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...

We studied the survival of 195 patients with agnogenic myeloid metaplasia (AMM) diagnosed between 1962 and 1992 in an attempt to stratify patients into risk groups. Median survival was 42 months. Adverse prognostic factors for survival were age > 60 years, hepatomegaly, weight loss, low hemoglobin level (Hb), low or very high leukocyte count (WBC), high percentage of circulating blasts, male sex, and low platelet count. A new scoring system based on two adverse prognostic factors, namely Hb < 10 g/dL and WBC < 4 or > 30 x 10(3)/L, was able to separate patients in three groups with low (0 factor), intermediate (1 factor), and high (2 factors) risks, associated with a median survival of 93, 26, and 13 months, respectively. An abnormal karyotype (32 cases of 94 tested patients) was associated with a short survival, especially in the low-risk group (median survival of 50 v 112 months in patients with normal karyotype). The prognostic factors for acute conversion were WBC > 30 x 10(3)/L and abnormal karyotype. Thus, hemoglobin level and leukocyte count provide a simple prognostic model for survival in AMM, and the adverse prognostic value of abnormal karyotype may be related to a higher rate of acute conversion.

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.

Survival of PMF is steadily improving, except in patients in poor-risk categories. This observation must be taken into account at the time of evaluating the survival impact of newer therapies for PMF, which are currently being tested in these patient subpopulations.

Low-dose thalidomide displays an acceptable toxicity profile and provides an objective and subjective advantage to a relevant portion of MMM patients.