losartan-potassium and Anemia--Sideroblastic

Topics: Acetamides; Aged; Anemia, Refractory; Anemia, Sideroblastic; Anti-Bacterial Agents; Arthroplasty; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Combined Modality Therapy; Comorbidity; Diabetes Mellitus, Type 2; Diagnosis, Differential; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Linezolid; Methicillin-Resistant Staphylococcus aureus; Obesity, Morbid; Oxazolidinones; Polypharmacy; Postoperative Complications; Prosthesis-Related Infections; Reoperation

The present meta-analysis was undertaken to (1) assess erythroid response rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa as a monotherapy, (2) gain further insights into predictors of response rates, and (3) compare the erythroid response rates observed with epoetin alfa and darbepoetin alfa. A systematic review of studies from 1990 to 2006 in MDS patients treated with epoetin alfa or darbepoetin alfa was performed and yielded 30 studies evaluating a total of 1,314 patients (epoetin alfa: 22 studies, 925 patients; darbepoetin alfa: eight studies, 389 patients). Pooled estimates of erythroid response rates, stratified by the International Working Group criteria (IWGc) and treatment group, were calculated using random-effects meta-analysis methods. Univariate meta-regression analyses were further conducted to identify study characteristics associated with erythroid response rate. The pooled estimate of erythroid response rate was significantly higher for epoetin alfa IWGc studies (57.6%) as compared to non-IWGc studies (31.6%; p < 0.001). Study factors predictive of higher response rate in the epoetin alfa IWGc studies included higher proportion of patients with RA/RARS (p < 0.001), lower mean baseline serum erythropoietin level (p = 0.007), and fixed dosing regimen (p < 0.001). There was no significant difference in the pooled erythroid response rates between the two agents (epoetin alfa: 57.6% vs. darbepoetin alfa: 59.4%; p = 0.828). The current study reported significantly higher erythroid response rates predominantly in the more recent studies that primarily utilized IWGc to define response. With the use of standardized patient selection and response evaluation methods, epoetin alfa and darbepoetin alfa yielded comparable erythroid response rates in MDS patients.

Topics: Aged; Anemia; Anemia, Refractory; Anemia, Sideroblastic; Blood Transfusion; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Evaluation; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Most adult patients with hematopoietic failure due to myelodysplastic syndrome (MDS) are treated with supportive care measures, including hematopoietic growth factors (epoetin alfa, darbepoetin alfa, filgrastim, pegfilgrastim, sargramostim), red blood cell or platelet transfusions, and antimicrobial agents. Allogeneic stem cell transplantation can be curative, but only a small subset of patients are eligible for transplantation, and until recently there were few options other than supportive care for transplant-ineligible patients. Since 2004, the US Food and Drug Administration (FDA) has approved three new therapies specifically for the indication of MDS: two DNA methyltransferase inhibitors (azacitidine and decitabine) and an immunomodulatory agent (lenalidomide). Several other drugs are used by clinicians for treatment of patients with MDS, but are not specifically FDA-approved for this indication. With several therapeutic options available, yet none of them effective in the majority of cases, it can be challenging for clinicians to choose the most appropriate treatment for an individual patient. Here we discuss a risk-based management approach to MDS that incorporates recent data regarding these new therapies. While many questions remain about the optimal use of newer agents, the long-standing perception of MDS as a syndrome where therapeutic nihilism is the only realistic approach is slowly beginning to change.

Topics: Anemia, Sideroblastic; Antilymphocyte Serum; Azacitidine; Benzoates; Decitabine; Deferasirox; DNA Modification Methylases; Enzyme Inhibitors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Histone Deacetylase Inhibitors; Humans; Immunosuppressive Agents; Interleukin-11; Iron Chelating Agents; Lenalidomide; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Prognosis; Risk; Stem Cell Transplantation; Thalidomide; Triazoles

Topics: Anemia; Anemia, Sideroblastic; Dose-Response Relationship, Immunologic; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Myelodysplastic Syndromes; Neutropenia

Erythropoietin (epo) can be used to improve the anaemia of patients with myelodysplastic syndromes (MDS), but the efficacy is relatively low and the treatment is expensive. So far, no individual clinical trial has been sufficiently extensive to provide a basis for a decision model for the use of epo in MDS. This meta-analysis included 17 original articles with a total of 205 patients with MDS who had been treated with epo. 33 patients (16%) showed a significant response to treatment. Patients with refractory anaemia with ring sideroblasts (RAS) showed a lower response rate than all other patients (7.5% v 21%, P = 0.010). The difference in response rate between patients with and without transfusion need was also highly significant (10% v 44%, P < 0.001). The serum level of epo was significantly lower in the responding patients, but this parameter on its own could not be used to identify patients with a favourable response. FAB group (RAS versus others), transfusion need and s-epo (>/< 200 U/l) were combined in a model to provide information about the probability of response in different groups of patients. Patients with no transfusion requirement and MDS other than RAS showed a response rate of > or = 50%, irrespective of their serum level of epo. In patients with RAS and s-epo > 200 U/l, no response was observed. In the remaining groups the response rates varied between 9% and 33%. This meta-analysis shows that the efficacy of epo in MDS in general was low, but that groups of patients with an acceptable response rate could be identified.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Anemia, Refractory; Anemia, Sideroblastic; Blood Transfusion; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Erythrocytes; Erythropoietin; Humans; Kidney Failure, Chronic; Rats; Renal Dialysis

PTH may participate in the genesis of the anemia of uremia through at least three pathways. These include inhibition of erythropoiesis, shortening survival of RBCs and inducing fibrosis of bone marrow cavity. A possible fourth mechanism through which PTH may contribute to the anemia of uremia is its effect on platelets. PTH inhibits platelet aggregation [53] and, as such, may play an important role in the genesis of the bleeding tendencies and the consequent blood loss in uremia.

Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Colony-Forming Units Assay; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Hematopoietic Stem Cells; Hemolysis; Hemorrhage; Humans; Hyperparathyroidism, Secondary; In Vitro Techniques; Mice; Parathyroid Hormone; Uremia

Topics: Anemia; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Arthritis, Rheumatoid; Bone Marrow; Chronic Disease; Copper; Disease Models, Animal; Endotoxins; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Freund's Adjuvant; Hematocrit; Humans; Infections; Iron; Mononuclear Phagocyte System; Neoplasms; Porphyrins; Protein Binding; Rats; Transferrin

Treatment with recombinant human erythropoietin (rHuEpo) improves anaemia in approximately 20% of patients with myelodysplastic syndromes (MDS). We investigated the potential advantage of a prolonged administration of rHuEpo to achieve higher erythroid response rates (RR) in 281 MDS patients: 118 with refractory anaemia (RA), 77 with refractory anaemia and ringed sideroblasts (RARS), 59 with refractory anaemia with excess of blasts and blast count < 10% (RAEB-I), and 27 with RAEB and blast count between 11-20% (RAEB-II). rHuEpo was given subcutaneously at a dose of 150 U/kg thrice weekly, for a minimum of 26 weeks. Response to treatment was evaluated after 12 and 26 weeks of therapy. The overall RR was 45.1%; the RR for RA, RARS, RAEB-I and RAEB-II were 48.3%, 58.4%, 33.8% and 13% respectively. A significant increase in RR was observed at week 26 in RA, RARS and RAEB-I patients, as the response probability increased with treatment duration. The RR was higher in the good cytogenetic prognostic group and serum Epo level of > 150 U/l at baseline predicted for non-response. The median duration of response was 68 weeks and the overall risk of leukaemic transformation was 21.7%. These results suggest that prolonged administration of rHuEpo produces high and long-lasting erythroid RR in MDS patients with low blast counts, particularly in those with pretreatment serum Epo levels of < 150 U/l and good cytogenetic prognosis.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Anemia, Sideroblastic; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Treatment Outcome

As anemia is frequently the main problem in myelodysplastic syndromes (MDS), we studied the efficacy of human erythropoietin (rhEpo) in stimulating the erythroid lineage in 14 patients, starting with 40 U/kg three times a week and doubling the dose every 6 weeks until a response was observed. The highest doses administered were 80 (n = 1), 160 (n = 4), 320 (n = 8) and 640 U/kg (n = 1). One patient (refractory anemia with an excess of blasts, RAEB) showed an increase of hemoglobin, white blood cells and platelets with 80 U/kg rhEpo. However, this patient developed acute leukemia while on therapy. Two other patients (RAEB and RAEB in transformation) also transformed to acute leukemia. In the other 11 patients no response was observed. There was no correlation between in vitro culture data and in vivo responsiveness. The treatment was well tolerated and no nonhematological side effects were observed. From this study we conclude that rhEpo, even when given at high doses, has a low response rate in patients with MDS. Further investigation is needed in order to clarify whether rhEpo increases the potential risk of transformation to acute leukemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Anemia, Sideroblastic; Blood Platelets; Bone Marrow; Drug Evaluation; Erythrocytes; Erythropoietin; Female; Hemoglobins; Humans; Leukocytes; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Activin Receptors, Type II; Aged; Anemia, Sideroblastic; Azacitidine; Disease Progression; Erythrocyte Transfusion; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hematinics; Humans; Immunoglobulin Fc Fragments; Kaplan-Meier Estimate; Lenalidomide; Male; Proportional Hazards Models; Recombinant Fusion Proteins; Salvage Therapy; Treatment Failure

Patients with refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) are difficult to treat because the cytoreductive treatment might be beneficial for the thrombocytosis component but harmful for the RARS component. As lenalidomide has shown to be efficacious in both myelodysplastic syndromes and myeloproliferative neoplasms, we have treated 2 RARS-T patients, who were transfusion dependent, with lenalidomide. We report the results of lenalidomide treatment in these patients and show that lenalidomide has clinical activity in this rare disorder. Both patients became transfusion independent, and 1 of the patients attained indeed a complete molecular remission.

Topics: Aged, 80 and over; Anabolic Agents; Anemia, Refractory; Anemia, Sideroblastic; Antineoplastic Agents; Erythropoietin; Humans; Hypertension, Pulmonary; Janus Kinase 2; Lenalidomide; Male; Middle Aged; Mutation; Pulmonary Embolism; Pyridoxine; Reverse Transcriptase Polymerase Chain Reaction; Thalidomide; Thrombocytosis; Vitamin B Complex

Topics: Anemia, Sideroblastic; Bone Marrow; Erythropoietin; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Pyridoxine; Recombinant Proteins; Renal Dialysis; Risk Assessment; Treatment Outcome; Vitamin B 6 Deficiency

Erythroid apoptosis in low-risk myelodysplastic syndrome (MDS) maybe mediated via mitochondrial release of cytochrome c and subsequent caspase activation. In the present study, we compared the in vitro and in vivo effects of proerythroid treatment with erythropoietin + granulocyte colony-stimulating factor (G-CSF) on myelodysplastic erythropoiesis regarding apoptosis and preferential growth of clones with cytogenetic abnormalities.. We enrolled 15 refractory anemia (RA) and 11 refractory anemia with ringed sideroblasts (RARS), including 5q- aberration, monosomy 7, and trisomy 8, before initiation of treatment and followed nine patients after successful treatment. The effects of G-CSF and erythropoietin were assessed. The expression of G-CSF receptor (G-CSFR) was explored during erythroid maturation. The relative growth of erythroid progenitors with cytogenetic aberrations in presence of erythropoietin was investigated.. Significant redistribution of cytochrome c was seen before treatment at all stages of erythroid differentiation. This release was blocked by G-CSF during the whole culture period and by erythropoietin during the latter phase. Both freshly isolated glycophorin A+ bone marrow cells and intermediate erythroblasts during cultivation retained their expression of G-CSFR. Cytochrome c release and caspase activation were significantly less pronounced in progenitors obtained from successfully treated nonanemic patients and showed no further response to G-CSF in vitro. Moreover, erythropoietin significantly promoted growth of cytogenetically normal cells from 5q- patients, whereas no such effect was observed on erythroblasts from monosomy 7 or trisomy 8 patients.. We conclude that growth factors such as erythropoietin and G-CSF can act both via inhibition of apoptosis of myelodysplastic erythroid precursors and via selection of cytogenetically normal progenitors.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Sideroblastic; Apoptosis; Bone Marrow Cells; Caspases; Cytochromes c; Enzyme Activation; Erythroid Precursor Cells; Erythropoietin; Glycophorins; Granulocyte Colony-Stimulating Factor; Humans; In Vitro Techniques; Middle Aged; Monosomy; Receptors, Granulocyte Colony-Stimulating Factor; Recombinant Proteins; Trisomy

The anemia of low-risk myelodysplastic syndromes (MDS), refractory anemia (RA) and RA with ringed sideroblasts (RARS), may respond to treatment with hematopoietic growth factors (GF)); erythropoietin (Epo) +/- granulocyte colony-stimulating factor (G-CSF). The present study was designed to assess whether functional iron deficiency may develop in MDS patients receiving these treatments.. Erythrocyte scattergrams from 34 patients with RA and RARS (untreated, transfused, or GF-treated with partial or complete erythroid response) were analyzed with Bayer-Advia equipment.. In untreated RARS, the proportion of hypochromic erythrocytes (Hypo-e, median 6.2%, range 1.1-8%) and hypochromic reticulocytes (Hypo-r, median 45%, range 22-48%), as well as mean corpuscular volume (MCV, median 101 fL) were significantly elevated compared to corresponding values in controls. These values increased further after GF-treatment (median 11%, 57%, and 105 fL, respectively), in spite of improved hemoglobin values and adequate body iron stores. The values observed in untreated RA patients largely fell within the normal range, and there was no significant influence of GF treatment. Notably, the hemoglobin content of reticulocytes (MCHr) did not differ between MDS and controls, and was not influenced by GF treatment.. The red cell population in RARS shows morphological abnormalities in terms of varying but overall increased size, and reduced hemoglobin concentration. The proportion of abnormal cells increases after successful pro-erythroid GF treatment, indicating that GF promote erythroblast survival, and maturation into erythrocytes. Hence, the finding of hypochromic red cells should not routinely be interpreted as a marker for Epo-induced functional iron deficiency in MDS.

Topics: Anemia, Refractory; Anemia, Sideroblastic; Blood Cell Count; Drug Therapy, Combination; Erythrocyte Indices; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Ferritins; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Iron; Iron Deficiencies; Methylmalonic Acid; Reticulocytes; Risk; Transferrin

We have published previously a prototype of a decision model for anaemic patients with myelodysplastic syndromes (MDS), in which transfusion need and serum erythropoietin (S-Epo) were used to define three groups with different probabilities of erythroid response to treatment with granulocyte colony-stimulating factor (G-CSF) + Epo. S-Epo 500 U/l and >/= 2 units/month for a poor response, whereas the presence of only one negative prognostic marker predicted an intermediate response. A total of 53 patients from a prospective study were included in our evaluation sample. Patients with good or intermediate probability of response were treated with G-CSF + Epo. The overall response rate was 42% with 28.3% achieving a complete and 13.2% a partial response to treatment. The response rates were 61% and 14% in the good and intermediate predictive groups respectively. The model retained a significant predictive value in the evaluation sample (P < 0.001). Median duration of response was 23 months. Scores for global health and quality of life (QOL) were significantly lower in MDS patients than in a reference population, and fatigue and dyspnoea was significantly more prominent. Global QOL improved in patients responding to treatment (P = 0.01). The validated decision model defined a subgroup of patients with a response rate of 61% (95% confidence interval 48-74%) to treatment with G-CSF + Epo. The majority of these patients have shown complete and durable responses.

Topics: Aged; Anemia; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Anemia, Sideroblastic; Blood Transfusion; Decision Support Techniques; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Prospective Studies; Quality of Life; Treatment Outcome

We describe a woman with severe neutropenia and dependency on red blood cell transfusions who had previously undergone Billroth II surgery and whose bone marrow (BM) showed morphologic characteristics typical of myelodysplastic syndrome (MDS) with ringed sideroblasts. She had transient reversal of anemia and severe neutropenia after therapy with erythropoietin and granulocyte colony-stimulating factor. Because of relapse while receiving growth factors, the patient was referred for allogeneic BM transplantation. A pretransplantation nutritional evaluation revealed severe copper deficiency, and her hematologic abnormalities resolved fully with copper therapy. This case shows that copper deficiency should be an integral part of the differential diagnosis of sideroblastic MDS, even in patients not requiring parenteral nutrition.

Topics: Adult; Anemia, Sideroblastic; Bone Marrow; Bone Marrow Transplantation; Copper; Diagnosis, Differential; Erythrocyte Transfusion; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Neutropenia; Recurrence

Treatment with granulocyte colony-stimulating factor plus erythropoietin may improve haemoglobin levels in patients with ringsideroblastic anaemia (RARS) and reduce bone marrow apoptosis. We studied bone marrow from 10 RARS patients, two of whom were also investigated after successful treatment. Mononuclear, erythroid and CD34+ cells were analysed with regard to proliferation, apoptosis, clonogenic capacity and oncoprotein expression, in the presence or absence of Fas-agonist, Fas-blocking antibody 2 and caspase-3 inhibitor. During culture, RARS bone marrow cells showed higher spontaneous apoptosis (P < 0.05) and caspase activity (P < 0.05)) than bone marrow cells from healthy donors. Eight out of nine patients had reduced growth of erythroid colony-forming units (CFU-E) (< 10% of control) and granulocyte-macrophage CFU (CFU-GM) (< 50% of control) from CD34+ cells. Fas ligation increased apoptosis and decreased colony growth equally in RARS and controls, but caused significantly more caspase activation in RARS (P < 0.01). Fas-blocking antibody showed no significant inhibitory effect on spontaneous apoptosis or ineffective haematopoiesis, as measured using phosphatidylserine exposure, the terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling technique, caspase activity or clonogenic growth. Caspase inhibition reduced apoptosis, increased proliferation and enhanced erythroid colony growth from CD34+ cells in RARS, but showed no effect on normal cells. CFU-E improved > 1000% after successful treatment. Thus, erythroid apoptosis in RARS is initiated at the CD34+ level and growth factor treatment may improve stem cell function. Enhanced caspase activation at the stem cell level, albeit not mediated through endogenous activation of the Fas receptor, contributes to the erythroid apoptosis in RARS.

Topics: Aged; Anemia, Sideroblastic; Antigens, CD34; Apoptosis; Case-Control Studies; Caspase 3; Caspases; Enzyme Activation; Erythropoietin; fas Receptor; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; In Situ Nick-End Labeling; Linear Models; Middle Aged

Acute monoblastic leukemia (acute myeloid leukemia [AML], French-American-British type M5a) with leukemia cutis developed in a patient 6 weeks after the initiation of erythropoietin (EPO) therapy for refractory anemia with ringed sideroblasts. AML disappeared from both marrow and skin after the discontinuation of EPO. Multiparameter flow cytometric analysis of bone marrow cells demonstrated coexpression of the EPO receptor with CD45 and CD13 on the surface of blasts. The incubation of marrow cells with EPO, compared to without, resulted in 1.3- and 1.6-fold increases, respectively, in tritiated thymidine incorporation and bromodeoxyuridine incorporation into CD13(+) cells. Clinical and laboratory findings were consistent with the EPO-dependent transformation of myelodysplastic syndrome (MDS) to AML. It is concluded that leukemic transformation in patients with MDS treated with EPO may be EPO-dependent and that management should consist of the discontinuation of EPO followed by observation, if clinically feasible.

Topics: Aged; Anemia, Sideroblastic; Bone Marrow; CD13 Antigens; Erythropoietin; Flow Cytometry; Humans; Leukemia, Monocytic, Acute; Leukocyte Common Antigens; Male; Myelodysplastic Syndromes; Receptors, Erythropoietin; Skin

Leptin is a 16 kDa protein hormone involved in food intake, energy expenditure regulation and numerous other physiological processes. Recently, leptin has been demonstrated to stimulate hematopoietic stem cells in vitro. The aim of our study was to measure serum leptin and erythropoietin levels in patients with sideropenic (n = 18) and pernicious anemia (n=7) before and during anemia treatment. Blood samples for the blood count, leptin and erythropoietin determinations were obtained by venepunction at the time of the diagnosis of anemia and after partial and complete anemia recovery. The relationships of serum leptin levels to erythropoietin levels and blood count parameters were also studied. No significant differences in serum leptin levels between the groups studied were found. The serum leptin levels in none of groups were modified by treatment of anemia (basal levels, the levels during treatment and after anemia recovery were 13.1+/-14.5 vs 12.8+/-15.6 vs 12.0+/-14.8 ng/ml in patients with sideropenic anemia and 7.8+/-8.5 vs 9.5+/-10.0 vs 8.9+/-6.6 ng/ml in patients with pernicious anemia). The erythropoietin levels were higher at the time of anemia in both groups and decreased significantly after partial or complete recovery. Serum leptin levels in both groups correlated positively with the body mass index. No significant relationships were found between serum leptin levels and erythropoietin values or various parameters of the peripheral blood count. We conclude that serum leptin levels in patients with sideropenic and pernicious anemia positively correlate with the body mass index but are not influenced by the treatment of anemia.

Topics: Adult; Aged; Anemia, Pernicious; Anemia, Sideroblastic; Body Mass Index; Erythrocyte Count; Erythropoietin; Female; Ferrous Compounds; Hemoglobins; Humans; Leptin; Male; Middle Aged; Vitamin B 12

In order to reduce anaemia in patients with myelodysplastic syndromes (MDS) a stepwise treatment protocol including erythropoietin (EP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was designed. Thirty-seven MDS patients (stages I-III) with symptomatic anaemia were first given EPO 10,000 U s.c. 3 times weekly for 6 weeks. Those not responding, i.e. increased their haemoglobin levels > 15 g/l, proceeded into the second phase of the study where GM-CSF (200 micrograms/d. s.c. on weeks 1-6) was combined with EPO (10,000 U s.c. 3 times weekly on weeks 5-14). Following the initial EPO treatment phase, 14 of the 37 patients (38%) responded with increased haemoglobin levels. Responders were significantly different from non-responders in that their pre-treatment values of s-EPO, s-LDH and bone marrow blast cell counts were lower, their baseline haemoglobin levels higher and their transfusion dependency less pronounced. Eighteen of the 23 non-responders proceeded into the second phase, 13 of those were evaluable having completed the entire schedule. Three of the 13 initially EPO resistant patients (23%) responded to the GM-CSF/EPO combination with increased haemoglobin levels, suggesting a positive synergy between the two cytokines. Thus, the overall response rate to the present protocol was 46% (17 of 37 cases), but only a limited subset of the patients did clearly benefit from the combined GM-CSF/EPO administration. Therefore, we believe this step-wise approach to multiple growth factor treatment in MDS, starting with EPO alone and reserving the combination for refractory cases, has considerable advantages, taking into account both medical and socio-economical aspects.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Anemia, Sideroblastic; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Middle Aged

Topics: Anemia, Refractory; Anemia, Sideroblastic; Blood Transfusion; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Leukocyte Count; Myelodysplastic Syndromes

Different response patterns to recombinant human erythropoietin (rHuEpo) administration to anemic patients with myelodysplastic syndromes (MDS) are described. The biology of rHuEpo effect on erythropoiesis in patients with MDS has not been elucidated. However, until more biological information is obtained, it could be prudent to consider these response patterns as guidelines in the treatment of MDS. In the small but interesting series of nine patients with MDS only one responded to rHuEpo within the treatment period of eight weeks. Two additional patients continued the treatment on their own, and after 16 weeks a response was noted for the first time. A third patient was treated for only six weeks and a delayed response was recorded while off treatment for ten weeks. This response was also recorded 16 weeks from treatment initiation-as in the other two patients. A fourth patient with MDS developed transfusion related hemosiderosis and during iron chelation therapy the RBC transfusion rate dropped to a rate lower than the rate needed before the rHuEpo treatment. It is emphasized that in non responders, non-routine approaches should be considered.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Sideroblastic; Blood Transfusion; Chelation Therapy; Combined Modality Therapy; Deferoxamine; Erythrocyte Count; Erythropoietin; Female; Follow-Up Studies; Hemochromatosis; Humans; Male; Myelodysplastic Syndromes; Primary Myelofibrosis; Recombinant Proteins; Remission Induction; Transfusion Reaction; Treatment Outcome

Topics: Aged; Anemia, Refractory; Anemia, Sideroblastic; Child; Drug Evaluation; Erythropoietin; Female; Humans; Immunologic Factors; Male; Recombinant Proteins

We studied the efficacy of high doses (100,000 IU intravenously (IV)/twice a week) of human recombinant erythropoietin (rHuEpo) in patients with transfusion dependent myelodysplastic syndromes (MDS). Rationale for such dose of IV Epo was the poor in vitro response of MDS erythroid progenitors (CFU-E) to physiological concentrations of Epo, and the usual high endogenous serum Epo levels of MDS patients. Seventeen patients (nine males, eight females) were included, five refractory anaemia (RA), six RA with blasts excess (RAEB), five RA with ringed sideroblasts (RARS). Tolerance was good, except in three patients who experienced severe flu-like syndrome after Epo injection. None of the patients showed hypertension or developed anti rHuEpo antibodies. Three patients (17.6%) with RAEB had 35-60% reduction of transfusion requirements. No progression of disease occurred. Percentage of erythroblasts, endogenous baseline Epo level and in vitro cultures of erythroid progenitors did not correlate with response to Epo treatment. This study shows that very high IV doses induce only seldom and partial improvement in the status of transfusion dependent MDS. This rate of response, not higher than described with lower dosage, probably represents the maximum expectable response to rHuEpo in this category of patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Sideroblastic; Bone Marrow; Erythrocyte Transfusion; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Injections, Intravenous; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Responsiveness of bone marrow erythropoietic stem cells (CFU-E and BFU-E) to recombinant human erythropoietin (rh-Ep) was examined in vitro in 23 patients with aplastic anemia and 14 with myelodysplastic syndrome (MDS) to investigate the clinical use of rh-Ep for these diseases. Bone marrow mononuclear cells were cultured by methylcellulose methods for CFU-E and BFU-E assays. In normals, the CFU-E numbers reached a plateau of increase at Ep doses of almost 2-5 units, and no further increase was observed with the addition of larger Ep doses. In aplastic anemia, the responses of CFU-E to Ep were relatively good in nonsevere type and generally poor in severe type. However, the CFU-E numbers increased with increasing doses of Ep in some of the patients with aplastic anemia. Among the patients with MDS, the responses of CFU-E to Ep were relatively good in primary acquired refractory anemia (PARA) and primary acquired sideroblastic anemia. On the other hand, the responses of CFU-E to Ep were poor in refractory anemia with an excess of blasts (RAEB) and RAEB in transformation among the MDS patients. BFU-E responses to Ep were poor in severe aplastic anemia, RAEB, and RAEB-T. However, there are Ep responsive patients in some of aplastic anemia and PARA. High titers of rh-Ep were suggested to be effective clinically in some patients with aplastic anemia and those with PARA.

Topics: Anemia, Aplastic; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Anemia, Sideroblastic; Bone Marrow; Cells, Cultured; Dose-Response Relationship, Drug; Erythroid Precursor Cells; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins; Reference Values

Topics: Aged; Agranulocytosis; Anemia, Sideroblastic; Erythropoietin; Humans; Hypotension; Male; Neutropenia; Recombinant Proteins; Renin-Angiotensin System

A short review is presented of the primary and the secondary types of therapy-refractory anemia. Special emphasis is placed on the newest results obtained with therapeutic plasmapheresis and with recombinant human erythropoietin.

Topics: Anemia, Refractory; Anemia, Sideroblastic; Erythropoietin; Humans; Plasmapheresis; Red-Cell Aplasia, Pure

Bone marrow cells from three patients with idiopathic acquired sideroblastic anemia and one with X-linked sideroblastic anemia were simultaneously cultured in plasma clot and methylcellulose cultures in order to evaluate their erythroid colony (CFUE) cloning potential in these two systems. In contrast to normals, sideroblastic anemia bone marrow cells demonstrated a marked ability to form erythropoietin (Epo)-independent CFUE in methylcellulose culture, and were inhibited in their ability to generate CFUE in plasma clot culture even in the presence of Epo. Addition of citrated plasma to methylcellulose cultures inhibited Epo-independent CFUE growth, but not Epo-dependent growth, by both a normal and patients' bone marrow cells. These results demonstrate that bone marrow cells from some patients with sideroblastic anemia can undergo Epo-independent and Epo-dependent CFUE growth in vitro, and that there is a marked difference in CFUE growth depending on the type of clonal culture method used. It is suggested that the culture microenvironment, plasma, and sensitivity to Epo may be contributing factors which allow specific clones of sideroblastic anemia CFUE-forming cells to proliferate in vitro.

Topics: Anemia, Sideroblastic; Blood; Blood Coagulation; Child; Child, Preschool; Culture Media; Erythropoietin; Female; Humans; Male; Methylcellulose; Middle Aged; Stem Cells

The uptake of iron by bone marrow erythroblasts and its intracellular distribution have been studied in 23 patients with primary sideroblastic anaemia (SA), five patients with secondary SA and one patient with only non-ringed sideroblasts. EM of erythroblasts from 18 cases showed both mitochondrial iron deposits and cytoplasmic ferritin aggregates in all cases except the patient with only non-ringed sideroblasts. Iron uptake by erythroblasts in whole bone marrow was normal but there was a decreased incorporation into haem and an increased incorporation into cell stroma. Age matching of erythroblasts using Percoll density gradient centrifugation indicated that stromal iron incorporation was high at all stages of erythroblast development even before haem synthesis had become a major metabolic activity and in intermediate and late erythroblasts a real decrease in haem synthesis appeared less certain. These observations, together with the inability to correct the abnormality in vitro with either pyridoxal phosphate or delta amino-laevulinic acid suggest that the primary defect in SA may be an abnormality of mitochondrial iron metabolism rather than an abnormality of haem synthesis.

Topics: Adult; Aged; Aminolevulinic Acid; Anemia, Sideroblastic; Bone Marrow; Cytoplasm; Erythroblasts; Erythrocyte Indices; Erythrocytes; Erythropoietin; Female; Ferritins; Heme; Humans; Iron; Male; Middle Aged; Mitochondria; Pyridoxal Phosphate

In order to study the changes in erythroid precursor cells in primary acquired and secondary sideroblastic anemia, bone marrow cells from 4 patients with primary acquired sideroblastic anemia (PASA) and 3 patients with refractory anemia with excess of myeloblasts (RAEM) or erythroleukemia associated with an excess of ringed sideroblasts were cultured for erythroid colony-forming units (CFU-E). The number of CFU-E was markedly decreased in all 7 cases, and erythroid colonies formed consisted exclusively of normal-appearing erythroblasts, while ringed sideroblasts were observed in scattered single erythroblasts or in small aggregates of erythroblasts in primary as well as in secondary sideroblastic anemia. These findings may indicate the presence of 2 populations of erythroid progenitor cells in the bone marrow of patients with primary acquired and secondary sideroblastic anemia. A slight to moderate decrease in granulocyte-macrophage colony-forming units (GM-CFU) was observed in 3 cases of PASA. The decrease in GM-CFU, however, was marked in sideroblastic anemia associated with RAEM or erythroleukemia.

Topics: Aged; Anemia, Aplastic; Anemia, Sideroblastic; Colony-Forming Units Assay; Erythroblasts; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Iron; Leukemia, Erythroblastic, Acute; Male; Middle Aged

In the last decade a large increase of our basic understanding concerning erythropoietin and the regulation of erythropoiesis has led to improved methods for the cell culture of human bone marrow cells. These culture methods in turn have been applied to bone marrow failures with a remarkable increase in our knowledge of the pathogenesis of some of these conditions, particularly the aplasias. The pathogenesis of pure red cell aplasia has been elucidated, and 60% of these patients have been shown to respond to cytotoxic, immunosuppressive treatment. Bone marrow transplantation has proved to be very helpful in the treatment of aplastic anemia and has provided impetus for increased knowledge concerning the pathogenesis of the aplasia. Some of these patients may have suppression of marrow hematopoiesis by the marrow T-cells and can be successfully treated with antilymphocyte globulin or high-dose prednisolone. The future looks bright for further clinical advances concerning the bone marrow failures, but more must be learned about the pathogenesis of these anemias if improved methods of treatment are to be developed.

Topics: Aged; Anemia, Aplastic; Anemia, Sideroblastic; Animals; Bone Marrow; Cyclophosphamide; Erythropoiesis; Erythropoietin; Female; Humans; Pancytopenia; Prednisone; Primary Myelofibrosis

The responsivenes to erythropoietin of cultured bone marrow cells, obtained from 7 patients with refractory anemia with hyperplastic marrow, was studied. 5 of these patients' marrows also exhibited sideroblasti changes. Heme synthesis in cultured bone marow cells was either responsive to stimulation by erythropoietin, or completely refractory. The sensitivity of the bone marrow cells to the hormone was not related to either the clinical or laboratory findings.

Topics: Aged; Anemia, Aplastic; Anemia, Sideroblastic; Cells, Cultured; Erythropoiesis; Erythropoietin; Female; Heme; Humans; Male; Middle Aged

Defective arythropoiesis characterizes the sideroblastic anemias. The present studies were undertaken to assess the effects of isoniazid, an inhibitor of heme synthesis, on erythropoietin-induced erythroid maturation in hypertransfused mice. Isoniazid was administered at intervals during a wave of induced erythropoiesis, and the effects were assessed in both the bone marrow and peripheral blood. The data showed that isoniazid interfered with heme synthesis and erythroid maturation. The most inhibitory effect of isoniazid was noted at the intermediate normoblast stage. A transient increase in the reticulocyte nonheme iron pool was also found.

Topics: Anemia, Sideroblastic; Animals; Blood Cell Count; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Heme; Injections, Intradermal; Injections, Intravenous; Isoniazid; Mice; Reticulocytes

Topics: Adenosine Triphosphate; Anemia, Aplastic; Anemia, Sideroblastic; Aspartate Aminotransferases; Blood Transfusion; Carbon Dioxide; Diphosphoglyceric Acids; Electrophoresis, Starch Gel; Erythrocyte Count; Erythrocytes; Erythropoietin; Fructose-Bisphosphate Aldolase; Glutathione; Glyceraldehyde-3-Phosphate Dehydrogenases; Glycolysis; Hematocrit; Hemoglobins; Hexokinase; Humans; Hydrogen-Ion Concentration; Lactates; Methemoglobin; Oxygen Consumption; Phosphofructokinase-1; Phosphorus; Potassium; Reticulocytes; Sodium; Thalassemia

Topics: Anemia, Sideroblastic; Animals; Blood Transfusion; Cell Differentiation; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hematopoietic Stem Cells; Heme; Hemoglobinometry; Iron; Iron Radioisotopes; Leukocyte Count; Mice; Pyridoxine; Reticulocytes; Time Factors; Vitamin B 6 Deficiency

Topics: Anemia, Aplastic; Anemia, Sideroblastic; Animals; Biological Assay; Circadian Rhythm; Computers; Dialysis; Erythropoietin; Evaluation Studies as Topic; Female; Freeze Drying; Hemagglutination Tests; Hemoglobinuria, Paroxysmal; Humans; Iron Radioisotopes; Male; Methods; Mice; Mice, Inbred Strains; Microchemistry; Oxygen Consumption; Thalassemia; Ultrafiltration

Topics: Adult; Anemia, Sideroblastic; Bone Marrow Cells; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Exchange Transfusion, Whole Blood; Folic Acid; Humans; Iron; Isoniazid; Lupus Erythematosus, Systemic; Male; Megakaryocytes; Prednisone; Proteinuria; Pyridoxine; Vitamin B 12

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Sideroblastic; Bone Marrow Diseases; Erythropoietin; Female; Humans; Iron; Iron Isotopes; Kidney Failure, Chronic; Male; Middle Aged; Myeloproliferative Disorders; Oxymetholone

Topics: Anemia, Sideroblastic; Animals; Ascorbic Acid; Cobalt; Erythropoiesis; Erythropoietin; Humans; Lead Poisoning; Porphyrias; Porphyrins; Rats