Carrai, Valentina

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 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.

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.

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.