Myelodysplastic syndromes and acute myeloid leukemia exemplify the complexity of treatment allocation in older patients as options range from best supportive care, non-intensive treatment (e.g. hypomethylating agents) to intensive chemotherapy/hematopoietic cell transplantation. Novel metrics for non-disease variables are urgently needed to help define the best treatment for each older patient. We investigated the feasibility and prognostic value of geriatric/quality of life assessments aside from established disease-specific variables in 195 patients aged 60 years or over with myelodysplastic syndromes/acute myeloid leukemia. These patients were grouped according to treatment intensity and assessed. Assessment consisted of eight instruments evaluating activities of daily living, depression, mental functioning, mobility, comorbidities, Karnofsky Index and quality of life. Patients with a median age of 71 years (range 60-87 years) with myelodysplastic syndromes (n=63) or acute myeloid leukemia (n=132) were treated either with best supportive care (n=47), hypomethylating agents (n=73) or intensive chemotherapy/hematopoietic cell transplantation (n=75). After selection of variables, pathological activities of daily living and quality of life/fatigue remained highly predictive for overall survival in the entire patient group beyond disease-related risk factors adverse cytogenetics and blast count of 20% or over. In 107 patients treated non-intensively activities of daily living of less than 100 (hazard ratio, HR 2.94), Karnofsky Index below 80 (HR 2.34) and quality of life/'fatigue' of 50 or over (HR 1.77) were significant prognosticators. Summation of adverse features revealed a high risk of death (HR 9.36). In-depth evaluation of older patients prior to individual treatment allocation is feasible and provides additional information to standard assessment. Patients aged 60 years or over with newly diagnosed myelodysplastic syndromes/acute myeloid leukemia and impairments in activities of daily living, Karnofsky Index below 80%, quality of life/'fatigue' of 50 or over, are likely to have poor outcomes.Parameters detected by geriatric and quality of life assessment in 195 older patients with myelodysplastic syndromes and acute myeloid leukemia are highly predictive for outcome

Summary The molecular aetiology of polycythaemia vera (PV) remains unknown and the differential diagnosis between PV and secondary erythrocytosis (SE) can be challenging. Gene expression profiling can identify candidates involved in the pathophysiology of PV and generate a molecular signature to aid in diagnosis. We thus performed cDNA microarray analysis on 40 PV and 12 SE patients. Two independent data sets were obtained: using a two‐step training/validation design, a set of 64 genes (class predictors) was determined, which correctly discriminated PV from SE patients. Separately 253 genes were identified to be upregulated and 391 downregulated more than 1·5‐fold in PV compared with healthy controls (P < 0·01). Of the genes overexpressed in PV, 27 contained Sp1 sites: we therefore propose that altered activity of Sp1‐like transcription factors may contribute to the molecular aetiology of PV. One Sp1 target, the transcription factor NF‐E2 [nuclear factor (erythroid‐derived 2)], is overexpressed 2‐ to 40‐fold in PV patients. In PV bone marrow, NF‐E2 is overexpressed in megakaryocytes, erythroid and granulocytic precursors. It has been shown that overexpression of NF‐E2 leads to the development of erythropoietin‐independent erythroid colonies and that ectopic NF‐E2 expression can reprogram monocytic cells towards erythroid and megakaryocytic differentiation. Transcription factor concentration may thus control lineage commitment. We therefore propose that elevated concentrations of NF‐E2 in PV patients lead to an overproduction of erythroid and, in some patients, megakaryocytic cells/platelets. In this model, the level of NF‐E2 overexpression determines both the severity of erythrocytosis and the concurrent presence or absence of thrombocytosis.

Recently, a Jak2V617F mutation has been described in the vast majority of patients with polycythemia vera (PV) as well as in subsets of patients with essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). The question arises whether this mutation is observed in those patients with ET and IMF who have also displayed previously described molecular markers, notably the ability to form endogenous erythroid colonies (EECs), overexpression of polycythemia rubra vera 1 (PRV-1), and decreased c-Mpl expression. We therefore analyzed the Janus kinase 2 (Jak2) DNA sequence, EEC growth, PRV-1 expression, and c-Mpl (myeloproliferative) levels in a cohort of 78 myeloproliferative disorder (MPD) patients (42 ET, 22 PV, and 14 IMF). Presence of the Jak2V617F mutation was very highly correlated with PRV-1 overexpression and the ability to form EECs in all 3 subtypes of MPDs (P < .001 IntroductionIn 1951, Dameshek 1 coined the term myeloproliferative disorders (MPDs) for a group of 4 clinically related diseases. At the time, this included polycythemia vera (PV), essential thrombocythemia (ET), idiopathic myelofibrosis (IMF), and chronic myelogenous leukemia (CML). Today, CML is regarded as a separate entity, defined by the t(9;22)(q34;q11) translocation, the "Philadelphia (Ph Ϫ ) chromosome," which results in production of the breakpoint cluster region/Abelson (Bcr/Abl) fusion protein and is not found in the remaining 3 MPD subtypes. 2,3 Several aberrations have been described in patients with PV, ET, and IMF, but none appeared causally linked to the molecular pathogenesis. 4-7 However, 2 alterations, the growth of endogenous erythroid colonies (EECs) and overexpression of the polycythemia rubra vera 1 (PRV-1) mRNA, are highly correlated in individual patients with all 3 subtypes of MPD. 8,9 Therefore, we have proposed that EEC-positive, PRV-1-overexpressing MPD patients constitute a distinct molecular category. 10 In our model, EEC/PRV-1-positive ET and IMF patients are molecularly and clinically more similar to PV patients than to other patients who carry the same clinically defined diagnosis. [9][10][11] The recent description of a point mutation in the Janus kinase 2 (Jak2; Jak2V617F) in the majority of patients with PV as well as subgroups of patients with ET and IMF 12-14 allows us to correlate the presence of this mutation with the occurrence of other markers in individual patients. This analysis can refute or prove the hypothesis that EEC/PRV-1-positive MPD patients share a common molecular determinant of disease etiology. Study design PatientsPeripheral blood samples were obtained from 42 patients with essential thrombocythemia (ET), 22 patients with polycythemia vera (PV), and 14 patients with idiopathic myelofibrosis (IMF). The diagnosis of ET, PV, and IMF were made according to the World Health Organization (WHO) criteria. 15 Venous blood was anticoagulated with EDTA (ethylenediaminetetraacetic acid) or heparin and shipped by courier to the central laboratory without cooling. Maximum time interval between...