Bertozzi, Irene

Abstract Abstract 277 Background: Current information on the natural history of polycythemia vera (PV) is mostly derived from early studies based on the PV Study Group diagnostic criteria. The World Health Organization (WHO) diagnostic approach to PV is currently the gold standard. The main objective of the current study was to describe survival, disease complication rates and risk factors in WHO-defined PV. Methods: Under the auspices of an International Working Group, seven international centers of excellence for myeloproliferative neoplasms submitted a total of 1,430 patients, locally diagnosed with “WHO-defined PV”. The two principle investigators (AT and TB) reviewed all the cases and selected 1,263 patients who were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting Features: Median age was 60 years (range, 18–95; 51% females). The number of patients diagnosed between 1970–1990, 1991–2000, and 2001–2011 were 136 (11%), 337 (27%) and 790 (62%), respectively. Arterial/venous thrombosis history before or at diagnosis was documented in 142/73 and 80/42 patients, respectively. Other features at diagnosis included pruritus (37%), microvascular disturbances (29%), palpable splenomegaly (37%), abnormal karyotype (13%), and leukoerythroblastosis (6%). History of hypertension (45%), hyperlipidemia (17%), diabetes (9%), and tobacco use (15%) was also obtained. Results II: Clinical Course: To date, 228 (18%) deaths, 42 (3%) leukemic progressions, and 101 (8%) fibrotic transformations have been recorded. Post-diagnosis arterial or venous thrombosis occurred in 139 (11%) and 85 (7%) patients, respectively. Cytoreductive therapy had not been used in 342 (27%) patients whereas 154 (12%) patients were exposed to two or more cytoreductive drugs. Results III: Risk Factors: Multivariable analysis identified advanced age, leukocytosis, venous thrombosis history and abnormal karyotype as significant (p<0.01) risk factors for overall survival (OS). Receiver operating characteristic (ROC) plots delineated ages 69 (AUC 0.83) and 59 (AUC 0.61) years and leukocyte count 13 × 109/L (AUC=0.61) as the best discriminant levels in this regard; HR (95% CI) were 11.4 (7.7–16.9) for age ≥70 years, 3.8 (2.6–5.7) for age 60–69 years, and 2.0 (1.5–2.6) for leukocyte count ≥15 × 109/L. Results IV: Risk Stratification: HR-based risk scores were assigned to age ≥70 years (3 points), age 60–69 years (2 points) and leukocyte count ≥15 × 109/L (one point), in order to create four risk groups: low (zero points; n=492; median survival 322 months), intermediate-1 (one or 2 points; n=353; median survival 208 months; HR 3.8, 95% CI 2.5–5.8), intermediate-2 (3 points; n=286; median survival 132 months; HR 10.7, 95% CI 6.9–16.5), and high (4 points; n=56; median survival 90 months; HR 22.7, 95% CI 13.9–37.1) (Figure 1). Similar results were obtained when analysis was restricted to the 1,011 JAK2 mutation-positive patients (Figure 2). The particular risk model was equally robust in predicting leukemia-free survival (p=0.001). Conclusions: Age and leukocyte count matter the most in predicting survival in PV. The current study suggests additional prognostic value from karyotype and venous thrombosis history. Disclosures: Vannucchi: Novartis: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Speakers Bureau; AOP-Orphan: Speakers Bureau.

Abstract Abstract 5148 INTRODUCTION. Patients presenting with a clinical picture of essential thrombocythemia (ET) can actually have an early/prefibrotic myelofibrosis (PMF), according to current WHO criteria, in about 18% of cases. Laboratory tests which are significantly different in early/prefibrotic PMF as compared with histologically confirmed ET (WHO-ET) include decreased gender-matched hemoglobin (Hb), increased white blood cell (WBC), platelet (PLT) counts and lactate dehydrogenase (LDH) values. AIM. To evaluate sensitivity (SE) and specificity (SP) of blood cell counts and LDH, at presentation, for the diagnosis of early/prefibrotic PMF vs. WHO-ET. METHODS. Five hundred thirty-six cases (50%) who had complete laboratory data measured at diagnosis constituted the exploratory set of our study and were derived from an international ET database. The discriminatory ability of Hb, WBC, PLT and LDH in correctly classifying patients in the early/prefibrotic PMF or WHO-ET groups was initially tested by plotting their Receiving Operating Characteristic (ROC) curves and comparing the relative Areas Under the Curve (AUC) with the value of 0.50 (which stands for the completely useless of the test). Three parameters with statistically significant discriminatory power were chosen (Hb, WBC and LDH) and thresholds searched in order to guarantee at least 90% of SE or SP. Finally, a diagnostic algorithm was designed. The validation set of this analysis was constituted by 321 patients with WHO-ET (n=62) or early/prefibrotic PMF (n=259) diagnosed by the same pathologist who confirmed the training set cohort and collected in the Institute for Pathology, University of Cologne, Germany. SE and SP for the same parameters and thresholds as well as the final diagnostic algorithm were applied to this set of patients to demonstrate the results' reproducibility. RESULTS. Sensitivity and specificity to recognize early/prefibrotic PFM have been evaluated by ROC curves. The best performance was found for LDH (AUC = 0.7059). WBC and Hb had super imposable curves, with AUC of 0.6279 and 0.6257, respectively. The worst performance was registered for PLT count: its AUC was only 0.5628, not significantly different from the reference value of 0.50 (p=0.154). Thresholds of Hb, WBC and LDH were searched to achieve at least 90% of SE or SP. HB < 12 g/dL for women or <13 g/dL for men, and WBC >= 13 x109/L had higher SP (92% and 91%, respectively). High SP is highly related to the presence of early/prefibrotic PMF (true positives). On the contrary, LDH < 200 mU/mL and WBC < 7 x109/L had good sensitivity (91% and 94%, respectively). High SE is highly related to the absence of early/prefibrotic PMF (true negatives). By applying these SE and SP values in a step-by-step algorithm, nearly half of patients (48%) could be classified as WHO-ET or early/prefibrotic PMF, assuming at each step a margin of error of less than 10%. For the remaining 50% of patients, laboratory results didn't allow to suspect or exclude the presence of early/prefibrotic PMF. In the validation set of 321 patients classified by WHO 2008 as true ET or early/prefibrotic PMF (Cologne cohort) SP of anemia was 84%, WBC < 7 x109/L or >= 13 x109/L had 91% and 81% of SE and SP, respectively. LDH values < 200 mU/mL had 85% of SE. By applying the same flow-chart, 46% of patients were classified as WHO-ET or early/prefibrotic PMF. CONCLUSIONS. The present study provides clinicians with laboratory parameters that should increase suspicion of early/prefibrotic PMF in a patient with a working clinical diagnosis of ET. In fact, while patients presenting clinically with ET can now be discriminated as true ET or early/prefibrotic PMF by adopting the WHO 2008 criteria that require bone marrow histology, an algorithm including baseline anemia, WBC count and LDH, allows this differentiation in about 50% of patients with a good approximation. However, for a definitive proof, bone marrow histology is still an integral part for final diagnosis. Disclosures: Vannucchi: Novartis: Honoraria.

Abstract Abstract 1746 Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification, that provides a guideline to distinguish ET from early/prefibrotic primary myelofibrosis. These two conditions differ in term of disease evolution and survival (Barbui et al, J. Clin. Oncol. 2011). To design a prognostic model for survival in WHO-defined ET (International Prognostic Score for Essential Thrombocythemia, IPSET), we studied 891 patients with strict WHO diagnostic criteria. Demographics have been presented elsewhere (Barbui et al, J. Clin. Oncol. 2011). We tested the prognostic impact on survival of age, prior thrombosis, leukocyte count, platelet count, hemoglobin level, JAK mutational status, splenomegaly. Harrell's C concordance statistics were used to set the best cutoff levels of continuous variables in order to predict survival. Univariate Cox proportional hazard regression showed that age over 60 years (P<.0001), leukocyte count greater than 11 x109/L (P<.0001), anemia (P=.04), platelet count greater than 1000 x109/L (P<.004) and prior history of thrombosis (P< 0001) were significant risk factors for survival. Age over 60 years (hazard ratio-HR- 6.5, 95% CI: 3.9–10.7; P<.0001), leukocyte count greater than 11 × 109/L (HR: 3.1, 95% CI: 2–4.7; P<.0001) and prior history of thrombosis (HR: 2.9, 95% CI: 1.9–4.5; P< 0001) retained statistical significance on survival by multivariable analysis and were included in the new prognostic model. We assigned each factor an integer weight close to the corresponding HR in the multivariable Cox regression: weight 2 for age over 60 years; weight 1 for leukocyte count greater than 11 x109/L and for prior thrombosis. Finally, we defined the IPSET score by allocating patients into three risk categories with significantly different survival according to the sum of weights: low risk (sum of weights=0; n= 342; median survival not reached), intermediate risk (sum=1-2; N=374; median survival 24.5 years), and high risk (sum=3-4, n=158; median survival 13.8 years). Fisher exact test did not reveal a difference in the distribution of the causes of death among IPSET categories. We validated the model in two independent cohorts: one from Germany (132 WHO-defined ET) and another from France (234 ET patients not strictly diagnosed according to WHO). Log rank test and Cox regression showed significant differences in term of survival among IPSET categories in both series. Finally, we designed an age-specific IPSET model for patients younger than 60 years (IPSET-y). Using the same methodology, we found that age over 45 years (weight 2), leukocyte count greater than 11 × 109/L (weight 1) and prior history of thrombosis (weight 1) were independent risk factors for survival. IPSET-y defined three risk categories (LR, sum=0; IR, sum=1-2; HR, sum=3–4) with a median survival not reached in LR and IR, and of 22.3 years in HR. In conclusion, IPSET, based on age over 60 years, leukocyte count greater than 11 x109/L and history of thrombosis allows prognostic assessment of WHO-defined ET. The validation process makes IPSET applicable in all patients phenotypically appearing as ET. IPSET models may be useful for treatment decision-making. Disclosures: Vannucchi: Italfarmaco: Consultancy; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals AG: Research Funding.

Abstract Abstract 3846 INTRODUCTION There is strong evidence indicating that the clear-cut separation of prefibrotic primary myelofibrosis (PMF) from essential thrombocythemia (ET) by consequent application of the World Health Organization (WHO) 2008 criteria is reflected in different, well defined clinical pictures and divergent prognoses (Barbui et al, JCO 2011,Thiele et al, Blood 2011). Very recently the specific risk profile for arterial and venous thrombosis in WHO- diagnosed ET was published (Carobbio et al, Blood 2011). In PMF so far all published data on vascular events were exclusively based on overt disease manifestations until now there are no data available regarding prefibrotic stages. Consequently, we aimed to evaluate the corresponding risk profile of patients with WHO-diagnosed prefibrotic PMF. METHODS A total number of 264 patients with WHO-defined prefibrotic PMF derived from either the Medical University of Vienna or an International Database (Barbui et al, JCO 2011) were studied. Nonfatal thrombotic events considered in this study were reported as rates per 100 patient-years and included transient ischemic attacks, thrombotic cerebrovascular accidents, coronary artery disease, myocardial infarction, peripheral arterial disease, deep vein thrombosis of peripheral vasculature, pulmonary embolism, and abdominal large vein thrombosis. Cardiovascular risks factors considered, comprised of arterial hypertension, diabetes mellitus and tobacco use. To evaluate risk factors for total thrombosis and for arterial and venous events in particular multivariate Cox- regression analysis including the co-variables sex, age, previous thrombotic event, laboratory parameters measured at diagnosis and need for cytoreductive and/or antiplatelet therapy during follow-up was calculated. P values less than 0.05 were considered as statistically significant. RESULTS After a median follow- up of 5.8 years (range0.0 – 27.2), the total rate of non fatal thrombotic events was 2.1% patient-years (95% CI, 1.5–2.8); the incidence of arterial events was higher (1.7% patient- years) than of venous events (0.6% patient-years).Considering thrombosis in general a higher white blood cell (WBC) count enhances the risk significantly (p=0.005; HR 1.15). This is also true in arterial events in particular (p=0.047; HR 1.12). A lower platelet count is associated with a higher risk for thrombotic events; for thrombosis in general this association is of borderline significance (p=0.056; HR 0.99), for arterial thrombosis in particular of significance (p= 0.042; HR 0.99). A lower hemoglobin level is associated with a higher risk for venous thrombosis (p=0.007; HR 0.59). CONCLUSION Leukocytosis appears as a risk factor for thrombosis in general and also for arterial thrombosis in particular in WHO-diagnosed prefibrotic PMF. Moreover, higher platelet counts seem to decrease significantly the risk for thrombotic events in general and arterial thrombosis in particular. Anemia is associated with a higher risk for venous thrombosis. These observations are partly in line with recently published findings in WHO-diagnosed ET (Carobbio et al,2011) and might indicate the existence of a specific risk profile for thrombotic events in prefibrotic PMF. This is the first study reporting data on the risk profile for thrombosis in WHO-diagnosed prefibrotic PMF. Certainly these findings ask for validation in a larger patient population. Disclosures: Gisslinger: Novartis: Speakers Bureau; Celgene Austria: Research Funding, Speakers Bureau; AOP-Orphan Pharmaceuticals AG: Speakers Bureau. Vannucchi:Novartis: Honoraria.

Abstract Abstract 457 Introduction- The 2008 World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (MPN) underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early, and at times prefibrotic, primary myelofibrosis (PMF) that clinically presents like ET. The value of such a distinction in predicting clinical outcome has been questioned by some investigators. Study Design- Clinician scientists and hematopathologists from seven international centers of excellence for ET convened to design a clinicopathologic database of patients locally diagnosed and treated as ET. Study eligibility criteria included availability of treatment-naïve BM specimens obtained within one year of diagnosis. All bone marrows subsequently underwent a central blinded re-review by the author of the pertinent WHO chapter (JT) who applied strict WHO guidelines to identify cases of early PMF that were spuriously diagnosed as ET. Results- Revision of the BM biopsies according to the WHO morphological criteria confirmed ET in 891 patients (81%). Diagnosis was revised to early, prefibrotic PMF in 180 patients (16%). The remaining 33 (3%) BM specimens were qualitatively inadequate for accurate classification or represented unclassified cases. i) At presentation, early PMF, as opposed to true ET, was characterized by higher leukocyte (p<0.0001) and platelet (p=0.002) counts, lower hemoglobin (p=0.01) and hematocrit (p=0.001) levels, higher serum lactate dehydrogenase level (p<0.0001), higher circulating CD34+ cell count (p=0.03) and higher rate of palpable splenomegaly. JAK2V617F mutational frequency was 60% in each of the two groups. ii) Median follow-up was 6.2 years for ET and 7.0 years for early PMF. During this period, the rates of arterial (1.2-1.4% patients/year) and venous (0.6 patients/year) thrombotic complications were similar in the two groups. However, patients with early PMF, as compared to those with ET, were more likely to develop overt myelofibrosis (1% vs. 0.5% patients/year; RR=2.0, p=0.04) or acute leukemia (0.6% vs. 0.1% patients/year; RR=5.2, p=0.001). Cumulative leukemic transformation rate at 10 and 15 years was 0.7% and 2.1% in true ET versus 5.8% and 11.7% in PMF Similarly, survival was significantly worse in patients with early PMF (mortality rate: 2.7% vs. 1.3% patients/year; RR=2.1, p=0.002).The 10 and 15-years overall survival rates were: 89% and 80% in true ET versus 76% and 59% in PMF. On multivariable analysis, other risk factors for poor survival were age > 60 years (HR=6.3, p<0.0001), a leukocyte count of > 11×109/L (HR=2.13, p<0.0001) and history of thrombosis (HR=3.0, p<0.0001). Conclusions- The current study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides seminal information on the survival and risk of leukemic transformation in strictly WHO-defined ET, which appears to be substantially better than previously assumed. Disclosures: No relevant conflicts of interest to declare.

Abstract Background In the recent International Prognostic Score for Thrombosis in essential thrombocythemia (IPSET-thrombosis), age and history of thrombosis were confirmed as independent risk factors for future thrombosis and the study also identified independent prothrombotic role for cardiovascular (CV) risk factors and JAK2 V617F mutation (Barbui et al. Blood 2012). Methods In the current study, we re-analyzed the original IPSET-thrombosis data in 1019 patients with WHO-defined ET in whom JAK2 mutational status was available, in order to quantify the individual contributions of JAK2 mutations and CV risk factors in conventionally-assigned low and high risk ET, as well as in age- versus thrombosis-defined high risk status. Results After a median follow-up of 6.8 and 5.0 years in conventionally-assigned low- and high-risk patients, respectively, the overall annual rate of total thrombosis (108 events) in conventionally-assigned low- and high-risk patients was 1.11%-pt/y (CI 0.81-1.52) and 2.46%-pt/y (CI 1.94-3.11) respectively (p=0.001), and the difference was mainly due to a higher frequency of arterial thrombosis in high-risk patients (p<0.001).The influence of JAK2 mutational status and CV-risk factors on the rate of thrombosis in conventionally assigned low- and high-risk groups is presented in the table. Table 1. Additional risk factors N (%) Event Rate % pts/yr (95% CI) P-value P-value P-value trend Low risk 506 (50) 39 1.11 (0.81-1.52) None 200 (40) 7 0.44 (0.21-0.92) ref Cardiovascular risk factor 36 (7) 3 1.05 (0.34-3.25) 0.220 0.227 JAK2V617F 213 (43) 21 1.59 (1.04-2.44) 0.001 0.217 Both 52 (10) 8 2.57 (1.29-5.15) <0.001 ref <0.001 High risk 513 (50) 69 2.46 (1.94-3.11) None 111 (22) 10 1.44 (0.78-2.68) ref Cardiovascular risk factor 44 (9) 4 1.64 (0.62-4.37) 0.909 0.067 JAK2V617F 222 (43) 30 2.36 (1.65-3.38) 0.168 0.082 Both 136 (27) 25 4.17 (2.82-6.17) 0.011 ref 0.005 The number of major arterial and venous thrombosis was reported as rates per 100 patient-years and the difference among groups was assessed by Mantel Cox log-rank test i) Conventionally-assigned low-risk group. Amongst 506 patients, 200 (40%) displayed neither JAK2 mutation nor CV risk factors and their annual rate of thrombosis was 0.44%, as opposed to 1.05% in the presence of CV risk factors (P=NS), 1.59% in the presence of JAK2 mutation (p=0.001) and 2.57% in the presence of both CV risk factors and JAK2 mutation (P<0.001). There was no significant difference when low-risk patients with both JAK2 mutation and CV risk factors were compared with either those with CV risk factors only (p=0.227) or those with JAK2 mutation only (p=0.217). ii) Conventionally assigned high-risk group: The absence or presence of one or both of the aforementioned additional risk factors for thrombosis were documented in 111 (22%), 44 (9%), 222 (43%) and 136 (27%) patients, respectively, with corresponding annual rates of thrombosis at 1.44%, 1.64%, 2.36% and 4.17% (Table). High-risk patients with both risk factors had a significantly higher risk of thrombosis compared to their counterparts with the absence of JAK2 mutations and CV risk factors (p=0.011). Additional analysis revealed limited enhancement of thrombosis risk by either JAK2 mutations or CV risk factors or both in patients whose high-risk status was defined by the presence of thrombosis history, regardless of age (P=NS). In contrast, the presence of JAK2 mutations, with or without CV risk factors, might have affected thrombosis risk in patients where high-risk status was defined by age alone (p=0.05). Conclusions The current study suggests the possibility of considering four risk categories in ET: "very low risk" group (age ≤60 years and without thrombosis history, JAK2 mutations or CV risk factors); "low risk" (age ≤60 years and without thrombosis history but with JAK2 mutations or CV risk factors); "intermediate risk" (age>60 years but without thrombosis history or JAK2 mutations); and "high risk" (thrombosis history at any age or JAK2 -mutated patients who are older than 60 years of age). Treatment recommendations for each one of the above-mentioned new risk categories should be examined in the context of prospective controlled studies. Disclosures Barbui: Novartis: Speakers Bureau. Vannucchi:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees. Buxhofer-Ausch:AOP Orphan: Research Funding. De Stefano:Novartis: Research Funding, Speakers Bureau; Janssen Cilag: Research Funding; Shire: Speakers Bureau; GlaxoSmithKline: Speakers Bureau; Bruno Farmaceutici: Research Funding; Roche: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Gisslinger:Janssen Cilag: Honoraria, Speakers Bureau; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Geron: Consultancy; Sanofi Aventis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

Abstract Background Current risk stratification in Polycythemia Vera (PV), is designed to estimate the likelihood of thrombotic complications. In ECLAP large prospective study of 1638 PV cases diagnosed by Polycythemia Vera Study Group (PVSG) criteria, risk factors were age over 65 years and prior thrombotic events. After the JAK2V617F discovery, diagnosis has undergone substantial revision by the World Health Organization (WHO). Consequently, current risk factors determination should be described in patients diagnosed by the most recent recommendations and requires a large sample size with reliable and sufficiently long clinical course documentation. Accordingly, the current study includes 1545 patients with strictly WHO-defined PV diagnosed and followed-up in seven centers from Italy, Austria and the United States, belonging to the International Working Group for Myeloproliferative Neoplasm (MPN) Research and Treatment (IWG-MRT). Objective and design 1) Describe the rate of thrombosis in this population; 2) Report the sites and frequency of recurrences after a first arterial or venous event; 3) Identify separately risk factors for arterial versus venous thrombosis and develop practically useful prognostic models. Results 1. Presenting features The characteristics of the cohort recruited reflected well the heterogeneity of epidemiologic and clinical features that are found in the routine clinical practice of PV. Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) and 114 (7.4%) patients, respectively. The frequencies of arterial and venous thrombosis were lower than those recorded in the ECLAP4 (27% and 11% respectively) but comparable to those reported in the recent Cyto-PV2 (arterial 17%, venous 12%) studies. The discrepancy might be partly related to earlier diagnosis in the post-ECLAP JAK2mutation era. 2. Thrombotic events after diagnosis Median follow-up was 6.9 years and treatment included aspirin (84%) and cytoreductive agents (73%), in addition to phlebotomy. Post-diagnosis total major thrombosis rate was 2.62% pt/yr, lower than reported in the ECLAP trial (4.4% pt/yr) but comparable to the Cyto-PV study (2.7% pt/yr) where management of cardiovascular risk factors was more intensive than in ECLAP. Arterial or venous thrombosis occurred in 184 (12%, rate: 1.59 % pts/yr) and 137 (9%, rate: 1.05 % pts/yr) patients, respectively. In addition, prior arterial events were associated in 75% of cases with subsequent arterial events and in the remaining 25% with venous thrombosis including splanchnic vein events. Moreover, patients with prior venous events had recurrences in venous district in 61% of cases and in the arterial district in 39%. 3. Risk factors for arterial versus venous thrombosis and prognostic models In multivariable analysis, arterial thrombosis was predicted by previous arterial event (HR 1.7, 95% CI 1.2-2.4), and hypertension (HR 1.6, 95% CI 1.2-2.2) while predictors of venous events were previous venous thrombosis (HR 2.6, 95% CI 1.5-4.4), and age ≥ 65 years (HR 1.7, 95% CI 1.2-2.5). We used the above-mentioned risk factors in order to develop prognostic models allowing to identify patients at different probability to develop arterial or venous thrombosis. For arterial thrombosis, the absence of previous arterial thrombosis and hypertension defined lower-risk (rate 1.27 % pts/yr) while the presence of one or both identified higher-risk patients (rate 2.04 % pts/yr). Previous venous event and/or age ≥ 65 years identified patients at higher risk of venous (rate 1.62 % pts/yr) thrombosis and, if absent, patients at lower risk (rate 0.78 % pts/yr). Conclusion The overall rate of thrombosis was half than in ECLAP and should be considered in future clinical trials. Of note, patients with a prior venous thrombosis had a more frequent subsequent recurrence in the venous district but a proportion of them (40%) had also arterial events; conversely, recurrences after previous arterial event were also registered in the leg and non-leg veins in 30 % of cases, indicating that in PV, venous and arterial thrombosis may share some common pathogenetic mechanisms. These findings may have practical implications and suggests antiplatelet therapy and anticoagulant therapy as the favorite choice to prevent arterial and venous thrombosis, respectively, but also suggests studies of antithrombotic drug combination. Disclosures No relevant conflicts of interest to declare.

Abstract Accurate prediction of thrombosis in essential thrombocythemia (ET) provides the platform for prospective studies exploring preventive measures. Current risk stratification for thrombosis in ET is 2-tiered and considers low- and high-risk categories based on the respective absence or presence of either age > 60 years or history of thrombosis. In an international study of 891 patients with World Health Organization (WHO)–defined ET, we identified additional independent risk factors including cardiovascular risk factors and JAK2V617F. Accordingly, we assigned risk scores based on multivariable analysis–derived hazard ratios (HRs) to age > 60 years (HR = 1.5; 1 point), thrombosis history (HR = 1.9; 2 points), cardiovascular risk factors (HR = 1.6; 1 point), and JAK2V617F (HR = 2.0; 2 points) and subsequently devised a 3-tiered prognostic model (low-risk = < 2 points; intermediate-risk = 2 points; and high-risk = > 2 points) using a training set of 535 patients and validated the results in the remaining cohort (n = 356; internal validation set) and in an external validation set (n = 329). Considering all 3 cohorts (n = 1220), the 3-tiered new prognostic model (low-risk n = 474 vs intermediate-risk n = 471 vs high-risk n = 275), with a respective thrombosis risk of 1.03% of patients/y versus 2.35% of patients/y versus 3.56% of patients/y, outperformed the 2-tiered (low-risk 0.95% of patients/y vs high-risk 2.86% of patients/y) conventional risk stratification in predicting future vascular events.

Abstract Diagnosis of essential thrombocythemia (ET) has been updated in the last World Health Organization (WHO) classification. We developed a prognostic model to predict survival at diagnosis, named IPSET (International Prognostic Score for ET), studying patients with WHO-defined ET. Age 60 years or older, leukocyte count ≥ 11 × 109/L, and prior thrombosis significantly affected survival, by multivariable Cox regression. On the basis of the hazard ratio, we assigned 2 points to age and 1 each to leukocyte count and thrombosis. So, the IPSET model allocated 867 patients into 3 risk categories with significantly different survival: low (sum of points = 0; median survival not reached), intermediate (sum = 1-2; median survival 24.5 years), and high (sum = 3-4, median survival 13.8 years). The IPSET model was further validated in 2 independent cohorts including 132 WHO-defined ET and 234 Polycythemia Vera Study Group–defined ET patients. The IPSET model was able to predict the occurrence of thrombosis, and not to predict post-ET myelofibrosis. In conclusion, IPSET, based on age ≥ 60 years, leukocyte count ≥ 11 × 109/L, and history of thrombosis allows prognostic assessment of WHO-defined ET and the validation process makes IPSET applicable in all patients phenotypically appearing as ET.