Therapeutic decision-making in primary myelofibrosis (PMF) is becoming more challenging because of the increasing use of allogeneic stem cell transplantation and new investigational drugs. To enhance this process by developing a highly discriminative prognostic system, 1054 patients consecutively diagnosed with PMF at 7 centers were studied. Overall median survival was 69 months (95% confidence interval [CI]: 61-76). Multivariate analysis of parameters obtained at disease diagnosis identified age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25 ؋ 10 9 /L, and circulating blast cells 1% or greater as predictors of shortened survival. Based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of these variables, 4 risk groups with no overlapping in their survival curves were delineated; respective median survivals were 135, 95, 48, and 27 months (P < .001). Compared with prior prognostic models, the new risk stratification system displayed higher predictive accuracy, replicability, and discriminating power. In 409 patients with assessable metaphases, cytogenetic abnormalities were associated with shorter survival, but their independent contribution to prognosis was restricted to patients in the intermediate-risk groups. JAK2V617F did not cluster with a specific risk group or affect survival. IntroductionPrimary myelofibrosis (PMF) 1 is classified as a chronic myeloproliferative disorder and characterized by variable degrees of cytopenia(s) and/or cytosis, a leukoerythroblastic blood picture, bone marrow fibrosis, and extramedullary hematopoiesis often resulting in hepatosplenomegaly. 2 From a pathogenesis standpoint, the disease features clonal proliferation involving pluripotent hematopoietic stem cells, 3,4 and clonal cell-derived cytokines are implicated for some of the disease aspects such as bone marrow fibrosis and extramedullary hematopoiesis. 2 Most recently, JAK2 5-7 and MPL 8-10 mutations were described in approximately 50% and 10% of patients with PMF, respectively. However, the precise pathogenetic contribution of these mutations is currently not well defined.PMF usually affects subjects with advanced age, 11 but young people are not necessarily spared. 12 Reported median survivals are variable and in the range of 4-7 years. 13,14 Previous studies have identified several adverse prognostic factors for survival, including advanced age, [15][16][17][18][19] marked anemia, 13-22 leukocytosis or leukopenia, 14,16,18,22 abnormal karyotype, 18,23-25 constitutional symptoms, 13,14,17,22 and presence of circulating blasts. 13,14,22 Based on some of these variables, several prognostic scoring systems have been proposed. 12,13,18,19,22,26 More recently, the prognostic value of blood CD34 ϩ cell count 27,28 and JAK2 mutational status [29][30][31] has also been evaluated.Current drug therapy for PMF has not been shown to influence survival and is often used for pal...

Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 ؋ 10 9 /L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time- IntroductionPrimary myelofibrosis (PMF) is a Philadelphia-negative myeloproliferative neoplasm (MPN) whose diagnostic criteria have been recently updated. 1 Among MPNs, PMF has the most heterogeneous clinical presentation, which may encompass anemia, splenomegaly, leukocytosis or leukopenia, thrombocytosis or thrombocytopenia, and constitutional symptoms. The discovery of the activating mutation JAK2 (V617F) in more than 70% of patients with MPNs 2 led to the development of new biochemically selective JAK2 inhibitors. 3 These agents are currently being tested in clinical trials that usually include patients with long disease history.Advanced age, 4-7 anemia, 4-11 red blood cell transfusion need, 12 leukopenia, 8 leukocytosis, 8 thrombocytopenia, 9 peripheral blast count, 4,6 systemic symptoms, 6,10 degree of microvessel density, 13 and cytogenetic abnormalities 5,7,9,[14][15][16] were shown to be associated with poor outcome in patients with PMF. The presence of the JAK2 (V617F) mutation per se does not seem to imply worse survival, 17 although a low JAK2 (V617F) allele burden seems associated with poorer outcome. 18,19 Recently, Cervantes et al 17 on behalf of the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) developed a prognostic scoring system to estimate survival of PMF patients. This model uses 5 factors (age older than 65 years, hemoglobin level Ͻ 100 g/L [10 g/dL], white blood cell count Ͼ 25 ϫ 10 9 /L, peripheral blood blasts Ն 1%, and presence of constitutional symptoms) to identify 4 risk categories with different survival.Prognostic models for PMF developed so far are based on the evaluation of risk factors present at diagnosis. However, the acquisition of additional risk factors during the disease course may substantially modify the patients' outcome. A dynamic prognostic model that accounts for modifications of the risk profile after diagnosis may prove useful in clinical practice. On behalf of IWG-MRT, first we investigated whether the acquisition anytime during follow-up of one or more of the prognostic factors identified by Cervantes et al 17 predicts survival. Then, a new prognostic score based on a time-dependent risk evaluation was developed: the Dynamic International Prognostic Scoring System (DIPSS) for PMF. MethodsThe study was carried out through an international cooperation on behalf of the IWG-MRT. An ad hoc database was developed for data collection. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From Study designThe Institutional Rev...

Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.

We recently defined a high-molecular risk category (HMR) in primary myelofibrosis (PMF), based on the presence of at least one of the five 'prognostically detrimental' mutated genes (ASXL1, EZH2, SRSF2 and IDH1/2). Herein, we evaluate the additional prognostic value of the 'number' of mutated genes. A total of 797 patients were recruited from Europe (n=537) and the Mayo Clinic (n=260). In the European cohort, 167 (31%) patients were HMR: 127 (23.6%) had one and 40 (7.4%) had two or more mutated genes. The presence of two or more mutations predicted the worst survival: median 2.6 years (hazard ratio (HR) 3.8, 95% confidence interval (CI) 2.6-5.7) vs. 7.0 years (HR 1.9, 95% CI 1.4-2.6) for one mutation vs 12.3 years for no mutations. The results were validated in the Mayo cohort and prognostic significance in both cohorts was independent of International Prognostic Scoring System (IPSS; HR 2.4, 95% CI 1.6-3.6) and dynamic IPSS (DIPSS)-plus (HR 1.9, 95% CI 1.2-3.1), respectively. Two or more mutations were also associated with shortened leukemia-free survival (HR 6.2, 95% CI 3.5-10.7), also Mayo validated. Calreticulin mutations favorably affected survival, independently of both number of mutations and IPSS/DIPSS-plus. We conclude that the 'number' of prognostically detrimental mutations provides added value in the combined molecular and clinical prognostication of PMF.

Criteria of response and definition of resistance and intolerance to hydroxyurea (HU) in polycythemia vera (PV) were proposed by the European LeukemiaNet (ELN). Such criteria were evaluated in 261 PV patients (median follow-up, 7.2 years) treated with HU for a median of 4.4 years. Complete response, partial response, and no response were observed in 24%, 66%, and 10% of patients, respectively. Achieving ELN response (complete or partial) or hematocrit response did not result in better survival or less thrombosis and bleeding. On the contrary, having no response in leukocyte count was associated with higher risk of death (HR, 2.7; 95% confidence interval [CI], 1.3%-5.4%; P ‫؍‬ .007), whereas lack of response in platelet count involved a higher risk of thrombosis and bleeding. Resistance and intolerance to HU was registered in 11% and 13% of patients, respectively. Resistance to HU was associated with higher risk of death (HR, 5.6; 95% CI, 2.7%-11.9%; P < .001) and transformation (HR, 6.8; 95% CI, 3.0%-15.4%; P < .001). In summary, fulfilling the ELN definition for response to HU was not associated with a benefit in the clinical outcome in PV, whereas response in platelet and white blood cell counts were predictive of less thrombohemorrhagic complications and better prognosis, respectively. Resistance to HU was an adverse prognostic factor. (Blood. 2012;119(6):1363-1369)

The effectiveness of antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia (ET) is not proven. In this study, the incidence rates of arterial and venous thrombosis were retrospectively analyzed in 300 lowrisk patients with ET treated with antiplatelet drugs as monotherapy (n ‫؍‬ 198) or followed with careful observation (n ‫؍‬ 102).

To determine the clinicohematological factors predictive for the appearance of major vascular complications (MVC) in patients with essential thrombocythemia (ET), 148 consecutive such patients were retrospectively assessed for the development of MVC during a median follow-up of 58.5 months. Seventy-seven patients had vascular risk factors, and 37 a history of MVC at ET diagnosis. Forty-nine MVC were registered in 33 patients during the follow-up period. The actuarial probability of MVC was 27% at 6 years in the whole series, 35.6% for patients above 60 years, and 21.4% for patients younger than 60 years, whereas only one of the 36 patients younger than 45 years had MVC. At multivariate analysis, age Ͼ60 years, history of major ischemia and hypercholesterolemia were the variables associated with an increased MVC risk. These results suggest that all ET patients above 60 years should be treated, whereas in younger patients treatment decisions should be primarily based on the existence of risk factors for MVC.

Summary. Myelofibrosis with myeloid metaplasia (MMM) isan uncommon disorder in young individuals, for whom haemopoietic stem cell transplantation offers the only possibility of cure. However, although the latter procedure is associated with significant morbidity and mortality, the clinical course of MMM is variable, with some patients surviving for less than a year and others showing an indolent course. Selection of young MMM patients for transplantation or other newer therapies is currently difficult since no prognostic data exists for this subgroup. In the present collaborative study a number of initial clinical and laboratory parameters have been evaluated for prognosis in 121 MMM patients aged 55 years or less. Median survival of the series was 128 months (95% CI 90-172). In the Cox proportional hazard regression model three initial variables were independently associated with shorter survival: Hb <10 g/dl (P < 0·0001), the presence of constitutional symptoms (fever, sweats, weight loss) (P ¼ 0·001), and circulating blasts у 1% (P ¼ 0·003). Based on the above three criteria, of the 116 patients with complete data, two groups were identified: a 'low-risk' group, characterized by 88 patients with up to one adverse prognostic factor, in whom MMM had an indolent course (median survival 176 months, 95% CI 130-188), and a 'high-risk' group, including 28 patients with two or three factors, who had a more aggressive disease (median survival 33 months, 95% CI 20-42). The above prognostic scoring system showed a high positive predictive value, sensitivity and specificity to predict survival in the series, and could be of help in making treatment decisions in young patients with MMM.