The myelodysplastic syndromes: predictive value of eight prognostic systems in 143 cases from a single institution.

BACKGROUND AND OBJECTIVE: Despite the fact that several prognostic systems for myelodysplastic syndromes (MDS) have been proposed, few studies have been designed to test their effectiveness in independent patient populations. The aim of this study was to compare the prognostic value of 8 previously described prognostic systems in a series of consecutive MDS patients observed at a single institution over a 10-year period. DESIGN AND METHODS: One hundred and forty-three patients were diagnosed as having myelodysplastic syndrome (MDS) according to the French-American-British (FAB) criteria. They were studied retrospectively in order to assess the prognostic value of the FAB classification and 7 other prognostic systems. RESULTS: On the basis of data at diagnosis, all investigated systems effectively stratified patients into groups with different life expectancies and identified a subset of patients with poor clinical outcome. However, the systems had different outcomes concerning median survival of patients classified as low-risk, ranging from less than 3 years for the Mufti scoring system to more than 8 years for the FAB classification modified according to Rosati et al. Moreover, patient distribution into different risk categories was quite different with the different prognostic systems. INTERPRETATION AND CONCLUSIONS: When applied to our case series, some of the prognostic systems had a much lower prognostic value than in the patient population from which they derived. This evidence suggests that testing of prognostic systems in independent case series is necessary before using the systems in clinical practice.

Cyclosporin-A in severe refractory anemia of myelofibrosis with myeloid metaplasia: a preliminary report.

BACKGROUND AND OBJECTIVE: Severe anemia is the outstanding problem in approximately 50 percent of patients with myelofibrosis with myeloid metaplasia (MMM). The present trial was based on the considerations that abnormal immune responses are frequently associated with MMM and that cyclosporin A (Cy-A) has proven to be effective in improving anemia in autoimmune disorders. The aim of this study was to evaluate the effect of Cy-A on anemia of MMM. DESIGN AND METHODS: We studied 10 patients with MMM and severe anemia who were not responsive to corticosteroids. Eight of them showed evidence of immune defects (direct or indirect Coombs' test, antinuclear or antimitochondrial antibodies, circulating immune complexes). Cy-A was delivered orally in two refracted doses of 5 mg per kilogram bw every day and the serum level of the drug was maintained between 100 and 200 ng/mL for at least 6 months. Clinical effects were measured by calculating a normalized transfusional need (NTN), and response was defined as about a 30% reduction in the initial transfusion requirement. Hematologic parameters, s-Epo, s-TfR, s-IL2R and lymphocyte flow cytometric analysis were also evaluated. The results were analyzed with the Student's t-test. RESULTS: Only 6 patients completed the entire 6 months of planned therapy. Three of these responded, with one no longer needing transfusions. A high CD4/CD8 ratio was predictive of response (mean value 4.7 +/- 3.5 in responders versus 0.9 +/- 0.4 in non-responders, p = 0.06). INTERPRETATION AND CONCLUSIONS: An immunomediated mechanism negatively affects erythropoiesis in MMM. Cy-A may be effective for patients with severe refractory anemia in this disease.

Red blood cell precursor mass as an independent determinant of serum erythropoietin level.

Serum erythropoietin (sEpo) concentration is primarily related to the rate of renal production and, under the stimulus of hypoxia, increases exponentially as hemoglobin (Hb) decreases. Additional factors, however, appear to influence sEpo, and in this work, we performed studies to evaluate the role of the red blood cell precursor mass. We first compared the relationship of sEpo with Hb in patients with low versus high erythroid activity. The first group included 27 patients with erythroid aplasia or hypoplasia having serum transferrin receptor (sTfR) levels < 3 mg/L (erythroid activity < 0.6 times normal), while the second one included 28 patients with beta-thalassemia intermedia having sTfR levels > 10 mg/L (erythroid activity > 2 times normal). There was no difference between the two groups with respect to Hb (8.3 +/- 1.6 v 8.0 +/- 1.3 g/dL, P > .05), but sEpo levels were notably higher in patients with low erythroid activity (1,601 +/- 1,542 v 235 +/- 143 mU/mL, P < . 001). In fact, multivariate analysis of variance (ANOVA) showed that, at any given Hb level, sEpo was higher in patients with low erythroid activity (P < .0001). Twenty patients undergoing allogeneic or autologous bone marrow transplantation (BMT) were then investigated. A marked increase in sEpo was seen in all cases at the time of marrow aplasia, disproportionately high when compared with the small decrease in Hb level. Sequential studies were also performed in five patients with iron deficiency anemia undergoing intravenous (IV) iron therapy. Within 24 to 72 hours after starting iron treatment, marked decreases in sEpo (up to one log magnitude) were found before any change in Hb level. Similar observations were made in patients with megaloblastic anemia and in a case of pure red blood cell aplasia. These findings point to an inverse relationship between red blood cell precursor mass and sEpo: at any given Hb level, the higher the number of red blood cell precursors, the lower the sEpo concentration. The most likely explanation for this is that sEpo levels are regulated not only by the rate of renal production, but also by the rate of utilization by erythroid cells.

Erythropoietin production and erythropoiesis in compensated and anaemic states of hereditary spherocytosis.

A compensated haemolytic state is defined by decreased red cell life-span without anaemia, i.e. by increased erythropoiesis in the absence of the physiological stimulus for erythropoietin (Epo) production. We evaluated s-Epo levels and the expansion of erythropoiesis (as measured by circulating transferrin receptor, s-TfR) in 32 patients with hereditary spherocytosis (HS) with the aim of verifying whether the enhanced erythropoiesis of compensated haemolysis was Epo-dependent. 20 of the patients (62.5%) had normal Hb values (> 12 g/dl in females and > 13 g/dl in males). Their compensated haemolytic state was the result of up to 8.2 times normal s-Epo and up to 3.9 times normal s-TfR levels, which were maintained by physiological regulation of erythropoiesis, as documented by the inverse dependence of Hb on s-Epo levels. Considering that patients with iron-deficiency anaemia represented the predicted physiological Epo response to anaemia, the observed/predicted in s-Epo ratio (O/P ratio) was calculated in HS patients with anaemia and was used as an index of the adequateness of Epo production. All the anaemic HS patients had an O/P ratio > 1, documenting inappropriately high s-Epo levels. This work demonstrates that the compensated haemolytic state of HS patients is produced by an inappropriately high s-Epo level, and that the pattern of Epo overproduction is a biological characteristic of the disease.

Performance characteristics of Hemox-Analyzer for assessment of the hemoglobin dissociation curve.

The Hemox-Analyzer (TCS, Medical Products Division, Southampton, PA) is an automatic system for determining the oxyhemoglobin dissociation curve (ODC) and P50 values. The ODC is recorded during deoxygenation with nitrogen gas and plotted on graph paper; the oxygen tension is detected by a Clark electrode, while the oxyhemoglobin fraction (%HbO2) is evaluated by a dual-wavelength spectrophotometer. Even though this instrument has been commercially available for more than 20 years, its performance characteristics have been assessed. We evaluated the performance characteristics of the Hemox-Analyzer. P50 was tested in 28 healthy volunteers, in 16 anemic and in 9 polycythemic patients. To test its precision we evaluated both inter- and intra-assay variability. The system shows good precision: standard deviation was 0.39 for assays in duplicate, CV = 1.9% for intra-assay and CV = 3.0% for inter-assay measurements. The mean P50 values were 25.2 +/- 1.5 mmHg in normal volunteers and 27.3 +/- 1.4 mmHg in anemic patients. The Hemox-Analyzer is a simple, quick and reliable instrument for recording the oxyhemoglobin dissociation curve. Both the P50 value and observation of the fine structure of the curve can furnish information about the delivery of oxygen to tissues.