, 43%) the rate was 1.4% pt/yr. In ET patients with JAK2 V617F+ allele burden ranging from 1 to 25% (N=190; 49%) the rate was 1.9 % pt/yr compared to 1.2 in PV patients (N=64, 19%); in the group with 26–50% the rate was 2.0 % pt/yr in ET (N=177; 45%) and 3.0 in PV patients (N=118, 36%); in cases of V617F+ allele burden greater than 50% the rate was 3.8 % pt/yr in ET (N=23; 6%) and 2.9 in PV patients (N=147, 45%). In conclusion, from this retrospective analysis, we conclude that in patients with ET harboring JAK2 V617F mutation the rate of stroke, myocardial infarction and venous thromboembolic complications is similar to that of PV patients and increases in dependence of V617F allele burden, supporting the hypothesis that ET and PV may be viewed as a continuum also in terms of vascular complications

Pharmacotherapy of essential thrombocythemia

Background: The natural history of essential thrombocythemia is characterized by an increased incidence of thrombotic and hemorrhagic events and, in the long-term, a tendency for disease transformation to myelofibrosis or acute leukemia. Advanced age and a prior history of thrombosis are the major predictors of thrombotic complications. Objective: The aim of this study was to outline the current evidence and the authors' opinion regarding the clinical management of patients with essential thrombocythemia. Methods: The study reviewed the pertinent literature addressing the management options for essential thrombocythemia patients. Results/conclusions: Cytoreductive agents can reduce the rate of thrombotic events, but do not affect the overall survival or rate of disease transformation. Thus, a risk-adapted strategy is recommended for the management of patients with essential thrombocythemia. High-risk patients with essential thrombocythemia should be treated with cytoreductive therapy and low-dose aspirin. Hydroxycarbamide is the agent of choice in most patients: however, interferon-α is a reasonable alternative in young patients, pregnancy or those intolerant of hydroxycarbamide. Low-risk patients can be safely observed. The management of intermediate-risk patients needs to be individualized: however, low-dose aspirin can be used after excluding acquired von Willebrand's disease. In the future we await the role of molecularly targeted therapy with JAK2 inhibitors in high-risk essential thrombocythemia patients.

198 INVITED Acute lymphoblastic leukaemia

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100 mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

200 INVITED What is known about HPV natural history? Current trends and variation in incidence, mortality and relation to screening programmes in Europe

Because the current therapy in polycythemia vera (PV) and essential thrombocythemia (ET) is aimed at lowering the risk of thrombosis, the risk classification system in these disorders is shaped according to thrombotic risk. Patients with either PV or ET can be stratified in a “high-risk” or “low-risk” category according to their age and previous history of thrombosis. Whether novel risk factors such as leukocytosis and JAK2 mutation may be included in the prognostic stratification requires confirmation in prospective future clinical studies. The identification and appropriate management of cardiovascular risk factors and the promotion of a healthy lifestyle in chronic myeloproliferative neoplasms (MPN), as in the general population, should be considered a cornerstone of vascular prevention. Blood hyperviscosity in PV is a major cause of vascular disturbances which severely impact on morbidity and mortality. An aggressive target of hematocrit lower than 45% in males and 42% in females has been advised by the European LeukemiaNet (ELN) group, although no convincing evidence of this recommendation is currently available. The efficacy and safety of low-dose aspirin (100 mg daily) in PV has been assessed in the European Collaboration on Low-dose Aspirin in Polycythemia (ECLAP) double-blind, placebo-controlled, randomized clinical trial. Translating evidence from the positive results of ECLAP to ET may be questionable. The most commonly used front-line therapy drugs for the treatment of high-risk PV and ET patients include hydroxyurea and alpha-interferon at any age while anagrelide is recommended as second line-therapy in resistant and intolerant ET patients. Busulphan is a front-line therapy in the elderly. By definition, children with ET are a population with low vascular risk unless a major thrombotic or hemorrhagic event has occurred. ELN recommends to prescribe cytoreductive drugs in children as a last resort. No results of clinical trials with JAK-2 inhibitor drugs in PV and ET are so far available.

Long-Term Incidence of Hematological Evolution in Three French Prospective Studies of Hydroxyurea and Pipobroman in Polycythemia Vera and Essential Thrombocythemia

Despite recent discoveries made in myeloproliferative disorders other than chronic myelogenous leukemia, which it is hoped will result in earlier diagnosis, and better evaluation and management of patients, hematological evolution to myelofibrosis, acute leukemia, and myelodysplastic syndromes (AL/MDS) remain major causes of long-term mortality in polycythemia vera (PV) and essential thrombocythemia (ET) patients. Evaluation of long-term leukemogenic risk of currently available drugs, therefore, is crucial. We report updated results of three French prospective trials of hydroxyurea and pipobroman in PV and ET patients with a median follow-up longer than 10 years. The results show that the incidence of AL/MDS is higher than previously reported with no evidence of a plateau (with approximately 40% of AL/MDS cases occurring after the 12th year of follow-up). Although hydroxyurea currently remains the first choice in the treatment of high-risk PV and ET patients, the use of nonleukemogenic drugs, such as interferon alpha (IFN-alpha) or anagrelide, should be assessed more widely in randomized trials using accurate diagnostic criteria and taking into account the presence of the JAK2 mutation, given that they may have an impact on disease evolution.