Müllauer, Leonhard

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 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.

Polycythemia vera (PV) is currently diagnosed by the World Health Organization (WHO) criteria regarding hemoglobin (HB) levels and JAK2V617F and related mutations or by the British Committee for Standards in Haematology (BCSH) guidelines predominantly based on hematocrit (HCT) values (>52% in men and >48% in women) in JAK2 mutated patients. We examined clinical features at diagnosis and outcome in 397 mutated PV patients showing a bone marrow (BM) morphology conforming with the WHO descriptions but including also cases with a HB level <18.5 g/dL in males (range 16.0–18.4) and <16.5 g/dL in females (range 15.0–16.4). These patients were regarded as masked PV (mPV) comprising 140 (35%) cases of our cohort. A comparison with the BCSH criteria based on HCT levels revealed a decrease of mPV patients to 59 (15%). In both classification systems, mPV patients were more males, presented more frequently with higher platelet counts, and increased BM reticulin fibrosis. A worsening of overall survival was documented in mPV patients in comparison with overt PV following the WHO (P = 0.011) as well as the BCSH (P = 0.0019) criteria. Risk factors for inferior survival in mPV were age >65 years and white blood cell count >15 × 109/L. Without these risk factors mPV patients had the same survival as overt PV suggesting that a fraction of patients with HB lower than that required for WHO diagnosis should still be considered as overt PV. This study has established the existence of mPV by two different classification systems based on either HB or HCT threshold values. Am. J. Hematol. 89:199–202, 2014. © 2013 Wiley Periodicals, Inc.

We examined the baseline features and clinical outcomes of 140 patients presenting with JAK2V617F positivity and a bone marrow morphology conforming with WHO criteria of polycythemia vera (PV), but a hemoglobin level of <18.5 g/dL in males (range 16.0–18.4) and <16.5 g/dL in females (range 15.0–16.4). This cohort operationally referred to as masked PV (mPV) was compared with 257 patients with overt PV and displayed male predominance, a more frequent history of arterial thrombosis and thrombocytosis. Incidence of thrombosis was similar between the two groups but mPV displayed significantly higher rates of progression to myelofibrosis and acute leukemia and inferior survival. In multivariable analysis mPV diagnosis was an independent predictor of poor survival along with age >65 years and leukocyte count >10 × 109/L. Our data suggest that mPV is a heterogeneous myeloproliferative neoplasia and not necessarily an early/ pre‐polycythemic form of classical PV that at onset in a small fraction of patients clinically may mimic essential thrombocythemia. On the other hand, the majority mPV may have a longer prodrome of undiagnosed PV or a disease biology akin to primary myelofibrosis‐post PV myelofibrosis that could explain the worsening of outcome in comparison to overt/classical manifestations. Am. J. Hematol. 89:52–54, 2014. © 2013 Wiley Periodicals, Inc.

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.

Abstract We examined the prevalence and prognostic relevance of bone marrow reticulin fibrosis in 526 patients with World Health Organization–defined polycythemia vera evaluated at the time of initial diagnosis. Seventy-four patients (14%) displayed mostly grade 1 reticulin fibrosis, with only 2 cases showing higher-grade fibrosis. Presenting clinical and laboratory characteristics, including JAK2V617F allele burden, between patients with and without fibrosis were similar for the most part, with the exception of a higher prevalence of palpable splenomegaly in patients with fibrosis (P < .01). Patients with fibrosis were less prone to experience thrombosis during their clinical course (1.1 vs 2.7 per 100 patient-years; P = .03) and more prone to develop post-polycythemia vera myelofibrosis (2.2 vs 0.8 per 100 patient-years; P = .01). There was no significant difference between the 2 groups in terms of overall or leukemia-free survival. The present study clarifies the incidence, degree, and prognostic relevance of bone marrow fibrosis obtained at time of initial diagnosis of polycythemia vera.

Purpose The WHO diagnostic criteria underscore the role of bone marrow (BM) morphology in distinguishing essential thrombocythemia (ET) from early/prefibrotic primary myelofibrosis (PMF). This study examined the clinical relevance of such a distinction. Methods Representatives from seven international centers of excellence for myeloproliferative neoplasms convened to create a clinicopathologic database of patients previously diagnosed as having ET (N = 1,104). Study eligibility criteria included availability of treatment-naive BM specimens obtained within 1 year of diagnosis. All bone marrows subsequently underwent a central re-review. Results Diagnosis was confirmed as ET in 891 patients (81%) and was revised to early/prefibrotic PMF in 180 (16%); 33 patients were not evaluable. In early/prefibrotic PMF compared with ET, the 10-year survival rates (76% and 89%, respectively) and 15-year survival rates (59% and 80%, respectively), leukemic transformation rates at 10 years (5.8% and 0.7%, respectively) and 15 years (11.7% and 2.1%, respectively), and rates of progression to overt myelofibrosis at 10 years (12.3% and 0.8%, respectively) and 15 years (16.9% and 9.3%) were significantly worse. The respective death, leukemia, and overt myelofibrosis incidence rates per 100 patient-years for early/prefibrotic PMF compared with ET were 2.7% and 1.3% (relative risk [RR], 2.1; P < .001), 0.6% and 0.1% (RR, 5.2; P = .001), and 1% and 0.5% (RR, 2.0; P = .04). Multivariable analysis confirmed these findings and also identified age older than 60 years (hazard ratio [HR], 6.7), leukocyte count greater than 11 × 10 9 /L (HR, 2.01), anemia (HR, 2.95), and thrombosis history (HR, 2.81) as additional risk factors for survival. Thrombosis and JAK2V617F incidence rates were similar between the two groups. Survival in ET was similar to the sex- and age-standardized European population. Conclusion This study validates the clinical relevance of strict adherence to WHO criteria in the diagnosis of ET and provides important information on survival, disease complication rates, and prognostic factors in strictly WHO-defined ET and early/prefibrotic PMF.