The Philadelphia chromosome-negative (Ph-) chronic myeloproliferative neoplasms include the three well-known clinical entities polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Over time, patients with ET and PV may develop myelofibrosis (MF), and all three entities carry a risk of transformation into acute myeloid leukemia (AML). In a population-based survey during 1983-1999, we studied a total of 358 patients who were diagnosed with ET and PV in the city of Gothenburg, Sweden. At the time of diagnosis, evaluable bone marrow biopsy material was available from 280 of these patients. The current work was aimed at investigating the impact of peripheral blood counts, spleen size, and bone marrow biopsy findings at diagnosis on long-term survival and the risk of development of AML or MF in this well-defined unselected population. The variables evaluated were venous blood hemoglobin concentration, packed cell volume, white blood cell count, platelet count, and splenic enlargement; as to bone marrow biopsies, interest was focused on reticulin content, focal or generalized collagen formation, bone marrow cellularity, and megakaryocyte profile number. Over the median observation time of 15 yr, the patients with ET did not demonstrate any significant difference as to survival compared to the normal Swedish population (hazard ratio, 1.23; 95% confidence interval, 0.97-1.51; p= 0.089). The patients with PV, on the other hand, had a significantly shorter survival compared to general population (hazard ratio, 1.66; 95% confidence interval, 1.38-1.99; p< 0.001). A lower hemoglobin concentration at diagnosis of ET predicted poorer survival (p =0.0281), whereas patients with PV with splenic enlargement at diagnosis had a shorter survival (p =0.037). In the patients with ET, the risk of transformation to either MF or AML was significantly associated with low hemoglobin concentration and high white cell count at diagnosis (p =0.0037 and 0.0306, respectively). An increased reticulin content and hypercellularity in the bone marrow at diagnosis were also independent risk factors (p =0.0359 and 0.0103, respectively). The risk of transformation in patients with PV was significantly associated with splenic enlargement and increase in bone marrow reticulin content (p =0.0028 and 0.0164, respectively).

† GB and KA contributed equally to this study. SummaryThree hundred and twenty-seven patients from two population-based cohorts with an established diagnosis of polycythaemia vera were studied for prognostic risk factors for survival and leukaemia in a long-term survey. The relative survival (RS) was 72% and 46% at 10 and 20 years respectively, from the time of diagnosis. Multivariate analysis identified age >70 years, white blood cell count >13 9 10 9 /l and thrombo-embolism at diagnosis as independent risk factors. Patients with two or three of these factors had a 10 year RS of 26%, compared with 59% and 84% in patients with one and no risk factors, respectively. Age and leucocyte count are the main predicting factors for survival in polycythaemia vera.

The Philadelphia chromosome-negative (Ph-) chronic myeloproliferative disorders (MPD) have an inherent tendency for transformation into acute myelogenous leukaemia (AML). The long-term rate of leukaemic transformation in unselected MPD patients was studied in well-defined MPD populations in Gothenburg, Sweden and the Côte d'Or area, Burgundy, France, respectively. Over a median observation time of 15 yr, 56 subjects (7%) out of a total of 795 patients with Ph- MPD transformed to AML. The yearly incidence of AML transformation was 0.38% in polycythaemia vera (PV), 0.37% in essential thrombocythaemia (ET) and 1.09% in idiopathic myelofibrosis (IMF). The incidence of AML development was significantly higher in IMF as compared with both PV and ET (P = 0.002 and P = 0.02, respectively). Six of the patients who developed AML had never been treated with cytoreductive agents and two had only been exposed to interferon. In IMF, the average time from diagnosis to AML transformation was 42 +/- 33 months, which was significantly shorter than for both PV and ET (88 +/- 56 and 76 +/- 57 months; P = 0.0075 and P = 0.027, respectively). The time from diagnosis to AML transformation appears to be a continuous event as regards all three MPD entities. It was shown that 17 out of the 18 patients with PV who developed AML were females; this was true despite the fact that the male/female ratio for the whole PV group was 146/171 (0.85). As regards ET and IMF patients who transformed to AML, the gender ratio showed slight male predominance (1.33 and 1.13, respectively). The average survival time for the 56 MPD patients who developed AML was 4.6 +/- 5.5 (range 0-28) months and did not differ with respect to the three subtypes of pre-AML MPD.

We conclude that vascular complications among newly diagnosed patients had affected more than one-third of our study population. Risk factors for vascular complications prior to diagnosis were lower hemoglobin in PV, and the presence of JAK2 V617F mutation, higher age, and leukocytosis in ET.

Objective-Presence of the JAK2 V617F mutation in only 40-60% of patients with Essential Thrombocythemia (ET) underscores the heterogeneity of this myeloproliferative disorder (MPD). Several distinct mutations, either in JAK2 (exon 12) or in c-Mpl (W515L) have been described in subsets of other MPDs, Polycythemia vera (PV) and Idiopathic Myelofibrosis (IMF). Analogous to JAK2 V617F , these mutations cause constitutive JAK2 and STAT activation. It has therefore been proposed that constitutive activation of the JAK/STAT pathway underlies the molecular etiology of all MPDs. We investigated the alternative hypothesis that distinct alterations, separate from the JAK/ STAT signal transduction pathway, underlie a subset of JAK2 V617F -negative ET.Methods-cDNA microarrays and qRT-PCR were used to compare gene expression in 40 ET patients with and without the JAK2 V617F mutation.Results-Unsupervised clustering of gene expression patterns in ET patients revealed two distinct subclasses of patients. These subclasses differed in presence or absence of the JAK2 V617F mutation. Patients lacking the JAK2 V617F mutation displayed significantly lower expression of the JAK/STAT target genes Pim-1 and SOCS2. In addition, JAK2 V617F -negative patients showed lower levels of STAT3 phosphorylation.Conclusions-These data demonstrate that a large proportion of JAK2 V617F -negative ET patients do not display constitutive JAK/STAT signaling. Hence, we propose that alterations in different signal transduction pathways can lead to the clinical phenotype of ET. Elucidation of novel ETinducing changes will facilitate both a molecular classification of ET and the development of rationally designed therapies.