losartan-potassium and Myelodysplastic-Syndromes

Myelodysplastic syndromes (MDS) are malignant diseases arising from hematopoietic stem cells. Their overall incidence is 4 cases per 100 000 persons per year, and they are usually diagnosed when evaluating cytopenia. The median survival time is three years. Myelodysplastic syndromes take a variable course; one-quarter of patients go on to develop acute leukemia.. This review is based on publications retrieved by a selective search of the literature from 2013 to 2022, including relevant guidelines, in the PubMed database. The time period was chosen to reflect developments since the publication of the latest EHA guidelines in 2013.. The gold standard of diagnosis is cytomorphology of the blood and bone marrow, supplemented by banding cytogenetics, histomorphology, and somatic mutation analyses. The new classification proposed by the WHO incorporates the molecular and cytogenetic findings. The Molecular International Prognostic Scoring System (IPSS-M), which takes somatic mutations into account, is now available as an aid to prognostication. Quality of life evaluation with standardized instruments is helpful in many ways. Low-risk patients are treated supportively with erythrocyte transfusions and iron chelation therapy. Erythropoietin-a can be given to patients whose erythropoietin level is less than 200ng/mL, lenalidomide to those with a 5q deletion, and luspatercept to those with an SF3B1 mutation. High-risk patients should be evaluated as early as possible for allogeneic hematopoietic stem cell transplantation with curative intent. 5-azacytidine improves outcomes in patients for whom stem cell transplantation is not suitable.. Once a precise diagnosis has been established, new prognostic instruments such as the IPSS-M enable risk-adapted treatment based on the biological aspects of the patient's disease as well as his or her age and comorbidities.

Topics: Erythropoietin; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Male; Myelodysplastic Syndromes; Prognosis; Quality of Life

Myelodysplastic neoplasms (MDS), formerly known as myelodysplastic syndromes, are clonal hematopoietic malignancies that cause morphologic bone marrow dysplasia along with anemia, neutropenia, or thrombocytopenia. MDS are associated with an increased risk of acute myeloid leukemia (AML). The yearly incidence of MDS is approximately 4 per 100 000 people in the United States and is higher among patients with advanced age.. MDS are characterized by reduced numbers of peripheral blood cells, an increased risk of acute myeloid leukemia transformation, and reduced survival. The median age at diagnosis is approximately 70 years, and the yearly incidence rate increases to 25 per 100 000 in people aged 65 years and older. Risk factors associated with MDS include older age and prior exposures to toxins such as chemotherapy or radiation therapy. MDS are more common in men compared with women (with yearly incidence rates of approximately 5.4 vs 2.9 per 100 000). MDS typically has an insidious presentation, consisting of signs and symptoms associated with anemia, thrombocytopenia, and neutropenia. MDS can be categorized into subtypes that are associated with lower or higher risk for acute myeloid leukemia transformation and that help with therapy selection. Patients with lower-risk MDS have a median survival of approximately 3 to 10 years, whereas patients with higher-risk disease have a median survival of less than 3 years. Therapy for lower-risk MDS is selected based on whether the primary clinical characteristic is anemia, thrombocytopenia, or neutropenia. Management focuses on treating symptoms and reducing the number of required transfusions in patients with low-risk disease. For patients with lower-risk MDS, erythropoiesis stimulating agents, such as recombinant humanized erythropoietin or the longer-acting erythropoietin, darbepoetin alfa, can improve anemia in 15% to 40% of patients for a median of 8 to 23 months. For those with higher-risk MDS, hypomethylating agents such as azacitidine, decitabine, or decitabine/cedazuridine are first-line therapy. Hematopoietic cell transplantation is considered for higher-risk patients and represents the only potential cure.. MDS are diagnosed in approximately 4 per 100 000 people in the United States and are associated with a 5-year survival rate of approximately 37%. Treatments are tailored to the patient's disease characteristics and comorbidities and range from supportive care with or without erythropoiesis-stimulating agents for patients with low-risk MDS to hypomethylating agents, such as azacitidine or decitabine, for patients with higher-risk MDS. Hematopoietic cell transplantation is potentially curative and should be considered for patients with higher-risk MDS at the time of diagnosis.

Topics: Antineoplastic Agents; Azacitidine; Decitabine; Erythropoietin; Female; Hematinics; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Neutropenia; Prognosis; Thrombocytopenia

Erythropoiesis regulation is essential in normal physiology and pathology, particularly in myelodysplastic syndromes (MDS) and β-thalassemia. Several signaling transduction processes, including those regulated by inositides, are implicated in erythropoiesis, and the latest MDS or β-thalassemia preclinical and clinical studies are now based on their regulation. Among others, the main pathways involved are those regulated by transforming growth factor (TGF)-β, which negatively regulates erythrocyte differentiation and maturation, and erythropoietin (EPO), which acts on the early-stage erythropoiesis. Also small mother against decapentaplegic (SMAD) signaling molecules play a role in pathology, and activin receptor ligand traps are being investigated for future clinical applications. Even inositide-dependent signaling, which is important in the regulation of cell proliferation and differentiation, is specifically associated with erythropoiesis, with phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K) as key players that are becoming increasingly important as new promising therapeutic targets. Additionally, Roxadustat, a new erythropoiesis stimulating agent targeting hypoxia inducible factor (HIF), is under clinical development. Here, we review the role and function of the above-mentioned signaling pathways, and we describe the state of the art and new perspectives of erythropoiesis regulation in MDS and β-thalassemia.

Topics: Animals; beta-Thalassemia; Cell Differentiation; Cell Proliferation; Clinical Trials as Topic; Erythropoiesis; Erythropoietin; Glycine; Hematinics; Humans; Hypoxia-Inducible Factor 1; Isoquinolines; Ligands; Mice; Myelodysplastic Syndromes; Phosphatidylinositol 3-Kinases; Signal Transduction; Smad Proteins; Transforming Growth Factor beta; Type C Phospholipases

Myelodysplastic syndromes (MDS) are hematopoietic stem cell malignancies associated with an erythroid maturation defect, resulting in anemia. Treatments for MDS include erythropoiesis-stimulating agents (ESAs). The identification of prognostic markers is important to help predict response and improve outcomes. Various scoring systems have been developed to help predict response to ESAs. Despite limitations in its assessment, serum erythropoietin (sEPO) level is an important predictor of hematologic response to ESAs in patients with lower-risk MDS. Numerous studies have reported significantly lower sEPO levels among responders versus non-responders. Furthermore, treatment response is significantly more likely among those with sEPO levels below versus those above various cutoffs. Other prognostic indicators for response to ESAs include lower transfusion requirement, fewer bone marrow blasts, higher hemoglobin, lower serum ferritin, lower-risk MDS, and more normal cytogenetics. Studies of other MDS therapies (e.g., lenalidomide and luspatercept) have also reported that lower sEPO levels are indicative of hematologic response. In addition, lower sEPO levels (up to 500 IU/L) have been included in treatment algorithms for patients with lower-risk MDS to define whether ESAs are indicated. Lower sEPO levels are predictive of hematologic response-particularly to ESAs. Further, clinical trials should use sEPO thresholds to ensure more homogeneous cohorts.

Topics: Activin Receptors, Type II; Bone Marrow Cells; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Immunoglobulin Fc Fragments; Lenalidomide; Male; Myelodysplastic Syndromes; Prognosis; Recombinant Fusion Proteins; Risk Factors

Anemic patients with lower risk myelodysplastic syndromes are frequently treated with erythropoiesis stimulating agents (ESA), eventually in combination with granulocyte colony stimulating factor (G-CSF). However, the evidence for the efficacy of a combined treatment remains controversial. The goal of our analysis was to assess the available evidence for a combined treatment. We performed a systematic review and identified only nine eligible studies. In two randomized controlled trials (n = 98), erythroid response rates were 33% and 40% after low-/standard-doses of ESA alone (10,000-30,000 rHuEPO equivalents/week) versus 65% and 73% after combination treatment. In seven trials with sequential drug administration (n = 393), erythroid response rates ranged from 12% to 71% after full-doses of ESA alone (60,000-80,000 rHuEPO equivalents/week) and from 35% to 74% after combination therapy. Our analysis supports an additional efficacy of G-CSF added to low-/standard-dose ESA, but the available data remains controversial, if G-CSF is added to full-dose ESA.

Topics: Anemia; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Lower risk myelodysplastic syndromes (MDS), defined as MDS with a Revised International Prognostic Scoring System score ≤3.5 points, will remain a challenging entity in 2018. Supportive care continues to be the linchpin of treatment, although the options to reduce transfusion needs are broadening. To achieve red blood cell transfusion independence in non-del(5q) patients, erythropoiesis-stimulating agents remain a mainstay of therapy as long as endogenous erythropoietin levels are <500 U/L (and preferably <200 U/L). Experimental strategies for patients ineligible for erythropoiesis-stimulating agents or relapsing after gaining transfusion independence include immunosuppressive agents, transforming growth factor β inhibitors, and lenalidomide. All these alternatives have shown reasonable response rates in selected patient populations with lower risk MDS. Patients with del(5q) disease can derive long-term benefit from lenalidomide, and some patients remain transfusion free for extended periods even after discontinuation of the drug. In rare cases in which thrombocytopenia is the main clinical problem leading to clinically significant bleeding events, thrombopoietin receptor analogues may alleviate bleeding, increase platelet counts, and rarely lead to trilineage responses. It seems prudent to use these drugs only in patients with confirmed bone marrow blast counts <5%. Allogeneic stem cell transplantation is reasonable for patients with high molecular risk of progression and those failing several lines of treatment with signs of progression toward higher-risk MDS.

Topics: Algorithms; Allografts; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Lenalidomide; Myelodysplastic Syndromes; Stem Cell Transplantation; Thalidomide; Transforming Growth Factor beta

Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological diseases which are characterised by a uni- or multilineage dysplasia of haematological stem cells. Standard treatment is supportive care of the arising symptoms including red blood cell transfusions or the administration of erythropoiesis-stimulating agents (ESAs) in the case of anaemia or the treatment with granulocyte (G-CSF) and granulocyte-macrophage colony stimulating factors (GM-CSF) in cases of neutropenia.. The objective of this review is to assess the evidence for the treatment of patients with MDS with G-CSF and GM-CSF in addition to standard therapy in comparison to the same standard therapy or the same standard therapy and placebo.. We searched MEDLINE (from 1950 to 3 December 2015) and CENTRAL (Cochrane Central Register of Controlled Trials until 3 December 2015), as well as conference proceedings (American Society of Hematology, American Society of Clinical Oncology, European Hematology Association, European Society of Medical Oncology) for randomised controlled trials (RCTs). Two review authors independently screened search results.. We included RCTs examining G-CSF or GM-CSF in addition to standard therapy in patients with newly diagnosed MDS.. We used hazard ratios (HR) as effect measure for overall survival (OS), progression-free survival (PFS) and time to progression, and risk ratios for response rates, adverse events, antibiotic use and hospitalisation. Two independent review authors extracted data and assessed risk of bias. Investigators of two trials were contacted for subgroup information, however, no further data were provided. G-CSF and GM-CSF were analysed separately.. We screened a total of 566 records. Seven RCTs involving 486 patients were identified, but we could only meta-analyse the two evaluating GM-CSF. We judged the potential risk of bias of these trials as unclear, mostly due to missing information. All trials were randomised and open-label studies. However, three trials were published as abstracts only, therefore we were not able to assess the potential risk of bias for these trials in detail. Overall, data were not reported in a comparable way and patient-related outcomes like survival, time to progression to acute myeloid leukaemia (AML) or the incidence of infections was reported in two trials only.Five RCTs (N = 337) assessed the efficacy of G-CSF in combination with standard therapy (supportive care, chemotherapy or erythropoietin). We were not able to perform meta-analyses for any of the pre-planned outcomes due to inconsistent and insufficient reporting of data. There is no evidence for a difference for overall survival (hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.44 to 1.47), progression-free survival (only P value provided), progression to AML, incidence of infections and number of red blood transfusions (average number of 12 red blood cell transfusions in each arm). We judged the quality of evidence for all these outcomes as very low, due to very high imprecision and potential publication bias, as three trials were published as abstracts only. Data about quality of life and serious adverse events were not reported in any of the included trials.Two RCTs (N = 149) evaluated GM-CSF in addition to standard therapy (chemotherapy). For mortality (two RCTs; HR 0.88, 95% CI 0.62 to 1.26), we found no evidence for a difference (low-quality evidence). Data for progression-free survival and serious adverse events were not comparable across both studies, without evidence for a difference between both arms (low-quality evidence). For infections, red blood cell and platelet transfusions, we found no evidence for a difference, however, these outcomes were reported by one trial only (low-quality evidence). Time to progression to AML and quality of life were not reported at all.Moreover, we identified two cross-over trials, including 244 patients and evaluating GM-CSF versus placebo, without publishing results for each arm before crossing over. In addition, we identified two ongoing studies, one of which was discontinued due to withdrawal of pharmaceutical support, the other was terminated early, both wit. Although we identified seven trials with a total number of 486 patients, and two unpublished, prematurely finished studies, this systematic review mainly shows that there is a substantial lack of data, which might inform the use of G-CSF and GM-CSF for the prevention of infections, prolonging of survival and improvement of quality of life. The impact on progression to AML remains unclear.

Topics: Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Macrophage Colony-Stimulating Factor; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic

Myelodysplastic syndromes are a heterogeneous group of clonal haematological stem cell disorders. Allogeneic stem cells transplantation remains the only curative treatment but only a minority of patients are eligible for this treatment. In spite of this, it has become clear that treatment with lenalidomide and azanucleotides can lead to increased overall survival in particular subsets of patients with MDS. The relative silence on the therapeutic side is counter-balanced by major advances in the understanding of this heterogeneous disease. The introduction of high-throughput molecular techniques has resulted in the discovery that most patients harbour molecular aberrations, including pathways such as the spliceosome machinery previously not known to be involved. These newly discovered pathways will undoubtedly result in new therapeutic strategies for this difficult to treat disease.

Topics: Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Azacitidine; Blood Transfusion; Erythropoietin; Gene Expression Regulation, Neoplastic; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Myelodysplastic Syndromes; Neoplasm Proteins; Prognosis; Spliceosomes; Thalidomide; Transplantation, Homologous

Myelodysplastic syndromes (MDSs) represent clonal disorders mainly of the elderly that are characterized by ineffective hematopoiesis and an increased risk of transformation into acute myeloid leukemia. The pathogenesis of MDS is thought to evolve from accumulation and selection of specific genetic or epigenetic events. Emerging evidence indicates that MDS is not solely a hematopoietic disease but rather affects the entire bone marrow microenvironment, including bone metabolism. Many of these cells, in particular mesenchymal stem and progenitor cells (MSPCs) and osteoblasts, express a number of adhesion molecules and secreted factors that regulate blood regeneration throughout life by contributing to hematopoietic stem and progenitor cell (HSPC) maintenance, self-renewal and differentiation. Several endocrine factors, such as erythropoietin, parathyroid hormone and estrogens, as well as deranged iron metabolism modulate these processes. Thus, interactions between MSPC and HSPC contribute to the pathogenesis of MDS and associated pathologies. A detailed understanding of these mechanisms may help to define novel targets for diagnosis and possibly therapy. In this review, we will discuss the scientific rationale of 'osteohematology' as an emerging research field in MDS and outline clinical implications.

Topics: Animals; Bone Marrow; Cytokines; Disease Progression; Epigenesis, Genetic; Erythropoietin; Hematopoietic Stem Cells; Humans; Iron; Iron Overload; Mesenchymal Stem Cells; Myelodysplastic Syndromes; Osteoblasts; Parathyroid Hormone; Signal Transduction

The myelodysplastic syndromes are characterized by refractory cytopenias that lead to symptomatic anemia, bleeding, and increased risk for infections. For almost two decades, the use of darbepoetin and other erythropoietin stimulating agents to treat symptomatic anemia in lower-risk myelodysplastic syndromes has been a standard of care. This practice is supported by numerous Phase I/II studies and one Phase III study demonstrating the benefit of using erythropoietin stimulating agents alone, or in combination with granulocyte colony stimulating factor, for treatment of symptomatic anemia with the goal of decreasing red blood cell transfusion requirements. This review summarizes the published experience regarding the use of erythropoietin stimulating agents, with a special focus on darbepoetin, in patients with myelodysplastic syndrome and symptomatic anemia.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes

Topics: Antilymphocyte Serum; Azacitidine; Benzoates; Cyclosporine; Cytarabine; Deferasirox; Disease Progression; Drug Discovery; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Idarubicin; Immunosuppressive Agents; Iron Chelating Agents; Lenalidomide; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Quality of Life; Risk Assessment; Thalidomide; Triazoles

Topics: Allografts; Angiogenesis Inhibitors; Antimetabolites, Antineoplastic; Autografts; Azacitidine; Enzyme Inhibitors; Erythrocyte Transfusion; Erythropoietin; Hematopoietic Stem Cell Transplantation; Histocompatibility; HLA Antigens; Humans; Immunologic Factors; Immunosuppressive Agents; Induction Chemotherapy; Iron Chelating Agents; Lenalidomide; Myelodysplastic Syndromes; Recombinant Proteins; Thalidomide; Transplantation Conditioning

Erythropoiesis is finely regulated by two major cytokines, stem cell factor (SCF) and erythropoietin (Epo). Decrease levels of Epo result in caspase activation and erythroid progenitors apoptosis. However, normal erythroid cell maturation requests caspase activation and cleavage of various caspase substrates, except the erythroid transcription factor GATA-1, that is protected by interaction with the chaperone HSP70 in the nucleus. Therefore, molecular abnormalities associated with decrease of HSP70 expression in the nucleus may result in ineffective erythropoiesis characterized by apoptosis and impaired maturation of erythroid precursors. These findings open new potential targeted therapies for erythroid disorders.

Topics: Animals; Apoptosis; Caspases; Cell Differentiation; Cell Nucleus; Enzyme Activation; Erythroblasts; Erythrocyte Aging; Erythropoiesis; Erythropoietin; GATA1 Transcription Factor; HSP70 Heat-Shock Proteins; Humans; Myelodysplastic Syndromes; Neoplasm Proteins; Neoplasms; Protein Processing, Post-Translational; Proteolysis; Stem Cell Factor; Thalassemia

Anemia and transfusion need constitute major problems for patients with myelodysplastic syndromes (MDS) and are associated with reduced quality of life, poorer survival and an increased risk for transformation to AML. Treatment with erythropoiesis-stimulating agents (ESAs) is first-line treatment for the anemia of most patients with MDS. Erythropoietin acts synergistically with G-CSF to inhibit erythroid apoptosis and promote erythrocyte production. The median duration of response is 2-3 years, with patients responding for more than a decade. Onset of a permanent transfusion need is delayed if treatment is introduced early after the onset of symptomatic anemia. A positive effect on long-term outcome has been suggested by several large epidemiological studies, with no difference in the rate of leukemic transformation between treated and untreated patients. Moreover, responding patients show improvement of quality of life and exercise capacity. Response to treatment can be predicted by combining serum erythropoietin, transfusion rate, and flow cytometry profiling.

Topics: Apoptosis; Blood Transfusion; Erythroid Cells; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Quality of Life; Risk Factors; Time Factors

Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. Most MDS are characterized by anemia, and a number of cases progresses to acute myeloid leukemia (AML). Indeed, the molecular mechanisms underlying the MDS evolution to AML are still unclear, even though the nuclear signaling elicited by PI-PLCβ1 has been demonstrated to play an important role in the control of the balance between cell cycle progression and apoptosis in MDS cells. Here we review both the role of epigenetic therapy on PI-PLCβ1 promoter and the changes in PI-PLCβ1 expression in MDS patients treated for anemia.

Topics: Apoptosis; Bone Marrow; Cell Cycle; Cell Nucleus; Epigenesis, Genetic; Erythropoietin; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Phosphatidylinositols; Phospholipase C beta; Promoter Regions, Genetic; Signal Transduction

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and peripheral blood refractory cytopenias. MDS is recognized to be associated with an increased risk of symptomatic anemia, infectious complications and bleeding diathesis, as well as a risk of progression to acute myeloid leukemia, particularly in patients with a high IPSS score. The advent of use of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and recombinant erythropoietin (EPO) has improved symptoms in MDS patients in addition to some data that suggest there might be an improvement in survival. G-CSF is an effective therapeutic option in MDS patients, and it should be considered for the management of refractory symptomatic cytopenias. G-CSF and EPO in combination can improve outcomes in appropriate MDS patients such as those with lower-risk MDS and refractory anemia with ring sideroblasts (RARS) . This article reviews use of growth factors for lower-risk MDS patients, and examines the data for G-CSF, EPO and thrombopietic growth factors (TPO) that are available or being developed as therapeutic modalities for this challenging disease.

Topics: Anemia; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Neutropenia; Receptors, Fc; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin

The use of erythropoietic growth factors has become standard of care in many countries for lower risk myelodysplastic syndrome (MDS) patients. Throughout a large number of clinical trials, therapy with erythropoietic agents has consistently shown improvement of anemia and reduction of transfusion dependence. There is currently no evidence of safety issues of erythropoietins in MDS, including thrombosis, polycythemia, and progressive disease. Large retrospective comparative analyses have shown no increase in mortality in erythropoietin (EPO)-treated MDS patients. Doses of up to 80,000 IU/wk have successfully been employed and the addition of granulocyte colony-stimulating factor (G-CSF) can benefit previously unresponsive patients. Although several other combination therapies have been tested, apart from G-CSF, none has gained wide clinical acceptance. Thrombopoietic agents can alleviate thrombocytopenia and bleeding symptoms in lower risk MDS patients. However, concerns regarding a higher rate of transformation to acute myeloid leukemia and the fear of increased bone marrow fibrosis during treatment have hampered their clinical development.

Topics: Erythropoietin; Humans; Myelodysplastic Syndromes; Thrombopoietin

Myelodysplastic syndrome with erythroid hypoplasia or erythroblastopenia has not yet been clearly defined, and in most patients it is mistaken for acquired pure red cell aplasia. Including one additional patient reported in this article, a literature review revealed only 50 cases over the last 20 years. These patients were predominantly elderly males, all required regular packed red cell transfusions, and they had a poor prognosis, mainly because of acute transformation. The mechanisms of erythroid aplasia remain unclear. However, recent data suggest the association of an intrinsic stem cell defect with immunological implication.

Topics: Age Distribution; Blood Transfusion; Diagnosis, Differential; Erythroblasts; Erythropoietin; Evidence-Based Medicine; France; Humans; Myelodysplastic Syndromes; Prognosis; Red-Cell Aplasia, Pure; Risk Factors; Sex Distribution

Over the last decade, treatment approaches for patients with myelodysplastic syndromes (MDS) have improved significantly. Treatment of MDS is tailored to the specific risk characteristics of the patient. In general, patients are divided into lower- and higher-risk categories. Without therapy, prognosis of patients with higher-risk MDS is poor, and treatments should be directed to improve survival. Prognosis of patients with lower-risk MDS is more heterogeneous, and therapies are usually directed to minimize transfusion needs and potentially to alter the natural course of the disease. Treatment options for patients with higher-risk MDS include hypomethylating agents (azacitidine and decitabine), intensive chemotherapy (ICT), and allogeneic stem-cell transplantation (alloSCT). The use of the hypomethylating agents has transformed the approach to this patient population, in particular older individuals, for whom ICT and alloSCT are not an option. In lower-risk MDS, treatment strategies are used sequentially and usually include observation in patients with low risk and no transfusion dependency, growth factors, and lenalidomide for patients with alteration of chromosome 5 and anemia. The use of hypomethylating agents is less understood in this group of patients. AlloSCT is usually reserved for patients with lower-risk MDS closer to the time of transformation. In this short review, we discuss treatment alternatives for patients with MDS and delineate some of the ongoing challenges, including the development of better front-line strategies for patients with higher-risk disease, the concept of altering the natural course of the disease in lower-risk MDS, and the development of new treatment approaches for patients who do not benefit from hypomethylating agents.

Topics: Antimetabolites, Antineoplastic; Azacitidine; Decitabine; DNA Methylation; Epoetin Alfa; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lenalidomide; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins; Thalidomide; Transplantation, Homologous

Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias resulting from ineffective hemopoiesis. Anemia affects the vast majority of patients with MDS and contributes substantially to their symptoms. For more than 20 years, recombinant human erythropoietin has been available for clinical use, and it has been employed in an attempt to relieve MDS-related anemia. Erythropoietin-alpha, erythropoietin-beta, and more recently darbepoetin have been found to increase hemoglobin levels and abolish transfusion dependence in 19%-68% of MDS cases. This wide range in clinical response depends on several biological and clinical variables that allow the selection of patients with the highest probability of successful treatment. These agents are a mainstay in MDS therapy, but many issues are still open in terms of the initiation of therapy, the optimal dosage of erythropoietic stimulating agents (ESAs), the most efficient type of ESA, and the duration and outcome of such treatments. In this review, the mechanisms of response and predictive factors as well as an analysis of the clinical activity of ESAs in MDS therapy are presented.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Hematopoietic growth factors (HGFs) continue to be the most widely prescribed class of medications for patients with myelodysplastic syndromes (MDS), despite the advent of disease-modifying therapies for MDS (eg, azacitidine, decitabine, and lenalidomide) and the current absence of an MDS-specific US Food and Drug Administration (FDA)-approved indication for any of the HGFs. Erythropoiesis-stimulating agents (ESAs: epoetin alfa, darbepoetin alfa), myeloid growth factors (MGFs: filgrastim, pegfilgrastim, sargramostim), and the newest group of HGFs, thrombopoiesis-stimulating agents (TSAs: romiplostim, eltrombopag), can increase peripheral blood counts in some patients, and may ameliorate some of the signs and symptoms of MDS-associated bone marrow failure. Although HGFs are generally considered "supportive care" measures, recent data suggest that HGFs may alter the natural history of disease in MDS, either for better or worse. This review examines data on the safety and effectiveness of HGFs for patients with MDS.

Topics: Benzoates; Colony-Stimulating Factors; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematinics; Humans; Hydrazines; Myelodysplastic Syndromes; Patient Selection; Polyethylene Glycols; Pyrazoles; Receptors, Fc; Recombinant Fusion Proteins; Recombinant Proteins; Thrombopoietin

The myelodysplastic syndromes (MDS) are clonal bone marrow disorders that lead to underproduction of normal blood cells. The consequent cytopenias result in infections and bleeding complications. MDS transform to acute myeloid leukemia in one-third of patients. The number of diagnoses has exploded in the past decade as a result of increased recognition and understanding of the disease and the aging of the population. New therapies can extend life. MDS are now considered the most common form of leukemia, and in some cases deserve immediate intervention. This review describes common presentations of MDS, optimal diagnostic approaches, and therapies for lower-and higher-risk disease.

Topics: Age Distribution; Anemia; Anti-Bacterial Agents; Blood Cell Count; Chelation Therapy; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Anemia is the leading clinical manifestation in myelodysplastic syndromes (MDS), significantly altering quality of life. Darbepoetin alfa has recently been added to the armentarium of erythropoiesis stimulating agents (ESAs) for the treatment of anemia in MDS.. We review here the efficacy and safety data on the use of darbepoetin alfa in the management of anemia in MDS patients. Published reports covering the period from 2005 till today were reviewed, as well as updated guidelines on the use of ESAs.. Darbepoetin alfa administered, during correction phase, once a week or at longer intervals, yielded erythroid response rates comparing favourably with those obtained with recombinant human erythropoietin (rHuEPO) in lower-risk MDS. During maintenance phase, intervals between injections can be further increased in many responders. Quality of life was consistently improved in responders and the drug was overall well tolerated.. Those results, together with recent studies showing improved long-term outcomes in responders, support the use of darbepoetin, among other ESAs, for the treatment of anemia of lower-risk MDS, as recommended by international guidelines.

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes

Despite the remarkable progress in the treatment of patients with myelodysplastic syndromes (MDS) in the past decade, response to the hypomethylating agents azacitidine and decitabine in non-del(5q) MDS patients remains at approximately 50%, leaving half of patients needing treatment with essentially no options. As biologic insight into the molecular pathways that account for disease evolution and clinical heterogeneity is expanded, the arsenal of potential drugs that may elicit significant response is also increasing. One of the greatest challenges for the treating physician is to decide when to initiate therapy and which therapy (approved drug or newer agents still in clinical trial) is likely to be the most beneficial. While there is no single answer to these issues, there are several approaches that may be considered, and these are addressed in this review.. This review examines the clinical outcomes of the FDA-approved drugs as well as of the promising new therapies that are in current clinical trials.. The clinician now has multiple treatment options for patients with MDS. It is important to consider multiple factors before initiating therapy with disease-modifying drugs. This review presents some of the decision-making approaches that are in practice at present.. For the first time, various treatment options are available for patients with MDS. In light of the intense efforts now in progress, the next decade promises to be one of hope and excitement for both MDS patients and treating clinicians.

Topics: Azacitidine; Decitabine; DNA Methylation; Drug Approval; Erythropoietin; Humans; Iron Chelating Agents; Lenalidomide; Myelodysplastic Syndromes; Recombinant Proteins; Thalidomide; United States; United States Food and Drug Administration

Optimal management of patients with myelodysplastic syndromes (MDS) requires an insight into the biology of the disease and the mechanisms of action of the available therapies. This review focuses on low-risk MDS, for which chronic anaemia and eventual progression to acute myeloid leukaemia are the main concerns. We cover the updated World Health Organization classification, the latest prognostic scoring system, and describe novel findings in the pathogenesis of 5q- syndrome. We perform in depth analyses of two of the most widely used treatments, erythropoietin and lenalidomide, discussing mechanisms of action, reasons for treatment failure and influence on survival.

Topics: Antineoplastic Agents; Blood Transfusion; Chromosomes, Human, Pair 5; Disease Progression; Erythropoietin; Female; Humans; Immunosuppressive Agents; Iron Chelating Agents; Lenalidomide; Male; Myelodysplastic Syndromes; Recombinant Proteins; Sequence Deletion; Thalidomide; World Health Organization

Epoetin alpha (EPO) continues to be the initial treatment of choice for most anemic patients with myelodysplastic syndromes (MDS). Over the years, different therapeutic strategies have been adopted to optimize the clinical benefits of EPO in this setting.. In the current meta-analysis of published literature, erythroid response (ER) rates with EPO as a single agent versus its combination with granulocyte-colony-stimulating factor (G-CSF) or granulocyte-macrophage-colony-stimulating factor (GM-CSF) were compared.. The assessment indicated that the ER rates were comparable between the 2 EPO-based therapeutic strategies. Furthermore, EPO monotherapy at a higher dose of 60,000 to 80,000 U weekly produced significantly higher ER rates (64.5%) compared with the standard oncology dose of 30,000 to 40,000 U weekly either as a single agent (49%; P < .001) or in combination with G-CSF/GM-CSF (50.6% P = .007). In addition, when transfusion-dependent patients were assessed separately, both EPO monotherapy and its combination with G-CSF/GM-CSF produced comparable and appreciable levels of transfusion independence (28.8% and 24.8%, respectively).. In the current meta-analysis, higher doses of EPO demonstrated better ER rates compared with EPO at standard doses alone or in combination with G-CSF/GM-CSF. Furthermore, the authors concluded that prospective clinical studies are warranted to evaluate the use of higher doses of EPO in anemic patients with MDS.

Topics: Aged; Anemia; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins

Topics: Acute Disease; Aged; Azacitidine; Chelation Therapy; Chromosome Deletion; Chromosomes, Human, Pair 5; Clinical Trials as Topic; Decitabine; Disease Progression; DNA Methylation; Erythropoietin; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Lenalidomide; Leukemia, Myeloid; Myelodysplastic Syndromes; Severity of Illness Index; Thalidomide; Transplantation, Homologous

Topics: Antineoplastic Agents; Azacitidine; Clinical Trials as Topic; Decitabine; Drug Discovery; Drug Therapy, Combination; Erythropoietin; Humans; Lenalidomide; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic; Remission Induction; Thalidomide

The myelodysplastic syndromes (MDS) are a group of heterogeneous disorders characterized by ineffective hematopoiesis. A number of scoring systems have been developed but they are of limited value in guiding individual patient treatment decisions.. We have presented the benefits and limitations of various treatment approaches for MDS to help provide guidance in treatment decisions.. An extensive literature search on PubMed from 2000 to 2008 was done using MESH keywords MDS, treatment, 5-azacytidine, decitabine, lenalidomide, antithymocyte globulin.. In recent years there has been progress in supportive care and three agents have been approved for the treatment of MDS. With the exception of lenalidomide, which produced remarkable responses with 5q chromosomal deletion, these therapies benefit a minority of patients and the overall outcomes are still unsatisfactory. Allogeneic stem cell transplant remains the only curative option but the majority of MDS patients are not eligible because of older age and other medical problems. Immunosuppressive therapy is helpful in a fraction of patients. Several newer agents are being tested, offering promise for the future.

Topics: Age Factors; Antimetabolites, Antineoplastic; Arsenic Trioxide; Arsenicals; Blood Transfusion; Clinical Trials as Topic; Comorbidity; Disease Progression; Erythropoietin; Farnesyltranstransferase; Hematinics; Histone Deacetylase Inhibitors; Humans; Immunologic Factors; Myelodysplastic Syndromes; Oxides; Recombinant Proteins; Social Class; Stem Cell Transplantation

Treatment of myelodysplastic syndromes (MDS) has evolved to encompass a broad spectrum of therapies aiming to inhibit apoptosis, promote hemopoiesis, and reduce proliferation of clonal immature cells. A small but expanding cohort of patients with MDS may be cured, but for the majority the aim of treatment is to prolong survival and to improve quality of life. Patients with low-risk MDS mainly suffer from the effects of severe anemia and an important therapeutic goal is to maintain acceptable hemoglobin levels by optimal transfusion regimens or by erythropoietin+/-granulocyte-colony-stimulating factor, which normalizes hemoglobin levels or abolish transfusion need in around 40% of patients. Lenalidomide has emerged as a drug of choice for patients with low-risk MDS and a 5q deletion, leading to complete erythroid response and cytogenetic remission in 2/3 of patients. A small cohort of younger patients may show excellent responses to anti-thymocyte globulin. Patients with more advanced disease may respond to treatment with the hypomethylating agents azacytidine and decitabine, who both have been shown to prolong time to leukemic transformation / death in MDS. In addition, there are several new agents under clinical investigation targeted to potential mechanisms of disease and progression in MDS. New therapeutic drug include inhibitors of angiogenesis, histone deacetylation, tyrosine kinases and farnesylation, as well as drugs interacting with apoptotic mechanisms. The role of these, alone and in combination with more established therapies will be discussed.

Topics: Disease Progression; Epigenesis, Genetic; Erythropoietin; Humans; Immunosuppressive Agents; Intercellular Signaling Peptides and Proteins; Myelodysplastic Syndromes; Neutropenia; Remission Induction

Supportive care constitutes the basis of the management of patients with myelodysplastic syndromes (MDS). Appropriate treatment of cytopenia, as well as of other related complications, not only improves quality of life but also may positively affect the overall survival of patients. Anemia is the most common cytopenia in MDS, and the requirement for regular transfusions is a major clinical problem for patients with low-risk MDS. An important therapeutic goal in this patient group is to maintain acceptable hemoglobin levels without transfusions. Today, this goal can be achieved by treatment with erythropoietin (Epo) +/- granulocyte colony-stimulating factor (G-CSF), or by more targeted treatment such as antithymocyte globulin or lenalidomide in around 50% of patients. For the remaining patients, and for those who lose their therapeutic response, chronic transfusion therapy, with or without the addition of chelating agents, is the only option and it is important that this treatment is scheduled to meet the needs of the individual patient. Severe thrombocytopenia has recently been reported to respond to thrombopoietic agents, such as AMG 531.

Topics: Anemia; Colony-Stimulating Factors; Erythrocyte Transfusion; Erythropoietin; Hematopoiesis; Humans; Myelodysplastic Syndromes; Neutropenia; Prognosis; Recombinant Proteins; Thrombocytopenia

For cancer treatment-related anemia, it is recommended to use erythropoietin or darbepoetin alpha by the National Comprehensive Cancer Network (NCCN). The guideline proposed the risk assessment for anemia, as well. The introduction of erythropoietin or darbepoetin alpha for anemia in treated cancer patients is based on the improvement of quality of life. For patients with myelodysplastic syndrome (MDS), those with 5q- anomaly is recommended to use lenalidomide and low-risk MDS patients without 5q- and serum erythropoietin of less than 500 mU/ml are recommended to treat with erythropoietin or darbepoetin alpha. These new agents are currently under clinical trials in Japan.

Topics: Anemia; Benzoates; Clinical Trials as Topic; Darbepoetin alfa; Deferasirox; Erythropoietin; Hematinics; Humans; Iron Chelating Agents; Iron Overload; Lenalidomide; Myelodysplastic Syndromes; Neoplasms; Thalidomide; Triazoles

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

Myelodysplastic syndromes (MDS) are a group of complex diseases of the myeloid stem cell that result in chronic cytopenias. In some instances, these disorders may progress to acute myeloid leukemia. Patients with MDS frequently experience chronic, symptomatic anemia, and many become dependent on chronic transfusions of packed red blood cells. However, long-term transfusion dependence has clinical and economic consequences, including a potentially negative impact on patients' quality of life (QOL). Recently, studies have investigated various strategies to reduce or eliminate transfusion needs in MDS patients. Supportive measures with hematopoietic growth factors such as erythropoietin are often less effective in MDS-associated anemia than in anemia from other causes, but some patients may benefit from this approach. Treatment with other agents, such as antithymocyte globulin, azacitidine, decitabine, thalidomide, and lenalidomide, has resulted in transfusion independence in some subsets of MDS patients. Nurses who care for patients with MDS should be aware of the impact of transfusion dependence on the patient's QOL, as well as the benefits and risks of the various other treatment options available to these patients. Such knowledge will enable the nurse to provide accurate, relevant information, so that patients can make informed choices regarding treatment options for MDS.

Topics: Anemia; Antilymphocyte Serum; Antimetabolites, Antineoplastic; Azacitidine; Decitabine; Drug Costs; Erythrocyte Transfusion; Erythropoietin; Health Services Needs and Demand; Humans; Immunosuppressive Agents; Informed Consent; Myelodysplastic Syndromes; Nurse's Role; Oncology Nursing; Patient Education as Topic; Patient Selection; Quality of Life; Thalidomide; 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

Anemia is common in patients with cancer or myelodysplastic syndrome. Erythropoietic therapy offers an effective way to manage anemia by increasing hemoglobin levels, decreasing transfusion requirements, and alleviating symptoms. We reviewed data showing the feasibility and effectiveness of treatment with the erythropoiesis-stimulating protein darbepoetin alfa at extended dosing intervals to treat anemia in patients with cancer receiving multicycle chemotherapy. We also explored the darbepoetin alfa's potential for treating anemia in patients with myelodysplastic syndrome. Data from clinical studies and drug therapy evaluations confirm that darbepoetin alfa administered weekly, every 2 weeks, and every 3 weeks corrects and maintains hemoglobin levels in patients with chemotherapy-induced anemia. In addition, the data demonstrate that both weight-based and fixed dosing with darbepoetin alfa are effective, and that early intervention to treat anemia has clinical benefits. Darbepoetin alfa also is an effective treatment for anemia in patients with cancer not receiving chemotherapy, at extended dosing intervals of at least 3 weeks. Extended dosing for anemia treatment can provide benefits for patients, caregivers, and clinicians because it reduces the number of clinic visits needed and permits synchronizing anemia treatment with chemotherapy cycles. Data from recent studies suggest that darbepoetin alfa is effective for treating anemia in patients with myelodysplastic syndrome; this potential use is being investigated further in ongoing studies. Thus, darbepoetin alfa is an attractive therapy option for patients with chemotherapy or cancer-induced anemia. It allows increased flexibility and simplified dosing and may offer some benefit in the treatment of anemia in patients with myelodysplastic syndrome.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

The objective was to assess the efficacy and safety of erythropoiesis-stimulating proteins (ESPs) in anemia of myelodysplastic syndrome (MDS).. A systematic review and meta-analysis was conducted covering English-language studies published from 1980 to December 2005.. Fifty-nine studies qualified: five controlled trials (n = 354), all epoetin versus control (EvC); 51 epoetin single-arm studies (n = 1,650); and three darbepoetin single-arm studies (n = 102). In the EvC studies, epoetin patients demonstrated a significant advantage over controls in terms of hemoglobin (Hb) response (odds ratio, 5.2; 95% confidence interval, 2.5-10.8). Hb response was 48.1% in single-arm darbepoetin studies, 32.1% in epoetin single-arm studies, and 27.3% in EvC studies. Major Hb response averaged 38.8% in darbepoetin studies, 24.5% in epoetin single-arm studies, and 11.4% in EvC studies. Stratified analyses suggest that lower baseline erythropoietin levels, longer treatment durations, and concurrent iron may be associated with greater Hb response to ESPs. None of the analyzable predictors of Hb response (gender, baseline Hb, ESP type, and ESP duration) were significant in meta-regression analyses. In the few studies with quality-of-life measures, ESP groups attained a pre-post change (Functional Assessment of Cancer Therapy - Fatigue) that exceeded minimum clinically important differences. Selected adverse event rates did not differ between the epoetin and darbepoetin groups.. Published studies suggest that ESPs are efficacious in anemia of MDS. Hb response appears higher in darbepoetin patients than in epoetin patients, and safety appears comparable, but darbepoetin data are sparse, and there are as yet no direct comparison studies.

Topics: Erythropoiesis; Erythropoietin; Humans; Myelodysplastic Syndromes; Safety

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis resulting in peripheral cytopenia and by increased progression to acute myeloid leukemia (AML). Therapeutic interventions for MDS other than allogeneic stem cell transplantation have been palliative. Novel and targeted therapeutic agents such as the inhibition of farnesyltransferases and receptor tyrosine kinases, more potent thalidomide analogs, arsenic trioxide, immunomodulating agents, hypomethylating agents, and histone deacetylase inhibitors have shown encouraging results and may offer durable benefit to patients with MDS. Further development of rational therapies and improvements in the outcome of patients with MDS are likely to emerge from an increased understanding of the pathophysiology of these diseases.

Topics: Angiogenesis Inhibitors; Blood Transfusion; Clinical Trials as Topic; Combined Modality Therapy; Disease Progression; Drug Design; Drugs, Investigational; Enzyme Inhibitors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Multicenter Studies as Topic; Myelodysplastic Syndromes; Prognosis; Risk; Tretinoin

Recombinant human erythropoietins (rhEPO) reliably increase hemoglobin levels in cancer patients experiencing chemotherapy-associated anemia. However, in patients with "anemia of cancer" not being treated with chemotherapy, rhEPO appears less effective. Recently, two studies have been broadly discussed which have raised concern on the concomitant use of erythropoietin and chemo- or radiation therapy in cancer patients. In addition, use of rhEPO is generally not considered cost-effective. Thus, the application of rhEPO should be limited to indications with proven clinical benefit. This review will provide an overview of the state of the art use of rhEPO in anemic patients and will discuss future developments.

Topics: Anemia; Bone Marrow Transplantation; Clinical Trials as Topic; Cost-Benefit Analysis; Erythropoietin; Female; Humans; Male; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

Increased apoptosis of hematopoietic progenitors is a hallmark of myelodysplastic syndromes (MDS) and results in ineffective hematopoiesis. Erythroid apoptosis is thought to be the main mechanism underlying the severe anemia observed in the low-risk subgroups, refractory anemia (RA) and RA with ringed sideroblasts (RARS). Treatment with erythropoietin (Epo) alone or in combination with granulocyte colony-stimulating factor (G-CSF) may significantly improve anemia and reduce bone marrow apoptosis. A synergistic effect between Epo and G-CSF has been observed in the clinic, in particular in RARS. However, the molecular mechanisms beyond the anti-apoptotic effect of these growth factors have not been fully understood. This paper outlines the potential mechanisms underlying the augmented apoptosis during the erythroid differentiation in low-risk MDS as well as the anti-apoptotic effect of the growth factors.

Topics: Apoptosis; Cell Differentiation; DNA, Mitochondrial; Erythropoietin; Ferritins; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Mutation; Myelodysplastic Syndromes; Prognosis

Deletions of the long (q) arm of chromosome 5 [del(5q)]occur in patients with myelodysplastic syndromes (MDS) including, but not limited to, those who meet the WHO definition of the 5q- syndrome. Del(5q) MDS patients frequently have symptomatic anemia, and its treatment has traditionally consisted of RBC transfusions and, for some, iron chelation therapy. Erythropoietin, darbepoetin, hypomethylating agents, and lenalidomide can enhance erythropoiesis in MDS patients with anemia, increasing hemoglobin levels and abrogating RBC transfusion requirements. Lenalidomide is particularly active in treating the anemia of del(5q) MDS, which is especially relevant given the low response rate to erythropoietin in this group of patients. In a recent study of 43 MDS patients, 10 of 12 patients (83%) with del(5q) MDS achieved sustained RBC transfusion independence (or a > 2 g/dL increase in hemoglobin), compared with 57% of those with a normal karyotype and 12% of those with other karyotypic abnormalities. Complete cytogenetic remissions were achieved in 75% (nine of 12) of the del(5q) MDS patients, suggesting that lenalidomide targets a fundamental pathogenetic feature of MDS that is more pronounced in the presence of chromosomal 5q deletions. This review highlights some issues about the classification and treatment of del(5q) MDS.

Topics: Anemia, Hypochromic; Azacitidine; Bone Marrow; Chromosome Aberrations; Chromosomes, Human, Pair 5; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Gene Deletion; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Karyotyping; Lenalidomide; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Thalidomide

In early 2005, several groups of investigators studying myeloid malignancies described a novel somatic point mutation (V617F) in the conserved autoinhibitory pseudokinase domain of the Janus kinase 2 (JAK2) protein, which plays an important role in normal hematopoietic growth factor signaling. The V617F mutation is present in blood and marrow from a large proportion of patients with classic BCR/ABL-negative chronic myeloproliferative disorders and of a few patients with other clonal hematological diseases such as myelodysplastic syndrome, atypical myeloproliferative disorders, and acute myeloid leukemia. The JAK2 V617F mutation causes constitutive activation of the kinase, with deregulated intracellular signaling that mimics continuous hematopoietic growth factor stimulation. Within 7 months of the first electronic publication describing this new mutation, clinical molecular diagnostic laboratories in the United States and Europe began offering JAK2 mutation testing on a fee-for-service basis. Here, I review the various techniques used by research groups and clinical laboratories to detect the genetic mutation underlying JAK2 V617F, including fluorescent dye chemistry sequencing, allele-specific polymerase chain reaction (PCR), real-time PCR, DNA-melting curve analysis, pyrosequencing, and others. I also discuss diagnostic sensitivity, performance, and other practical concerns relevant to the clinical laboratorian in addition to the potential diagnostic utility of JAK2 mutation tests.

Topics: Base Sequence; Biomarkers; Erythropoietin; Humans; Janus Kinase 2; Models, Biological; Molecular Diagnostic Techniques; Molecular Sequence Data; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Polycythemia; Polymerase Chain Reaction; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Thrombocytosis

Refractory anaemia associated with excessive intramedullary erythroid apoptosis and dysplasia is a major feature of myelodysplastic syndromes (MDS). Recombinant human erythropoietin (specifically, epoetin alfa [EPO]) has been used in the therapy of MDS for many years. Initially, the erythroid response rates were modest, as EPO was used in all subgroups of MDS patients without discretion. However, with increased sophistication in patient selection and response evaluation criteria, there has been a significant improvement in the response rates to EPO therapy. This review discusses the evolution of therapeutic strategies incorporating EPO for the treatment of MDS.

Topics: Epoetin Alfa; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Supportive care with blood transfusion and administration of hematopoietic growth factors (eg, erythropoietin, colony-stimulating factors) has been the standard of care for patients with low-risk myelodysplastic syndromes (MDS), a group of disorders characterized by hyperproliferation of the bone marrow and ineffective hematopoiesis. However, the development of new drugs, including lenalidomide, azacitidine, and decitabine, has led to a new era of more effective treatment for MDS. Further, the use of classification and risk stratification has allowed for the identification of individuals who are expected to benefit from some therapies while simultaneously excluding over-treatment and unnecessary toxicity in those who are unlikely to benefit from specific drugs. In this Clinical Roundtable Monograph, the faculty discusses the epidemiology, classification, and risk stratification for MDS, medical and nursing issues associated with supportive care and the new therapies for low-risk MDS, and patient education and other strategies for the optimization of quality of life in patients with low-risk MDS.

Topics: Antimetabolites, Antineoplastic; Blood Transfusion; Erythropoietin; Hematinics; Hematopoiesis; Humans; Myelodysplastic Syndromes; Patient Education as Topic; Quality of Life; Risk Factors; Risk Management

Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]. This review examines the clinical experience from the MDS-001 and MDS-003 clinical trials that led to this approval, the results of biological correlates supporting the targets of drug action, and the results from a non-del(5q) multicenter study (MDS-002). Lenalidomide treatment resulted in both erythroid and cytogenetic responses in the majority of patients with del(5q), accompanied by reductions in inflammatory cytokine generation and marrow microvessel density and improvement in primitive hematopoietic progenitor recovery. Central pathology review showed that resolution of cytologic dysplasia was common in patients with del(5q) but was infrequent in erythroid-responding patients without the chromosome 5 deletion. These findings indicate that lenalidomide promotes erythropoiesis in lower-risk MDS, with two apparently distinct mechanisms of action: suppression of the ineffective del(5q) clone and promotion of effective erythropoiesis in non-del(5q) MDS progenitors. These studies identified lenalidomide as a highly active erythropoietic- and cytogenetic-remitting agent in lower-risk MDS patients who otherwise would not be expected to benefit from recombinant erythropoietin therapy. The most common adverse reactions include dose-dependent neutropenia and thrombocytopenia that are more pronounced in patients with del(5q) in whom early suppression of the clone is expected.

Topics: Anemia; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 5; Drug Delivery Systems; Erythropoiesis; Erythropoietin; Humans; Immunosuppressive Agents; Lenalidomide; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic; Recombinant Proteins; Thalidomide; Treatment Outcome

During the past 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndrome (MDS). MDS is a clonal disorder characterized by ineffective hematopoiesis, which can lead to either fatal cytopenias or acute myelogenous leukemia (AML). Risk-adapted treatment strategies were established because of the high median age (60-75 years) of the MDS patients and the individual history of the disease (number of cytopenias, cytogenetic changes, transfusion requirements). Allogeneic bone marrow transplantation currently offers the only potentially curative treatment, but this form of therapy is not available for the typical MDS patient, who is >60 years of age. Therapy with erythropoietin and G-CSF has improved the quality of life of selected patients. The development of small molecules directed against specific molecular targets with minimal adverse effects is the hope for the future. Innovative uses of immunomodulatory agents and the optimizing of cytotoxic treatment should continue to help in the treatment of MDS.

Topics: Aged; Bone Marrow Transplantation; Cause of Death; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Pancytopenia; Prognosis; Survival Rate

Topics: Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Growth Substances; Humans; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Myelodysplastic syndromes (MDS) are clonal disorders of the haemopoietic stem cell characterized by peripheral cytopenias that are the result of abnormal haemopoietic differentiation and maturation. Approximately 90% of MDS patients present with anemia at the beginning or during the course of the disease and often require transfusions. The rationale for treating anemic MDS patients with recombinant human erythropoietin (rHuEpo), alone or in combination with other growth factors, is based on the possibility of overcoming the defective proliferation and maturation of erythroid precursors through the inhibition of bone marrow apoptosis, the enhancement of the differentiation of preleukemic progenitor cells or the stimulation of the growth of residual normal haematopoietic cells. Clinical trails have shown that rHuEpo, alone or in combination with recombinant human granulocyte colony-stimulating factor, is a useful drug for the treatment of anemia in low-risk MDS patients, and the same trials have identified patients who are more likely to respond to maximize benefits, to minimize adverse effects, and to avoid misuse or abuse. However, further research is required to determine whether this treatment has any real impact on quality of life and on life expectancy, thus allowing recommendations to be made about rHuEpo use in MDS patients with a degree of certainty.

Topics: Algorithms; Apoptosis; Cell Proliferation; Erythropoietin; Europe; Granulocyte Colony-Stimulating Factor; Guidelines as Topic; Hematopoietic Stem Cells; Humans; Myelodysplastic Syndromes; Outcome Assessment, Health Care; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Stem Cells; Treatment Outcome

Myelodysplastic syndromes (MDS) are a heterogeneous group of progressive bone marrow neoplastic disorders associated with increased risk for transformation to acute leukemia. Hallmarks of MDS are peripheral blood cytopenias (especially anemia), frequently with hypercellular bone marrow, and dysplastic changes in one or more hematopoietic lineages. The wide variation in clinical presentation has confounded treatment strategies and hindered the development of new therapies. However, improved classification and prognostic systems are providing a more refined stratification of patients, helping to guide treatment and management decisions as well as to appropriately select patients for clinical trials. Patients with International Prognostic Scoring System classifications of low- and intermediate-1 (Low/Int-1) risk are considered to have "low-risk" MDS. These patients are primarily treated with low-intensity supportive care, especially red blood cell transfusions, to treat their symptoms and maintain their quality of life. In small subsets of Low/Int-1-risk patients with MDS, hematopoietic cytokines or antithymocyte globulin may reduce transfusion requirements. The drawbacks to these treatments are high failure rates, even with improved predictive models, and the high cost of cytokines. Regardless of risk category, a patient's age and existing comorbidities must be factored into treatment decisions. It is anticipated that trials with new and investigational agents may soon provide definitive treatments for patients with Low/Int-1-risk MDS when used alone or in conjunction with supportive measures.

Topics: Antilymphocyte Serum; Disease Management; Erythrocyte Transfusion; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Quality of Life

Topics: Anemia; Biomarkers; Diagnostic Techniques, Endocrine; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Myelodysplastic Syndromes; Nephrotic Syndrome; Polycythemia; Radioimmunoassay; Reference Values; Specimen Handling

Myelodysplastic Syndrome (MDS) comprises a heterogeneous group of clonal hemopathies derived from an abnormality affecting a multipotent hematopoietic stem cell and characterized by maturation defects resulting in ineffective hematopoiesis. It most frequently occurs in elderly patients. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Most MDS patients, due to their age and co morbidity, are not eligible for allogeneic hematopoietic stem cell transplantation; the only established curative regimen. The effect of available lineage-specific growth factors is limited to improvement of single lineages and has not resulting in the survival benefit. Treatment with low dose Ara-C is disappointing in regard to response rate or duration. No benefit has been demonstrated in differentiation inducers such as retinoids and Vitamin D3 as single agents. We report a case of a patient with transfusion dependent MDS who was not a candidate for allogeneic stem cell transplantation or cytotoxic chemotherapy, who also failed to response to erythropoietin support but had a favorable response to 5-azacitidine. His blood transfusion requirement reduced significantly, and was correlated with the remarkable improvement of the pancytopenia, particularly anemia and thrombocytopenia after receiving the investigational therapy with 5-azacitidine. In summary, 5-azacitidine appears to be a promising alternative therapy for patient with refractory anemia secondary to MDS.

Topics: Aged; Anemia; Antimetabolites, Antineoplastic; Azacitidine; Blood Transfusion; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Male; Myelodysplastic Syndromes; Thrombocytopenia

Thalidomide exerts in vitro heterogeneous biological effects on hematopoiesis which have supported its possible use in treating myelodysplastic syndromes (MDS). Some recent clinical trials have confirmed that thalidomide may improve anemia and, less frequently, other cytopenias, in a proportion of younger patients with low-risk MDS (11-56%, on intention-to-treat analysis). Of interest, erythroid responses may be achieved also in transfusion-dependent subjects with high serum levels of endogenous erythropoietin, a subset of MDS patients with little chance of responding to recombinant erythropoietin, alone or in combination with G-CSF. Older patients, however, often do not tolerate the drug even at very low doses. How thalidomide acts in MDS is not clear. Some data suggest several mechanisms possibly involving stimulation of erythropoiesis through activation of physiological compensative mechanisms and reduction of apoptosis. The combination of thalidomide with other molecules active on hematopoiesis and the use of more effective and less toxic analogs are currently under clinical investigation.

Topics: Angiogenesis Inhibitors; Clinical Trials as Topic; Erythropoietin; Fibroblast Growth Factor 2; Hepatocyte Growth Factor; Myelodysplastic Syndromes; Thalidomide; Vascular Endothelial Growth Factor A

In spite of recent advances in the treatment of myelodysplastic syndromes (MDS), supportive care remains a very important part of the therapy. Red blood cells transfusions are the most important component of this supportive care. They transiently relieve anemia symptoms and alleviate their effects on quality of life and daily functioning. Platelet transfusion therapy is less frequently needed, at least in low-risk MDS. Dealing with an increased risk of infections linked to neutropenia, mainly by broad spectrum antibiotics, is also needed, more often in advanced stages of [dict: MDS] or when the MDS evolves to acute myeloid leukemia. Chronic red blood cell transfusions expose patients to various side-effects, including blood components intolerance reactions and alloimmunization risks, but also increased frequency of iron overload, a more significant problem in low-risk heavily transfused MDS patients, who have prolonged life expectancy. The use of growth factors is becoming a more and more important part of current supportive care. High-dose erythropoietin is able to reduce or suppress red blood cell transfusions needs in selected subgroups of MDS. The short-term use of granulocyte colony-stimulating factor is also often proposed in infections, although not formally established by prospective trials. Although trials of growth factors with thrombopoeitic activity have been performed with interleukin 11 and are underway with thrombopoeitin, none of them are available for routine use.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Growth Substances; Hemorrhage; Humans; Myelodysplastic Syndromes; Neutropenia; Recombinant Proteins; Thrombocytopenia

Topics: DNA Modification Methylases; Enzyme Inhibitors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Histone Deacetylase Inhibitors; Humans; Immunologic Factors; Myelodysplastic Syndromes; Recombinant Proteins; Stem Cell Transplantation; Topotecan

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Hematologic Neoplasms; Humans; Lymphoproliferative Disorders; Myelodysplastic Syndromes; Prognosis; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Anemia is a frequent symptom encountered in hematological malignancies at diagnosis or in the course of the disease. Allogeneic transfusions were, until recently, the only treatment available and used only for severe anemia. Erythropoietin is currently an important alternative especially for treatment and even to prevent severe anemia. It has been assessed for the treatment of chemotherapy related anemia in NHL, myeloma and CLL with a significant reduction of blood transfusions and prevention of grade 3-4 anemia in 51% of patients. In myelodysplasia, the more effective regimen is the association of G-CSF and Epo. In the setting of allogeneic bone marrow transplantation, it reduces the time to red cell engraftment and probably the number of blood cell unit per patient in contrast with autologous stem cell transplant. All these studies assessed the efficacy of Epo in hematological malignancies but needs further trials including the assessment of the quality of life and economical parameters.

Topics: Anemia; Erythropoietin; Hematologic Diseases; Hematologic Neoplasms; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Anemia is a common finding in patients with hematologic malignancies and most commonly can be attributed to the anemia of chronic disease compounded by the myelotoxic effects of chemotherapy. Symptoms of anemia include fatigue, and the patient's quality of life may be impaired. Possible treatments for the anemia are to do nothing, to transfuse with red cells, or to treat with recombinant human erythropoietin (rhEPO). rhEPO has become standard treatment for the anemia in chronic renal failure and has been successfully used in anemia secondary to malignancy. In patients with lymphoproliferative diseases, rhEPO increases the hemoglobin concentration, decreases the need for transfusion, and improves the patients' quality of life. Disadvantages of rhEPO include its cost, efficacy in only around 60% of patients, and delay of 4 to 8 weeks before maximum benefit is achieved. The anemia in patients with myelodysplasia responds less well to rhEPO. Misuse of rhEPO is common in the clinical setting but usually not of clinical importance. Misuse to enhance sporting prowess is probably rare but has potentially serious consequences.

Topics: Anemia; Doping in Sports; Erythropoietin; Humans; Lymphoproliferative Disorders; Medication Errors; Myelodysplastic Syndromes; Primary Myelofibrosis; Treatment Outcome

Anemia has been reported in approximately 40%-70% of patients with hematologic malignancies, with severity depending on the type and stage of disease and whether the patient has received myelosuppressive chemotherapy. Growing evidence supports the role of epoetin alfa in correcting anemia and improving quality of life (QOL) in patients with hematologic malignancies. Clinical practice guidelines recommend the use of epoetin alfa in patients with cancer-related anemia (including patients with hematologic malignancies) and hemoglobin levels < or =10 g/dL. Epoetin alfa treatment is optional for patients with cancer-related anemia and hemoglobin levels>10 g/dL and <12 g/dL, depending on clinical circumstances. A prospective, open-label, randomized trial evaluating hematologic response, transfusion use, and QOL after immediate or delayed epoetin alfa treatment in mildly anemic patients (hemoglobin< or =12 g/dL) undergoing chemotherapy for chronic lymphocytic leukemia, multiple myeloma, or lymphoma was recently completed. Study objectives included determining any correlation between changes in hemoglobin level and QOL and assessing any correlation between QOL measures and health care resource use. Interim results suggest that epoetin alfa treatment in patients with hematologic cancers and hemoglobin< or =12 g/dL who are receiving chemotherapy increases hemoglobin, functional capacity, well-being, work and productivity, and health resource use. Further evaluation of alternative epoetin alfa dosing schedules and use of epoetin alfa in treating anemia in patients with specific hematologic malignancies is ongoing.

Topics: Anemia; Clinical Trials as Topic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Linear Models; Multiple Myeloma; Myelodysplastic Syndromes; Quality of Life; Random Allocation; Recombinant Proteins

Although erythropoietin (EPO) deficiency is not responsible for the anemia of myelodysplasia, pharmacologic doses of recombinant human EPO (rHuEPO, epoetin alfa) and epoetin beta have been studied extensively as treatment of anemia in myelodysplastic syndrome (MDS). When an epoetin is used as a single growth factor in patients with MDS, clinically meaningful responses occur in only a small minority of patients (16%). Patients who are transfusion-dependent are less likely to respond than patients who are transfusion-independent. Serum EPO level has a weak association with response rate and cannot be used to select or exclude patients from empirical trials of epoetins. The dose schedule commonly used as initial treatment 40,000 U/week, is consistent with clinical observations, but an optimal dose schedule has not been determined. The combination of an epoetin and granulocyte colony-stimulating factor (G-CSF) produces a higher erythroid response rate (36%) than the regimen of epoetin alone, but we have found no randomized trial data to support this point. However, the design of the clinical trials, which included adding G-CSF after epoetin alone had failed, supports the hypothesis that combined use of growth factors, rather than just higher doses of epoetin, is responsible for the high response rate observed with the combination of epoetin and G-CSF. Unfortunately, as in the case of epoetin alone, patients who are transfusion-dependent (> or =2 U red blood cells/month) are less likely to respond to combined growth factor therapy. Although the ability of patients with MDS to show an erythroid response to epoetin is of biologic interest, because of high costs and the limited response rate in transfusion-dependent patients, epoetin therapy, with or without G-CSF, cannot be regarded as a definitive therapy for the anemia of MDS.

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Neutrophils; Time Factors

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized clinically by refractory cytopenias in one or more myeloid cell lines and an increased probability of transformation to acute leukemia. Supportive care remains the mainstay of therapy in MDS and frequently includes monotherapy and combination therapy with hematopoietic growth factors, such as erythropoietin, granulocyte colony-stimulating factor, and granulocyte macrophage colony-stimulating factor. Clinical trials have demonstrated the ability of growth factors to improve neutropenia and anemia in selected patients with MDS, which may have clinical, quality-of-life, and economic benefits for patients even though overall survival has not been improved. This paper reviews the role of hematopoietic growth factors in the treatment of MDS.

Topics: Clinical Trials as Topic; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Myelodysplastic Syndromes; Recombinant Proteins

As the major regulator of erythropoiesis in man, erythropoietin inhibits the programmed cell death of committed erythroid precursors. In cancer patients, a relative erythropoietin deficiency is coupled with a decreased responsiveness to the substance mediated by the effects of inflammatory cytokines on the marrow and on ferrokinetics, leading to a high incidence of anemia. Two recombinant human erythropoietin (rhEPO) preparations--epoetin alfa (Epogen, Procrit) and epoetin beta (Marogen)--as well as a modified erythropoietic compound (darbepoetin alfa [Aranesp]) are in clinical use. Part 2 of this two-part series on hematopoietic agents reviews the use of these erythropoietic factors and their effect on the anemia that develops in cancer patients. Thrombopoietic factors and progenitor cell-mobilizing factors are also briefly addressed.

Topics: Anemia, Aplastic; Erythropoietin; Hematinics; Humans; Medical Oncology; Myelodysplastic Syndromes; Neoplasms; Practice Patterns, Physicians'; Quality of Life; Recombinant Proteins

Myelodysplastic syndromes (MDS) are a heterogeneous group of hemopoietic progenitor cell disorders, and patients with MDS regularly develop anemia and frequently become transfusion-dependent. Treatment with erythropoietin (EPO) has been tried to correct anemia with only limited success with response rates ranging from 16% to 25%. However, it is becoming evident that the generally rather low response rate of EPO in patients with MDS will be improved by the combination of EPO with either G-CSF or GM-CSF.. Here, we analyzed the results from the literature (six papers and one abstract using EPO plus G-CSF, and seven papers using EPO plus GM-CSF).. Among all trials the cytokine dose and schedule varied, and the response criteria were not uniform. The average response rate for improving anemia was 41% in 207 patients treated with EPO and G-CSF, and 26% in 154 patients treated with EPO and GM-CSF. There were higher response rates for refractory anemia (RA) (45%), ringed sideroblasts (RARS) (47%), and excess of blasts (RAEB) (38%) compared with blasts in transformation (RAEBT) (17%) for the treatment with EPO plus G-CSF. The corresponding response rates for treatment with EPO plus GM-CSF were 30% (RA), 29% (RARS), 16% (RAEB), and 0% (RAEBT), respectively. Prolonged administration even showed a higher increment in the response rates.. In conclusion, the combination of EPO with G-CSF is probably superior to EPO plus GM-CSF. There seems to be a positive correlation between the duration of cytokine treatment and response rates, and higher response rates in early MDS stages compared to advanced entities. However, controlled studies are mandatory to evaluate the role of the combined cytokine treatment in patients with MDS.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Myelodysplastic Syndromes; Recombinant Proteins

The treatment of the myelodysplastic syndrome (MDS) has formerly been supportive, primarily blood transfusions. Treatment with the growth factor erythropoietin, in combination with granulocyte-colony stimulating factor or granulocyte-macrophage colony stimulating factor is accompanied by a decline in the need for blood transfusions in about 40% of the patients. Likewise, the risk of infections is reduced. Immunosuppressive therapy with cyclosporine and antithymocyte globulin is also capable of improving the cytopenia in about 50% of the patients. Allogeneic bone marrow transplantation is the only possibility of cure in MDS, but the procedure is associated with high mortality. This treatment modality is therefore only recommended for younger patients, who are in a complete remission after being treated for acute myeloid leukaemia or are otherwise in a high risk group. The prognosis is poor, with an overall median survival of about 15 months. A simple scoring system has been elaborated and is based upon the percentage of myeloblasts in the bone marrow, a chromosomal analysis, and the number of cell lines with cytopenia. This system is able to distinguish between three distinct groups of patients with a highly different prognosis (low, intermediate, high risk), which is also of importance when evaluating the best treatment for the individual patient.

Topics: Blood Transfusion; Bone Marrow Transplantation; Colony-Stimulating Factors; Erythropoietin; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Prognosis; Survival Rate

Topics: Aged; Anemia, Refractory, with Excess of Blasts; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy; Middle Aged; Myelodysplastic Syndromes

Anemia is a common complication in patients with hematologic malignancies, and is caused by a variety of mechanisms, including neoplastic cell infiltration into the bone marrow, hemolysis, nutritional deficiencies, and defects in erythropoiesis as a result of the disease itself or cytotoxic therapy. The anemia associated with multiple myeloma is caused by inadequate erythropoietin levels consequent to renal impairment and the effect of inflammatory cytokines. The degree of anemia can have prognostic importance, as is the case with multiple myeloma, or be a significant indicator of disease stage, as noted with chronic lymphocytic leukemia. Anemia results in fatigue, exhaustion, dizziness, headache, dyspnea, and decreased motivation, seriously affecting a patient's quality of life. Since anemia is so prevalent in hematologic malignancy patients, its treatment must be an integral part of disease management, to improve quality of life and to possibly increase potential survival. Clinical studies have shown that effectively treating anemia and increasing hemoglobin levels using recombinant human erythropoietin (rHuEPO, epoetin alfa) has a significant effect on transfusion requirements and quality of life.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Multiple Myeloma; Myelodysplastic Syndromes; Prognosis; Quality of Life; Recombinant Proteins; Survival Rate

Anemia is a common complication in patients with hematologic malignancies, with incidence rates ranging up to 63%. In myelodysplastic syndromes, anemia is an essential feature of the disease. The decrease in hemoglobin may lead to several symptoms such as fatigue, exhaustion, and impaired quality of life, and it may worsen prognosis. Before the introduction of recombinant human erythropoietin (rHuEPO, epoetin alfa), red blood cell transfusions were the traditional treatment for improvement of Hb levels. Transfusions, however, are associated with several adverse events and risks, have only transient effects, and have a limited capacity to ameliorate the symptoms of anemia. Epoetin alfa represents a physiologic treatment option, especially in the long-term treatment of cancer- and cancer treatment-associated anemia, and is well tolerated, with response rates as high as 80%. Epoetin alfa is less effective in the treatment of the anemia of myelodysplastic syndrome, but appears to be synergistic with granulocyte-colony stimulating factor. However, not every patient responds to epoetin alfa; to avoid unnecessary interventions and costs, predictors of response have been proposed. This article outlines the advantages and disadvantages of the two major treatment forms of anemia: transfusions and epoetin alfa. Representative studies on the efficacy of epoetin alfa in anemic patients with hematologic malignancies as well as models to predict response to epoetin alfa treatment are summarized.

Topics: Anemia; Blood Transfusion; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Myelodysplastic Syndromes; Prevalence; Recombinant Proteins

The myelodysplastic syndromes (MDS) are clonal hematological disorders characterized by ineffective hematopoiesis manifested by anemia, neutropenia, thrombocytopenia or a combination. Correction of these cytopenia is a priority in MDS without excess of blasts. Treatment of anemia depends mainly on erythrocyte transfusions. However with the ability of recombinant human hematopoietic growth factor many trials have been promoted. In vitro, erythroid progenitors from MDS patients are able to differentiate but they require much higher concentrations of erythropoietin than normal progenitors. Trials using rHu-Epo alone are disappointing. Combining rHu-Epo and rHu-G-CSF induces more encouraging results showing a synergistic effect particularly clear in sideroblastic anemia. Patients with low endogenous Epo level and low transfusion need are more likely to respond. Clinician should be able in the future to identify MDS patients with a chance of reversal of anemia or transfusion dependency.

Topics: Anemia; Erythropoietin; Growth Hormone; Growth Substances; Humans; Myelodysplastic Syndromes; Recombinant Proteins

The use of hematopoietic growth factors has increased rapidly during the last decade. Among the growth factors available, erythropoietin (EPO) was the first growth factor to be used clinically. To date, EPO has shown activity in the treatment of the tumor-associated anemia and for correction of tumor hypoxia, however, when compared with transfusion of erythrocytes EPO treatment did not significantly prolong survival in cancer patients in any published study so far. Recently, novel extramedullary EPO receptors have been identified leading to a better understanding of the molecular mechanisms of action of EPO. Results from these experiments and from several clinical studies suggest that EPO treatment may be beneficial for patients with (chronic) infections (HIV, inflammatory bowel disease, septic episodes) and for treatment of the fatigue syndrome following cancer chemotherapy. In addition, EPO may also improve stem cell engraftment following high-dose chemotherapy and can increase survival rates of patients with aplastic anemia and myelodysplastic syndrome. Currently, new EPO derivatives, synthetic fusion proteins and gene therapeutic studies are under clinical investigation suggesting that the EPO-induced effects may be increased significantly by these agents in the future.

Topics: Anemia, Aplastic; Chronic Disease; Erythropoietin; Fatigue; Genetic Therapy; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; HIV Infections; Humans; Infections; Myelodysplastic Syndromes; Receptors, Erythropoietin; Recombinant Proteins

Topics: Animals; Bone Marrow Cells; Cell Adhesion; Cell Count; Cell Cycle; Cells, Cultured; Cytokines; Erythropoietin; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Myelodysplastic Syndromes; Recombinant Proteins; Stromal Cells; Transplantation, Heterologous

The myelodysplastic syndromes are a heterogeneous family of hematologic disorders characterized by ineffective hematopoiesis. Because of the interpatient variability regarding prognosis and morbidity, management of myelodysplastic syndromes continues to be a challenge to clinical hematologists. Pancytopenia and defective function of neutrophils and platelets carry a high risk of infectious or hemorrhagic complications. Erythropoietin is perhaps the most commonly used therapeutic option, second only to transfusion; improvement of erythropoiesis is seen in approximately 20% of patients, mainly in those with relatively preserved erythroid function and no or low transfusion requirements. Coadministration of erythropoietin with either granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor may increase the response rate up to 50%. Although prophylactic administration of granulocyte- or granulocyte-macrophage colony-stimulating factor cannot be recommended, treatment of febrile neutropenia might benefit from administration of granulocyte- or granulocyte-macrophage colony-stimulating factor in addition to antibiotics.

Topics: Apoptosis; Cytokines; Erythropoietin; Hematopoietic Stem Cell Mobilization; Humans; Myelodysplastic Syndromes; Pancytopenia; Risk Factors

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders with a variable clinical course and prognosis. Treatment should be individualized based on the patient's age, subtype, percent blasts in the marrow, and cytogenetics. The use of the International Prognostic Scoring Index is helpful in assigning prognosis. The standard of care for low-risk patients is supportive care. Low-risk patients with symptomatic anemia should be considered for a trial of erythropoietin. The serum erythropoietin (EPO) level may help predict response to treatment. The treatment of the symptomatic and high-risk patient is unclear. Low-dose cytarabine, amifostine, and 5-azacitidine can induce responses in selected patients, but the duration of responses is short, and treatment does not appear to prolong survival. Intensive chemotherapy should be reserved for high-risk, younger patients. Topotecan and intermediate cytarabine appear to have an active regimen, but remissions are short. Younger patients who present with high-risk MDS without an antecedent history of MDS should receive intensive acute myeloid leukemia (AML) induction chemotherapy. Younger patients with high-risk MDS and an HLA-compatible donor should be offered an allogeneic stem cell transplant.

Topics: Age Factors; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Prognosis; Risk Factors; Survival Rate

The correction of anemia in patients with chronic renal failure (CRF) has become the most important application of recombinant human erythropoietin (rHuEpo). The merits of rHuEpo therapy in patients with CRF are overt. Firstly, patients with CRF have an absolute deficiency in endogenous erythropoietin production and a relatively low maintenance dose of rHuEpo (often less than 100 IU/kg body weight per week) is effective in avoiding regular transfusions in the majority of the patients with CRF. Secondly, rHuEpo is able to avoid long-term complications of frequent transfusions (hemochromatosis, transfusion-transmissible diseases). Thirdly, patients with uremia notice a considerable improvement in quality of life (QOL) after initiation of rHuEpo. These advantages justify administration of this costly drug in CRF patients. The use of rHuEpo outside the setting of uremia do, however, not cover the complete spectrum of beneficial effects as compared to its use in (pre)dialysis patients. The aim of this overview is to provide some annotations on recently approved (cisplatin-induced anemia, preoperative anemia, zidovudine-related anemia) and possibly future (several types of malignancy and inflammation) indications for rHuEpo in non-uremic patients, leaving out the correction of anemia due to relatively uncommon disorders in the Dutch population (such as sickle cell anemia and thalassemia).

Topics: Anemia; Anti-HIV Agents; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Chemotherapy, Adjuvant; Erythropoietin; Female; Humans; Male; Multiple Myeloma; Myelodysplastic Syndromes; Recombinant Proteins; Uremia; Zidovudine

Topics: Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes

Anemia is a frequent complication in hematologic malignancies. In advanced stages of chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and myeloma, anemia usually develops in parallel with marrow involvement. However, anemia may occur in the absence of overt infiltration of bone marrow by malignant cells. When all other causes of anemia (such as chronic bleeding, vitamin deficiency, hemolysis, and pure red blood cell aplasia) are eliminated, anemia can be related to "anemia of chronic disorders." Myelodysplastic syndromes are characterized by cytopenias. Anemia is very frequent, and nearly 90% of patients present with anemia during the evolution of the disease. In this disorder, erythroid progenitors are defective for their proliferation and maturation, as shown by in vitro culture techniques. Moreover, these patients often have a high endogenous serum erythropoietin level. The rationale for treating these patients with epoetin alfa is the possibility of overcoming the defective proliferation by pharmacologic doses of epoetin alfa. The response rate was rather low with epoetin alfa alone. Combinations with earlier-acting cytokines, such as recombinant human granulocyte colony-stimulating factor, have been tested in an attempt to improve response rates.

Topics: Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Clinical Trials as Topic; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Topics: Anemia; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia; Anemia, Aplastic; Erythropoietin; Humans; Multiple Myeloma; Myelodysplastic Syndromes

In myelodysplastic syndromes (MDS), pancytopenia and defective function of neutrophils and platelets lead to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. Supportive care including red blood cell and platelet transfusions are still the cornerstone of therapeutic management. However, the clinical use of the recombinant hematopoietic growth factors has enlarged the range of therapeutic applications in patients with MDS. It is possible to reverse neutropenia in MDS patients by administration of G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte-monocyte colony stimulating factor). Because of the lower incidence of adverse events, G-CSF is preferable. However, neither G-CSF nor GM-CSF have been shown to reduce the rate of severe infection or mortality from infection when given prophylactically. In the case of a severe infection, therapeutic administration of G-CSF together with antibiotics might be justified in otherwise neutropenic MDS patients. Preliminary data suggest it to be possible to identify MDS patients with a higher than 50% chance of reversal of anemia or transfusion dependency by treatment with high-dose erythropoietin (EPO). Since patients with only slight impairment of erythropoiesis and no transfusion dependency have the highest response rates but need EPO the least, pharmacoeconomic analyses are urgently needed. Controlled randomized trials will have to ascertain whether combinations of EPO with G-CSF or GM-CSF are of benefit. Clinical studies with thrombopoietin (megakaryocyte growth and differentiation factor) have to be initiated to find out whether thrombocytopenia in MDS can be reversed.

Topics: Aged; Cytarabine; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Interleukin-3; Interleukin-6; Middle Aged; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic

Topics: Apoptosis; Bone Marrow; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blood Transfusion; Bone Marrow; Clinical Trials as Topic; Clone Cells; Cytokines; Erythropoietin; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Hormones; Humans; Myelodysplastic Syndromes; Retinoids

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

Recent advances in the molecular genetics of myelodysplastic syndromes (MDS) have shed new light on the pathogenesis of MDS allowing a better understanding of the defects of differentiation of the transformed clone and suppression of normal hematopoiesis. The clinical hematologist, however, continues to be challenged with the treatment of patients with MDS. Pancytopenia and defective function of neutrophils and platelets lead to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. Supportive care including red blood cell and platelet transfusions are still the cornerstone of therapeutic management. While prophylactic administration of G-CSF or GM-CSF cannot be recommended, treatment of febrile neutropenia might benefit from administration of G-CSF in addition to antibiotics. Administration of high-dose erythropoietin will improve erythropoiesis in around 20% of the patients, mainly in those with rather preserved erythroid function and no or low transfusion need. Coadministration of erythropoietin with either G-CSF or GM-CSF could increase the response rate. Allogeneic stem cell transplantation still is the only curative treatment and prolongs survival. Intensive chemotherapy for advanced MDS is possible with an acceptably low rate of early death and a complete remission rate between 45% to 60%, while initial results of autologous transplantation are promising.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-3; Interleukin-6; Myelodysplastic Syndromes; Prognosis

Myelodysplastic syndrome (MDS) comprises a group of heterogeneous clonal bone marrow disorders leading to peripheral cytopenia(s) and hypercellular marrow in the majority of the patients. The morphology of the cell lines is characterized by dysplastic features in some or all cell lines. The FAB classification has divided MDS in five subgroups, namely (1) RA (refractory anemia); (2) RARS (refractory anemia with ring sideroblasts); (3) CMML (chronic myelomonocytic leukemia); (4) RAEB (refractory anemia with excess blasts); and (5) RAEB-T (refractory anemia with excess blasts in transformation). Myelodysplastic syndrome remains primarily a disease of the elderly. With a reported median age of 74.4 years, patients have a chronic relentless course with complication of cytopenias, and a significant number of MDS patients, especially from the RAEB and RAEB-T categories, end up in acute myeloid leukemic transformation. Cytogenetic abnormalities are present in 40-58% of the cases and can provide not only help in diagnosis, but also understanding regarding the clinical course and prognostic aspect. Management of MDS is quite pragmatic and at this stage far from satisfactory. Various modalities have included use of differentiating agents, aggressive chemotherapy, bone marrow transplant and, more recently, significant interest has been generated in the use of hematopoietic growth factors. Differentiating agent trials have been unrewarding so far; chemotherapy trials have resulted in less benefit and more early toxic deaths, especially in the elderly MDS patients where the disease predominates. Bone marrow transplant appears suitable for some patients who are at a younger age. Salvation from this disease is being searched in the proper usage of hematopoietic growth factors and cytokines. There has been concern, however, that usage of growth factors has led to early and enhanced transformation of these patients to frank acute leukemic states. This concept appears to be somewhat refuted by newer controlled trials with GM-CSF and G-CSF, emphasizing that the acute leukemic transformation is the natural course of the disease and is not hastened by growth factor use. Preliminary studies are also suggesting that a combination of growth factors, especially G-CSF and erythropoietin as compared to chemotherapies, could be more beneficial in prolonging the survival of MDS patients who have progressed to the acute leukemic phase. More studies are needed for the understanding of t

Topics: Aged; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes

Topics: Aclarubicin; Antibiotics, Antineoplastic; Cytokines; Erythropoietin; Ferritins; Humans; Iron; Myelodysplastic Syndromes; Prognosis

Topics: Cytarabine; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-3; Myelodysplastic Syndromes

With the identification and recombinant production of the hematopoietic growth factors, these cytokines have been evaluated in the treatment of primary bone marrow failure states and after myelosuppressive chemotherapy or radiotherapy. A lot of clinical trials with hematopoietic factors have been performed in patients with haematologic and oncologic diseases within the last decade. Granulocyte colony-stimulating factor [G-CSF], granulocyte macrophage colony-stimulating factor [GM-CSF], interleukin-3, interleukin-2, erythropoietin and in phase I/II trials thrombopoietin [TPO] are available for the clinical use. At the present, there is a broad use of growth factors. Most studies have been done with G-CSF and GM-CSF, their beneficial effects are proven regarding improvement of hematopoietic recovery after chemotherapy. This results in a marked reduction of infectious risks and a shortening of drug- and radiation-induced myelosuppression. CSFs are most important in mobilizing peripheral blood progenitor cells [PBPC] and have allowed high dose therapy to be given to patients who would not have been able to undergo conventional bone marrow transplantation. However, an improved outcome and improved survival rates with standard chemotherapy protocols couldn't be documented by studies up to now, even though higher chemotherapy doses are possible by the use of hematopoietic factors.

Topics: Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neoplasms; Thrombopoietin

Topics: Anemia, Refractory, with Excess of Blasts; Bone Marrow Transplantation; Colony-Stimulating Factors; Combined Modality Therapy; Drug Therapy, Combination; Erythropoietin; Humans; Myelodysplastic Syndromes; Transplantation, Homologous

Topics: Bone Marrow Transplantation; Calcitriol; Cytarabine; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Isotretinoin; Myelodysplastic Syndromes; Prognosis; Transplantation, Homologous

Topics: Drug Administration Schedule; Erythropoietin; Humans; Myelodysplastic Syndromes

Epoetin alfa is a recombinant form of the principal hormone responsible for erythrogenesis, erythropoietin. Already an established treatment for anaemia associated with renal failure, epoetin alfa may also be used to correct anaemia in other patient groups. The drug increases the capacity for autologous blood donation in patients scheduled to undergo surgery and attenuates the decrease in haematocrit often seen in untreated autologous donors. However, transfusion requirements did not significantly decrease in many trials. Epoetin alfa also accelerates red blood cell recovery after allogeneic--but not autologous--bone marrow transplant. Limited data in patients with adult rheumatoid arthritis suggest that while epoetin alfa increases haematocrit/haemoglobin levels, overall clinical rheumatological status may not improve. However, the drug did improve quality of life in a small cohort of children with juvenile rheumatoid arthritis in addition to correcting anaemia. Response rates to treatment with epoetin alfa in patients with anaemia associated with cancer range between 32 and 85%. Anaemia associated with cancer chemotherapy also responds well to treatment with the drug as does anaemia associated with zidovudine therapy in patients with acquired immune deficiency syndrome (AIDS). Studies evaluating the use of epoetin alfa as treatment for anaemia of prematurity have used different methodologies and dosages, making overall analysis difficult. Nevertheless, it appears that high dosages are necessary for response. Results from 1 study suggest that treatment with epoetin alfa appears to be more costly than transfusional support in this application; the relevance of this finding is questionable, however, given that the aim of treatment with epoetin alfa is elimination of transfusion requirements. The incidence of many adverse events associated with epoetin alfa treatment in patients with renal failure (hypertension, seizures and thromboembolic events) has been minimal in patients without renal failure. Adverse events occurred at a similar rate in placebo and epoetin alfa recipients in placebo-controlled trials evaluating the use of the drug as treatment for anaemia in patients with cancer receiving chemotherapy or patients with AIDS receiving zidovudine. In summary, epoetin alfa is an effective alternative to blood transfusion, reducing anaemia and producing consequent improvements in quality of life in many nonrenal applications. It was more effective than pla

Topics: Absorption; Anemia; Blood Donors; Blood Transfusion; Bone Marrow Transplantation; Dosage Forms; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Injections, Subcutaneous; Myelodysplastic Syndromes; Recombinant Proteins; Risk Assessment

The myelodysplastic syndromes are a group of hematologic disorders that adversely affect the levels of hemoglobin, platelets, erythrocytes, and leukocytes. Although the cause of this syndrome is unknown, new diagnostic techniques have facilitated identification and classification of these diseases into five categories: refractory anemia (refractory cytopenia), refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia. Cytogenetic abnormalities may be present in more than 55% of the patients. Symptomatic patients should be assessed relative to life-threatening versus non-life-threatening cytopenias and age. Management consists of primarily supportive measures, although certain approaches that are currently being used or under investigation, such as concomitant administration of erythropoietin and other growth factors, show promise for the future.

Topics: Erythropoietin; Hematocrit; Humans; Myelodysplastic Syndromes; Preleukemia

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

Recombinant human erythropoietin has been available for clinical use since 1985. It was an immediate success in treating the anemia of chronic renal failure and has also enjoyed some objective success in the treatment of other anemias in either a therapeutic or prophylactic setting, but the issues of appropriate patient selection and cost-benefit ratios are still unresolved. This review discusses the most recent literature concerning the use of recombinant human erythropoietin for the anemia associated with cancer, HIV infection, myelodysplasia, prematurity, autologous blood transfusion, bone marrow transplantation, and chronic renal failure.

Topics: Anemia; Blood Transfusion, Autologous; Erythropoietin; HIV Infections; Humans; Infant, Newborn; Infant, Premature, Diseases; Kidney Failure, Chronic; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

Clinical trials with hematopoietic growth factors (granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, and erythropoietin) have been performed in patients with myelodysplastic syndromes. Absolute neutrophil counts can be readily raised to within the normal range by treatment with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. Moderate increases in platelet counts have been reported for approximately 20% of patients during treatment with interleukin-3. Treatment with high-dose erythropoietin leads to an increase in hematocrit or decrease in transfusion needs in 15% to 20% of patients, but an improved response rate of approximately 40% has been reported for the combined treatment of erythropoietin with either granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor. Although meta-analyses of published phase I/II trials allow a rough estimation of response rates and an improved selection of patients who are most likely to respond, phase III trials have not yet been published.

Topics: Clinical Trials as Topic; Cytokines; Drug Therapy, Combination; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Myelodysplastic Syndromes

Topics: Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Interleukin-3; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia, Aplastic; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia; Myelodysplastic Syndromes

This article attempts to summarize the current information regarding the clinical application of recombinant human erythropoietin in patients with myelodysplastic syndromes (MDS). To date, more than 300 MDS patients have been reported to be treated with recombinant human erythropoietin. The response patterns have been variable, but in general they range from 20% to 30%. The hormone has been shown to be safe and nontoxic.

Topics: Clinical Trials as Topic; Cytokines; Drug Therapy, Combination; Erythropoietin; Growth Substances; Humans; Myelodysplastic Syndromes; Recombinant Proteins

To study the usefulness of different published epidemiological and analytic parameters to decide the treatment with human recombinant erythropoietin (rHuEPO) of anaemic patients with myelodysplastic syndromes (MDS).. We have revised 10 published series compiling 115 patients, studying age, sex, initial diagnosis, route of administration and posology, criteria of response, duration of the study, dosis with the response was obtained, response according to initial diagnosis, duration of responses, and effect of the treatment on other hematopoietic series. We have made a comparison between responders and non-responders based on epidemiological and analytical parameters.. We have compiled 115 patients with a rate of global response of 23.5%. We have not found significative differences between the route (s.c. or i.v.) or frequency of administration, however the number of responses was higher when rHuEPO was administered three times weekly. A great variability in the criteria of response was observed among the different studies. Most of studies have a duration of three months but we have observed significative differences in the number of responses when the study is longer. We have not found significative differences between responders and non-responders with respect to age, sex, used dosis, transfusional dependency and degree of transfusional dependency, basal serum erythropoietin, time since diagnosis, transfusional period, haemoglobin level among non-transfusion dependent patients and haemoglobin level among transfusion dependent patients. We have found significative differences with respect to initial diagnosis, a higher rate of responses was observed in the refractory anaemia with excess of blasts (RAEB) group. We have not found a higher rate of transformations into acute myeloid leukaemia (AML) among these patients. The effects of the treatment on other haematopoietic series can be considered as anecdotical.. The different epidemiological and analytic parameters published up to now are not useful in the decision of including an anaemic patient with MDS in the treatment with rHuEPO. Those patients with RAEB can be benefited with the treatment with rHuEPO. The concomitant use of other cytokines could improve these results.

Topics: Anemia; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Erythropoietin (EPO) is a glycoprotein produced primarily by the kidney in response to tissue hypoxia, and is the principal factor regulating red blood cell production. It stimulates erythroid precursors in the bone marrow to proliferate and mature into morphologically identifiable red blood cells. This hormone acts by binding to specific high-affinity receptor on erythroid precursors. Failure to produce adequate quantities of EPO leads to severe anemia, a situation most often encountered in patients with end stage renal disease. With the application of recombinant DNA technology, the gene for this hormone has been molecularly cloned, sequenced and expressed in a biologically active form in mammalian cells. The recombinant EPO has been demonstrated to correct anemia in patients with severe end stage renal disease and alleviate their transfusion requirements. It has also been studied for anemia associated with HIV infection/zidovudine therapy, in cancer, rheumatoid arthritis, and prematurity. In addition it has been studied as a facilitator of autologous blood predeposit in patients scheduled for elective surgery and as a perisurgical adjuvant to hasten hematologic recovery and possibly avoid the need for homologous transfusion after elective surgery. When administered with the current guidelines EPO appears to be safe drug with favorable risk/benefit ratio.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

Topics: Clinical Trials as Topic; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-3; Interleukin-6; Myelodysplastic Syndromes

Topics: Aged; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-3; Myelodysplastic Syndromes; Recombinant Proteins; Stem Cell Factor

Topics: Anemia; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Myelodysplastic syndrome is a frustrating disorder, which until recently lacked effective treatment. Patients usually succumb to infection, bleeding complications, or progression to acute leukemia. Recombinant cytokines such as granulocyte macrophage-colony stimulating factor, granulocyte-colony stimulating factor, interleukin-3, and erythropoietin have been used to ameliorate the cytopenias associated with this disease. Small clinical trials in myelodysplastic syndrome patients, using cytokines with myeloid activity (G-CSF, GMCSF, IL-3), have shown consistent elevations in the white blood cell counts with little success in elevating hemoglobin or platelets. Erythropoietin is able to increase the hemoglobin in a small group of myelodysplastic syndrome patients. Future trials using combinations of these cytokines may lead to multilineage effects.

Topics: Animals; Cricetinae; Cytokines; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-3; Myelodysplastic Syndromes

Clinical trials with hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF], interleukin-3, erythropoietin] have been done in patients with myelodysplastic syndromes. Treatment with GM-CSF or G-CSF has resulted in an increase of neutrophil counts into the normal range in the vast majority of patients. Progression to acute leukemia does not appear to occur more frequently in the patients receiving GM-CSF or G-CSF. Increases in platelet counts and hemoglobin levels have been reported after treatment with interleukin-3 and erythropoietin, respectively, although the response is only seen in a minority of treated patients. Combination therapy with GM-CSF and low-dose cytosine arabinoside has been studied, but present data do not indicate an advantage over other treatment strategies. Cytogenetic and molecular genetic analyses demonstrate that both normal and malignant precursor cells are stimulated by cytokine therapy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Myelodysplastic Syndromes

Clinical trials with hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor [GM-CSF], granulocyte colony-stimulating factor [G-CSF], interleukin-3, or erythropoietin) have been performed on patients with myelodysplastic syndromes. Absolute neutrophil counts can be readily raised to within the normal range by treatment with GM-CSF or G-CSF. Increases in platelets and hemoglobin have been reported after treatment with interleukin-3 and erythropoietin, respectively. Cytogenetic and molecular genetic analyses have demonstrated that both normal and malignant precursor cells are stimulated by cytokine therapy.

Topics: Cytarabine; Drug Synergism; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Interleukin-3; Myelodysplastic Syndromes

The hemopoietic growth factors are peptide hormones that are known to be responsible for the in vitro and in vivo proliferation of bone marrow progenitor cells into mature differentiated cells. These cytokines have had a major impact on the management of patients with cytopenias and have been extensively used as an adjunct to the management of patients with hematologic malignancies, with or without prior intensive chemotherapy. Other potential uses, being rigorously studied, include the potential mobilization of stem cells as well as recruitment phase-specific cells into the cell cycle, thus providing a more sensitive environment for targeting specific chemotherapeutic agents.

Topics: Acute Disease; Anemia; Anemia, Aplastic; Bone Marrow Transplantation; Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Leukemia; Myelodysplastic Syndromes; Neutropenia

Topics: Anemia; Bone Marrow Transplantation; Clinical Trials as Topic; Double-Blind Method; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Interleukin-3; Macrophage Colony-Stimulating Factor; Myelodysplastic Syndromes; Neoplasms; Paraneoplastic Syndromes; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Adult; Aged; Bone Marrow; Cell Division; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Middle Aged; Myelodysplastic Syndromes

Topics: Erythropoietin; Hemoglobins; Humans; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

Topics: Acquired Immunodeficiency Syndrome; Anemia; Antineoplastic Agents; Bone Marrow Transplantation; Drug Evaluation; Erythropoiesis; Erythropoietin; Forecasting; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Kidney Failure, Chronic; Myelodysplastic Syndromes; Neutropenia; Radiation Injuries; Recombinant Fusion Proteins

Topics: Acquired Immunodeficiency Syndrome; Anemia, Aplastic; Colony-Stimulating Factors; Erythropoietin; Hematologic Diseases; Hematopoiesis; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Interferon Type I; Interferon-gamma; Interferons; Interleukin-3; Leukemia; Leukemia, Hairy Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Recombinant Proteins; Thrombocythemia, Essential

Topics: Animals; Colony-Stimulating Factors; Erythropoietin; Growth Substances; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myeloid; Leukopenia; Mice; Myelodysplastic Syndromes; Recombinant Proteins

Erythropoiesis-stimulating agents are first choice for treating anemia in low-risk MDS. This double-blind, placebo-controlled study assessed the efficacy and safety of epoetin-α in IPSS low- or intermediate-1 risk (i.e., low-risk) MDS patients with Hb ≤ 10.0 g/dL, with no or moderate RBC transfusion dependence (≤4 RBC units/8 weeks). Patients were randomized, 2:1, to receive epoetin-α 450 IU/kg/week or placebo for 24 weeks, followed by treatment extension in responders. The primary endpoint was erythroid response (ER) through Week 24. Dose adjustments were driven by weekly Hb-levels and included increases, and dose reductions/discontinuation if Hb > 12 g/dL. An independent Response Review Committee (RRC) blindly reviewed all responses, applying IWG-2006 criteria but also considering dose adjustments, drug interruptions and longer periods of observation.A total of 130 patients were randomized (85 to epoetin-α and 45 to placebo). The ER by IWG-2006 criteria was 31.8% for epoetin-α vs 4.4% for placebo (p < 0.001); after RRC review, the ER was 45.9 vs 4.4% (p < 0.001), respectively. Epoetin-α reduced RBC transfusions and increased the time-to-first-transfusion compared with placebo.Thus, epoetin-α significantly improved anemia outcomes in low-risk MDS. IWG-2006 criteria for ER may require amendments to better apply to clinical studies.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Double-Blind Method; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Treatment Outcome

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5-24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement-erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).

Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Darbepoetin alfa; Erythropoietin; Female; Hemoglobins; Humans; Male; Myelodysplastic Syndromes; Risk

After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.

Topics: Aged; Anemia; Angiogenesis Inhibitors; Blood Transfusion; Chromosome Deletion; Chromosomes, Human, Pair 5; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Humans; Lenalidomide; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm Staging; Prognosis; Prospective Studies; Risk Factors; Thalidomide

Non-del(5q) transfusion-dependent low/intermediate-1 myelodysplastic syndrome (MDS) patients achieve an erythroid response with lenalidomide in 25% of cases. Addition of an erythropoiesis-stimulating agent could improve response rate. The impact of recurrent somatic mutations identified in the diseased clone in response to lenalidomide and the drug's effects on clonal evolution remain unknown. We investigated recurrent mutations by next-generation sequencing in 94 non-del(5q) MDS patients randomized in the GFM-Len-Epo-08 clinical trial to lenalidomide or lenalidomide plus epoetin β. Clonal evolution was analyzed after 4 cycles of treatment in 42 cases and reanalyzed at later time points in 18 cases. The fate of clonal architecture of single CD34(+)CD38(-) hematopoietic stem cells was also determined in 5 cases. Mutation frequency was >10%: SF3B1 (74.5%), TET2 (45.7%), DNMT3A (20.2%), and ASXL1 (19.1%). Analysis of variant allele frequencies indicated a decrease of major mutations in 15 of 20 responders compared with 10 of 22 nonresponders after 4 cycles. The decrease in the variant allele frequency of major mutations was more significant in responders than in nonresponders (P < .001). Genotyping of single CD34(+)CD38(-) cell-derived colonies showed that the decrease in the size of dominant subclones could be associated with the rise of founding clones or of hematopoietic stem cells devoid of recurrent mutations. These effects remained transient, and disease escape was associated with the re-emergence of the dominant subclones. In conclusion, we show that, although the drug initially modulates the distribution of subclones, loss of treatment efficacy coincides with the re-expansion of the dominant subclone. This trial was registered at www.clinicaltrials.gov as #NCT01718379.

Topics: Aged; Anemia, Macrocytic; Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Chromosome Deletion; Chromosomes, Human, Pair 5; Clonal Evolution; Clone Cells; DNA Mutational Analysis; Erythropoietin; Female; Humans; Lenalidomide; Male; Myelodysplastic Syndromes; Recombinant Proteins; Thalidomide; Treatment Outcome

The efficacy of azacitidine in patients with anemia and with lower-risk myelodysplastic syndromes, if relapsing after or resistant to erythropoietic stimulating agents, and the benefit of combining these agents to azacitidine in this setting are not well known. We prospectively compared the outcomes of patients, all of them having the characteristics of this subset of lower-risk myelodysplastic syndrome, if randomly treated with azacitidine alone or azacitidine combined with epoetin-β. High-resolution cytogenetics and gene mutation analysis were performed at entry. The primary study endpoint was the achievement of red blood cell transfusion independence after six cycles. Ninety-eight patients were randomised (49 in each arm). Median age was 72 years. In an intention to treat analysis, transfusion independence was obtained after 6 cycles in 16.3% versus 14.3% of patients in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=1.00). Overall erythroid response rate (minor and major responses according to IWG 2000 criteria) was 34.7% vs. 24.5% in the azacitidine and azacitidine plus epoetin-β arms, respectively (P=0.38). Mutations of the SF3B1 gene were the only ones associated with a significant erythroid response, 29/59 (49%) versus 6/27 (22%) in SF3B1 mutated and unmutated patients, respectively, P=0.02. Detection of at least one "epigenetic mutation" and of an abnormal single nucleotide polymorphism array profile were the only factors associated with significantly poorer overall survival by multivariate analysis. The transfusion independence rate observed with azacitidine in this lower-risk population, but resistant to erythropoietic stimulating agents, was lower than expected, with no observed benefit of added epoetin, (clinicaltrials.gov identifier: 01015352).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Biomarkers; Cytogenetic Analysis; DNA Mutational Analysis; Drug Resistance; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Polymorphism, Single Nucleotide; Recombinant Proteins; Survival Analysis; Treatment Outcome

Topics: Administration, Oral; Blood Transfusion; Erythropoietin; Humans; Hydroxamic Acids; Indoles; Myelodysplastic Syndromes; Panobinostat

This phase II prospective study aimed to evaluate the efficacy and safety of 5-days azacytidine (5d-AZA) in patients with low-risk myelodysplastic syndromes (MDS). Second, single-nucleotide polymorphism (SNP) genetic profile and phosphoinositide-phospholipase C (PI-PLC) β1 levels were studied to evaluate possible biologic markers able to predict the hematologic response.. The study tested a lower intensity schedule of azacytidine. The treatment plan consisted of 75 mg/sqm/d subcutaneous administered for 5 days every 28 days, for a total of 8 cycles.. Thirty-two patients were enrolled in the study. The overall response rate was 47% (15 of 32) on intention-to-treat and 58% (15 of 26) for patients completing the treatment program. In this latter group, 5 (19%) achieved complete remission (CR) and 10 (38%) had hematologic improvement, according to the International Working Group (IWG) criteria. Three patients have maintained their hematologic improvement after 37, 34, and 33 months without other treatments. Moreover, 21 and 2 of 26 cases completing 8 cycles were transfusion-dependent for red blood cells and platelets at baseline, respectively. Of these, 7 (33%) and 2 (100%) became transfusion-independent at the end of the treatment program, respectively. Grade 3-4 neutropenia occurred in 28% of patients and 4 patients died early due to infections or hemorrhage. SNP results were not significantly correlated to the clinical outcome, whereas PI-PLCβ1 level anticipated either positive or negative clinical responses.. 5d-AZA is safe and effective in a proportion of patients with low-risk MDS. PI-PLCβ1 gene expression is a reliable and dynamic marker of response that can be useful to optimize azacytidine therapy.

Topics: Aged; Aged, 80 and over; Azacitidine; Drug Administration Schedule; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Hematologic Tests; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Phospholipase C beta; Polymorphism, Single Nucleotide; Prospective Studies; Treatment Outcome; Wnt1 Protein

The objective of this study was to examine whether treatment with recombinant human erythropoietin (rHuEPO), previously found to be associated with a positive effect on cell-mediated immunity and humoral immunity (hepatitis B vaccine), is associated with an improved response to the seasonal influenza (flu) vaccine. Three groups received flu vaccine: healthy controls, hematologic patients not treated with rHuEPO ("No EPO" group), and hematologic patients receiving rHuEPO for their anemia ("EPO" group). Anti-flu Ab titer was measured (complement fixation test) from blood samples drawn before and approximately 3-4 weeks, 7-8 weeks and 4 months after vaccination. Nineteen healthy subjects were compared with 17 No EPO and 17 EPO patients. Mean ages were 59.5, 61.3, and 73.1 years, respectively (EPO patients were older; p = 0.005). In the healthy group, the percentage of those sustaining only a partial (twofold) response, a strong (fourfold or greater) response, and an overall response (combined partial and strong responses) were 31.6%, 57.9%, and 89.5%, respectively. In the No EPO group, values were 35.3%, 17.6%, and 52.9%, respectively. EPO group results were similar to those of the healthy controls: 23.5%, 58.8%, and 82.4% (p = 0.016, EPO vs. No EPO). In conclusion, hematologic patients (NoEPO group) respond poorly to the flu vaccine, compared with healthy subjects, and rHuEPO treatment is associated with an improved immune response to the flu vaccine in hematologic patients, with titers similar to those of healthy subjects.

Topics: Aged; Anemia; Antibodies, Viral; Erythropoietin; Female; Hematinics; Hematologic Neoplasms; Hemoglobins; Humans; Immunocompromised Host; Influenza A virus; Influenza Vaccines; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Vaccination

Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500 IU/L received DAR 500 μg once every 2 weeks for 12 weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56 % at 12 and 24 weeks, respectively. Addition of G-CSF rescued 22 % of non-responders. In 48 % of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12 weeks, and its most discriminant cutoff value was 100 IU/L. QoL and VO2max showed improvement over time in responders, compared with non-responders. With a median follow-up of 52 months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70 %, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2 weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Exercise; Exercise Tolerance; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Male; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Risk; Survival Analysis; Treatment Outcome

We previously reported a 60% erythroid response rate with recombinant erythropoietin + 13-cis retinoic acid + dihydroxylated vitamin D3 in 63 elderly myelodysplastic patients (median age 75 years) with unfavourable features for response to erythropoietin alone [70% transfusion-dependent, 35% refractory anaemia with ring sideroblasts/refractory anaemia with excess of blasts type 1 (RAEB1), 70% with International Prognostic Scoring System (IPSS) Intermediate-1 or -2]. This report updates that case study at a 7-year follow-up, and compared the impact on overall survival of erythroid response to known prognostic factors. The erythroid response duration (median 17 months; 22 in non-RAEB patients, with 20% patients in response after 6 years of therapy) was longer than in most studies with erythropoietin alone. Overall survival (median 55 months in non-RAEB, 15 in RAEB1 patients) was negatively affected by RAEB1 diagnosis, IPSS and WPSS intermediate scores and transfusion-dependence. In the multivariate analysis, erythroid response maintained an independent positive impact on survival, particularly in non-RAEB patients in the first 3 years from diagnosis (90% survival compared to 50% of non-responders). In conclusion, the long-term follow-up confirmed the achievement, by our combined treatment, of fairly long-lasting erythroid response in the majority of MDS patients with unfavourable prognostic features for response to erythropoietin: this translated in a survival benefit that was independent from other prognostic features.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Calcitriol; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Humans; Isotretinoin; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins; Survival Analysis; Treatment Outcome

The erythropoietic effects of lenalidomide are cytokine dependent, suggesting that the erythroid hematologic improvement (HI-E) rate may be augmented by combined treatment (CT) with recombinant human erythropoietin (rhu-EPO) in myelodysplastic syndrome (MDS). In the present study, we explored the benefits of CT and the relationship between lenalidomide pharmacokinetics and hematologic toxicity in transfusion-dependent patients with low- to intermediate-1-risk MDS who failed prior rhu-EPO. In stage I, patients received 10 or 15 mg/d of lenalidomide monotherapy. At week 16, erythroid nonresponders (NRs) were eligible for CT with rhu-EPO 40 000 U/wk. Among 39 patients, HI-E response rate to monotherapy was 86% (6 of 7) in del(5q) and 25% (8 of 32) in non-del(5q) patients (10 mg, 17.7%; 15 mg, 33.3%). Twenty-three patients proceeded to CT, with 6 (26.0%) achieving HI-E. In 19 non-del(5q) patients, 4 (21.1%) showed HI-E. Mean baseline serum EPO in non-del(5q) patients was lower in monotherapy and CT responders than in NR (not statistically significant). Thrombocytopenia was significantly correlated with lenalidomide area under the plasma concentration-time curve (P = .0015), but severity of myelosuppression did not. The benefits of lenalidomide plus rhu-EPO are currently under investigation in a phase 3 Eastern Cooperative Oncology Group (ECOG)-sponsored intergroup study. This study is registered at www.clinicaltrials.gov as NCT00910858.

Topics: Aged; Antineoplastic Agents; Area Under Curve; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Humans; Lenalidomide; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Risk; Severity of Illness Index; Thalidomide; Thrombocytopenia; Treatment Outcome

Current guidelines support the use of erythropoiesis-stimulating agents for the treatment of anemia associated with low-risk myelodysplastic syndromes (MDS).. Single-arm, open-label, multi-center, phase 2 trial that evaluated the efficacy and safety of darbepoetin alfa (DA) in patients with low or intermediate-risk MDS, hemoglobin <100 g/L, erythropoietin (EPO) levels <500 IU/L and transfusion requirements <2 units/month over the preceding 2 months. Erythroid response (major [MaR] or minor [MiR]) and fatigue (Functional Assessment of Cancer Therapy-Fatigue [FACT-F]) were evaluated at 8, 16 and 24 weeks. DA was initiated at 300 μg weekly. For patients who did not achieve MaR by 8 weeks, filgrastim 300 μg weekly was added.. clinicaltrials.gov identifier: NCT01039350.. Forty-four patients (72.7% transfusion independent) were included. Median age was 76.0 years (range 41.3-92.4), 54.5% were male, and 90.9% presented ECOG Status (0-1). Eighteen patients received filgrastim. An erythroid response was achieved by 31 of 44 patients (70.5%) at week 8 (47.7% MaR, 22.7% MiR), 31 of 44 patients (70.5%) at week 16 (61.4% MaR, 9.1% MiR), and 32 of 44 patients (72.7%) at week 24 (61.3% MaR, 11.4% MiR). Mean (95% CI) change in FACT-F at week 24 was 3.61 (0.72 to 6.51). Baseline EPO levels <100 IU/L were a predictive factor of response. DA was well tolerated. Four mild (two iron deficiencies, flu syndrome and headache) and one fatal (thromboembolic event) adverse events were considered related to darbepoetin alfa.. A fixed dose of 300 μg of darbepoetin alfa weekly (with or without filgrastim) seems to be an effective and safe treatment for anemic patients with low or intermediate-risk MDS, low transfusion burden and EPO levels <500 IU/L. Results may not be extrapolable to unselected MDS patients.

Topics: Adult; Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Risk Factors

Prolonged administration of methyl transferase inhibitors may increase response rates in myelodysplastic syndromes (MDS). Fourteen MDS patients with anemia and less than 10% marrow blasts received azacitidine 50 mg/m(2) thrice weekly for 2 weeks every 4 weeks; 7 also received weekly erythropoietin. The response rate of 43% did not improve the rates reported with other azacitidine administration schedules, so the study was closed. A decreased apoptosis of primitive erythroid progenitors and increased expression of BclX(L) was observed with treatment in responding patients compared to non-responders. Azacitidine may modulate BclX(L) and improve erythropoiesis through reduction of apoptosis in primitive erythroid progenitor population in MDS.

Topics: Aged; Aged, 80 and over; Anemia; Antimetabolites, Antineoplastic; Apoptosis; Azacitidine; bcl-X Protein; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Flow Cytometry; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis

Forty-eight patients with early myelodysplastic syndrome (MDS) without excess of blasts, with average initial serum ferritin levels of 2739.5 μg/L (range 825-11287 μg/L), were treated with deferiprone (L1) in a daily dose of 40-90 mg/kg. Median duration of chelation treatment was 10.9 months (range 4-24 months). Chelation was effective (maintained or decreased iron stores) in 16 out of 22 patients (73%) with serum ferritin levels <2000 μg/L in contrast to only 12 out of 26 patients with serum ferritin levels >2000 μg/L. Combination of L1 with recombinant human erythropoietin (rHuEPO) (30-40 kU/week) resulted in effective chelation in five additional patients with serum ferritin levels >3000 μg/L. Incidence of adverse effects was comparable to that in thalassemic patients. Gastrointestinal symptoms represented the most frequent adverse effect of L1 therapy (37.5% of patients) that limited an effective escalation of the daily dose of the drug and led to discontinuation of the treatment for six patients. A decreased number of granulocytes was observed in five (13%) patients and agranulocytosis occurred in two patients (4%). Granulocyte counts were restored after cessation of L1 treatment and administration of granulocyte colony stimulating factor (G-CSF) in all but one patient. Administration of L1 in a daily dose of at least 75 mg/kg may represent an alternative approach in treatment of mild and moderate iron overload in MDS patients who cannot be treated with deferasirox (DFRA) or deferoxamine (DFO).

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Deferiprone; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Granulocyte Colony-Stimulating Factor; Humans; Iron Chelating Agents; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Pyridones; Recombinant Proteins; Treatment Outcome

Anaemia in low-risk myelodysplastic syndromes (MDS) is associated with reduced quality of life (QoL). Response to treatment with erythropoietin ± granulocyte colony-stimulating factor (G-CSF) is associated with improved QoL, but whether transfusion therapy with higher haemoglobin (Hb) target levels has similar effects is unknown. The objective for this prospective phase II Nordic multicentre trial was to assess QoL, response rate and physical function in elderly anaemic MDS patients treated to a target Hb level of >120 g/L.. Thirty-six elderly patients with low- and intermediate-1 risk MDS received darbepoetin (DA) 300 μg/wk, with the addition of G-CSF if no response. If the Hb target was reached at 16 wk, treatment was maintained until week 26. Remaining patients were transfused to reach the target level for at least 8 wk..   Twenty-seven patients completed the study. Response rate to DA ± G-CSF was 67% in evaluable patients and 56% according to intention to treat. Eighteen patients reached the target Hb level according to protocol. QoL scores for fatigue, dyspnoea, constipation, and physical, role and social functioning improved significantly during study, with similar results for transfused and untransfused patients. Maintaining Hb >120 g/L did not confer a higher transfusion rate, once the target was reached. In two of fourteen patients, magnetic resonance imaging T2* indicated cardiac iron overload, however, without association with ferritin levels.. In elderly anaemic MDS patients, an increment in haemoglobin is associated with improved QoL, whether induced by growth factor treatment or transfusion therapy.

Topics: Aged; Aged, 80 and over; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Female; Ferritins; Filgrastim; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Magnetic Resonance Imaging; Male; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Treatment Outcome

To evaluate efficacy, safety, changes in biological features, and quality of life (QoL) in low-risk anemic patients with MDS treated with darbepoetin alfa (DPO), 41 patients received DPO 150 microg weekly for 24 weeks. The dose was increased to 300 microg weekly in non-responsive patients. During treatment, 10/17 (59%) transfusion-dependent (TD) and 13/23 (56%) transfusion-free (TF) patients responded. In TF patients, Hb increased from 9.2 +/- 0.9 g/dL to 10.3 +/- 1.4 g/dL by 24 weeks (p = 0.004). The mean response duration was 22 weeks (95% CI: 19.7-24.0) in TF patients compared with 15.1 weeks (95% CI: 13.3-17.5) in TD patients. Response to treatment was associated with increases in QoL. Decreases in the percentage of apoptotic progenitor cells (p = 0.007) and CD34+ cells (p = 0.005) were observed. These results confirm previous studies demonstrating the safety and efficacy of DPO in anemic patients with MDS. Biological changes and improvement in QoL were associated with response. Adequate dosing is to be determined.

Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Combined Modality Therapy; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Prospective Studies; Quality of Life; Regression Analysis; Treatment Outcome

Serum erythropoietin level less than 100U/L and a transfusion requirement of less than 2 units per month are the best predictive factors for response to treatment by erythropoiesis-stimulating agents in low/int-1 myelodysplastic syndromes. To investigate the factors influencing the response to erythropoiesis-stimulating agents, we enrolled 127 low/int-1 myelodysplastic syndrome patients at diagnosis in a biological study of erythropoiesis. The 54 non-responders had a significantly lower number of burst-forming unit-erythroid and colony-forming unit-erythroid than responders. Erythropoietin-dependent proliferation and survival, and phospho (p)-ERK1/2 expression in steady state and after erythropoietin stimulation were defective in cultured erythroblasts. By flow cytometry, p-ERK1/2 was significantly lower in bone marrow CD45(-)/CD71(+)/GPA(-)cells from non-responders compared to responders or controls. Receiver Operator Characteristic curve analysis showed that this flow cytometry test was a sensitive biomarker for predicting the response to erythropoiesis-stimulating agents.

Topics: Aged; Aged, 80 and over; Biomarkers; Cell Proliferation; Cells, Cultured; Erythroblasts; Erythropoiesis; Erythropoietin; Female; Flow Cytometry; Gene Expression Regulation, Enzymologic; Hematinics; Humans; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Myelodysplastic Syndromes

This Phase II study evaluated darbepoetin alfa (DA) in 24 patients with predominantly low or intermediate-1 risk myelodysplastic syndrome (MDS). Intra-patient dose escalation of DA was undertaken in three 6-week dose cohorts until a major erythroid response was achieved: 4.5 mcg/kg/week, 9 mcg/kg/week, and 9 mcg/kg/week plus granulocyte-colony stimulating factor (G-CSF) 2.5 mcg/kg twice weekly. Patients with refractory anemia with ringed sideroblasts (RARS) commenced DA at 9 mcg/kg/week. The weight-based dosing regimen translated into a median starting DA dose of 390 mcg/week. Erythroid responses were observed in 16/24 patients (67%; 12 major and 4 minor), with a median response duration of 11 months in major responders. Addition of G-CSF generated a major erythroid response in 7/15 patients (47%) who suboptimally responded to DA alone. DA was well tolerated, except for worsening of baseline mild hypertension and renal insufficiency in one patient with diabetes. IPSS score <0.5 and RBC transfusions <2 units/month increased the probability of an erythroid response. A minority of subjects (12%) developed low-level non-neutralizing anti-DA antibodies. Our data indicate that weekly weight-based dosing of DA, with the addition of G-CSF in selected individuals, can be an effective erythropoietic option in a high proportion of lower-risk MDS patients.

Topics: Adult; Aged; Aged, 80 and over; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes

The efficacy of human recombinant erythropoietin (rEPO) in myelodysplastic syndromes (MDS) has generally been best in untransfused patients with 'refractory anaemia' according to the World Health Organization (WHO). We treated 63 MDS patients [excluding refractory anaemia with excess blasts, type 2 (RAEB2)] with a previously tested combination of 13-cis-retinoic acid and dihydroxylated vitamin D3 +/- 6-thioguanine in addition to rEPO. Most patients were categorized as refractory cytopenia with multilineage dysplasia and RAEB1, with intermediate 1 International Prognostic Scoring System (IPSS) score; all had Hb <95 g/l, and 70% required regular erythrocyte transfusions. Treatment was well tolerated, and erythroid response rate according to new International Working Group criteria was 60%: 50% in RAEB1 and 64% in non-RAEB patients (P = 0.383). Response rate was not affected by transfusion requirement (63%; 58% in untransfused), IPSS and WHO Prognostic Scoring System scores, and weekly rEPO dosage (30-50 000 U vs. 80 000 U). Median response duration was 16 months. Median survival reached 14 months for RAEB1 and 55 months for non-RAEB patients, with a significant difference in the latter between responders and non-responders (median 82 months vs. 44 months; P = 0.036). Our combined therapy, independent of rEPO dosage, achieved in patients with unfavourable response predictors, a rate of anaemia improvement comparable to the best obtained in lower risk patients by high-dose rEPO.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Calcitriol; Drug Therapy, Combination; Erythropoietin; Female; Humans; Isotretinoin; Kaplan-Meier Estimate; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Risk; Survival Rate; Treatment Outcome; Vitamins

Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-beta and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500 U/l or other cytopenia(s) (absolute neutrophilic count <1.0 G/l or platelets <50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500 U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-beta-ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Erythropoietin; Female; Humans; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Neutrophils; Platelet Count; Recombinant Proteins; Thrombocytopenia; Treatment Outcome; Tretinoin; Young Adult

This phase 3 prospective randomized trial evaluated the efficacy and long-term safety of erythropoietin (EPO) with or without granulocyte colony-stimulating factor plus supportive care (SC; n = 53) versus SC alone (n = 57) for the treatment of anemic patients with lower-risk myelodysplastic syndromes. The response rates in the EPO versus SC alone arms were 36% versus 9.6%, respectively, at the initial treatment step, 47% in the EPO arm, including subsequent steps. Responding patients had significantly lower serum EPO levels (45% vs 5% responses for levels < 200 mU/mL vs > or = 200 mU/mL) and improvement in multiple quality-of-life domains. With prolonged follow-up (median, 5.8 years), no differences were found in overall survival of patients in the EPO versus SC arms (median, 3.1 vs 2.6 years) or in the incidence of transformation to acute myeloid leukemia (7.5% and 10.5% patients, respectively). Increased survival was demonstrated for erythroid responders versus nonresponders (median, 5.5 vs 2.3 years). Flow cytometric analysis showed that the percentage of P-glycoprotein(+) CD34(+) marrow blasts was positively correlated with longer overall survival. In comparison with SC alone, patients receiving EPO with or without granulocyte colony-stimulating factor plus SC had improved erythroid responses, similar survival, and incidence of acute myeloid leukemia transformation.

Topics: Aged; Drug Therapy, Combination; Erythropoietin; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Male; Myelodysplastic Syndromes; Prognosis; Prospective Studies; Quality of Life; Recombinant Proteins; Risk Factors; Survival Rate; Treatment Outcome

Patients with myelodysplastic syndromes (MDS) often develop anaemia resulting in frequent transfusions and fatigue. Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) approved for treating chemotherapy-induced anaemia. This single-arm, phase 2 study examined the efficacy of darbepoetin alfa 500 microg every 3 weeks (Q3W) for treating anaemia in low-risk MDS patients (after 6 weeks, poor responders received darbepoetin alfa 500 microg every 2 weeks). The primary end-point was the incidence of erythroid responses (International Working Group criteria) after 13 weeks of therapy. Secondary end-points included the incidence of erythroid responses at weeks 28 and 55, [or weeks 27 and 53 for dose escalations to every two weeks (Q2W)], and safety parameters. Analyses were stratified by the patient's previous ESA therapy status [ESA-naïve (n = 144) vs. prior ESA-treated (n = 62)]. After 13 weeks of therapy, 49% of ESA-naïve patients and 26% of prior ESA-treated patients achieved a major erythroid response. After 53/55 weeks, 59% of ESA-naïve patients and 34% of prior ESA-treated patients achieved a major erythroid response; 82% of ESA-naïve patients and 55% of prior ESA-treated patients achieved target haemoglobin of 110 g/l. Thromboembolic or related adverse events occurred in 2% of patients; no pulmonary embolisms were reported. In conclusion, darbepoetin alfa, 500 microg Q3W appeared well tolerated and increased haemoglobin levels in low-risk MDS patients.

Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Darbepoetin alfa; Disease Progression; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Fatigue; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myelodysplastic Syndromes; Time Factors; Treatment Outcome

Topics: Aged; Aged, 80 and over; Anemia; Cytogenetic Analysis; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

We analyzed prognostic factors of response, response duration, and possible impact on survival of epoetin alpha, epoetin beta, or darbepoetin alpha (DAR) with or without granulocyte colony-stimulating factor in 403 myelodysplastic syndrome (MDS) patients. Sixty-two percent (40% major and 22% minor) and 50% erythroid responses were seen, and median response duration was 20 and 24 months according to IWG 2000 and 2006 criteria, respectively. Significantly higher response rates were observed with less than 10% blasts, low and int-1 International Prognostic Scoring System (IPSS), red blood cell transfusion independence, serum EPO level less than 200 IU/L, and, with IWG 2006 criteria only, shorter interval between diagnosis and treatment. Significantly longer response duration was associated with major response (IWG 2000 criteria), IPSS low to INT-1, blasts less than 5%, and absence of multilineage dysplasia. Minor responses according to IWG 2000 were reclassified as "nonresponders" or "responders" according to IWG 2006 criteria. However, among those IWG 2000 minor responders, response duration did not differ between IWG 2006 responders and nonresponders. Multivariate adjusted comparisons of survival between our cohort and the untreated MDS cohort used to design IPSS showed similar rate of progression to acute myeloid leukemia in both cohorts, but significantly better overall survival in our cohort, suggesting that epoetin or DAR treatment may have a favorable survival impact in MDS.

Topics: Aged; Blast Crisis; Cohort Studies; Disease-Free Survival; Erythrocyte Transfusion; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Myelodysplastic Syndromes; Predictive Value of Tests; Survival Rate; Time Factors

We investigated the therapeutic activity of recombinant erythropoietin (r-EPO) in association with thalidomide in 30 patients with myelodysplastic syndromes (MDS), previously treated with r-EPO (n.15, group A) or thalidomide (n.15, group B) as single agents, respectively, without any significant benefit on their anemia. Four patients of group A and three of group B (23.3%) achieved an erythroid response, according to International Working Group (IWG) criteria. After 12 weeks, responders of group A continued with thalidomide alone, those of group B with r-EPO alone. All responses were maintained, thus suggesting they were likely due to the second drug adjuncted (thalidomide for group A and r-EPO for group B), rather than to a combined effect. Our results do not support the hypothesis of a synergistic activity for the association of r-EPO and thalidomide on anemia of MDS. It seems, instead, that two populations of patients can be identified, according to their sensitivity to r-EPO or, alternatively, to thalidomide.

Topics: Adult; Aged; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Recombinant Proteins; Thalidomide; Treatment Outcome

Haemopoietic growth factors (HGF), i.e. erythropoietin [recombinant human erythropoietin (rHEPO)] or granulocyte colony stimulating factor (G-CSF), alone or in combination, have largely been used to treat anemia in myelodysplastic syndromes (MDS), but whether combined rHEPO and G-CSF is really superior to rHEPO alone is still under debate. In particular, randomized studies comparing front-line rHEPO vs rHEPO+G-CSF are still lacking. The aim of this study was to compare the effects of "standard" doses of rHEPO with the combination of rHEPO and G-CSF in the treatment of anemic patients with low-risk MDS in a prospective randomized trial. Anemic patients with low-risk MDS were randomly assigned to receive either rHEPO (10,000 IU s.c. three times a week) or the same dosage of rHEPO+G-CSF (300 mug s.c. twice a week) for a minimum of 8 weeks. Patients who were unresponsive to rHEPO were offered the combination therapy for another 8 weeks, whereas non-responders to rHEPO+G-CSF were considered "off study". Responders continued the treatment indefinitely. Both haematological response and changes in quality-of-life (QoL) scores (Functional Assessment of Cancer Therapy-Anemia) were recorded and evaluated. Thirty consecutive patients [10 refractory anemia (RA), 5 RA with ringed sideroblasts, 7 refractory cytopenia with multilineage dysplasia, 5 RA with less than 10% blasts and 3 5q-syndrome] were enrolled in the study. All of them (15 in the rHEPO arm and 15 in the rHEPO+G-CSF arm) were valuable after the first 8 weeks of treatment. Erythroid response was observed in 6/15 (40%) patients in the rHEPO arm and in 11/15 (73.3%) patients in the rHEPO+G-CSF arm. In 4/9 (44.4%) patients who were unresponsive to rHEPO, the addition of G-CSF induced erythroid response at 16 weeks. No relevant adverse effects were recorded for either treatment in any of the study patients. Erythroid response to HGF was associated with a relevant improvement in QoL. Twenty responders continued the treatment. Afterwards, 8/20 (40%) discontinued therapy because of the following: losing response (2), progression to high-risk MDS (3) and death due to other causes (3). The remaining 12 are still responding and continuing treatment, with a median follow-up of 28 months. Progression to acute leukemia was cumulatively observed in 4/30 (13.3%) patients (2 in each arm). Although our data were obtained from a relatively small cohort of patients, they indicate that the rHEPO+G-CSF treatment is more effecti

Topics: Aged; Aged, 80 and over; Anemia; Disease Progression; Disease-Free Survival; Erythropoiesis; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Remission Induction; Risk Factors

Five, repeatedly transfused, patients with refractory anemia (RA) or RA with ringed sideroblast (RARS) subtypes of myelodysplastic syndrome (MDS), with serum ferritin (SF) levels of > 2,000 microg/L, and one female with Hb E [beta26(B8)Glu --> Lys]/beta0-thalassemia (thal) with an SF level of 1,760 microg/ L, were treated with deferiprone (L1) at the dose of 4-6 g per day for at least 26 months. Beginning in the second month, all patients received recombinant human erythropoietin (rHuEPO) at the dose of 150 IU/kg thrice weekly, subcutaneously for 24 months. A significant increase in iron excretion after combined administration of L1 and rHuEPO compared to treatment with L1 as a single agent, was observed in all patients. The amount of excreted iron in urine ranged from 7.5 to almost 20 mg per day. In one patient, a response to rHuEPO resulted in transfusion independence and her SF decreased from 2086 to 879 microg/L. In four MDS patients, who remained dependent on red blood cell (RBC) transfusions, simultaneous administration of L1 and rHuEPO enabled the stabilization of SF levels, despite continuing iron load from the transfusions. Combined administration of rHuEPO and oral iron chelators may potentiate mobilization of storage iron and maintain iron balance in transfusion-dependent iron overloaded early MDS patients.

Topics: Administration, Oral; Anemia, Refractory; Deferiprone; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Ferritins; Humans; Injections, Subcutaneous; Iron; Iron Chelating Agents; Myelodysplastic Syndromes; Pyridones; Recombinant Proteins

We randomized 21 patients with low-risk myelodysplastic syndromes (MDS) to receive a single subcutaneous bolus of recombinant erythropoietin (epoietin) +/- granulocyte-colony stimulating factor (G-CSF), or placebo and monitored erythropoietic response over 7 days. In this small study, the reticulocyte response at day 7 was highly predictive of subsequent response to a therapeutic trial of epoietin + G-CSF.

Topics: Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Ferritins; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Lenograstim; Myelodysplastic Syndromes; Predictive Value of Tests; Receptors, Transferrin; Recombinant Proteins; Reticulocyte Count; Single-Blind Method; Treatment Outcome

An open-label, phase II non-randomised trial was conducted with darbepoetin (DAR), an erythropoiesis-stimulating factor with prolonged half-life, at a weekly dose of 300 mug subcutaneously in 62 anaemic patients with myelodysplastic syndrome (MDS) with an endogenous erythropoietin (EPO) level <500 mU/ml. Most of the patients were classified as low or intermediate 1 according to the International Prognostic Scoring System. After 12 weeks, 44 (71%) patients had an erythroid response (34 major and 10 minor), including eight of 13 patients who were previous non-responders to conventional EPO. Two additional responses (one minor and one major) occurred, in 10 non-responders, after the addition of granulocyte colony-stimulating factor (G-CSF). Thirty-six of the 46 total responders (31/35 major and 5/11 minor) continued to respond on maintenance DAR after a median of 40 weeks (range 4-84). Median dose of DAR required to maintain response was 300 microg every 14 d. The only prognostic factors of favourable response were low endogenous EPO level and low or absent red blood cell transfusion requirement. Those results suggest that high-dose DAR alone yields high erythroid response rates in anaemia of lower risk MDS, possibly equivalent to those obtained with conventional EPO + G-CSF, although this will need to be confirmed in larger and randomised trials.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Drug Administration Schedule; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Injections, Subcutaneous; Male; Middle Aged; Myelodysplastic Syndromes; Risk Factors; Treatment Outcome

This study evaluated the impact of a new epoetin alfa dosing regimen on quality of life (QOL), transfusion requirements, and hemoglobin (Hb) levels in 133 patients with low-risk myelodysplastic syndrome (MDS) and Hb < or =10 g/dl. Epoetin alfa 40,000 IU was given subcutaneously twice weekly; after 4 weeks, the dose could be reduced to 40,000 IU weekly in patients achieving erythroid response. QOL was assessed using the functional assessment of cancer therapy-anemia (FACT-An) questionnaire. FACT-An scores increased on average by 7.5 after 4 weeks and by 8.8 after 8 weeks compared with baseline. FACT-An scores were positively associated with Hb values (r=0.53, P<0.01). The mean FACT-An score increase at week 8 was 10.2 in responders and 5.6 in nonresponders. The overall erythroid response rate at week 8 was 68%: 74% in transfusion-independent patients and 59% in transfusion-dependent patients. Of all responders at week 8, response was maintained in 86% at week 12, 71% at week 16, 65% at week 20, and 54% at week 24. Treatment was generally well tolerated. Our data provide new and encouraging results regarding the benefits of 40,000 IU biweekly induction doses followed by 40,000 IU weekly in improving QOL, correcting anemia, and reducing transfusion requirements in low-risk MDS patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Risk; Surveys and Questionnaires

We report long-term results of treatment of myelodysplastic syndrome (MDS) with erythropoietin and granulocyte colony-stimulating factor (G-CSF). A total of 129 patients were followed up 45 months after last inclusion in the Nordic MDS Group studies. Erythroid response rate was 39% and median response duration 23 months (range, 3-116 months or more). Complete responders showed longer response duration than partial responders (29 versus 12 months, P = .006). The International Prognostic Scoring System (IPSS) groups Low/Intermediate-1 (Low/Int-1) had longer response duration than Int-2/High (25 versus 7 months, P = .002). The time until 25% developed acute myeloid leukemia (AML) was longer in the good and intermediate predictive groups for erythroid response compared with the poor predictive group (52 versus 13 months, P = .008). Only 1 of 20 long-term responders developed AML. We assessed the effect on long-term outcome by comparing treated patients with untreated patients selected from the IPSS database using multivariate Cox regression, adjusting for major prognostic variables. There was no difference in survival (odds ratio [OR], 0.9; 95% confidence interval [CI], 0.7-1.2; P = .55) or risk of AML evolution (OR, 1.3; 95% CI, 0.7-2.2; P = .40) between treated and untreated patients. Patients with high/intermediate probability of response and with IPSS Low/Int-1 show frequent and durable responses without adverse effects on outcome, while other patients should not be considered candidates for this treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Anemia; Cell Transformation, Neoplastic; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis; Survival Analysis; Treatment Outcome

The hematological and quality of life (QoL) changes associated with darbepoetin alfa (DA) therapy were assessed in anemic patients with previously untreated low- and intermediate-1-risk myelodysplastic syndrome (MDS).. Fifty-three patients received DA administered subcutaneously once a week for 24 weeks. Treatment was initiated at 150 microg fixed dose and was doubled if after the first 12 weeks there was no or suboptimal erythroid response.. The final response rate was 24/53 (45%), with 21 major and three minor responses. Most of the responses (21/24; 87.5%) were obtained at the dose of 150 microg. With a median follow-up of 9.4 months, 17 patients maintain their response. Treatment was well tolerated with no relevant side-effects. MDS progression was observed in one case. Increases in hemoglobin levels were positively correlated with improved QoL scores using both the linear analog scale assessment (energy level, r = 0.429, P = 0.036; daily activities, r = 0.653, P < 0.001; overall well-being, r = 0.457, P = 0.024) and the Functional Assessment of Cancer Therapy-Anemia questionnaire (r = 0.247, P = 0.025). In multivariate analysis, only low levels (<200 IU/l) of endogenous erythropoietin predicted response to DA therapy.. DA is an active, safe and well tolerated treatment for anemia in a substantial proportion of patients with low- and intermediate-1-risk MDS, and has a positive impact on the patients' QoL.

Topics: Aged; Aged, 80 and over; Anemia; Apoptosis; Blood Transfusion; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Subcutaneous; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life; Risk Factors; Treatment Outcome

In this prospective study we evaluate the effects of high-dose recombinant human erythropoietin (rHuEPO) on quality of life (QOL) and brain function in patients with low-risk myelodysplastic syndromes (MDS) (<10% marrow blasts). Preliminary data are reported.. Eleven consecutive patients were given rHuEPO (40,000 IU two times a week) for 12 wk. Responsive patients continued with 40,000 IU/wk for further 12 wk. Changes in QOL were assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An) self-report. Neurophysiological evaluation at the start of the therapy (t0) included duplex scanning of neck vessels, transcranial Doppler sonography (TCD), a complex neuropsychological evaluation, and quantitative electroencephalography (qEEG). Eight patients completed the neurophysiological evaluation after 24 wk (t1).. Six patients (55%) achieved an erythroid response after 12 wk, which was maintained after 24 wk of treatment. FACT-An score showed a relevant improvement between t0 and t1 in these patients. At baseline, TCD showed a mean cerebral blood flow (CBF) velocity in the upper normal range. Abnormalities in brain function were observed in five patients. In the eight patients who were re-evaluated at t1, improvement was observed in three responding patients, two of them with abnormal values at t0. A strict correlation between QOL and neurophysiological improvements was not observed.. A high-dose induction phase with rHuEPO followed by maintenance therapy may be an effective therapeutic schedule for low-risk MDS patients. The erythroid response was associated with positive changes in the QOL. Neurophysiological improvements occurred only in a part (50%) of responding patients, mainly those who showed altered results at baseline.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Brain; Electroencephalography; Erythropoietin; Fatigue; Humans; Middle Aged; Myelodysplastic Syndromes; Neuropsychological Tests; Patient Selection; Quality of Life; Recombinant Proteins; Surveys and Questionnaires

In myelodysplastic syndromes (MDS), anemia responds to recombinant human erythropoietin (rHuEPO) alone and in combination with recombinant human granulocyte-colony-stimulating factor (rHuGCSF) in 10% to 20% and in 35% to 40% of patients, respectively. We randomly divided 60 patients with low-grade anemic MDS and serum EPO levels lower than 500 IU/L (500 mU/mL) into 2 groups: rHuEPO + rHuG-CSF (arm A) and supportive care (arm B). After 12 weeks, those who had erythroid responses were given rHuEPO alone for 40 additional weeks. They were also given rHuG-CSF if they had relapses. A response was considered major if the hemoglobin (Hb) level was 115 g/L (11.5 g/dL) or higher and minor Hb increase was 15 g/L (1.5 g/dL) or more or if it remained stable without transfusion. Ten of 24 patients responded in arm A, and 0 of 26 responded in arm B (P =.01). Eight patients in arm A continued rHuEPO therapy alone, and 6 had relapses. Responses were always restored when rHuG-CSF was reintroduced. Mean direct costs per patient were 26,723 euros (arm A) and 8,746 euros (arm B). Quality of life was assessed with a Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale. Similar percentages of patients from both arms showed significant clinical improvement. rHuEPO plus rHuG-CSF led to responses in 41.7% of MDS patients. This treatment was expensive. No effect on quality of life was demonstrated.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cost-Benefit Analysis; Drug Costs; Erythropoietin; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Treatment Outcome

The in vivo effect of recombinant human erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) combined treatment on CD34(+) cells was evaluated by fluorescence in situ hybridization (FISH) in 13 myelodysplastic syndrome (MDS) patients with known cytogenetic abnormalities. After treatment, responsive patients presented a significantly lower proportion of FISH abnormal CD34(+) cells than before treatment (P = 0.003), and in comparison with unresponsive cases (P = 0.007). Response to treatment was associated with a reduced degree of apoptosis in CD34(+) cells (P = 0.021): however, no difference in telomere length was observed in responsive patients after growth factor administration. Although the number of patients analysed was relatively small, the present data suggest that, in MDS patients, response to rHuEpo and G-CSF may be related to the proliferation of karyotypically normal but potentially defective CD34(+) progenitor cells.

Topics: Aged; Aged, 80 and over; Antigens, CD34; Apoptosis; Bone Marrow Cells; Cell Division; Chromosome Aberrations; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Telomere; Treatment Outcome

Once-weekly dosing of recombinant human erythropoietin (rhEPO) in patients with myelodysplastic syndromes (MDS) has not been investigated thoroughly. We performed a clinical trial to evaluate the effects of this new dosing regimen in patients with MDS who were unresponsive to the conventional three-times-weekly schedule.. Forty-eight patients with low- or intermediate-risk MDS were enrolled in a 12-week study. rhEPO alpha (rhEPOalpha) was administered once-weekly by subcutaneous injection with a starting dose of 40,000 U fixed dose. The drug dosage was increased to 60,000 U fixed dose if after 6 weeks there was no or suboptimal erythroid response.. Clinically significant responses were seen in 13 (27%) patients, with 11 improving their response after dose escalation of rhEPOalpha. Only one patient (case 23) maintains a response after a follow-up period of 14 months. All other patients had responses lasting between 10 and 43 weeks, with a median time to relapse of 20 weeks. Treatment was well tolerated, with no relevant adverse events. Response to therapy was associated with significantly higher concentrations of circulating erythroid blast-forming units and a decrease of the bone marrow fraction of apoptic CD34+ cells.. Once-weekly rhEPOalpha therapy results in an improvement of erythropoiesis in a subset of MDS patients who are unresponsive to conventional dosing, and may act by inhibiting apoptosis of erythroid precursors. These results warrant further investigation of this dosing regimen either alone or in combination with other agents.

Topics: Aged; Aged, 80 and over; Antigens, CD34; Apoptosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Flow Cytometry; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins; Treatment Outcome

A phase II trial was conducted to explore the efficacy and tolerability of combining thalidomide (100 mg/d p.o.) with an erythropoietic growth factor (darbepoietin-alpha 2.25 micro g/kg/d s.c.) in patients with low-to-intermediate-risk myelodysplastic syndromes (MDS). However, the trial had to be discontinued early because of an unexpectedly high incidence of thromboembolic events. Of the first seven patients enrolled, two developed deep-vein thrombosis and one died of massive pulmonary embolism. We concluded that thalidomide might significantly increase the thromboembolic risk of erythropoietic proteins in MDS patients. Careful clinical surveillance and thrombosis prophylaxis (heparin or oral anticoagulation) should be considered for MDS patients undergoing combined treatment with thalidomide and erythropoietic growth factors.

Topics: Aged; Anticoagulants; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Heparin, Low-Molecular-Weight; Humans; Immunosuppressive Agents; Middle Aged; Myelodysplastic Syndromes; Pulmonary Embolism; Thalidomide; Thromboembolism; Venous Thrombosis

Thirteen patients with low-to-intermediate risk myelodysplastic syndrome (MDS) received recombinant erythropoietin (r-EPO) at the single, weekly dose of 40.000 U for at least 8 weeks. Five patients (38.4%) achieved a major erythroid response (increased haemoglobin levels > 2 g/dl and/or transfusion independence), which is currently maintained after 3-11 months, without modification of r-EPO dose. This study suggests that 40.000 U r-EPO given once a week may be at least as effective as the more frequent (daily or three times a week) administrations of the drug usually employed in MDS patients.

Topics: Aged; Blood Transfusion; Drug Administration Schedule; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Anemia has been reported in approximately 40%-70% of patients with hematologic malignancies, with severity depending on the type and stage of disease and whether the patient has received myelosuppressive chemotherapy. Growing evidence supports the role of epoetin alfa in correcting anemia and improving quality of life (QOL) in patients with hematologic malignancies. Clinical practice guidelines recommend the use of epoetin alfa in patients with cancer-related anemia (including patients with hematologic malignancies) and hemoglobin levels < or =10 g/dL. Epoetin alfa treatment is optional for patients with cancer-related anemia and hemoglobin levels>10 g/dL and <12 g/dL, depending on clinical circumstances. A prospective, open-label, randomized trial evaluating hematologic response, transfusion use, and QOL after immediate or delayed epoetin alfa treatment in mildly anemic patients (hemoglobin< or =12 g/dL) undergoing chemotherapy for chronic lymphocytic leukemia, multiple myeloma, or lymphoma was recently completed. Study objectives included determining any correlation between changes in hemoglobin level and QOL and assessing any correlation between QOL measures and health care resource use. Interim results suggest that epoetin alfa treatment in patients with hematologic cancers and hemoglobin< or =12 g/dL who are receiving chemotherapy increases hemoglobin, functional capacity, well-being, work and productivity, and health resource use. Further evaluation of alternative epoetin alfa dosing schedules and use of epoetin alfa in treating anemia in patients with specific hematologic malignancies is ongoing.

Topics: Anemia; Clinical Trials as Topic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Linear Models; Multiple Myeloma; Myelodysplastic Syndromes; Quality of Life; Random Allocation; Recombinant Proteins

In vitro studies suggest that all-trans retinoic acid (ATRA) synergizes with erythropoietin (EPO) for the stimulation of hematopoiesis in patients with myelodysplastic syndrome (MDS). A clinical trial was performed to evaluate whether a combination of these agents was effective in relieving the cytopenias associated with MDS. Twenty-seven patients with low- or intermediate-risk MDS were enrolled in a 12-week study. ATRA was administered orally at the dose of 80 mg/m(2) per day in 2 divided doses for 7 consecutive days every other week. Recombinant human EPO was given subcutaneously 3 times a week. The EPO dose was initiated at 150 U/kg and was increased to 300 U/kg if after 6 weeks there was no or there was suboptimal erythroid response. Patients who responded to therapy were continued on ATRA and EPO at the same doses for 6 additional months (extension phase). Further treatment was given to patients with a continued response. Clinically significant erythroid responses with increases of hemoglobin levels of at least 1 g/dL or reduction of transfusion needs were seen in 13 (48%) patients, with 4 showing improved responses after dose escalation of EPO. Ten (37%) patients displayed continued responses during 6 months of extended treatment, and 7 (26%) are still responsive after a follow-up period of 13 months. Neutrophil responses were observed in 5 of 12 patients with neutropenia, and platelet responses were observed in 6 of 9 patients with thrombocytopenia. Three patients displayed trilineage responses that were sustained during continuation therapy. Side effects were observed in all patients but were of mild entity and did not require discontinuation of therapy. It is concluded that the combination ATRA + EPO is an effective and well-tolerated treatment for patients with low- and intermediate-risk MDS. The optimal ATRA and EPO schedule and the role of maintenance treatment remain to be determined and warrant further investigation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Synergism; Erythropoietin; Female; Follow-Up Studies; Hematopoiesis; Hemoglobins; Humans; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Neutrophils; Platelet Count; Recombinant Proteins; Treatment Outcome; Tretinoin

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with prolonged anemia caused by defective erythropoietin (Epo) production. We enrolled 34 recipients of an allogeneic HSCT in three consecutive trials to determine the optimal utilization of recombinant human erythropoietin (rhEpo) therapy in this setting.. In the first trial (n = 7), rhEpo 1400 U/kg/week was given from day 1 until a hemoglobin (Hb) level of 10 g/dL was achieved, for a maximum of 60 days. In the second trial, rhEpo 500 U/kg/week was given to achieve Hb levels of 13 to 14 g/dL in 13 anemic patients with fatigue 56 to 1440 days after transplant. In the third trial, rhEpo was scheduled to start on day 35 in 14 patients at a dose of 500 U/kg/week with the aim of achieving Hb levels of 13 to 14 g/dL.. In trial 1, erythroid recovery to 1% reticulocytes and red blood cell transfusion independence were faster, but the number of transfusions was not reduced compared to 10 controls. Responses were brisk in trial 2, with transfusion independence achieved after a median of 1 week in 12 of 13 patients, and 2-g Hb increments or Hb values of 11, 12, and 13 g/dL after 6, 7, 10, and 10 weeks, respectively. Transfusions were significantly reduced in the first month of rhEpo therapy. In trial 3, transfusion independence was obtained after a median of 1 week in 13 of 14 patients, and 2-g Hb increments or Hb values of 11, 12, and 13 g/dL after 3, 4, 6, and 8 weeks, respectively. Transfusions rates were considerably reduced compared to the previous month in the same patients or compared to controls undergoing peripheral blood or marrow transplant without rhEpo.. Anemia after allogeneic HSCT is exquisitely sensitive to rhEpo. The benefit is minimal when it is given early post-transplant, as used in all trials to date. However, the rate of major response is greater than 90% when rhEpo is started after day 35. These data provide the basis on which to conduct a prospective, randomized, placebo-controlled trial of rhEpo therapy after allogeneic HSCT.

Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Transplantation; Child; Cyclosporine; Drug Administration Schedule; Erythropoietin; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Lymphoma, Non-Hodgkin; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Thrombocytosis; Transplantation, Homologous

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

The outcome of continued EPO therapy was studied in 18 responding MDS patients. The EPO dose was reduced in a stepwise fashion to find the lowest possible maintenance dose. Relapses of anemia were associated with either progressive disease or reduction of the administered EPO dose. In the latter group second responses to renewed EPO therapy were readily achieved. Long-term responses were seen in about a third of the patients. Thus, it seems safe to reduce the EPO dose among responding patients. This approach may have advantages both from a medical and a socio-economic perspective.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Survival Rate; Treatment Outcome

Amifostine is a cytoprotective agent mainly used in cancer therapies, in order to ameliorate the toxic effects of anticancer chemotherapy and radiotherapy. In the past years an intriguing number of applications of amifostine have been identified; one of these is bone marrow cells protection and stimulation. Amifostine was administered in seven patients with myelodysplastic syndromes, four males and 3 females aged between 67 and 78 years old, in order to estimate its efficacy in reducing the need for red blood cells transfusions. Two patients had RAEB, four RA and one RARS. The drug was administered in an outpatient basis in a dose of 300 mgr/m2, three times weekly for at least four weeks. We administered at the same time erythropoietin 10.000 U subcutaneously. All patients received daily supplementation of oral ferrum sulfate and folic acid. Three patients, a woman with RA and two men, one with RA and another with RAEB improved the levels of Hb beyond 12,0 gr/dl and did not receive blood transfusions after the second week of treatment. The drug was well tollerated without any side effects in all of the patients.

Topics: Aged; Amifostine; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Blood Transfusion; Bone Marrow Cells; Cytoprotection; Erythropoietin; Female; Humans; Male; Myelodysplastic Syndromes; Outpatients; Recombinant Proteins

Ineffective hematopoiesis leading to profound cytopenias represents a major clinical problem in the management of patients with myelodysplastic syndrome (MDS). The aminothiol amifostine has shown to promote multilineage hematopoiesis both in vivo and in vitro in patients with MDS. We have treated 10 patients with 250 mg/m2 amifostine thrice weekly in combination with erythropoietin for 4 consecutive weeks followed by 2 weeks observation. Responding patients received the same 6 week schedule, while nonresponder received G-CSF in addition to erythropoietin and amifostine during the second treatment course. All patients experienced single or multilineage hematologic improvement, but only 2 reached transfusion independency. Moreover, response was durable only in a minority of patients and thus additional studies are warranted to further define the potential interaction of amifostine and growth factors.

Topics: Aged; Aged, 80 and over; Amifostine; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Cell Lineage; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Middle Aged; Myelodysplastic Syndromes; Treatment Outcome

Interleukin-11 (IL-11) is a thrombopoietic cytokine that attenuates postchemotherapy thrombocytopenia at doses of 50 microg/kg/d subcutaneously. Very little is known about the activity of IL-11 in patients with bone marrow failure states.. Our preliminary experience with IL-11 at doses of 50 microg/kg/d suggested that patients with bone marrow failure developed significant peripheral and pulmonary edema after the prolonged dosing necessary for treating these conditions. We, therefore, initiated a study of low-dose IL-11 (starting dose, 10 microg/kg/d).. Sixteen patients were assessable for response. Six patients had diploid cytogenetics; the others had a variety of chromosomal abnormalities. Six (38%) of 16 patients showed a platelet response to IL-11, and two had a multilineage response (to IL-11 alone, n = 1; to IL-11 plus G-CSF and erythropoietin, n = 1). The median increase in peak platelet counts was 95 x 10(9)/L above baseline in the responders (range, increase of 55 x 10(9)/L to 130 x 10(9)/L above baseline). Responders included five of 11 patients with myelodysplasia and one of four patients with aplastic anemia. Response durations were 12, 13, 14+, 25, 30, and 30+ weeks. Side effects of IL-11 were mild (peripheral edema, n = 7; conjunctival injection, n = 7; myalgia, n = 1; all grade 1). Seven patients had no side effects.. Our pilot study suggests that administration of low-dose IL-11 (10 microg/kg/d) can raise platelet counts without significant toxicity in selected thrombocytopenic patients with bone marrow failure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Bone Marrow Cells; Child; Child, Preschool; Drug Administration Schedule; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-11; Karyotyping; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Platelet Count; Thrombocytopenia

This randomized, placebo-controlled trial was designed to assess the efficacy and safety of therapy with granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (epoetin alfa) in anemic, neutropenic patients with myelodysplastic syndrome. Sixty-six patients were enrolled according to the following French-American-British classification: refractory anemia (20), refractory anemia with excess blasts (35), refractory anemia with ringed sideroblasts (9), and refractory anemia with excess blasts in transformation (2). Patients were stratified by their serum erythropoietin levels (less than or equal to 500 mU/mL, n = 37; greater than 500 mU/mL, n = 29) and randomized, in a 2:1 ratio, to either GM-CSF (0.3-5.0 microg/kg.d) + epoetin alfa (150 IU/kg 3 times/wk) or GM-CSF (0.3-5.0 microg/kg.d) + placebo (3 times/wk). The mean neutrophil count rose from 948 to 3831 during treatment with GM-CSF +/- epoetin alfa. Hemoglobin response (increase greater than or equal to 2 g/dL, unrelated to transfusion) occurred in 4 of 45 (9%) patients in the GM-CSF + epoetin alfa group compared with 1 of 21 (5%) patients with GM-CSF + placebo group (P = NS). Percentages of patients in the epoetin alfa and the placebo groups requiring transfusions of red blood cells were 60% and 92%, respectively, for the low-endogenous erythropoietin patients and 95% and 89% for the high-endogenous erythropoietin patients (P = NS). Similarly, the average numbers of units of red blood cells transfused during the 12-week study in the epoetin alfa and the placebo groups were 5.9 and 9.5, respectively, in the low-endogenous erythropoietin patients and 9.7 and 8.6 in the high-endogenous erythropoietin patients (P = NS). GM-CSF +/- epoetin alfa had no effect on mean platelet count. Treatment was well tolerated in most patients, though 10 withdrew from the study for reasons related predominantly to GM-CSF toxicity. (Blood. 2000;95:1175-1179)

Topics: Anemia; Blood Transfusion; Double-Blind Method; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Neutropenia; Placebos; Recombinant Proteins

The phosphorylated aminothiol agent amifostine (Ethyol) protects bone marrow and other tissues from toxicity due to ionizing radiation and antineoplastic drugs, and stimulates progenitors from normal and myelodysplastic bone marrow. Contrasting results have been published so far on the effectiveness of amifostine in correcting cytopenia in patients with myelodysplastic syndromes (MDS).. In a pilot phase II study we treated 26 patients with low risk MDS (13 RA, 2 RARS, 2 CMML, 9 RAEB with blasts < 10%) with amifostine (200 mg/m(2 )x 3/week for 4 weeks).. Hemoglobin concentration, reticulocyte, neutrophil and platelet counts increased respectively in 6 (23%), 11 (42%), 13 (50%) and 9 (34%) of patients. Red cell transfusions were reduced (> 50%) in 4/26 patients and abolished in 1/26. Unexpectedly a significant decrease in soluble transferrin receptor level at week 4 of therapy, compared to the basal level (p<0.04), was observed in the whole population of patients.. Amifostine can ameliorate cytopenia in some patients with MDS, with few and mild side effects. Neutropenia is more likely to be corrected than anemia or thrombocytopenia. Mechanisms underlying this biological effect remain to be clarified.

Topics: Aged; Aged, 80 and over; Amifostine; Blood Cell Count; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Pancytopenia; Pilot Projects; Radiation-Protective Agents; Receptors, Transferrin; Thrombopoietin

Treatment with recombinant human erythropoietin (rhEPO) improves anaemia in approximately 20% of the patients with myelodysplastic syndromes (MDS). Recent reports suggest that a combination treatment with rhEPO plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) given for up to 18 weeks may result in a higher erythroid response rate than with rhEPO alone. We investigated the potential advantage of an even more prolonged schedule of combined rhG-CSF and rhEPO treatment to obtain and maintain stable responses. In a phase II study, 33 patients with MDS [17 with refractory anaemia (RA), eight with RA with ringed sideroblasts (RARS), eight with RA with excess blasts (RAEB) with bone marrow blast counts less than 20%] were scheduled to receive at least 36 weeks of combined therapy with rhG-CSF and rhEPO. Seventeen of 28 evaluable patients demonstrated an erythroid response [61%; 95% confidence interval (CI) 41-78] after 12 weeks of treatment. The erythroid response rate was 80% (20 of 25 evaluable patients; 95% CI 59-93) after 36 weeks. Seven of these responses developed between week 12 and week 36, whereas two initially responding patients became refractory. The cytokine therapy was generally well tolerated. Nineteen of the 20 patients responding after 36 weeks continued to be treated with both cytokines. After 1 year and 2 years of continuous combined treatment, 50% of the initially included patients showed a continuing response. Our results suggest that a prolonged combination treatment with rhG-CSF and rhEPO is highly effective in achieving a stable and long-lasting erythroid response in many patients with MDS and low blast count.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Disease-Free Survival; Drug Administration Schedule; Drug Therapy, Combination; Erythrocyte Count; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Time Factors; Treatment Outcome

Twenty-two patients with myelodysplastic syndrome were treated with combined recombinant human erythropoietin and recombinant human interleukin 3 (rHuIL-3). All 22 patients were evaluable for toxicity and 21/22 for response. Thirteen patients (62%) required rHuIL-3 dose reduction because of toxicity. Nineteen experienced a 50% or greater rise in neutrophil count. Of seven patients with initial platelet counts of > 100,000, three experienced increases of > 15,000/ml while an equal number had a comparable decline. Five patients (21%) experienced a significant rise in reticulocyte count, and two transfusion-dependent patients experienced a significant decrease in transfusions. Erythroid burst-forming units were increased by > or = 50% in nine of 11 patients after combined therapy. Similar changes were seen in multipotential colony-forming units. Clinical responses were comparable to results obtained with epo alone while toxicities due to IL-3 were significant.

Topics: Aged; Blood Cell Count; Drug Therapy, Combination; Erythropoietin; Hematopoietic Stem Cells; Humans; Interleukin-3; Middle Aged; Myelodysplastic Syndromes; Patient Dropouts

In vitro studies have indicated that granulocyte-macrophage colony-stimulating factor (GM-CSF) synergizes with erythropoietin (EPO) for the production of erythroid precursors in patients with myelodysplastic syndrome (MDS). We performed a clinical trial to evaluate whether the combination of these growth factors was effective in relieving the cytopenias associated with MDS. 31 anaemic patients with low and intermediate-risk primary MDS were enrolled in a 12-week study. Therapy was initiated with GM-CSF at 1 microgram/kg/d.s.c., and then adjusted to either normalize or double the absolute neutrophil count. EPO was given subcutaneously on alternate days starting from day 2. The EPO dose was initiated at 150 U/kg and increased to 300 U/kg if after 6 weeks there was no or suboptimal erythroid response. 26 patients completed the study treatment. All evaluable cases had a neutrophil response. Clinically significant erythroid responses with increases of haemoglobin levels of at least 1 g/dl and/or reduction of transfusion needs were seen in 9/26 (34.6%), five patients improving their response after dose escalation of EPO. Treatment had no apparent effect on mean platelet counts, a single case displaying a trilineage response. An elevated bone marrow erythroid infiltration and low concentrations of circulating tumour necrosis factor-alpha were the only predictors of haemoglobin response both in univariate and in multivariate analysis. We conclude that the combination GM-CSF + EPO can abrogate neutropenia and substantially relieve transfusion requirements in a large proportion of patients with low and intermediate risk MDS. However, in vivo synergy between these growth factors for the production of erythroid precursors is not supported by our data.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count

The aim of this prospective study was to determine whether treatment with a combination of GM-CSF and erythropoietin (rhEpo) can improve the anemia associated with low risk myelodysplastic syndrome (MDS), namely refractory anemia (RA), RA with ring sideroblasts (RAS), and RA with excess of blasts (RAEB) with bone marrow blasts less than 10%. Eligibility criteria included an Hb level of less than 10.5 g/dl for newly diagnosed patients, or symptomatic anemia. GM-CSF was given at a dose of 3 microg/kg s.c. on days 1-2, rhEpo at a dose of 60 U/kg s.c. on days 3-5. No treatment was given on days 6-7. Patients were followed-up with full blood count on a weekly basis. The treatment was repeated for a total of 6 weeks. At that time, if a rise in Hb above 1.5 g/dl had not been achieved, the dose of rhEpo increased to 120 U/kg. Post-treatment evaluation was performed at the completion of 12 weeks. Erythroid response was defined as good (GR), if an increase in untransfused Hb values above 2 g/dl or a 100% decrease in red blood cell transfusion requirements, over the treatment period was observed, while an increase in untransfused Hb values 1-2 g/dl or a >50% decrease in transfusion requirements, were considered as partial response. Responders continued to receive the same treatment until disease progression. Nineteen patients (13 male and six female) with a median age of 69 years were enrolled in the study. The FAB subtypes were: RA one case, RAS eight cases and RAEB 10 cases. Ten of 19 patients (52.6%) responded to the treatment: 7/19 (36.8%) achieved a GR and 3/19 (15.8%) a PR. Six of eight (75%) patients with RAS, one case with RA and 3/10 (30%) of cases with RAEB responded to treatment. Pretreatment serum epo levels were generally low (less than 200 Mu/ml) in responding patients. At the completion of the initial 12 weeks, 8/12 responding patients (5 RAS, 2 RAEB and 1 RA) continued to receive the same treatment. All responding patients with RAS continued to show an erythroid response in a time period from 3 to 24 months, whilst one patient with RA and two with RAEB did not have a continuing response at 2, 4 and 12 months, respectively. The above data suggest that the combination of rhEpo and GM-CSF should be recommended in all cases with RARS. However, the clear indication of this combination for other patients with MDS remains to be determined.

Topics: Aged; Aged, 80 and over; Analysis of Variance; Anemia, Refractory, with Excess of Blasts; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Recombinant Proteins; Risk Factors

Anemia leading to transfusion is probably the most important problem in patients with myelodysplastic syndromes (MDS). Human recombinant erythropoietin (rHuEpo) and granulocyte colony-stimulating factor (G-CSF) have been used to treat patients with anemia of MDS, but fewer than 50% respond. The aim of this work was to evaluate the benefit of rHuEpo +/- G-CSF treatment and to isolate the response predictive variables in a group of selected patients with MDS.. A non-randomized multicenter trial was carried out in 32 patients with MDS. The inclusion criteria were age >= 18 years, refractory anemia (RA) or refractory anemia with ringed sideroblasts, Hb <= 100 g/L or receiving transfusions and serum erythropoietin <= 250 U/L. These patients were treated with subcutaneous rHuEpo (300 U/kg) three times a week for 8 weeks. In the case of partial response (PR) or no response (NR) subcutaneosly administered G-CSF (1 microg/kg) three times a week was added to the rHuEpo for 8 more weeks. If the patient achieved complete response (CR) or PR in the second phase, he was included in a follow-up phase of 24 weeks in which the dose of growth factors was tapered down. Several variables, including the score published by the Scandinavian-American group, were used as possible predictive variables.. An erythroid response was observed in 16 patients (50%); in 12 it was a CR and in 4 it was a PR. During the period of rHuEpo administration, 7 CR and 4 PR (34.4%) were documented. Of the 14 patients in whom G-CSF was added to rHuEpo, 7 (50%) responded (3 CR and 4 PR). No major side-effects associated with growth factors were observed. The multivariate analysis showed that of the different variables evaluated only the Scandinavian-American response score was significant with a relative probability of response of 11.8 (95% confident intervals: 2.5-53) when this score was > +1 (77% of cases responded). In contrast, when this score was <= 1 only 15 % of the cases responded.. Use of the Scandinavian-American response score is to be recommended in a patient-oriented approach to treating MDS cases with the Epo and G-CSF. Treatment with rHuEpo and G-CSF is safe, its main drawback being its cost. However, a long-term study evaluating the regimen's cost-benefit ratio is warranted.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Patient Compliance; Predictive Value of Tests; Recombinant Proteins

Treatment with erythropoietin (epo) may improve the anemia of myelodysplastic syndromes (MDS) in approximately 20% of patients. Previous studies have suggested that treatment with the combination of granulocyte colony-stimulating factor (G-CSF) and epo may increase this response rate. In the present phase II study, patients with MDS and anemia were randomized to treatment with G-CSF + epo according to one of two alternatives; arm A starting with G-CSF for 4 weeks followed by the combination for 12 weeks, and arm B starting with epo for 8 weeks followed by the combination for 10 weeks. Fifty evaluable patients (10 refractory anemia [RA], 13 refractory anemia with ring sideroblasts [RARS], and 27 refractory anemia with excess blasts [RAEB]) were included in the study, three were evaluable only for epo as monotherapy and 47 for the combined treatment. The overall response rate to G-CSF + epo was 38%, which is identical to that in our previous study. The response rates for patients with RA, RARS, and RAEB were 20%, 46%, and 37%, respectively. Response rates were identical in the two treatment groups indicating that an initial treatment with G-CSF was not neccessary for a response to the combination. Nine patients in arm B showed a response to the combined treatment, but only three of these responded to epo alone. This suggests a synergistic effect in vivo by G-CSF + epo. A long-term follow-up was made on 71 evaluable patients from both the present and the preceding Scandinavian study on G-CSF + epo. Median survival was 26 months, and the overall risk of leukemic transformation during a median follow-up of 43 months was 28%. Twenty patients entered long-term maintenance treatment and showed a median duration of response of 24 months. The international prognostic scoring system (IPSS) was effective to predict survival, leukemic transformation, and to a lesser extent, duration of response, but had no impact on primary response rates.

Topics: Aged; Aged, 80 and over; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Treatment Outcome

A pilot study was performed to determine the efficacy of 13-cis-retinoic acid (CRA) and alpha-tocopherol (AT) with increasing doses of recombinant human erythropoietin (rHuEPO) in anemic patients with primary myelodysplastic syndrome (MDS), to determine response rate and to determine the dose requirement and long-term effects of rHuEPO therapy on the transition to acute non-lymphocytic anemia and survival of these patients. Twenty-four consecutive MDS patients were entered into the study. Patients were stratified according to their FAB classification at study entry. Therapy consisted of a 6 month trial of CRA (100 mg m(-2) day(-1) and AT (800 mg day(-1)) with rHuEPO (150 units kg(-1) body weight subcutaneously three times a week). The rHuEPO dose was escalated to daily doses at 2 months, and 300 U kg(-1) body weight given three times a week for another 2 months and continuing therapy after 6 months in responsive patients. Response was measured by elimination of transfusions requirement (partial response, PR) and normal hemoglobin level and complete blood counts (complete response, CR). Observed responses for the 23 evaluable patients were 2 CR and 6 PR (34.8%). Odds ratio analysis showed that patients with anemia alone were 14 times more likely to respond than patients with pancytopenia (p = 0.06). In our study, two patients (8%) transformed to acute leukemia in CRA + AT + rHuEPO-treated patients. Median survival of 34 months with a median follow-up of 17 months (range 3-70 months) was observed. The response rates with the addition of rHuEPO to CRA and AT was similar but occurs earlier at 2 months compared to 6-10 months with CRA and AT alone and did not alter survival. There was no increase in the risk for leukemia in the group treated with rHuEPO. Response to either therapy appeared to be limited to patients in the early stages of MDS.

Topics: Aged; Anemia; Erythropoietin; Female; Humans; Isotretinoin; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Recombinant Proteins; Treatment Outcome; Vitamin E

To evaluate the effect of recombinant human erythropoietin (rHuEpo) on the haemoglobin level and transfusion requirement in low-risk myelodysplastic syndromes (MDS), 87 patients were enrolled in a randomized double-blind placebo-controlled study, 44 patients were assigned to epoetin alpha (150 U/kg/d s.c. for 8 weeks) and 43 to placebo arms. MDS types were homogenous in both groups: refractory anaemia (RA) 47.7-48.8%. refractory anaemia with ringed sideroblasts (RAS) 20.5-25.6%, refractory anaemia with excess of blasts (RAEB) (blasts < 10%) 31.8-25.6%, 14/38 evaluable patients responded to epoetin alpha versus 4/37 to placebo (P=0.007). 50% of RA responded to epoetin alpha versus 5.9% to placebo (P=0.0072), RAS 37.5% v 18.2% (P=0.6) and RAEB 16.7% v 11.1% (P=1.00). 60% of non-pretransfused patients responded to epoetin alpha (Hb 8.35< or = 0.73 to 10.07+/-1.87 g/dl), whereas a slight decrease was observed in the placebo group (8.4+/-0.66 to 8.19+/-0.92 g/dl) (P=0.0004). Percentage of transfused patients was similar in both arms. Basal erythropoietin (Epo) serum levels > 200 mU/l predicted for a non-response. At week 4 sTfR levels were increased > 50% in responders (P=0.013), whereas an increase < 18% predicted for non-response (P=0.006). Leucocyte and platelet counts were not influenced by epoetin alpha treatment. Adverse events occurred in 31.8% of the rHuEpo-treated versus 42.99%) of the placebo-treated patients (P=0.2), and seven patients did not complete the course. In conclusion, rHuEpo was effective in the treatment of low-risk MDS. RA subtype, no transfusions prior to rHuEpo therapy, and low basal Epo levels were associated with higher probability of response. Soluble transferrin receptor level at the fourth week was an early predictor of response.

Topics: Adult; Aged; Double-Blind Method; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Risk Factors

The efficacy and safety of recombinant human erythropoietin (rhEPO) were tested when given subcutaneously (s.c.) in an escalating dose of 2000-10,000 units (U) daily in 60 patients with cancer-related anaemia (CRA). A positive response, defined as an increase in haemoglobin more than 2 g/dl and independence of blood transfusions was observed in 23 of 48 evaluable patients (48%) within a median of 8 wk. In detail, rhEPO corrected anaemia in 11 of 14 patients (79%) with malignant lymphoma, in 8 of 15 patients (53%) with multiple myeloma and in 4 of 10 patients (40%) with a solid tumour. The median dose of rhEPO in successful cases was 5000 U daily. Four patients with agnogenic myeloid metaplasia and 5 with myelodysplastic disorder failed to respond to rhEPO. No patient had any severe side effects. Pretreatment serum erythropoietin levels appeared to be a weak predictor for response to rhEPO treatment. In conclusion, rhEPO seems to be safe and effective in correcting CRA in certain groups of patients.

Topics: Adolescent; Adult; Aged; Anemia; Blood Transfusion; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Lymphoma; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Neoplasms; Primary Myelofibrosis; Recombinant Proteins; Reticulocyte Count; Transferrin

A study of bone marrow morphology and apoptosis was undertaken in 51 patients with myelodysplastic syndromes (MDS) treated with granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO). In 19 of these patients (37%), a significant improvement in the hemoglobin level was found after treatment. Apoptosis was measured using a nick-end labeling (TUNEL) technique. Patients with MDS had a significantly higher percentage of labelled (apoptotic) cells in the bone marrow compared to healthy individuals (56.3 +/- 3.8% vs. 16.2 +/- 1.4%, p = 0.0001). Patients with RAS showed a lower percentage of apoptotic cells than patients with RA (68.5 +/- 9% vs. 46.5 +/- 4.8%, p < 0.05), while patients with RAEB did not differ significantly from either RA or RAS. In the patients who responded to treatment, the bone marrow samples displayed significant morphological changes. The percentages of erythroid precursors and myeloblasts were reduced after treatment, and patients who had ring sideroblasts before treatment also showed a reduction in the percentage of these cells. Total erythroid index also decreased in responding patients. The percentage of apoptotic cells decreased significantly in responding patients (58.8 +/- 4.8% before treatment vs. 44.5 +/- 5.5% after treatment, mean reduction 18.3%, p = 0.0003), whereas no significant change was found in non-responding patients. Our results suggest that one important mechanism behind the positive effects of treatment with G-CSF and EPO is a reduction in the degree of ineffective hematopoiesis in MDS.

Topics: Apoptosis; Bone Marrow; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Male; Myelodysplastic Syndromes; Retrospective Studies

We measured pretreatment serum levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in 25 patients with myelodysplastic syndrome receiving recombinant human erythropoietin (rhEPO) at dosages up to 300 U/kg thrice weekly for 12 weeks. Both TNF-alpha and IL-1 beta levels were measured using commercially available enzyme-linked immunoassays. A complete response (CR) was defined as a rise in untransfused haemoglobin concentrations of at least 2 g/dl or a 100% decrease in RBC transfusion requirements over the treatment period; a partial response (PR) was an increase in untransfused haemoglobin values of 1-2 g/dl or a decrease in RBC transfusion requirements equal to or greater than 50%; no response (NR) was defined as a response less than a PR. After 12 weeks of rhEPO treatment, four patients showed a CR, five patients a PR, and 16 patients NR. Serum levels of both TNF-alpha (80.5 %/- 64.8 vs 8.1 +/- 4.2 ng/l, P < 0.001) and IL-1 beta (60.4 +/- 49.9 vs 8.9 +/- 4.7 ng/l, P < 0.001) were higher in MDS patients than in a group of 28 normal controls. Responders (CR + PR) showed significantly lower serum levels of TNF-alpha than non-responders (21.6 +/- 26.2 vs 106.3 +/- 60.8 ng/l, P < 0.001), whereas IL-1 beta concentrations between those who benefited from therapy and unresponsive cases were not significantly different (39.8 +/- 48.9 vs 73.4 +/- 48.2 ng/l, P = 0.120). It is noteworthy that TNF-alpha levels were within the normal range in all responsive patients but one, whereas all non-responders presented elevated cytokine concentrations. No relationship was found between TNF-alpha or IL-1 beta values and haemoglobin levels, transfusion requirement, serum EPO or ferritin concentrations. We conclude that pre-treatment TNF-alpha levels might help to select those MDS patients who are most likely to benefit from rhEPO treatment.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Interleukin-1; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins; Treatment Outcome; Tumor Necrosis Factor-alpha

Previous studies have shown that approximately 40% of patients with myelodysplastic syndrome (MDS) and anaemia respond to treatment with human recombinant granulocyte-CSF (G-CSF) plus erythropoietin (epo). The present study was designed to investigate pre-treatment variables for their ability to predict erythroid responses to this treatment. 98 patients with MDS (30 RA, 31 RARS, 32 RAEB, five RAEB-t) were treated with a combination of G-CSF (0.3-3.0 microg/kg/d, s.c.) and epo (60-300 U/kg/d, s.c.) for at least 10 weeks. Minimum criteria for erythroid response was a 100% reduction of red blood cell (RBC) transfusion need or an increase in haemoglobin level of > or = 1.5 g/dl. 35 patients (36%) showed responses to treatment. Medium duration of response was 11-24 months. In multivariate analysis, serum erythropoietin levels and initial RBC-transfusion need retained high statistical significance (P < 0.01). Using pre-treatment serum epo levels as a ternary variable (< 100, 100-500 or > 500 U/l) and RBC transfusion need as a binary variable (< 2 or > or = 2 units per month), the analysis provided a predictive score for erythroid response. This score divided patients into three groups: one group with a high probability of erythroid responses (74%), one intermediate group (23%) and one group with poor responses to treatment (7%). This predictive scoring system could be used in decisions regarding use of these cytokines for treating the anaemia of MDS, both for defining patients who should not be given the treatment and for selecting patients for inclusion in prospective trials.

Topics: Aged; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Forecasting; Granulocyte Colony-Stimulating Factor; Humans; Leukocyte Count; Male; Multivariate Analysis; Myelodysplastic Syndromes; Neutrophils; Treatment Outcome

Recombinant human erythropoietin (rhEPO) at pharmacological doses was used to improve anemia and reduce the transfusional requirements of 43 patients with myelodysplastic syndrome (MDS). rhEPO was given by s.c. injection three times per week for 12 weeks. The EPO dose was started at 150 IU/kg and was increased to 300 IU/kg if after 6 weeks there was no or suboptimal erythroid response. Responses were defined as being a complete response (CR), partial response (PR), or no response (NR). A CR was considered a rise in untransfused hemoglobin concentrations of at least 2 g/dl or a 100% decrease in RBC transfusion requirements over the treatment period. A PR was defined as an increase in untransfused hemoglobin values of 1-2 g/dl or a decrease in RBC transfusion requirements equal to or greater than 50%. NR was defined as responses less than a PR. Patients who responded to therapy were continued on rhEPO at the same dose for 6 additional months. An objective response (CR and PR) was observed in 7 of 42 (16.7%) assessable cases after 6 weeks of treatment at the dose of 150 IU/kg. Dose escalation (300 IU/kg) in nonresponders resulted in another six patients attaining a rise in hemoglobin concentrations. The final response rate was 13 of 41 (31.7%); 4 patients became transfusion independent. Therapy was tolerated well, with no relevant side effects. MDS progression was seen in one case. An elevated bone marrow erythroid infiltration (erythroid index) and detectable pretreatment circulating erythroid progenitors (burst-forming units-erythroid) were the best predictors of hemoglobin response when we controlled for other variables. These data suggest that rhEPO has a role in the treatment of certain patients with MDS, particularly in those with a high erythroid index and detectable circulating erythroid burst-forming units.

Topics: Adult; Aged; Aged, 80 and over; Blood Transfusion; Bone Marrow; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Time Factors

Differentiation induction therapy is being tested in myelodysplastic syndromes to ameliorate maturation defects and to restore normal hematopoietic function. To this end, 17 patients (eight with refractory anemia, two with refractory anemia and ring sideroblasts, and seven with refractory anemia and excess of blast cells) were treated with a combination of all-trans-retinoic acid (ATRA), granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and alpha-tocopherol for durations of 8-16 weeks. Absolute neutrophil counts increased in all patients; platelet counts increased in five patients with discontinuation of transfusion needs in two of four transfusion-dependent patients. Stimulation of erythropoiesis was seen in eight patients with an increase in hemoglobin concentration in three, a discontinuation of transfusion requirements in another three, and a significant increase in reticulocyte counts as the only parameter in two patients. Clinically important multilineage responses with increases of hemoglobin levels or discontinuation of transfusion needs were thus seen in six patients (35.3%) with three patients having a trilineage response. Serum erythropoietin concentrations did not differ significantly between responders and nonresponders, but the erythroid response was accompanied by a rise in the serum transferrin receptor levels. In the bone marrow, the myeloid-to-erythroid ratio and the maturation index of myeloid cells increased during therapy, while the percentage of blast cells did not change. Cytogenetic analysis demonstrated the persistence of the abnormal clones. Prior to therapy, nonresponders had a significantly higher serum TNF level than responders. Serum concentrations of TNF-alpha and soluble TNF-alpha receptor significantly increased during therapy, but mainly in the patients without an erythroid and platelet response. Soluble IL-2 receptor and soluble ICAM-1 concentrations both increased. This pilot study demonstrates that treatment with ATRA/G-CSF/EPO/tocopherol is well tolerated, leading to normalization of neutrophil counts in most, and to improvement of platelets and red blood cells in a significant subgroup of patients.

Topics: Adult; Aged; Aged, 80 and over; Blood Cell Count; Bone Marrow; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Tretinoin; Vitamin E

One hundred and sixteen (116) anaemic patients with myelodysplastic syndromes (MDS) were treated with recombinant human erythropoietin (r-HuEpo) in an open-label, multicentre, compassionate treatment trial; 100 patients received therapy for > or = 4 weeks and were evaluable for efficacy. The distribution of FAB subtypes was: 44 RA, 40 RARS, eight RAEB, two RAEB-t, one CMML, and five not specified. Mean baseline haematocrit was 24.5%, and the mean prestudy transfusion requirement in the 12 weeks immediately prior to study entry was 6.5 units. r-HuEpo treatment was initiated at a dose of 150 U/kg three times weekly, with dose escalations of 50 U/kg monthly (up to 300 U/kg 3x/week) permitted if the haematocrit failed to rise. Response to therapy was defined as either an increase in haematocrit of > or = 6 percentage points over baseline, unrelated to transfusion, or a > or = 50% decrease in transfusion requirement in the last 3 months of study treatment, compared to the baseline period (12 weeks). By these criteria, 28% (28/100) of patients responded to r-HuEpo treatment. Overall, 86% (24/28) of patients responding to therapy had baseline Epo levels < or = 100 mU/ml. Response rates by FAB subtype were: RA 39% (17/44), RARS 17.5% (7/40) and RAEB 12.5% (1/8). Additionally, a 54% (15/28) response rate was seen in RA patients with baseline Epo levels < or = 100 mU/ml. Responses to therapy were durable and generally occurred at r-HuEpo doses of 150-200 U/kg t.i.w. There were no reports of thrombosis, seizures or therapy-related hypertension. The data show that patients with MDS, especially those with the RA and RARS subtypes, can benefit from treatment with r-HuEpo. Those patients with baseline Epo levels < or = 100 mU/ml were most likely to respond to therapy.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Treatment of myelodysplastic syndromes (MDS) with recombinant human erythropoietin (Epo) is successful in only 10% to 25% of patients. We performed a pilot study in 10 anaemic patients with MDS to examine whether sequentially applied recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and Epo improves haemoglobin levels and/or reduces red blood cell transfusion requirements. Morphological diagnoses of patients were refractory anaemia (RA) in 3 cases, RA with ring sideroblasts in 3 cases and RA with excess blasts in 4 cases. GM-CSF was given subcutaneously at a dose of 150 micrograms/m2/d during the initial 10 days. From day 11, Epo was administered by subcutaneous injections for 8 weeks at a dose of 100 U/kg/d and subsequently at an escalated dose of 200 U/kg/d in 3 patients. Changes in reticulocyte counts, haemoglobin levels, RBC support and ferrokinetic parameters were compared with pretreatment values. Two out of 8 evaluable patients showed a rise in haemoglobin levels at week 8 and 10, respectively, and lost their transfusion dependency for a period of 13 and 27 weeks. In 1 patient, haemoglobin level increased only after dose escalation of Epo (200 U/kg/d). Leukocyte counts remained uneffected by treatment with Epo, while 1 patient showed a 4-fold increase in platelet numbers. Toxicity was mild. Two patients died of pneumonia and global heart failure, respectively, unrelated to growth factor therapy. Based on this pilot study, we conclude that sequential treatment with GM-CSF and Epo does not increase erythroid responses in anaemic patients with MDS. Because of the delayed increase in haemoglobin in both responders, we surmise that the beneficial effects were induced by Epo alone.

Topics: Adult; Aged; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Platelet Count; Recombinant Proteins

We conducted a Phase I-II trial of recombinant human erythropoietin-beta (rhEPO) in patients with myelodysplastic syndrome (MDS). Patients with anemia and pathologically confirmed MDS were eligible for the study. Treatment consisted of rhEPO by subcutaneous injection thrice weekly for 6 weeks at one of three dose levels (100 U/kg (three patients), 200 U/kg (three patients) and 400 U/kg (14 patients)). Ferrous sulfate (325 mg po tid) was also administered if the transferrin saturation was below 30% (two patients). Patients were monitored with weekly CBC, white cell differential, and reticulocyte counts. Bone marrow examinations were performed at the conclusion of the treatment period and after a 2 week washout period. Patients who responded to therapy were continued on rhEPO at the same dose for 6 additional months. Response criteria included: 50% reduction in transfusion requirements compared with the 6 week pre-study period; doubling of reticulocyte count that was maintained on two determinations at least 1 week apart; or an increase in hemoglobin by at least 1.2 gm/dl without transfusions. Pre-treatment factors potentially predictive of response were analyzed by univariate analysis and in a multivariate fashion by classification and regression trees. Seven of the twenty patients sustained an untransfused rise in serum hemoglobin > or = 1.2 gm/dl. Four of the sixteen patients (including three of seven patients experiencing a rise in serum hemoglobin) who were transfusion-dependent prior to the study achieved a reduction or elimination of their transfusion requirements. Five of thirteen patients who received rhEPO during the extension phase had a continued response. A low baseline erythropoietin level (< 50 mU/ml) was the best predictor of hemoglobin response when controlling for other variables. rhEPO has a role in the treatment of certain patients with MDS, particularly in those whose endogenous serum erythropoietin levels are not markedly elevated.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

To evaluate the efficacy of subcutaneous erythropoietin (r-huEPO) in patients with myelodysplastic syndrome (MDS) requiring periodical blood transfusion.. The study was performed on 9 MDS patients distributed as follows: 4 with refractory anaemia, 2 with refractory anaemia with ringed sideroblasts, 2 with chronic myelomonocytic leukaemia and 1 with refractory anaemia with excess blasts in transformation. All the patients had been diagnosed at least three months earlier and had a mean monthly transfusion requirement of 3.5 blood units (range, 2-5.3). Baseline serum EPO levels were assessed by ELISA, subcutaneous r-huEPO was given at a doses of 10,000 IU three times a week. A positive response was defined as increase of haemoglobin rates in 1 g/dL or decrease of transfusion requirements in 50%. A negative response was registered when the haemoglobin rates or transfusion requirements were maintained in the patient. The results were evaluated 4,6 and 12 weeks after the beginning of the treatment.. Response to treatment was seen in five patients (56%), who showed increased haemoglobin rates and in four of them (45%) no transfusions were needed since the onset of this therapy. The positive response to r-huEPO appeared within the 4th week of treatment. The four unresponsive patients (44%) showed no changes in spite of prolonged treatment. Positive responses correlated with increased red-cell progenitors in the bone marrow and decreased myelo/erythroid ratio. No severe untoward effects were seen with this treatment, and mild local pain at the sites of injection was alleviated by warming the r-huEPO solution before administration.. MDS with symptomatic anaemia can be initially treated with r-huEPO for 4 weeks, although it seems advisable to maintain this treatment in respondents until the maximal response has been attained. On the contrary, when no response is seen in that period treatment must be discontinued.

Topics: Aged; Aged, 80 and over; Anemia; Blood Pressure; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Female; Ferritins; Humans; Immunologic Factors; Injections, Subcutaneous; Iron; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Transferrin; Treatment Outcome

We treated myelodysplastic syndrome patients (MDS) with both recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human erythropoietin (EPO) to determine whether such combination therapy resulted in improvement of their anemias. Twenty-four of 28 patients begun on study completed the protocol and were evaluable for erythroid responses. Therapy was initiated with G-CSF at 1 micrograms/kg administered by daily subcutaneous injection and adjusted to either normalize or double the neutrophil count. EPO was then administered by daily subcutaneous injection at a dose of 100 U/kg and dose-escalated to 150 and 300 U/kg every 4 weeks while continuing the G-CSF. Changes in absolute reticulocyte count, hematocrit level, and need for RBC transfusions were compared with pretreatment values as well as other blood cell counts. Ten of 24 patients (42%) had erythroid responses, whereas all patients had neutrophil responses. Six previously transfused patients no longer required RBC transfusions during the treatment period. Erythroid responses were found to be independent of patient age, French-American-British subtype, duration of disease, prior RBC transfusion requirements, or cytogenetic abnormalities at presentation. Pretreatment serum EPO levels were lower in erythroid-responding as compared with nonresponding patients (median 157 v 600 U/L; P = .05). The combined treatment modality was generally well tolerated. We conclude that a substantial percentage of MDS patients had both erythroid and myeloid responses when treated with the combination of G-CSF and EPO.

Topics: Adult; Aged; Anemia; Drug Combinations; Erythropoiesis; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

The safety and efficacy of recombinant human erythropoietin (epoetin alpha) were investigated in anemic patients with myelodysplastic syndrome (MDS) whose hemoglobin (Hb) concentration was less than 10g/dl. Epoetin alpha was given subcutaneously daily at a dose of 3,000IU/body for two weeks and the dosage was increased to 6,000IU, 12,000IU, and 24,000IU at two week interval when the increment of Hb was insufficient. Patients in whom the Hb concentration increased by more than 1g/dl or whose blood transfusion requirement reduced to below 50% were considered to be cases of effective treatment. The overall rate of effectiveness was 20.6% (7/34). Response to epoetin alpha treatment was better in patients with refractory anemia (RA) or RA with ringed sideroblasts (RARS). The high dose epoetin alpha (12,000-24,000IU/body/day) was required for the patients to respond. These results suggest that the high dose subcutaneous epoetin alpha treatment is effective for the anemia associated with MDS in terms of increasing Hb concentration and reducing blood transfusion.

Topics: Adolescent; Adult; Aged; Anemia; Erythropoietin; Hemoglobins; Humans; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Sixteen patients (ages 53 to 85) with myelodysplastic syndrome (MDS) were treated with recombinant human erythropoietin (rHuEPO) to observe its effects on hematopoiesis. All were transfusion dependent and had Hb levels less than 9.0 g/dl and less than 10% marrow blasts. Eight patients had refractory anemia (RA), one had refractory anemia with excess blasts (RAEB), and seven had refractory anemia with ringed sideroblasts (RARS). A response was defined as an increase in Hb by greater than 2 g/dl and/or a decrease in transfusion requirement by greater than 50%. Patients were considered to be evaluable if on study greater than two months. Three of thirteen evaluable patients had a response. One patient with RA had a sustained trilineage hematologic response with no evidence of disease progression. None of the patients had trouble with hypertension or with thrombotic events. This suggests than an occasional patient with MDS will respond to rHuEPO. In some patients, this may be beneficial clinically.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Bone Marrow; Drug Tolerance; Erythropoietin; Hematopoiesis; Humans; Middle Aged; Myelodysplastic Syndromes

As the importance of recombinant human erythropoietin (r-HuEPO) therapy has been clearly demonstrated in anaemic patients with chronic renal failure (CRF), we carried out an open, non-randomized, non-placebo-controlled trial of high-dose intravenous (i.v.) r-HuEPO (100,000 U twice weekly) therapy in 14 anaemic, transfusion-dependent patients. Clinical response was defined by a rise in haemoglobin concentration to 9-11 g/dl and/or a reduction in the transfusion requirement during the treatment period compared with the 12 weeks before treatment. Eight patients completed the 12-week treatment and 4 were still under treatment, 1 at 10 weeks, 2 at 8 weeks and 1 at 4 weeks. Only those patients completing treatment were included in the efficacy evaluation. After treatment there was no significant change in haemoglobin concentrations, reticulocyte counts, or transfusion requirements. However, the number of patients included is too low to allow any definitive conclusion to be made.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.

Topics: Adult; Aged; Anemia, Refractory; Bone Marrow; Drug Evaluation; Erythroid Precursor Cells; Erythropoietin; Female; Ferritins; Hematologic Diseases; Humans; Iron; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Lymphoproliferative Disorders; Male; Middle Aged; Myelodysplastic Syndromes; Primary Myelofibrosis; Receptors, Transferrin; Recombinant Proteins

We have conducted several phase I/II clinical studies in a total of 65 MDS patients utilizing recombinant human hematopoietic growth factors including GM-CSF, IL-3, and EPO. Twenty-seven patients with MDS were treated with either continuous i.v. infusion or single daily s.c. injection of rhGM-CSF at dosages from 15 micrograms/m2 to 1000 micrograms/m2. All of them exhibited white cell responses during the treatment cycles, but no sustained rise in reticulocytes or platelets was recorded. In four of the patients, all with > or = 15% blast cells in the bone marrow, the percentage of circulating blast cells increased during treatment with rhGM-CSF (at dosages of 500 micrograms/m2 and 1000 micrograms/m2, respectively), although no leukemic conversion occurred. Of 9 patients treated so far with rhIL-3 at single daily s.c. dosages of 60 micrograms/m2, all exhibited white cell responses; 8 exhibited significant improved platelet and reticulocyte counts. Nineteen further patients received rhEPO for a period of 14 weeks by s.c. (10,000 U five times weekly) or i.v. bolus administration (150-450 U/kg). None of these patients experienced an increase in white cell and platelet counts. A significant increase of the reticulocyte count was recorded in 3 patients only. Another strategy involves the recruitment of leukemic cells into the cell cycle by hematopoietic growth factors followed by treatment with cycle-specific cytostatic agents. Therefore in 10 patients administration of rhGM-CSF (250 g/m2/day x 14, s.c.) was combined with Ara-C treatment (20 mg/m2/day x 14; s.c.). Initial results of this pilot study available in 5 patients indicated that this approach may control leukemic cell proliferation and may increase number of mature myeloid cells in both bone marrow and peripheral blood. A similar approach utilizing rhIL-3 in conjunction with Ara-C is on-going.

Topics: Blood Cell Count; Cytarabine; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; Interleukin-3; Myelodysplastic Syndromes; Recombinant Proteins

Twenty patients with myelodysplastic syndromes (MDS) entered a randomized, placebo-controlled, double-blind trial designed to evaluate the efficacy and toxicity of high doses of recombinant human erythropoietin (rhEPO). Patients completing the trial were eligible to receive rhEPO as part of an open-label study. Eighteen patients were transfusion dependent; 10 had refractory anemia (RA), and 10 had refractory anemia with ringed sideroblasts (RARS). A response to rhEPO was defined as an increase in hematocrit of 4 percentage points or more over baseline, or the elimination of all transfusions with the hematocrit stable at the baseline level. In the double-blind trial, 1 patient (12.5%) receiving rhEPO responded, as compared with no responses in the placebo group. Overall, responses occurred in 4 of 17 patients (24%) receiving rhEPO at a dose of 1,200 to 1,600 U/kg intravenously (IV) twice weekly. Changes in granulocyte or platelet counts were not observed. Despite the administration of high doses of rhEPO, toxicity attributable to rhEPO was not observed in either the double-blind or open-label study. Response to rhEPO was not significantly related to age, gender, type of MDS, time since diagnosis, time since initiation of transfusion therapy, or baseline serum EPO. These studies indicate that rhEPO can be administered safely in very high doses to patients with MDS and that 24% of these patients will respond with increased erythropoiesis.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Double-Blind Method; Erythropoietin; Female; Hematocrit; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Placebos; Recombinant Proteins

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: Adult; Aged; Aged, 80 and over; Anemia; Anemia, Aplastic; Blood Transfusion; Erythrocyte Indices; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Patients with myelodysplastic syndromes and ring sideroblasts (MDS RS) are clinically characterized by severe anemia and transfusion need. Erythropoiesis-stimulating agents (ESAs), which stimulate hemoglobin production and early maturation of erythroid precursors, are effective only in a portion of patients and for limited time. Luspatercept, an inhibitor of the TGF-beta pathway, is beneficial in unblocking late-stage erythropoiesis and has been approved for MDS RS patients failing or not-candidate to ESAs. ESAs and/or luspatercept failure represents an unmet clinical need and most patients become life-long transfusion dependent. Here, we describe the clinical combination of luspatercept with ESAs (subcutaneous epoetin alpha 40-80 000 IU/week) in seven MDS RS patients. Two patients had ESAs as pre-existing therapy, while five were re-challenged with ESAs as add-on treatment due to luspatercept failure. Three patients achieved hematologic improvement, and one became transfusion independent. No adverse events were noted. This is the first clinical evidence that stimulating both early and late-stage erythropoiesis may offer a further option for this challenging patient population.

Topics: Erythropoiesis; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Fusion Proteins; Recombinant Proteins

This study was undertaken to evaluate the long-term clinical efficacy of epoetin alfa and darbepoetin alfa in patients with myelodysplastic syndrome (MDS) in a real-life setting.. A total of 204 patients with low-risk or intermediate-1-risk MDS who received epoetin alfa or darbepoetin alfa were included. Hemoglobin levels and transfusion needs were recorded before treatment and at 12 months, 24 months, 36 months, and 48 months of treatment.. At the 36-month (p=0.025) and 48-month (p=0.022) visits, epoetin alfa yielded significantly higher hemoglobin levels compared to darbepoetin alfa. Transfusion needs were also significantly lower with epoetin alfa compared to darbepoetin alfa at 24 months (p=0.012) and in the low-risk group compared to the intermediate-risk group at 24 months (p=0.018), 36 months (p=0.025), and 48 months (p<0.001). Treatment response rates at the 24-month, 36-month, and 48-month visits in the epoetin alfa (43.0%, 33.6%, and 27.1%), darbepoetin alfa (29.9%, 22.7%, and 16.5%), low-risk (39.3%, 30.0%, and 26.0%), and intermediate-risk (29.6%, 24.1%, and 11.1%) groups were lower than those obtained at 12 months, and the values differed significantly for the 36-month and 48-month visits with values ranging from p<0.05 to p<0.001.. This real-life long-term ESA extension study investigated the clinical efficacy of epoetin alfa and darbepoetin alfa for up to 48 months, revealing that treatment efficacy reached a plateau starting from the 24. Myelodisplastik sendromlu (MDS) hastalarda epoetin alfa ve darbepoetin alfa tedavisinin gerçek yaşam ortamında uzun-dönem klinik etkinliğini değerlendirmek.. Bu çalışmaya düşük veya orta-1 risk grubu MDS tanısı ile epoetin alfa veya darbepoetin alfa tedavisi almış 204 hasta dahil edildi. Hemoglobin düzeyleri ve transfüzyon gereksinimi, tedaviden önce ve tedavinin 12., 24., 36. ve 48. aylarında değerlendirildi.. Epoetin alfa, darbepoetin alfa ile kıyaslandığında, 36. ay (p=0,025) ve 48. aylarda (p=0,022) anlamlı şekilde daha yüksek hemoglobin düzeylerini sağladı. Transfüzyon gereksinimi 24. ayda (p=0,012) epoetin alfa grubunda darbepoetin alfa grubuna göre, 24. ay (p=0,018), 36. ay (p=0,025) ve 48. aylarda (p<0,001) ise düşük risk grubunda orta risk grubuna göre anlamlı şekilde daha düşük olarak bulundu. Tedavi yanıt oranları 24. ay, 36. ay ve 48. aylarda epoetin alfa (%43,0, %33,6 ve %27,1), darbepoetin alfa (%29,9, %22,7 ve %16,5), düşük risk (%39,3, %30,0 ve %26,0) ve orta risk (%29,6, %24,1 ve %11,1) gruplarında 12. ay yanıt oranlarına göre daha düşük olup, 36. ve 48. aylarda bu değişim istatistiksel olarak anlamlı idi (p<0,05 ile <0,001 arası).. Epoetin alfa ve darbepoetin alfanın 48 aylık klinik etkililiğinin değerlendirildiği bu gerçek-yaşam uzun-dönem ESA çalışmasında, tedavi etkililiğinin tedavinin 24. ayından başlayarak plato evresine eriştiği ve devamında tedavi yanıt oranlarında, tedavi tipi, risk durumu veya cinsiyetten bağımsız olarak süregiden bir düşüşün gerçekleştiği saptandı. Bununla birlikte, epoetin tedavisi alan grupta darbepoetin ile tedavi edilen gruba göre ve düşük risk grubu hastalarda orta risk grubu hastalara göre, hemoglobin düzeyleri anlamlı şekilde daha yüksek olup, transfüzyon gereksiniminde de belirgin azalma olduğu tespit edildi.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Few effective therapies are available to treat patients with relapsed/refractory myelodysplastic neoplasms (MDS). Luspatercept was shown to display good efficacy in a phase 3 clinical trial for lower-risk MDS (LR-MDS) patients, yet real-world data are limited, especially in China. Therefore, data from patients diagnosed as having MDS with low blasts and SF3B1 mutation (MDS-SF3B1) and MDS with SF3B1 mutation and thrombocytosis were retrospectively analyzed. Of the 23 enrolled patients, 17 (73.9%) were males (median age 67 years: range 29 to 80 years). Previously, a total of 22 (95.7%) patients had received recombinant human erythropoietin (rhEPO), 9 (39.1%) roxadustat, 7 (30.4%) lenalidomide and 3 (13.0%) hypomethylating agents (HMA). The median treatment time was 22.9 weeks (9.0-32.4). At week 12, 60.9% (14/23) of the patients achieved a hematologic improvement-erythroid (HI-E) response. Red blood cell transfusion independence (RBC-TI) for ≥ 8 weeks was found in 57.1% (8/14) of transfusion-dependent patients. The median hemoglobin concentration was 84 g/L, and patients had significantly higher hemoglobin concentrations after 12 weeks of treatment (P < 0.001). It is noteworthy that responders had a greater reduction in serum ferritin (P = 0.021). Those with serum EPO < 500 IU/L at baseline tended to have a higher HI-E rate (P = 0.081), but only patients in non-transfusion and low transfusion burden (LTB) subgroups had statistical differences (P = 0.024). The most commonly occurring adverse events were blood bilirubin increase (17.4%), fatigue (13.0%) and dizziness (13.0%). Luspatercept was effective and tolerated well in refractory LR-MDS-SF3B1 patients. In particular, baseline non-transfusion and LTB patients exhibited a greater response rate to treatment.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins; Retrospective Studies

Anemia is a common condition, but its causes are often unclear, especially in elderly adults. Erythropoietin (EPO) levels are known to be elevated in myelodysplastic syndrome and hematologic malignancies, but decreased in chronic benign anemia. This study aimed to investigate whether EPO levels could be used to identify underlying bone marrow diseases including malignancies, among elderly anemic patients with unclear etiology. This single centered retrospective study included patients presented with isolated anemia and had their EPO levels measured at their first visit. Patients were divided into two groups: bone marrow disease and benign etiologic anemia, based on observation and bone marrow test results. Out of 1180 patients reviewed, 81 patients with anemia of unclear etiology were identified, including 67 with benign anemia and 14 with bone marrow disease. Statistically significant difference in EPO levels between these two groups (P < 0.001) were observed. The receiver operating characteristic curve analysis showed that an EPO cut-off value of 36.4 mU/mL had a sensitivity and specificity of 92.8% and 94.0% for detecting underlying bone marrow disease, respectively. We suggest measuring serum EPO levels can aid in the early detection of benign anemia from bone marrow disease, including malignancies, with high sensitivity and specificity.

Topics: Adult; Aged; Anemia; Erythropoietin; Humans; Myelodysplastic Syndromes; Neoplasms; Retrospective Studies

Darbepoetin alfa (DA) is used to treat anemia in lower-risk (IPSS low or int-1) myelodysplastic syndromes (MDS). However, whether mutations can predict the effectiveness of DA has not been examined. The present study aimed to determine predictive gene mutations. The primary endpoint was a correlation between the presence of highly frequent (≥ 10%) mutations and hematological improvement-erythroid according to IWG criteria 2006 by DA (240 μg/week) until week 16. The study included 79 patients (age 29-90, median 77.0 years; 52 [65.8%] male). Frequently (≥ 10%) mutated genes were SF3B1 (24 cases, 30.4%), TET2 (20, 25.3%), SRSF2 (10, 12.7%), ASXL1 (9, 11.4%), and DNMT3A (8, 10.1%). Overall response rate to DA was 70.9%. Multivariable analysis including baseline erythropoietin levels and red blood cell transfusion volumes as variables revealed that erythropoietin levels and mutations of ASXL1 gene were significantly associated with worse response (odds ratio 0.146, 95% confidence interval 0.042-0.503; p = 0.0023, odds ratio 0.175, 95% confidence interval 0.033-0.928; p = 0.0406, respectively). This study indicated that anemic patients who have higher erythropoietin levels and harbor ASXL1 gene mutations may respond poorly to DA. Alternative strategies are needed for the treatment of anemia in this population. Trial registration number and date of registration: UMIN000022185 and 09/05/2016.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Humans; Male; Middle Aged; Mutation; Myelodysplastic Syndromes; Repressor Proteins

Topics: Biomarkers; Chromosome Deletion; Chromosomes, Human, Pair 5; Erythropoietin; Humans; Lenalidomide; Myelodysplastic Syndromes

Erythropoiesis stimulating agents (ESAs) represents the principal treatments for anemia in patients with lower-risk myelodysplastic syndromes (MDS). Pre-treatment erythropoietin (EPO) level and previous blood transfusion requirement are the two major predictors for response to ESAs. However, most evidence was derived from Western countries whereas there have been limited data in patients with Asian background.. We retrospectively collected data on patients with low-risk MDS who received ESAs. Erythroid response was evaluated according to IWG 2006 criteria. MDS subtypes, r-IPSS, baseline hemoglobin (Hb), ESAs dosage and erythropoietin level were reviewed from medical records. Gene mutations were analyzed in patients' blood or bone marrow at diagnosis by 40-gene myeloid panel targeted sequencing. Clinical and laboratory parameters were compared between erythroid responder and non-responder groups.. A total of 47 patients were recruited in the study. The median age at diagnosis of the patients in this cohort was 77 years (IQR, 70-83) and 44.7% were male. The median revised international prognostic scoring system (R-IPSS) score of patients was 2.5. Response rate to ESAs was 46.8% (22/47). Median EPO level in responders was significantly lower than non-responders (27.7 vs. 59.1 U/L, p=0.02). Median ESAs dosage in responder group was 30,000 units per week. Cytogenetic abnormalities were detected in 27.3% and 24% of the responder and non-responder groups, respectively. Of 22 patients with available 40 gene mutation targeted sequencing, ASXL1, IDH2 and TET2 represented the 3 most common mutations and were found in 22%, 22% and 17%, respectively. There were no differences in cytogenetic abnormalities and gene mutations between groups. Patients who responded to ESAs showed a higher 5-year overall survival (OS) compared to non-responders (5-year OS 75% vs. 60.9%; p=0.008).. We conclude that a low serum EPO level is a predictive factor for responsiveness to ESAs in Asian patients with low-risk MDS.

Topics: Aged; Aged, 80 and over; Anemia; Asian People; Blood Transfusion; Chromosome Aberrations; Dioxygenases; DNA-Binding Proteins; Erythropoietin; Female; Hematinics; Humans; Isocitrate Dehydrogenase; Male; Mutation; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis; Repressor Proteins; Retrospective Studies; Survival Rate

The first-line therapy for patients with low-risk myelodysplastic syndromes (MDSs) commonly consists of erythropoietin stimulating agents (ESAs), with a response rate ranging from 34 to 62%. For nonresponder patients, outside clinical trials, blood transfusions are the most frequent therapeutic option, with detrimental effect on the quality of life and with risks of iron-overload. Since no studies have been yet conducted on this topic, we investigated the potential predictive role of bone marrow (BM) histological evaluation in patients treated with ESAs.. We performed a morphological and immunohistochemical retrospective analysis of BM biopsies of 96 patients with low-risk MDSs subsequently treated with ESAs.. In our series, substantial morphological overlap was found between responder and nonresponder patients. On the contrary, patients with a percentage of CD34-positive blasts >3% or with p53 protein expression <1% responded with a significantly higher frequency to ESAs.. Our study reinforces the role of BM biopsy as diagnostic tool in MDSs, being also able to supply information related to response to ESAs and to its loss over time.

Topics: Antigens, CD34; Biopsy; Blood Cell Count; Bone Marrow; Bone Marrow Cells; Erythropoietin; Female; Humans; Immunohistochemistry; Male; Myelodysplastic Syndromes; Retrospective Studies; Tumor Suppressor Protein p53

To assess the level of erythropoietin (EPO) in blood sera of patients with different subtypes of myelodysplastic syndromes (MDS) from different risk subgroups and to determine its prognostic role.. EPO was measured by enzyme-linked immunosorbent assay in peripheral blood of 54 patients with different MDS subtypes according to the French-American-British (FAB) classification. The comparison group consisted of 15 healthy individuals. Complete blood count (hemoglobin, leukocyte and platelet levels) was determined and bone marrow cells were characterized morphologically. The overall and leukemia-free survivals were estimated by Kaplan - Meier method.. The level of ЕРО in MDS was reliably higher in comparison with healthy persons (p < 0.01, Mann - Whitney test). No statistically significant difference was found in serum EPO concentration between the groups of patients with low- and high-risk MDS (603.5 pg/ml vs 721.0 pg/ml; p > 0.05). In transfusion-dependent patients, the level of EPO was significantly higher than in other patients, which may be due to increased endogenous EPO secretion resulting from chronic hypoxia. A negative correlation was revealed between EPO level and Hb level as well as between EPO level and percentage of blast cells in bone marrow in high-risk MDS patients but not in patients with less aggressive variants of MDS. Instead, patients with low-risk MDS had a negative relationship between concentrations of EPO and tumor necrosis factor alpha (p = 0.06, Kendall's tau test). No significant difference was found between EPO concentration in cases differing by bone marrow cellularity or the presence of cytogenetic abnormalities. An EPO concentration below 200 pg/ml was a predictor of shorter overall survival in patients with all MDS subtypes (p < 0.05, Mann - Whitney test). In patients with all FAB disease subtypes, there was no relationship between the leukemia-free survival and serum EPO concentration.. This study shows that lower serum EPO level may be considered as one of the additional adverse prognostic factors in MDS patients.

Topics: Aged; Biomarkers; Disease Progression; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis

Topics: Aged, 80 and over; Bone Marrow; Erythroblasts; Erythropoiesis; Erythropoietin; Humans; Male; Myelodysplastic Syndromes

Our aim is to investigate the clinical characteristics of low- and intermediate-risk myelodysplastic syndrome (MDS) with pure red cell aplasia (PRCA).. We retrospectively reviewed the patients of low- and intermediate-risk MDS patients who had been diagnosed with PRCA in our hospital between January 2010 and December 2019.. There were 6 low- and intermediate-risk MDS patients with PRCA in our study, 1 male and 5 females, with a median age of 63.5 (50-75) years. It accounted for 7.7% (6/78) of all diagnosed PRCA cases and 1.67% (6/359) of diagnosed MDS cases during the same period. All patients were treated with multiple drugs, including recombinant human erythropoietin, cyclosporine, glucocorticoids, androgen, sirolimus, intravenous immunoglobulin and decitabine. Two patients achieved complete remission, two patients achieved partial remission and became blood transfusion independent. Two patients had no response and one patient died.. Low- and intermediate-risk MDS with PRCA was difficult to treat, but the prognosis was good.

Topics: Aged; Androgens; Cyclosporine; Erythropoietin; Female; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Red-Cell Aplasia, Pure; Retrospective Studies; Sirolimus

Topics: Aged; Aged, 80 and over; Biosimilar Pharmaceuticals; Blood Transfusion; Darbepoetin alfa; Drug Substitution; Epoetin Alfa; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins

Refractory anaemia (RA) among myelodysplastic syndrome (MDS) is associated with a partial functional iron deficit and may require transfusions. In low-risk lymphoma and solid tumour patients, iron support improves erythropoietin (EPO) cost-effectiveness in treating anaemia. The aim of this study is to see if oral sucrosomial iron support improves the cost-effectiveness of EPO treatment in MDS patients affected by low-risk RA. We treated patients with EPO only or with EPO plus oral sucrosomial iron or intravenous (i.v.) iron. The need for transfusions was lowest in the group taking oral iron (p = 0.016) or not receiving supplementation at all (p = 0.022). We compared costs of EPO with i.v. ferric gluconate or oral sucrosomial iron supplementation or no iron supplementation. The oral iron group had fewer side effects, fewer patient medical visits in the out-patient setting, and fewer transfusions; this led to higher savings on direct hospital costs and indirect patient costs (lost days at work) and translated into a 50% abatement of overall expenditures. EPO treatment-related expenditures in MDS-RA patients were lowest with oral sucrosomial iron supplementation (Sideral®), with a longer interval between EPO administration in maintenance treatment, quicker hemoglobin recovery, lower ferritin increase and fewer blood transfusions.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Dietary Supplements; Disease Progression; Erythropoietin; Female; Ferric Compounds; Ferritins; Health Care Costs; Humans; Iron; Italy; Male; Myelodysplastic Syndromes; Treatment Outcome

Topics: Adult; Aged; Aged, 80 and over; Chelation Therapy; Erythropoietin; Female; Hematinics; Humans; Iron Chelating Agents; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Signal Transduction; STAT5 Transcription Factor; Tumor Suppressor Proteins

In the randomized, phase 3, MDS-005 study (NCT01029262), lenalidomide-induced red blood cell transfusion independence (RBC-TI) in 27% of transfusion-dependent patients with lower-risk non-del(5q) myelodysplastic syndromes (MDS) ineligible for or refractory to erythropoiesis-stimulating agents. To determine the influence of erythropoietin (EPO) level on response, 155 patients treated with lenalidomide in MDS-005 were categorized into four groups by baseline EPO level. The EPO >500 mU/mL group had higher RBC transfusion burden and the lowest proportion of patients with ring sideroblasts ≥15% versus lower EPO groups. Achievement of RBC-TI ≥8 weeks inversely correlated with EPO level, ranging from 42.5 to 15.5%. EPO level did not affect erythroid hematologic improvement response (36.2-44.4%). This analysis suggests patients with lower EPO levels experience the strongest benefit from lenalidomide. Although meaningful improvements were observed in some patients with EPO level >500 mU/mL, new treatments are needed for this population.

Topics: Erythrocyte Transfusion; Erythropoietin; Humans; Lenalidomide; Myelodysplastic Syndromes; Thalidomide

In end-stage renal disease (ESRD) patients receiving dialysis, anemia is common and related to a higher mortality rate. Erythropoietin (EPO) resistance and iron refractory anemia require red blood cell transfusions. Myelodysplastic syndrome (MDS) is a disease with hematopoietic dysplasia. There are limited reports regarding ESRD patients with MDS. We aim to assess whether, for ESRD patients, undergoing dialysis is a predictive factor of MDS by analyzing data from the Taiwan National Health Insurance Research Database. We enrolled 74,712 patients with chronic renal failure (ESRD) who underwent dialysis and matched 74,712 control patients. In our study, we noticed that compared with the non-ESRD controls, in ESRD patients, undergoing dialysis (subdistribution hazard ratio [sHR] = 1.60, 1.16-2.19) and age (sHR = 1.03, 1.02-1.04) had positive predictive value for MDS occurrence. Moreover, more units of red blood cell transfusion (higher than 4 units per month) was also associated with a higher incidence of MDS. The MDS cumulative incidence increased with the duration of dialysis in ESRD patients. These effects may be related to exposure to certain cytokines, including interleukin-1, tumor necrosis factor-α, and tumor growth factor-β. In conclusion, we report the novel finding that ESRD patients undergoing dialysis have an increased risk of MDS.

Topics: Adult; Aged; Anemia; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Interleukin-1; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Proportional Hazards Models; Renal Dialysis; Renal Insufficiency, Chronic; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Erythropoiesis-stimulating agents effectively improve the hemoglobin levels in a fraction of anemic patients with myelodysplastic syndromes (MDS). Higher doses (HD) of recombinant human erythropoietin (rhEPO) have been proposed to overcome suboptimal response rates observed in MDS patients treated with lower "standard doses" (SD) of rhEPO. However, a direct comparison between the different doses of rhEPO is lacking.. A cohort of 104 MDS patients treated with HD was retrospectively compared to 208 patients treated with SD in a propensity score-matched analysis to evaluate hematological improvement-erythroid (HI-E) rate induced by the different doses of rhEPO. The impact of rhEPO doses on survival and progression to leukemia was also investigated.. Overall HI-E rate was 52.6%. No difference was observed between different rhEPO doses (P = .28) in matched cohorts; in a subgroup analysis, transfusion-dependent patients and patients with higher IPSS-R score obtained a higher HI-E rate with HD, although without significant impact on overall survival (OS). Achievement of HI-E resulted in superior OS. At univariate analysis, a higher HI-E rate was observed in transfusion-independent patients (P < .001), with a lower IPSS-R score (P < .001) and lower serum EPO levels (P = .027). Multivariate analysis confirmed that rhEPO doses were not significantly related to HI-E (P = .26). There was no significant difference in OS or progression to leukemia in patients treated with HD vs SD.. SD are substantially equally effective to HD to improve anemia and influencing survival in MDS patients stratified according to similar propensity to be exposed to rhEPO treatment.

Topics: Aged; Aged, 80 and over; Anemia; Disease Progression; Erythrocyte Indices; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Propensity Score; Proportional Hazards Models; Recombinant Proteins; Retrospective Studies; Treatment Outcome

Topics: Erythropoietin; Hematopoiesis, Extramedullary; Humans; Myelodysplastic Syndromes; Sacrum

Compelling evidence has emerged for the relevance of flow cytometry (FC) in the diagnostic work-up of myelodysplastic syndromes (MDS) but due to technical issues, the erythroid lineage has been under investigated, specifically in the therapeutic context.. Using the "no red cell lysis" method developed to set up the RED-score, we specifically quantified the fraction of CD117/c-KIT-expressing erythroid precursors in a cohort of 144 MDS patients and studied the correlation with response to erythropoiesis-stimulating agents (ESA) in a sub cohort of 63 low-risk MDS patients.. We confirmed the previously reported increase in CD117/c-KIT-expressing erythroid precursors in a subset of MDS patients and demonstrated a strong association between a cut off of CD117/c-KIT-expressing erythroid precursors ≥3% and ESA response (P = 0.001), independent of red blood cell requirement. From our observations, we hypothesized that a decrease in CD117/c-KIT-expressing erythroid precursors could be a mechanism of ESA failure. Moreover, the fraction of CD117/c-KIT-expressing erythroid precursors was correlated with progression-free survival in low-risk MDS patients (P = 0.018). In vitro, we demonstrated in an EPO dependent cell line that CD117/c-KIT expression is necessary for cell survival under EPO stimulation.. The quantification of the CD117/c-KIT-expressing erythroid precursors could be proposed as a new theranostic and prognostic marker in MDS treated by ESA. Future studies will be required to determine whether modulating CD117/c-KIT expression and signaling could be used to improve anemia in MDS. © 2019 International Clinical Cytometry Society.

Topics: Biomarkers; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Gene Expression; Hematinics; Humans; Male; Myelodysplastic Syndromes; Primary Cell Culture; Prognosis; Progression-Free Survival; Prospective Studies; Proto-Oncogene Proteins c-kit; Risk; Theranostic Nanomedicine

Red blood cell transfusions remain one of the cornerstones in supportive care of lower-risk patients with myelodysplastic syndromes. We hypothesized that patients develop oxidant-mediated tissue injury through the formation of toxic iron species, caused either by red blood cell transfusions or by ineffective erythropoiesis. We analyzed serum samples from 100 lower-risk patients with myelodysplastic syndromes at six-month intervals for transferrin saturation, hepcidin-25, growth differentiation factor 15, soluble transferrin receptor, non-transferrin bound iron and labile plasma iron in order to evaluate temporal changes in iron metabolism and the presence of potentially toxic iron species and their impact on survival. Hepcidin levels were low in 34 patients with ringed sideroblasts compared to 66 patients without. Increases of hepcidin and non-transferrin bound iron levels were visible early in follow-up of all transfusion-dependent patient groups. Hepcidin levels significantly decreased over time in transfusion-independent patients with ringed sideroblasts. Increased soluble transferrin receptor levels in transfusion-independent patients with ringed sideroblasts confirmed the presence of ineffective erythropoiesis and suppression of hepcidin production in these patients. Detectable labile plasma iron levels in combination with high transferrin saturation levels occurred almost exclusively in patients with ringed sideroblasts and all transfusion-dependent patient groups. Detectable labile plasma iron levels in transfusion-dependent patients without ringed sideroblasts were associated with decreased survival. In conclusion, toxic iron species occurred in all transfusion-dependent patients and in transfusion-independent patients with ringed sideroblasts. Labile plasma iron appeared to be a clinically relevant measure for potential iron toxicity and a prognostic factor for survival in transfusion-dependent patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Blood Transfusion; Erythropoietin; Female; Humans; Iron; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Proportional Hazards Models

Topics: Bone Marrow Cells; Erythroblasts; Erythropoiesis; Erythropoietin; Gastrointestinal Hemorrhage; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Myelodysplastic Syndromes

Studies showed red cell distribution width (RDW) can improve the detection of morphological changes in red blood cells and the understanding of their contribution to dyserythropoiesis in myelodysplastic syndrome (MDS). The purpose of the study was to evaluate dyserythropoiesis in MDS by RDW analysis and to explore the utility of RDW in clinical practice. We retrospectively analyzed laboratory and clinical data of 101 patients (59 patients was refractory anemia (RA) according to the French-American-British (FAB) classification). In patients with RA, RDW was showed weak inverse correlation with both hemoglobin concentration (Hb) (r

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Erythroblasts; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cell Transplantation; Hemoglobins; Humans; Immunosuppressive Agents; Lenalidomide; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Retrospective Studies; Survival Analysis; Young Adult

Lenalidomide therapy represents meaningful progress in the treatment of anemic patients with myelodysplastic syndromes with del(5q). We present our initial lenalidomide experience and the positive effect of combining erythropoietin and steroids with lenalidomide in refractory and relapsed patients. We treated by lenalidomide 55 (42 female; 13 male; median age 69) chronically transfused lower risk MDS patients with del(5q) (45) and non-del(5q) (10). Response, meaning transfusion independence (TI) lasting ≥ eight weeks, was achieved in 38 (90%) of analyzed patients with del(5q), of whom three achieved TI only by adding erythropoietin ± prednisone. Another five patients responded well to this combination when their anemia relapsed later during the treatment. In the non-del(5q) group only one patient with RARS-T reached TI. Cytogenetic response was reached in 64% (32% complete, 32% partial response). The TP53 mutation was detected in 7 (18%) patients; four patients progressed to higher grade MDS or acute myeloid leukemia (AML). All seven RAEB-1 patients cleared bone marrow blasts during lenalidomide treatment and reached complete remission (CR); however, three later progressed to higher grade MDS or AML. Lenalidomide represents effective treatment for del(5q) group and combination with prednisone and erythropoietin may be used for non-responders or therapy failures.

Topics: Aged; Aged, 80 and over; Chromosomes, Human, Pair 5; Czech Republic; Erythropoietin; Female; Genes, p53; Glucocorticoids; Humans; Immunologic Factors; Lenalidomide; Male; Middle Aged; Myelodysplastic Syndromes; Prednisone; Recurrence; Remission Induction; Risk Factors

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Cell Differentiation; Erythroid Precursor Cells; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes

Myelodysplastic syndrome (MDS) is a heterogeneous malignant hematologic disease with median overall survival ranging from six months to more than ten years. Solid tumor rarely occurs in combination with MDS and the underlying pathogenesis and prognostic significance still remain controversial.. Here we report a relative low risk myelodysplastic syndrome-refractory cytopenia with multilineage dysplasia (MDS-RCMD) patient, with a rare t(1; 19)chromosome translocation. This patient also suffered from gastric carcinoma.. Gastric carcinoma, Myelodysplastic syndrome with t (1; 19) chromosome translocation.. This patient received radical operation for gastric carcinoma and erythropoietin infusion.. The patient took follow up visits every 2 to 3 months in past years and now he is in stable disease without further treatment.. We reviewed the mechanism of MDS complicated by solid tumor and concluded the potential mechanisms of this patient. The interactions between potential factors may play a role in oncogenesis which, however, need an in-depth study of its operating mechanism.

Topics: Anemia, Refractory; Bone Marrow; Carcinoma; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Cytogenetic Analysis; Erythropoietin; Gastrectomy; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Stomach Neoplasms; Translocation, Genetic; Treatment Outcome

Topics: Abnormal Karyotype; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Dexamethasone; Erythroblasts; Erythropoietin; Female; Humans; Immunoglobulin D; Melphalan; Multiple Myeloma; Myelodysplastic Syndromes; Neutrophils; Proto-Oncogene Proteins c-myc

The precise diagnostic tests and subsequent prognostic stratification for patients with myelodysplastic syndrome (MDS) are often cumbersome, yet they are the basis of successful therapy. Diverse treatment options are available for these patients; however, the decisions in real-life are often not grounded on the available evidence. Although the International Prognostic Scoring System and revised International Prognostic Scoring System are still driving the medical approach to MDS patients, additional variables must be considered when therapeutic intervention is needed. A rational scheme for first-line therapy is described that allows for the possibility of selecting the optimal individual therapy for MDS patients.

Topics: Algorithms; Azacitidine; Decitabine; Enzyme Inhibitors; Erythrocyte Transfusion; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Risk Factors; Transplantation, Homologous

Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int - 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level < 100 mIU/mL (OR 8.7, p < 0.0001). We propose a new ESA response score, consisting of (a) IPSS low score (1 point) and (b) serum EPO levels < 100 mIU/ml (2 points), yielding scores ranging from 0 to 3, with response rates varying from 17 to 81%. The Nordic score has validity but we observed lower than the expected response rates in the best risk group. Our proposed scoring system appears more discriminating but needs validation.

Topics: Canada; Erythropoietin; Female; Ferritins; Hematinics; Humans; Infant; Infant, Newborn; L-Lactate Dehydrogenase; Male; Models, Biological; Myelodysplastic Syndromes; Prospective Studies; Registries

Accumulating evidence implicates innate immune activation in the pathobiology of myelodysplastic syndromes. A key myeloid-related inflammatory protein, S100A9, serves as a Toll-like receptor ligand regulating tumor necrosis factor-α and interleukin-1β production. The role of myelodysplastic syndrome-related inflammatory proteins in endogenous erythropoietin regulation and response to erythroid-stimulating agents or lenalidomide has not been investigated. The HepG2 hepatoma cell line was used to investigate

Topics: Calgranulin B; Erythropoiesis; Erythropoietin; Hep G2 Cells; Humans; Lenalidomide; Myelodysplastic Syndromes; Thalidomide; Tumor Necrosis Factor-alpha

In most patients, anemia is present when myelodysplastic syndrome is diagnosed. Although darbepoetin α is the first-choice supportive therapy for low-risk myelodysplastic syndrome, half of all patients develop a loss of response to darbepoetin α within 12 months. However, few reports have described supportive therapy after the loss of response to darbepoetin α.. We herein present a case involving a 65-year-old Japanese woman with low-risk myelodysplastic syndrome whose erythropoiesis-stimulating agent treatment was switched from darbepoetin α to epoetin β pegol (continuous erythropoietin receptor activator) to treat transfusion-dependent anemia. The frequent transfusions required to treat the anemia resulted in transfusion-associated circulatory overload. The transfusion-dependent anemia was initially treated with darbepoetin α, which negated the requirement for transfusion. However, after 12 months of darbepoetin α therapy, the hemoglobin concentration sharply declined. We switched her therapy from darbepoetin α to continuous erythropoietin receptor activator to avoid transfusion. After initiation of continuous erythropoietin receptor activator therapy, the hemoglobin concentration gradually increased and transfusion was not required. At the time of writing, no progression of the anemia had occurred.. Although darbepoetin α is the first-choice supportive therapy for low-risk myelodysplastic syndrome, continuous erythropoietin receptor activator might be considered the second-choice therapy.

Topics: Aged; Anemia; Erythropoietin; Female; Humans; Myelodysplastic Syndromes; Polyethylene Glycols; Treatment Outcome

Topics: Aged; Aged, 80 and over; Bone Marrow Cells; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Receptors, Transferrin; Retrospective Studies

New drug development for neoplasm treatment is nowadays based on molecular targets that participate in the disease pathogenesis and tumor phenotype. Herein, we describe a new specific pharmacological hematopoietic cell kinase (HCK) inhibitor (iHCK-37) that was able to reduce PI3K/AKT and MAPK/ERK pathways activation after erythropoietin induction in cells with high HCK expression: iHCK-37 treatment increased leukemic cells death and, very importantly, did not affect normal hematopoietic stem cells. We also present evidence that HCK, one of Src kinase family (SFK) member, regulates early-stage erythroid cell differentiation by acting as an upstream target of a frequently deregulated pathway in hematologic neoplasms, PI3K/AKT and MAPK/ERK. Notably, HCK levels were highly increased in stem cells from patients with some diseases, as Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML), that are associated with ineffective erythropoiesis These discoveries support the exploration of the new pharmacological iHCK-37 in future preclinical and clinical studies.

Topics: Adult; Aged; Cell Death; Enzyme Inhibitors; Erythropoiesis; Erythropoietin; Female; GATA1 Transcription Factor; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Molecular Targeted Therapy; Myelodysplastic Syndromes; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-hck; Signal Transduction; Young Adult

Topics: Aged; Aged, 80 and over; CD28 Antigens; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Erythropoietin; Female; Humans; Lymphocyte Activation; Lymphocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; T-Lymphocytes

Topics: Aged; Anemia, Macrocytic; Bone Marrow; Erythropoietin; Fatigue; Humans; Lenalidomide; Myelodysplastic Syndromes; Stem Cell Transplantation; Thalidomide

Low-risk myelodysplastic syndromes (MDS) show several immunologic abnormalities, including increased frequency of autoimmune manifestations and/or overt autoimmune diseases, whose prognostic significance still remains controversial.. We studied the presence of erythroblast antibodies in mitogen-stimulated bone marrow (BM) cultures of 70 patients with early-stage MDS (refractory anemia and refractory anemia with ringed sideroblasts).. Sixty-six percent of patients showed positive erythroblast antibodies, along with BM erythroid hyperplasia and a hemolytic picture in the peripheral blood. Supernatants from positive cultures induced an increase of overall cellularity, the appearance of erythroblastic clustering, and dyserythropoietic signs in normal BM. We identified CD45(dim) Gly-A(dim) CD71(bright) cells (red blood cell precursors at different maturation stage) as the target of the antibodies. Erythropoietin (EPO) levels were reduced and EPO receptors (EPO-R) increased in BM culture supernatants from positive patients. However, flow cytometric analysis showed that neither EPO nor EPO-R was involved in an abnormal stimulation driven by these autoantibodies. Values of the proapoptotic protein Bax were increased in positive patients and Bcl-2 levels were decreased, although not significantly.. MDS patients with anti-erythroblast autoimmunity showed increased BM apoptosis, suggesting that the autoimmune reaction may contribute to an unfavorable BM microenvironment for optimal erythropoiesis.

Topics: Adult; Aged; Aged, 80 and over; Antibodies; Apoptosis; Bone Marrow Cells; Erythroblasts; Erythropoietin; Female; Humans; Immunoglobulin G; Male; Middle Aged; Mitogens; Myelodysplastic Syndromes

Myelodysplastic syndromes (MDSs) are heterogeneous clonal haematopoeitic stem cell disorders characterized by ineffective haematopoeisis, cytopenias and risk of progression to AML. We studied 150 MDS patients for cytogenetic aberrations and 60 patients with normal karyotype and 40 patients harboring cytogenetic abnormalities for copy number variations (CNVs). Cytogenetic abnormalities were detected in 46% of patients with a majority of patients harboring abnormalities of chromosome 7 and del (20q) at frequencies of 16% and 12% respectively. We explored the potential of quantitative multiplex PCR assay of short fluorescent fragments (QMPSF) to identify CNVs and correlated the findings with cytogenetic data and disease prognosis. CNVs (n=31) were detected in 28.3% of karyotypically normal and 23% patients with abnormal karyotype. Genetic losses or deletions (n=26) were more frequent than duplications (n=5). EPO (7q22) and SEC-61(7p11) emerged as new candidate genes susceptible to genetic losses with 57.7% deletions identified in regions on chromosome 7. The CNVs correlated with International Prognostic Scoring System (IPSS) intermediate disease risk group. Our integrative cytogenetic and copy number variation study suggests that abnormalities of chromosome 7 are predominant in Indian population and that they may play a secondary role in disease progression and should be evaluated further for asserting their clinical significance and influence on disease prognosis.

Topics: Chromosome Aberrations; Chromosomes, Human, Pair 7; DNA Copy Number Variations; Erythropoietin; Gene Deletion; Humans; India; Myelodysplastic Syndromes; Prognosis; SEC Translocation Channels

In many elderly patients with anemia, a specific cause cannot be identified. This study investigates whether erythropoietin levels are inappropriately low in these cases of "anemia of unknown etiology" and whether this trend persists after accounting for confounders.. This study includes all anemic patients over 60 years old who had erythropoietin measured between 2005 and 2013 at a single center. Three independent reviewers used defined criteria to assign each patient's anemia to one of ten etiologies: chronic kidney disease, iron deficiency, chronic disease, confirmed myelodysplastic syndrome (MDS), suspected MDS, vitamin B12 deficiency, folate deficiency, anemia of unknown etiology, other etiology, or multifactorial etiology. Iron deficiency anemia served as the comparison group in all analyses. We used linear regression to model the relationship between erythropoietin and the presence of each etiology, sequentially adding terms to the model to account for the hemoglobin concentration, estimated glomerular filtration rate (eGFR) and Charlson Comorbidity Index.. A total of 570 patients met the inclusion criteria. Linear regression analysis showed that erythropoietin levels in chronic kidney disease, anemia of chronic disease and anemia of unknown etiology were lower by 48%, 46% and 27%, respectively, compared to iron deficiency anemia even after adjusting for hemoglobin, eGFR and comorbidities.. We have shown that erythropoietin levels are inappropriately low in anemia of unknown etiology, even after adjusting for confounders. This suggests that decreased erythropoietin production may play a key role in the pathogenesis of anemia of unknown etiology.

Topics: Aged; Aged, 80 and over; Anemia; Anemia, Iron-Deficiency; Biomarkers; Chronic Disease; Comorbidity; Erythropoietin; Female; Folic Acid Deficiency; Glomerular Filtration Rate; Hematologic Tests; Hemoglobins; Humans; Linear Models; Male; Middle Aged; Myelodysplastic Syndromes; Renal Insufficiency, Chronic; Retrospective Studies; Vitamin B 12 Deficiency

Topics: Adalimumab; Anti-Inflammatory Agents; Antibodies, Monoclonal, Humanized; Crohn Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Randomized Controlled Trials as Topic; Receptors, Fc; Recombinant Fusion Proteins; Thrombopoietin; Treatment Outcome; Tumor Necrosis Factor-alpha

The aim of the present study was to assess the role of a concomitant type 2 diabetes as a potentially negative factor in the management of low-risk myelodysplastic syndrome (MDS) patients treated with high-dose (40,000 UI s.c. 2 times/week) recombinant human erythropoietin (EPO) alpha (rHuEPO alpha).. One hundred and forty patients (M/F 69/71, median age 76, interquartile range [IR] 68-81) were included in the analysis: 27/140 (19.2%) had a concomitant type 2 diabetes.. No difference was reported between patients with and without diabetes as to the grade of anemia, the EPO endogenous levels and the need for transfusional requirement at baseline. Erythroid response was achieved in 79/140 patients (56.4%): factors associated with response were lower EPO levels (P < 0.0001), higher baseline Hb levels (P < 0.0001) and transfusion independence (P < 0.0001). Diabetes was not predictive of response: 17/27 (62.9%) patients with diabetes were responsive to high-dose EPO compared with 62/113 (54.8%) patients without diabetes (P = 0.446). This was confirmed in multivariate analysis, controlling for the effects of Hb levels, transfusion-dependence and serum EPO levels. No difference was observed in relapse rate, response duration and OS between patients with and without diabetes.. Concomitant type 2 diabetes was not a major concern in the management of MDS patients.

Topics: Aged; Diabetes Mellitus, Type 2; Erythropoietin; Female; Humans; Male; Myelodysplastic Syndromes

Erythropoiesis-stimulating agents (ESAs) are used to ameliorate anemia in lower-risk myelodysplastic syndromes (MDS). Serum erythropoietin (EPO) level <500 IU/L is widely accepted as a major predictive factor for response to ESAs. However, few data about EPO levels in the Japanese population are available. We therefore evaluated distribution of serum EPO levels in Japanese patients with MDS. Forty-three cases were analyzed; 30 were classified as lower-risk MDS (low or intermediate-1 by the international prognostic scoring system). Twenty-two cases were transfusion dependent. The overall median hemoglobin level was 7.7 g/dL. The median value of serum EPO was 254 IU/L (range: 16.4-23,000). Serum EPO levels had a strong inverse correlation with hemoglobin levels, and a significantly larger proportion of patients showed high EPO levels (>500 IU/L) in the transfusion-dependent group. In the higher-risk group, no significant correlation between EPO and hemoglobin was observed. Regression analyses showed that serum EPO of 500 IU/L corresponds to 8.29 g/dL of hemoglobin in lower-risk MDS. The results indicate that patients with hemoglobin levels of 8.0 g/dL or more, who are still transfusion independent, may be good candidates for ESA treatment.

Topics: Adult; Aged; Aged, 80 and over; Asian People; Erythrocyte Indices; Erythropoietin; Female; Humans; Japan; Male; Middle Aged; Myelodysplastic Syndromes

Erythropoiesis-stimulating agents (ESAs) reduce red blood cell (RBC) transfusions in approximately 40% of patients with myelodysplastic syndrome (MDS) in clinical trials. We studied the association of timing of ESA initiation, agent (epoetin alfa, darbepoetin) and number of weeks of ESA use with response in MDS patients in routine practice.. Patients diagnosed with MDS from 2001 to 2005 were identified in the Surveillance Epidemiology and End Results-Medicare linked database. The study cohort consisted of patients with new-onset transfusion dependence (TD). All patients received an ESA at least once during the study period, which began the week that criteria for TD were met and continued until transfusion independence (TI). Kaplan-Meier statistics and Cox Proportional Hazard models were used to assess relationships between time to ESA initiation, agent and number of weeks of ESA use and TI attainment.. Of 610 TD patients treated with ESAs, 210 (34.4%) achieved TI. Median time from ESA initiation to TI was 13 weeks. Shorter time from TD to ESA initiation and use of darbepoetin were associated with higher probability of achieving TI. The probability of achieving TI decreased beyond 8 weeks of treatment, and was very low beyond 16 weeks (8-15 weeks: HR=0.64, 16-31 weeks: HR=0.25, 32+ weeks HR=0.10).. In this observational, population-based study, variations in ESA administration impacted response in transfusion-dependent MDS patients, with higher response rates with early administration and use of darbepoetin, and low response likelihood in non-responders beyond 16 weeks of therapy.

Topics: Aged; Aged, 80 and over; Blood Transfusion; Darbepoetin alfa; Databases, Factual; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Retrospective Studies

Single Cell Network Profiling (SCNP) is a multiparametric flow cytometry-based assay that quantifiably and simultaneously measures changes in intracellular signaling proteins in response to in vitro extracellular modulators at the single cell level. Myelodysplastic syndrome (MDS) is a heterogeneous clonal disorder of hematopoietic stem cells that occurs in elderly subjects and is characterized by dysplasia and ineffective hematopoiesis. The functional responsiveness of MDS bone marrow (BM) hematopoietic cells, including functionally distinct myeloid and erythroid precursor subsets, to hematopoietic growth factors (HGF) and the relationship of modulated signaling to disease characteristics is poorly understood.. SCNP was used first to examine the effects of age on erythropoietin (EPO) and granulocyte colony stimulating factor (GCSF)-induced signaling in myeloid, nucleated red blood cells (nRBC), and CD34 expressing cell subsets in healthy BM (n = 15). SCNP was then used to map functional signaling profiles in low risk (LR) MDS (n = 7) for comparison to signaling in samples from healthy donors and to probe signaling associations within clinically defined subgroups.. In healthy BM samples, signaling responses to HGF were quite homogeneous (i.e., tightly regulated) with age-dependent effects observed in response to EPO but not to GCSF. Despite the relatively small number of samples assayed in the study, LR MDS could be classified into distinct subgroups based on both cell subset frequency and signaling profiles.. As a correlate of underlying genetic abnormalities, signal transduction analyses may provide a functional and potentially clinically relevant classification of MDS. Further evaluation in a larger cohort is warranted.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia, Refractory, with Excess of Blasts; Bone Marrow Cells; Erythroid Cells; Erythropoietin; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Intercellular Signaling Peptides and Proteins; Middle Aged; Myelodysplastic Syndromes; Myeloid Cells; Signal Transduction; Young Adult

Topics: Aged; Aged, 80 and over; alpha-Globins; Asymptomatic Diseases; beta-Globins; Blood Transfusion; Bone Marrow; Delayed Diagnosis; Diagnosis, Differential; Erythropoiesis; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Heterozygote; Humans; Incidental Findings; Male; Myelodysplastic Syndromes; Phenotype; Thalassemia

International guidelines for myelodysplastic syndrome (MDS) state that the standard therapy for lower risk MDS patients with symptomatic anemia of serum erythropoietin (EPO) <500 IU/L is erythroid-stimulating agents (ESAs). The objective of this study is to examine the distribution of EPO levels in lower risk MDS patients, and to inquire into the relationship of EPO distribution to hemoglobin levels and transfusions. Twenty cases of lower risk MDS (low or intermediate-1 by the International Prognostic Scoring System) with hemoglobin level <90 g/L at our institution were enrolled. Eight received more than two units of transfusions per month. Median hemoglobin level was 78 g/L. EPO levels ranged between 26.4 and 11300 IU/L (median 645 IU/L), including 10 cases (50 %) with >500 IU/L. EPO levels were inversely correlated to hemoglobin levels, especially in the cases without transfusion support (p < 0.001, R = 0.92). The rate of the cases with EPO <500 IU/L was significantly higher in the group without transfusion than the others (p = 0.020). Considering that, in Japan, the indication for transfusion is around 70 g/L of hemoglobin for chronic diseases, it may be possible to improve anemia in a subset of lower risk MDS cases by administration of ESAs before transfusions are required.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Risk Factors

To investigate the efficacy and impact factors in lower-risk [International prognostic scoring system (IPSS) low or intermediate-1 risk] myelodysplastic syndrome (MDS) patients treated with recombinant human erythropoietin (rhEPO) alone or in combination with recombinant human granulocyte colony- stimulating factor (rhG-CSF).. A total of 52 consecutive lower-risk MDS patients received subcutaneous injection of rhEPO alone or in combination with rhG-CSF at least 8 weeks, the rhEPO dose would be reduced slowly to stop or kept at minimum to maintain the response when the best efficacy achieved and maintained for 4 weeks. Their clinical features, efficacy, survival and the predictors of efficacy were analyzed retrospectively.. The overall response rate was 51.9% (27/52) with 33.3%(9/27) achieving complete remission (CR) and 66.7%(18/27) achieving erythroid response (HI-E). In multivariate analysis, sEPO level (less than 500 U/L), BFU-E count (more than 25/10⁵ BMMNC), intermediate and high doses rhEPO±rhG-CSF therapy were independent predictors of better response. The median therapy period was 8(2-45) months and the median efficacy duration was 37(6-94) months (38 months for CR, 36 months for HI-E). Ten of the 27 responsive patients relapsed and 40% of them had disease progressions. Hemoglobin levels and karyotype affect response duration. Median overall survival was 47(6-114) months on a 37(6-114) months median follow-up. In multivariate analysis, ages (less than 60 years old), karyotype (good or intermediate) and response to rhEPO±rhG-CSF therapy may have a favorable survival impact on MDS.. rhEPO, alone or in combination with rhG-CSF, is a useful drug for the treatment of anemia in lower-risk MDS patients and has favorable impact on life expectancy.

Topics: Adult; Aged; Aged, 80 and over; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Retrospective Studies; Treatment Outcome; Young Adult

Myelodysplastic syndromes (MDS) are common in elderly patients. Recombinant human erythro-poietin (rHuEPO) has been widely used to treat anemia in lower risk MDS patients, but few data are known about rHuEPO treatment in the very elderly patient group. In order to investigate the role of rHuEPO treatment in terms of response, overall survival (OS), and toxicity in a very elderly MDS patient group, 93 MDS patients treated with rHuEPO when aged ≥80 years were selected among MDS cases enrolled in a retrospective multicenter study by the cooperative group Gruppo Romano Mielodisplasie (GROM) from Jan 2002 to Dec 2010. At baseline, median age was 82.7 (range 80-99.1) with a median hemoglobin (Hb) level of 9 g/dl (range 6-10.8). The initial dose of rHuEPO was standard (epoetin alpha 40,000 IU/week or epoetin beta 30,000 IU/week) in 59 (63.4 %) patients or high in 34 (36.6 %) (epoetin alpha 80,000 IU/week) patients. We observed an erythroid response (ER) in 59 (63.4 %) patients. No thrombotic event was reported. Independent predictive factors for ER were low transfusion requirement before treatment (p = 0.004), ferritin <200 ng/ml (p = 0.017), Hb >8 g/dl (p = 0.034), and a high-dose rHuEPO treatment (p = 0.032). Median OS from rHuEPO start was 49.3 months (95 % CI 27.5-68.4) in responders versus 30.6 months (95 % CI 7.3-53.8) in resistant patients (p = 0.185). In conclusion, rHuEPO treatment is safe and effective also in the very elderly MDS patients. However, further larger studies are warranted to evaluate if EPO treatment could be worthwhile in terms of quality of life and cost-efficacy in very old patients.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Drug Evaluation; Epoetin Alfa; Erythropoietin; Female; Ferritins; Gastrointestinal Diseases; Hematocrit; Humans; Hypertension; Kaplan-Meier Estimate; Male; Multicenter Studies as Topic; Myelodysplastic Syndromes; Prognosis; Proportional Hazards Models; Recombinant Proteins; Retrospective Studies; Thrombosis

Erythropoietin (EPO) stimulates proliferation of early-stage erythrocyte precursors and is widely used for the treatment of chronic anemia. However, several types of EPO-resistant anemia are characterized by defects in late-stage erythropoiesis, which is EPO independent. Here we investigated regulation of erythropoiesis using a ligand-trapping fusion protein (ACE-536) containing the extracellular domain of human activin receptor type IIB (ActRIIB) modified to reduce activin binding. ACE-536, or its mouse version RAP-536, produced rapid and robust increases in erythrocyte numbers in multiple species under basal conditions and reduced or prevented anemia in murine models. Unlike EPO, RAP-536 promoted maturation of late-stage erythroid precursors in vivo. Cotreatment with ACE-536 and EPO produced a synergistic erythropoietic response. ACE-536 bound growth differentiation factor-11 (GDF11) and potently inhibited GDF11-mediated Smad2/3 signaling. GDF11 inhibited erythroid maturation in mice in vivo and ex vivo. Expression of GDF11 and ActRIIB in erythroid precursors decreased progressively with maturation, suggesting an inhibitory role for GDF11 in late-stage erythroid differentiation. RAP-536 treatment also reduced Smad2/3 activation, anemia, erythroid hyperplasia and ineffective erythropoiesis in a mouse model of myelodysplastic syndromes (MDS). These findings implicate transforming growth factor-β (TGF-β) superfamily signaling in erythroid maturation and identify ACE-536 as a new potential treatment for anemia, including that caused by ineffective erythropoiesis.

Topics: Activin Receptors, Type II; Anemia; Animals; Bone Morphogenetic Proteins; Disease Models, Animal; Drug Therapy, Combination; Erythrocyte Count; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Growth Differentiation Factors; Haplorhini; Hematinics; Humans; Ligands; Mice; Myelodysplastic Syndromes; Rats; Recombinant Fusion Proteins; Reticulocyte Count; Signal Transduction; Smad2 Protein; Smad3 Protein

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and a risk of progression to acute myeloid leukemia (AML). Anemia affects the course of disease, quality of life (QOL), and cognitive function of MDS patients. Erythroid-stimulating agents (ESAs) are effective; however, not all patients respond to ESAs. To evaluate the effectiveness of a biosimilar epoetin α (Binocrit) for the treatment of anemia in low-/intermediate-1 risk MDS patients and to evaluate the impact of ESAs on QOL and on cognitive function, 24 consecutive patients aged over 65 years were treated with Binocrit at 40,000 IU once a week for 12 weeks and were followed for at least 3 months. Responsive patients continued with 40,000 IU once a week for a further 12 weeks. Changes in QOL were assessed by the Functional Assessment of Cancer Therapy-Anemia (FACT-An), while cognitive assessment was carried out by mini-mental state examination (MMSE). All patients completed 12 weeks of therapy. Sixteen patients (66.67 %) achieved an erythroid response (ER), 15 patients (62.5 %) became transfusion independent and remained free from transfusion requirement for at least 3 months, while two patients had reduction in transfusion requirement of at least four RBC transfusions/8 weeks compared with the pretreatment transfusion requirement. Seven patients were nonresponders (29.1 %), of whom four patients were low risk and three intermediate-I risk. Seven transfusion-independent patients were low risk, and eight were intermediate-1 risk. Median hemoglobin (Hb) values were significantly higher after treatment in responders (p < 0.001). ER was maintained after 24 weeks. Statistically significant positive correlations between improvement in Hb and variations in patients' mini-mental (Spearman's Rho = 0.54, p < 0.01) and FACT-An scores (Spearman's Rho = 0.59, p < 0.003) were demonstrated. This preliminary study shows that Binocrit is promising for the treatment of anemia of MDS patients. ER positively correlates with improvements in patients' cognitive status and positive changes in QOL.

Topics: Aged; Aged, 80 and over; Anemia; Biosimilar Pharmaceuticals; Brain; Epoetin Alfa; Erythropoietin; Female; Humans; Leukemia, Myeloid, Acute; Male; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Retrospective Studies; Risk

Topics: Aged; Anemia, Hemolytic; Coombs Test; Cyclosporine; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Humans; Leukemia, Large Granular Lymphocytic; Male; Myelodysplastic Syndromes; Prednisolone

This study was aimed to investigate the changes of erythropoietin (EPO), hemoglobin(Hb) and recombinant EPO (rEPO) levels in MDS patients receiving iron chelation therapy, and to explore the relationship between EPO and serum ferritin(SF). A total of 172 MDS patients and 30 healthy controls were studied. The levels of SF, EPO, serum iron (SI), total iron binding capacity (TIBC), C-reaction protein (CRP) and Hb were measured respectively, the level of SF was adjusted according to the changes of CRP. Among them, there were 34 cases of low-risk (SF>1 000 mg/L) receiving deferoxamine therapy, whose changes of SF, EPO, SI, TIBC, Hb levels were detected and compared before and after treatment. Besides, the difference in the incidence of EPO resistance in iron overload group and non-iron overload group was assessed before and after therapy, and 58 cases of low-risk and EPO<1 000 U/L MDS patients were given rEPO therapy. The results showed that the level of EPO in non-iron overload group was higher than that in the normal control group (997.44 ± 473.48 vs 467.27 ± 238.49, P < 0.05). Obviously, the level of EPO in iron overload group was higher than that in non-iron overload group and control group (3257.59 ± 697.19 vs 997.44 ± 473.48, P = 0.012, 3257.59 ± 697.19 vs 467.27 ± 238.49, P = 0.002). Otherwise, the incidence of EPO resistance in iron overload group was higher than that in non-iron overload group (18/35 vs 2/23, P = 0.001), and the level of EPO and SF was positively related to each other in iron overload group (r = 0.310,P = 0.036). After receiving iron chelation therapy, the levels of SF, SI, TIBC and EPO in iron overload group were significantly lower than that before therapy (3942.38 ± 641.82 vs 2266.35 ± 367.31, P = 0.028;48.61 ± 10.65 vs 28.52 ± 12.61, P = 0.034;59.84 ± 12.62 vs 33.76 ± 15.43, P = 0.045;3808.01 ± 750.22 vs 1954.78 ± 473.18, P = 0.042). Moreover, the level of Hb increased (35 ± 18 vs 57 ± 21, P = 0.046) and the EPO resistance in some patients was decreased. It is concluded that iron chelation therapy can improve the efficacy of EPO to alleviate EPO resistance in patients wtih anemic MDS, decrease the pathological level of EPO, enhance Hb levels and reduce the dependency on blood transfusion.

Topics: Adult; Aged; C-Reactive Protein; Case-Control Studies; Chelation Therapy; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Overload; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Aged; Darbepoetin alfa; Epidural Space; Erythropoietin; Female; Hematinics; Hematopoiesis, Extramedullary; Humans; Male; Myelodysplastic Syndromes; Spinal Cord Compression; Thoracic Vertebrae; Time Factors; Withholding Treatment

The Hellström-Lindberg score (HLS) (1997) is designed to predict erythroid response to erythropoietin treatment in myelodysplastic patients. In order to test the validity of this scoring system, 58 patients affected by myelodysplastic syndrome, treated with a "standard dose" approach between 2001 and 2010, were analyzed. The response to erythropoietin treatment was evaluated in accordance with the "international working group" (IWG) criteria. Among the patients only two were scored "poor," 12 "intermediate," and 44 "good" (15 of whom were scored "3" and 29 "4"). Although the system was verified as a predictive tool for response to erythropoietin therapy, we noted that of patients scored as "good," those with a numerical score of "4" responded more frequently than did those scored "3", as evaluated under both the 2006- and 2000-IWG ("major response") criteria. The modest response rate in patients scoring "3" did not show a difference in response rate in comparison to the "intermediate" group. The present data suggest that only patients scoring "4" on the scale may show an adequate response to the standard dose erythropoietin therapy, while frontline high-dose therapy should be offered to other patients. A further analysis considering endogenous erythropoietin as a possible determinant of response revealed the optimal cut-off value of 80 mIU/mL, instead of the value of 100 mIU/mL utilized by the HLS.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Databases, Factual; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Risk Factors; ROC Curve; Treatment Outcome

Erythropoiesis-stimulating agents (ESA) are used commonly to reduce symptomatic anemia in patients with myelodysplastic syndromes (MDS). We assessed population-based patterns of ESA use relative to treatment guidelines using data from the Surveillance, Epidemiology, and End Results (SEER) registries, with linked Medicare claims providing detailed treatment data from 2001 through 2005. The study found widespread use (62%) of ESA in Medicare beneficiaries with MDS. Similar ESA use rates regardless of risk status, low frequency (45%) of serum erythropoietin determination prior to ESA initiation, and high prevalence (60.4%) of short-duration ESA episodes suggest clinically important discrepancies between actual practice and guideline-recommended therapy.

Topics: Adult; Aged; Aged, 80 and over; Darbepoetin alfa; Drug Utilization; Epoetin Alfa; Erythropoietin; Female; Guideline Adherence; Hematinics; Humans; Male; Medicare; Middle Aged; Myelodysplastic Syndromes; Practice Guidelines as Topic; Practice Patterns, Physicians'; Recombinant Proteins; Registries; United States

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Male; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Erythropoietin; Female; Genotype; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

The onset of myelodysplastic syndromes (MDS) is usually around the age of 70. Despite this, most clinical trials are restricted to younger subjects. Thus, the management of elderly patients with MDS is not always optimal. Physiologically, elderly patients show characteristics that differ from those of younger patients and that condition their pharmacological treatment. In this regard, the comprehensive geriatric assessment (CGA) becomes particularly important. This document gathers conclusions from the 1(st) Meeting of Members of the Sociedad Española de Medicina Geriátrica and the Sociedad Española de Hematología y Hemoterapia, with the objective of proposing the establishment of CGA instruments to assist in the decision-making process of elderly patients with MDS. The results of this consensus document will focus on the diagnosis, prognosis, treatment and management of adverse events in this age group.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Blood Transfusion; Decision Support Techniques; Deferoxamine; Erythropoietin; Health Status Indicators; Humans; Lenalidomide; Myelodysplastic Syndromes; Prognosis; Siderophores; Thalidomide

Topics: Acute Kidney Injury; Adult; Blood Component Transfusion; Bone Marrow; Cell Lineage; Combined Modality Therapy; Darbepoetin alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematuria; Humans; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphohistiocytosis, Hemophagocytic; Male; Mycophenolic Acid; Myelodysplastic Syndromes; Pancytopenia; Pericarditis; Prednisone; Proteinuria; Recombinant Proteins

Topics: Chromosome Deletion; Chromosomes, Human, Pair 5; Erythrocyte Transfusion; Erythropoietin; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias as a result of ineffective hematopoiesis. Little is known about alterations in signal transduction pathways in MDS.. Multiparameter flow cytometry was used to evaluate the proteolytic activation of caspase-3 and the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein kinase (MAPK), and STAT5 specifically in defined CD34(+), CD45(+), or CD71(+)CD45(-) bone marrow (BM) cells from 60 MDS cases and normal controls, both at baseline and following stimulation with granulocyte colony-stimulating factor (G-CSF) and erythropoietin.. In CD71(+)CD45(-) cells from a subpopulation of 36 MDS cases who were predicted to be responsive by clinical parameters (endogenous erythropoietin levels, transfusion dependency, percentage of blasts in the BM), erythropoietin failed to activate ERK1/2 or STAT5 in 23 of 36 cases, but it was effective in 13 of 36 cases, although to a significantly lower degree than in CD71(+)CD45(-) cells from healthy donor BM. The erythropoietin response in vivo correlated with in vitro erythropoietin-dependent STAT5 activation in 20 of 22 cases. STAT5 was significantly activated at baseline in MDS cells compared with normal controls, whereas caspase-3 was activated in CD34(+) and CD45(+) MDS cells, and was activated more often in the RA and RAEB-1 MDS subtypes. G-CSF stimulation activated ERK1/2 and STAT5 equally in MDS and normal CD34(+) cells.. Abnormalities in the response to growth factors are restricted to erythropoietin stimulation in CD71(+)CD45(-) cells and correlate with the clinical response to erythropoietin. Activation of baseline signal transduction for proliferative and apoptotic signals is altered in MDS but with different patterns among the various BM subpopulations.

Topics: Aged; Apoptosis; Bone Marrow Cells; Cell Proliferation; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Male; Myelodysplastic Syndromes

Inositide signaling pathways can have a role in the Myelodysplastic Syndromes (MDS) progression to acute myeloid leukemia. Erythropoietin (EPO) is currently used in low-risk MDS, where it successfully corrects anemia in 50-70% of patients. However, some MDS patients are refractory to this treatment and little is known about the exact molecular mechanisms underlying the effect of EPO in these subjects. Here, we investigated the role of inositide pathways in low-risk MDS treated with EPO, mainly focusing on the Akt/PI-PLC (Phosphoinositide-Phospholipase C) gamma1 axis, which is activated by the EPO receptor, and PI-PLCbeta1/Cyclin D3 signaling, as Cyclin D3 is associated with hematopoietic proliferation and differentiation. Interestingly, EPO responder patients showed a specific activation of both the Akt/PI-PLCgamma1 pathway and beta-Globin gene expression, while nonresponders displayed an increase in PI-PLCbeta1 signaling. Moreover, in normal CD34+ cells induced to erythroid differentiation, PI-PLCbeta1 overexpression abrogated both EPO-induced Akt phosphorylation and beta-Globin expression. Overall, these findings suggest that PI-PLCbeta1 can act as a negative regulator of erythroid differentiation and confirm the involvement of Akt/PI-PLCgamma1 pathway in EPO signaling, therefore contributing to the comprehension of the effect of EPO in low-risk MDS and possibly paving the way to the identification of MDS patients at higher risk of refractoriness to EPO treatment.

Topics: Aged; Aged, 80 and over; beta-Globins; Blotting, Western; Case-Control Studies; Cell Differentiation; Cell Nucleus; Cyclin D3; Erythropoietin; Follow-Up Studies; Humans; Immunoenzyme Techniques; Middle Aged; Myelodysplastic Syndromes; Phosphatidylinositols; Phospholipase C beta; Phospholipase C gamma; Phosphorylation; Prognosis; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Messenger; Signal Transduction

A 79-year-old man was admitted to the hospital because of a 20-lb weight loss, low back pain, and leg weakness. He had a 1-year history of fibrotic myelodysplasia, possibly therapy related, with a highly complex chromosome karyotype. Radiologic evaluation showed extensive destructive bone lesions, retroperitoneal lymphadenopathy, and evidence for thoracic spinal cord compression. Core biopsies of a retroperitoneal lymph node showed groups of large, immature-appearing mononuclear cells which, on Wright-stained touch preparation, appeared similar to dysplastic erythroid precursors noted on recent marrow aspirate smears. Immunohistochemical staining showed negativity of neoplastic cells to an extensive panel of nonhematopoietic and myeloid markers, and positivity for CD117, glycophorin A, and CD71, consistent with a diagnosis of erythroblastic sarcoma. This lesion is a very unusual variant of myeloid sarcoma and has been described only rarely in the medical literature.

Topics: Abnormal Karyotype; Adenocarcinoma; Aged; Azacitidine; Biopsy, Large-Core Needle; Bone Marrow; Bone Marrow Neoplasms; Bone Neoplasms; Combined Modality Therapy; Disease Progression; Drug Therapy, Combination; Erythroblasts; Erythropoietin; Fatal Outcome; Humans; Lymph Nodes; Male; Myelodysplastic Syndromes; Rare Diseases; Rectal Neoplasms; Sarcoma, Myeloid

Topics: Anemia; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Treatment Outcome

For more than 20 years erythropoietin (rHEPO) has largely been used to treat anemia in myelodysplastic syndromes (MDS). Early clinical trials showed erythroid responses in no more than 15-25% of patients. In the last decade, a better selection of MDS patients suitable for a therapeutic challenge with rHEPO, alone or in combination with G-CSF, allowed for an increased response-rate, averaging around 40%. More recently, an even higher percentage of responses have been obtained using higher-doses of rHEPO (up to 80,000 IU/weekly) in lower-risk MDS patients. This treatment however, especially at such high doses, is costly and not easily affordable for prolonged periods. The aim of this study was to verify if the use of "standard" doses of rHEPO could induce a satisfying response-rate with a less expensive treatment schedule in IPSS-defined "lower-risk" MDS anemic patients. From January 2005 to December 2009 a total of 55 consecutive anemic (Hb ≤ 10 g/dL) patients (29 males, 26 females, median age 78 years) with low-intermediate-1 risk MDS were treated after informed consent with rHEPO (40,000 IU once a week subcutaneously) for at least 3 months; at the end of this period, erythroid response was assessed, and responders were allowed to continue the treatment indefinitely, whereas non-responders were considered "off study". Both efficacy and safety of the treatment were recorded and evaluated. After 3 months of treatment, 36 out of 55 (65.5%) patients achieved an erythroid response to rHEPO according to IWG 2006 criteria. Higher response-rates to rHEPO were related with both lower IPSS and particularly WPSS scores. Treatment was safe, and only 1 patient had to discontinue the treatment because of unmanageable side-effects. Among the 36 responders, 28 (77%) maintained the response after a median follow-up of 46 months. Our data indicate that standard doses of rHEPO are at least as effective as higher-doses for correcting anemia in lower-risk MDS patients; in this clinical scenario, this schedule allows for a consistent reduction of costs without precluding the achievement of a durable erythroid response.

Topics: Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins; Risk Factors

We investigated the efficacy of alpha recombinant human erythropoietin (α-rHuEPO) administered as single agent to 133 patients affected by myelodysplastic syndromes referring to our Institution in the last 10 years. WPSS score was "very low" in 67%, "low" in 19%, "intermediate" in 14%. The starting schedule was: 40,000 IU bi-weekly, with reduction or suspension, when necessary, in responsive patients. According to new IWG criteria, response rate (RR) was 75%, 66%, 59% after 8, 16, 24 weeks, respectively. Comparing "very low" and "low/intermediate" risk, RR was 81% vs. 43% (P < 0.001); 70% vs. 45% (P = 0.040); 63% vs. 42% (P = NS) after 8, 16, 24 weeks. RR was significantly influenced by transfusion dependence (P = 0.039) and basal serum EPO level (P < 0.001). Mean Hb value was 94 ± 11 g/l before therapy; 114 ± 19 after 8 weeks (P < 0.001); 116 ± 18 after 16 weeks (P < 0.001); 114 ± 17 after 24 weeks (P < 0.001). Reduction or suspension of therapy significantly affected Hb level after 4 (P < 0.001) and 8 weeks (P < 0.01). Conversely, restart of full dosage significantly enhanced again Hb level after 4 (P < 0.01) and 8 weeks (P < 0.001). 65% patients are alive (mean survival: 74 weeks). Seventy percent are alive in the "very low risk" group and 38% in "low/intermediate risk" group (P < 0.001). Overall mean follow-up was 69 weeks (range, 8-376): it was 80 weeks in responsive patients (max 376) and 38 weeks in patients who progressively became unresponsive (max 168) (P < 0.01). Median response was 36 weeks, with 33% of patients still responding after one year. Treatment was well tolerated.

Topics: Aged; Aged, 80 and over; Anemia; Blood Transfusion; Cohort Studies; Drug Monitoring; Drug Resistance; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins; Retrospective Studies; Survival Analysis; Time Factors

Anemia in IBD is the result of a combination of iron deficiency and anemia of chronic disease. Therapy of IBD is relief of inflammation, but the drugs usage may cause the development hemolytic anemia and myelodysplastic syndrome. We studied the effect of basic therapy on the incidence of anemia and assess the impact of modern biological therapies on the main markers of AHZ. A total of 153 patients with ulcerative colitis (UC) and 53 patients with Crohn's disease (CD), which at the time of the study received basic anti-inflammatory therapy for at least 1 year. All patients underwent blood tests, iron metabolism parameters were determined by the level of erythropoietin and G-gepsidina C reactive protein. Modern biological therapy increases the effectiveness of the treatment of anemia in patients with IBD. The use of Remicade gives a quick positive response, which is due to the decrease of gepsidin negative influence on iron metabolism and unlocking the synthesis of erythropoietin. The use of MSCs does not inhibit the synthesis of erythropoietin, and is likely to stimulate erythropoiesis at the erythroblast precursors.

Topics: Anemia, Hemolytic; Anemia, Iron-Deficiency; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antimicrobial Cationic Peptides; C-Reactive Protein; Colitis, Ulcerative; Crohn Disease; Erythroblasts; Erythropoiesis; Erythropoietin; Hepcidins; Humans; In Vitro Techniques; Incidence; Infliximab; Male; Myelodysplastic Syndromes; Risk Factors; Time Factors

This was a retrospective, comparative study focused on the extended follow-up of 192 transfusion-dependent patients with myelodysplastic syndromes treated (n. 83) or not treated (n. 109) with recombinant erythropoietin alpha (r-EPO) as single agent during the course of their disease. The results supported the safety of this treatment in the long term and also showed a significant survival advantage (median 52 months vs. 31 months, p<0.0095) in responding patients as compared to non-responding ones or to subjects never treated with r-EPO. At multivariate analysis, response to r-EPO maintained an independent prognostic value on OS.

Topics: Adult; Aged; Aged, 80 and over; Blood Transfusion; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Retrospective Studies; Survival Rate; Treatment Outcome

There is little published information on the everyday clinical management of myelodysplastic syndromes in real world practice.. We conducted a cross-sectional study of all patients with myelodysplastic syndromes attending 74 French centers in a 1-week period for inpatient admission, day-hospital care or outpatient visits.. Nine hundred and seven patients were included; 67.3% had lower-risk myelodysplastic syndromes (International Prognostic Scoring System: low or intermediate-1). Karyotype had been analyzed in 82.5% of the cases and was more often of intermediate or poor risk in patients under 65 years old compared with those who were older. Red blood cell transfusions accounted for as many as 31.4% of the admissions. Endogenous erythropoietin level was less than 500 IU/L in 88% of the patients tested. Erythroid stimulating agents had been or were being used in 36.8% of the lower risk patients, iron chelation in 31% of lower risk patients requiring red blood cell transfusions and lenalidomide in 41% of lower risk patients with del 5q. High-dose chemotherapy, hypomethylating agents, low dose cytarabine and allogeneic stem cell transplantation had been or were being used in 14.8%, 31.1%, 8.8% and 5.1%, respectively, of higher-risk patients.. Karyotype is now assessed in most patients with myelodysplastic syndromes, and patients under 65 years old may have more aggressive disease. Apart from erythroid-stimulating agents and, in higher-risk myelodysplastic syndromes, hypomethylating agents, specific treatments are used in a minority of patients with myelodysplastic syndromes and red blood cell transfusions still represent the major reason for hospital admission.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Cohort Studies; Cross-Sectional Studies; Disease Management; Erythrocyte Transfusion; Erythropoietin; Female; France; Hematopoietic Stem Cell Transplantation; Humans; Karyotyping; Male; Middle Aged; Myelodysplastic Syndromes; Time Factors; Young Adult

Myelodysplastic syndromes (MDS) are a group of clonal disorders of the bone marrow characterized by peripheral cytopenias. Standard treatment in low- and intermediate-I-risk MDS is supportive therapy consisting of regular transfusions and growth factors, that is, erythropoietin (Epo) and granulocyte-colony-stimulating factor (G-CSF). Because flow cytometric analysis of MDS bone marrow samples can identify clinically relevant subgroups regarding transfusion dependency and disease progression, we addressed the question whether flow cytometry (FCM) was instrumental in predicting response. In 46 patients with low- and intermediate-I-risk MDS that were treated with Epo/G-CSF, low Epo level and low transfusion need were associated with response to Epo/G-CSF. Interestingly, aberrant phenotype of myeloblasts identified nonresponders among patients with the greatest response probability according to the predictive model of Hellström-Lindberg et al. Moreover, aberrant FCM of myeloblasts acted as a significant biomarker for treatment failure in multivariate analysis. A new predictive model based on the basis FCM combined with previously validated Epo levels is proposed defining 3 subgroups with 94%, 17%, and 11% response probability. In conclusion, FCM may add significantly to well-known predictive parameters in selecting MDS patients eligible for Epo/G-CSF treatment. This is of relevance regarding prevention of treatment failure.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; Biomarkers; Bone Marrow Cells; Erythropoietin; Female; Flow Cytometry; Granulocyte Colony-Stimulating Factor; Humans; Immunophenotyping; Male; Middle Aged; Models, Biological; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Drug Resistance; Erythropoietin; Humans; Immunosuppressive Agents; Mycophenolic Acid; Myelodysplastic Syndromes; Recombinant Proteins

Although the anticancer activities of histone deacetylase (HDAC) inhibitors have been studied, a role for HDAC in normal hematopoiesis has not been clearly defined. Previous studies have shown that the potent HDAC inhibitor FK228 stimulates interleukin (IL)-3-mediated erythropoiesis. Here, we examined whether the widely used valproic acid (VPA) affects megakaryopoiesis as well as erythropoiesis.. CD34(+) cells were incubated in serum-free or serum-containing cultures with cytokines, with or without VPA.. In the serum-free cultures containing IL-3+stem cell factor (SCF), VPA significantly increased generation of CD61(+)GPA(-) megakaryocytic and a CD61(+)GPA(+) mixture of megakaryocytic and erythroid precursors from CD34(+) hematopoietic precursors at a pharmacological concentration (100 microg/mL). The increase in generation of megakaryocytic and erythroid precursors by VPA was confirmed by replating cultured cells with thrombopoietin+SCF and erythropoietin+SCF, respectively. VPA was as potent as FK228. In cultures with granulocyte-macrophage colony-stimulating factor+SCF, where CD61(-)GPA(+) erythroid precursors were mostly developed, VPA mainly enhanced the generation of CD61(-)GPA(+) erythroid precursors. In serum-containing cultures, only low numbers of CD61(+) or GPA(+) cells were developed with IL-3+SCF. Nevertheless, a substantial number of these cells were generated with VPA. Furthermore, these stimulating effects of VPA were observed by incubating CD34(+) cells from patients with myelodysplastic syndrome. Quantitative reverse transcription polymerase chain reaction showed that VPA enhanced GATA-2, but not GATA-1, messenger RNA expression with IL-3+SCF.. These results indicate a novel role for VPA in enhancing the potential of IL-3 to stimulate megakaryopoiesis as well as erythropoiesis and suggest a new therapeutic approach of epigenetic therapy for hematological disease.

Topics: Antigens, CD34; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; GABA Agents; GATA1 Transcription Factor; GATA2 Transcription Factor; Gene Expression Regulation; Humans; Integrin beta3; Interleukin-3; Megakaryocytes; Myelodysplastic Syndromes; RNA, Messenger; Stem Cells; Thrombopoiesis; Thrombopoietin; Valproic Acid

ESAs are increasingly used to treat anemia of lower risk MDS, even before RBC transfusion requirement. From a previously published patient cohort treated with ESAs, we selected 112 patients with de novo low or int-1 IPSS MDS with Hb<10 g/dl, serum EPO<500 UI/l and who had never been transfused. Erythroid response rate at 12 weeks was 63.1% (IWG 2006). In multivariate analysis, an interval between diagnosis and ESA onset<6 months, Hb level>9 g/dl, and serum EPO<100 UI/l predicted better response to ESA while shorter interval between diagnosis and ESA onset (p=0.01), lower serum EPO (p=0.04) and WHO diagnosis of RCMD-RS (p=0.03) were associated with longer response. Median interval from diagnosis to transfusion dependency was 80 months and 35 months, respectively, in patients with onset of ESA < 6 months and ≥ 6 months from diagnosis (p=0.007). Those results support early onset of ESA in lower risk MDS, to better avoid the consequences of anemia. Early introduction of ESA may also delay the need for RBC transfusions, hypothetically by slowing the disease course, but prospective studies are required to further assess this point.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Retrospective Studies; Risk; Treatment Outcome

Myelodysplastic syndrome (MDS) may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP) rs1617640 in the erythropoietin (EPO) promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS.. We genotyped the EPO rS1617640 SNP in 189 patients with MDS, 257 with acute myeloid leukemia (AML), 106 with acute lymphoblastic leukemia, 97 with chronic lymphocytic leukemia, 353 with chronic myeloid leukemia, and 95 healthy controls.. The G/G genotype was significantly more common in MDS patients (47/187; 25.1%) than in controls (6/95; 6.3%) or in patients with other leukemias (101/813; 12.4%) (all P < 0.001). Individuals with the G/G genotype were more likely than those with other genotypes to have MDS (odd ratio = 4.98; 95% CI = 2.04-12.13). Clinical and follow up data were available for 112 MDS patients and 186 AML patients. There was no correlation between EPO promoter genotype and response to therapy or overall survival in MDS or AML. In the MDS group, the GG genotype was significantly associated with shorter complete remission duration, as compared with the TT genotype (P = 0.03). Time to neutrophils recovery after therapy was significantly longer in MDS patients with the G/G genotype (P = 0.02).. These findings suggest a strong association between the rs1617640 G/G genotype and MDS. Further studies are warranted to investigate the utility of screening for this marker in individuals exposed to environmental toxins or chemotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Erythropoietin; Genetic Association Studies; Genotype; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Middle Aged; Myelodysplastic Syndromes; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Promoter Regions, Genetic; Treatment Outcome; Young Adult

Recent progresses have changed the paradigms for the treatment of MDS. Careful patient screening and prognostic stratification using IPSS score is necessary before any treatment decision. For lower-risk MDS where anemia is the major problem, treatment with ESA should be considered first. In patients who require red blood cells transfusions, iron overload must be monitored carefully in order to consider iron chelation therapy. A new drug such as lenalidomide which is active in MDS with del5q is currently under investigation in non-del5q MDS. For patients with higher-risk MDS, AML transformation is the major issue. Therefore aggressive treatment approaches such as allogeneic HSC transplant or intensive chemotherapy can be offered to selected subsets of patients. However, for the vast majority, demethylating agents and namely 5-azacytidine currently represent the standard of care. Patient information and participation in clinical trails are important aspects of the current management of MDS.

Topics: Anemia; Antineoplastic Agents; Blood Component Transfusion; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Myelodysplastic Syndromes; Pancytopenia; Pregnancy; Pregnancy Complications, Neoplastic; Recombinant Proteins

Topics: Aged; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Medicare Part D; Myelodysplastic Syndromes; Recombinant Proteins; United States

Topics: Adult; Aged; Aged, 80 and over; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Humans; L-Lactate Dehydrogenase; Male; Middle Aged; Myelodysplastic Syndromes; Protoporphyrins

Topics: Aged; Autoantibodies; Erythropoietin; Hemoglobinuria, Paroxysmal; Humans; Male; Myelodysplastic Syndromes

Lenalidomide has proven efficacy and safety and has been shown to reduce transfusion requirements and reverse cytogenetic abnormalities in lower-risk myelodysplastic syndromes (MDS). However, long-term follow-up data have not yet been reported. Here, we describe 6 patients with International Prognostic Scoring System low- or intermediate-1-risk MDS who began lenalidomide therapy between April 2002 and June 2003 as part of the MDS-001 study and who have maintained long-term therapy. Five of these patients had an ongoing requirement for red blood cell transfusions despite previous treatment with recombinant erythropoietin. One patient began lenalidomide therapy because of progressive and symptomatic anemia. To date, all patients maintained long-term transfusion independence (over 4.5 years) while receiving oral lenalidomide therapy, including 5 patients who remain on therapy. Sustained erythroid response was reported despite persistence of the deletion 5q [del(5q)] abnormality in 3 of the 4 patients with del(5q) at study entry. Side effects were largely predictable and manageable. The favorable outcomes presented here show that lenalidomide can induce durable erythroid responses with sustained transfusion independence that can exceed 6 years in patients with lower-risk MDS.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antineoplastic Agents; Chromosomes, Human, Pair 5; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Lenalidomide; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Thalidomide; Treatment Outcome

Topics: Aged; Anemia; Antimetabolites, Antineoplastic; Azacitidine; Cell Nucleus Shape; Chelation Therapy; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Male; Myelodysplastic Syndromes; Neutrophils; Panniculitis

Although the incidence of (myelodysplastic syndrome (MDS)) is higher among heart and lung transplant recipients than the general population, the same has not been shown in liver transplant (OLT) patients. We present the second known case of MDS after OLT. Case reports of MDS in OLT were identified using PubMed. Patient data were gathered from the patient and the medical record. A 54-year-old Caucasian man underwent OLT in 2003 and again in 2004 for hepatitis C-related cirrhosis. In 2007, the patient developed weakness, malaise, and shortness of breath. Laboratory studies revealed pancytopenia. Bone marrow biopsy showed MDS, with refractory anemia and excess blasts-1. The patient underwent chemotherapy and reduction in immunosuppression without a clinical response. Our experience suggested that MDS, although rare, should be considered in the differential diagnosis of pancytopenia after OLT. Once diagnosed, immunosuppression reduction, chemotherapy, and even stem cell transplantation may be the appropriate treatment in selected candidates.

Topics: Anemia; Antiviral Agents; Erythropoietin; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Liver Cirrhosis; Liver Transplantation; Male; Middle Aged; Myelodysplastic Syndromes; Polyethylene Glycols; Recombinant Proteins; Recurrence; Reoperation

Thiazolidinediones (TZDs) are frequently used pharmacotherapeutics for type II diabetes mellitus, which exert their effect through peroxisomal proliferator agonist receptor (PPAR) mediated increased insulin sensitivity. TZDs are known to cause marrow suppression and to stimulate adipogenesis. Case and cohort studies show TZDs worsen thyroid-associated orbitopathy. We present a case consistent with earlier reports of marrow suppressive pancytopenia manifesting as myelodysplastic syndrome, a new implication of hypoerythropoetinemia, and non-Graves'-associated proliferative proptosis.

Topics: Diabetes Mellitus, Type 2; Erythropoietin; Exophthalmos; Female; Humans; Hypoglycemic Agents; Lipodystrophy; Middle Aged; Myelodysplastic Syndromes; Rosiglitazone; Thiazolidinediones

The majority of patients with myelodysplastic syndromes (MDS) are older, and the incidence of these diseases is rising as the population ages. Clinicians are often uncertain about how to identify patients who may benefit from specific treatment strategies. The International Prognostic Scoring System is a widely used tool to assess risk of transformation to leukemia and guide treatment decisions, but it fails to take into account many aspects of treating elderly patients, including comorbid illness, secondary causes of MDS, prior therapy for MDS, and other age-related health, functional, cognitive, and social problems that affect outcome. Patients with lowrisk disease traditionally have been given supportive care, but evidence is increasing that treatment with lenalidomide or methyltransferase inhibitors may influence the natural history of the disease and should be used in conjunction with supportive-care measures. Supportive care of these patients also could be improved to enhance their quality of life and functional performance.

Topics: Aged; Anemia; Antineoplastic Agents; Azacitidine; Decitabine; Erythrocyte Transfusion; Erythropoietin; Humans; Iron Chelating Agents; Lenalidomide; Myelodysplastic Syndromes; Neutropenia; Thalidomide; Thrombocytopenia

To assess the effect of erythropoietin (EPO) plus granulocyte-colony stimulating factor (G-CSF) treatment on survival and leukemic transformation in myelodysplastic syndrome (MDS).. We compared the long-term outcome of patients with MDS treated with EPO plus G-CSF (n = 121) with untreated patients (n = 237) with MDS using multivariate Cox regression with delayed entry, for the first time adjusting for all major prognostic variables (WHO classification, karyotype, cytopenias, level of transfusion-need, age, and sex).. The erythroid response rate to EPO plus G-CSF was 39%, and the median response duration 23 months (range, 3 to 116+). In the multivariate analysis, treatment was associated with improved overall survival (hazard ratio, 0.61; 95% CI, 0.44 to 0.83; P = .002). Interestingly, this positive association was primarily observed in patients requiring fewer than 2 units of RBCs per month. Treatment was not linked to the rate of acute myeloid leukemia in any defined subgroup, including patients with an increase of marrow blasts or an unfavorable karyotype.. The inherent risk of leukemic evolution in MDS makes the current investigation highly relevant, in light of the recent reports of potential negative effects of EPO treatment on outcome in patients with cancer. We conclude that treatment of anemia in MDS with EPO plus G-CSF may have a positive impact on outcome in patients with no or low transfusion need, while not affecting the risk of leukemic transformation.

Topics: Aged; Anemia; Blood Transfusion; Cell Transformation, Neoplastic; Clinical Trials, Phase II as Topic; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Precancerous Conditions

Topics: Anemia; Antineoplastic Agents; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Severity of Illness Index

Pure red cell aplasia (PRCA) is a rare condition described in patients with chronic kidney disease during alpha-Epo treatment subcutaneous administered generated by anti-R-Epo antibodies. Recently two cases of PRCA have been reported in patients affected by myelodysplastic syndrome treated with R-Epo. We described one more case of PRCA in a patient with refractory anemia treated with R-Epo.

Topics: Adrenal Cortex Hormones; Aged; Blood Transfusion; Erythropoietin; Humans; Injections, Subcutaneous; Male; Myelodysplastic Syndromes; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Spontaneous apoptosis of bone marrow erythroid precursors accounts for the anemia that characterizes most low-grade myelodysplastic syndromes (MDS). We have shown that death of these precursors involved the Fas-dependent activation of caspase-8. To explore the pathway leading from caspase-8 activation to apoptosis, we transduced MDS bone marrow CD34(+) cells with a lentivirus encoding wild-type (WT) or endoplasmic reticulum (ER)-targeted Bcl-2 protein before inducing their erythroid differentiation. Both WT-Bcl-2 and ER-targeted Bcl-2 prevented spontaneous and Fas-dependent apoptosis in MDS erythroid precursors. ER-targeted Bcl-2 inhibited mitochondrial membrane depolarization and cytochrome c release in MDS erythroid precursors undergoing apoptosis, indicating a role for the ER in the death pathway, upstream of the mitochondria. MDS erythroid precursors demonstrated elevated ER Ca(2+) stores and these stores remained unaffected by ER-targeted Bcl-2. The ER-associated protein Bcl-2-associated protein (BAP) 31 was cleaved by caspase-8 in MDS erythroid precursors undergoing apoptosis. The protective effect of ER-targeted Bcl-2 toward spontaneous and Fas-induced apoptosis correlated with inhibition of BAP31 cleavage. A protective effect of erythropoietin against Fas-induced BAP31 cleavage and apoptosis was observed. We propose that apoptosis of MDS erythroid precursors involves the ER, downstream of Fas and upstream of the mitochondria, through the cleavage of the ER-associated BAP31 protein.

Topics: Anemia; Apoptosis; Calcium; Caspase Inhibitors; Endoplasmic Reticulum; Erythroid Precursor Cells; Erythropoietin; fas Receptor; Humans; Membrane Proteins; Mitochondria; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2

We report a rare case of deep vein thrombosis (DVT) secondary to erythropoietin (EPO) in an 89-year-old patient with myelodysplastic syndrome (MDS). The incidence of EPO-induced thrombotic episode increases with an absolute increase of hemoglobin (Hb) beyond >12 gm/dL or rate of increase of Hb level >1 gm/dL every 2 weeks.

Topics: Aged, 80 and over; Erythropoietin; Humans; Male; Myelodysplastic Syndromes; Venous Thrombosis

Guidelines for management of patients with myelodysplastic syndromes (MDS) have been generated by the National Comprehensive Cancer Network (NCCN) Myelodysplastic Syndromes Panel. Because MDS is a heterogeneous spectrum of disorders, these patients have been categorized into prognostic subgroups, predominantly using the International Prognostic Scoring System (IPSS). Several drugs have been used to treat these patients, and their selection and sequential recommended use by the panel depend on disease characteristics and responses to treatment. Recombinant erythropoietin alfa and darbepoetin alfa have been the mainstay of therapy for treating anemia associated with MDS. The FDA has recently approved several other drugs for treating MDS, including azacytidine and decitabine for all stages of disease, lenalidomide for low-risk anemic patients with del(5q) chromosomal abnormality, and deferasirox for treating iron overload. For iron chelation, deferoxamine is also used occasionally. Treatment with immunosuppressive therapy (antithymocyte globulin and cyclosporin) has been therapeutically beneficial for a subset of younger patients with MDS. Because the financial cost of these therapies are substantial and have received only limited attention, this article evaluates the costs of specific drugs and their sequential use in the lower-risk IPSS (low and intermediate-1) subgroups based on the NCCN guidelines. Results estimate an average annual cost for potentially anemia-altering drugs of $63,577 per patient, ranging from $26,000 to $95,000, depending on the specific therapies. In patients for whom the therapies fail, annual costs for iron chelation plus red blood cell transfusions are estimated to average $41,412. The economic impact of drug therapy should be weighed against the patient's potential for improvement in clinical outcomes, quality of life, and transfusion requirements.

Topics: Anemia; Antineoplastic Agents; Azacitidine; Cost of Illness; Costs and Cost Analysis; Darbepoetin alfa; Decision Support Techniques; Deferoxamine; Drug Costs; Drug Therapy; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Iron Chelating Agents; Lenalidomide; Myelodysplastic Syndromes; Practice Guidelines as Topic; Recombinant Proteins; Siderophores; Thalidomide; United States

Myelodysplastic syndromes (MDS) comprise a group of pathologically and cytogenetically distinct bone marrow disorders. Little is known about the characteristics of MDS patients, including their pathological and prognostic classifications, cytopenias, transfusion and supportive care needs, and treatment regimens. We describe these characteristics in a large group of recently diagnosed and existing (ie, established) MDS patients.. We conducted six consecutive cross-sectional surveys among US hematology and medical oncology specialists (identified from an American Medical Association [AMA] database of physicians who administer chemotherapy) between June 2005 and January 2007. A questionnaire collected data on the characteristics and treatment patterns of the 4-10 most recently seen MDS patients for each physician, including demographic data, transfusion needs, treatment approaches, and consideration for clinical trials or bone marrow transplantation.. A panel of 101 physicians who were geographically representative of physicians registered with the AMA characterized 614-827 patients per survey, for a total of 4514 responses. Among recently diagnosed patients, 55% were male (95% confidence interval [CI] = 52% to 59%), the median age at diagnosis was 71 years (range = 65-80 years), and 10% (95% CI = 8% to 12%) had MDS secondary to chemotherapy, radiation therapy, or environmental exposure. The median duration of MDS in established patients ranged from 13 to 16 months over the six surveys. Among recently diagnosed MDS patients, fewer patients with lower-risk disease than with higher-risk disease were dependent on either red blood cell transfusions (22% vs 68%) or platelet transfusions (6% vs 33%). More than 50% of all newly diagnosed and established patients used erythropoiesis-stimulating agents. A small percentage of all patients either had had or were being considered for bone marrow transplantation (recently diagnosed: 4%; established: 4% or less) or were being treated on clinical trials (recently diagnosed: 1%; established: 4% or less).. MDS patients in the United States have substantial transfusion needs, and use of erythropoiesis-stimulating agents and are seldom considered for bone marrow transplantation or clinical trials. These data may be useful in characterizing the health care resource use and pharmacoeconomic impact of MDS in the United States.

Topics: Adult; Aged; Blood Transfusion; Bone Marrow Transplantation; Cross-Sectional Studies; Darbepoetin alfa; Economics, Pharmaceutical; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Health Care Surveys; Health Resources; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Physicians; Prognosis; Retrospective Studies; Surveys and Questionnaires; United States

Topics: Aged; Darbepoetin alfa; Drug Therapy, Combination; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Leukocytosis; Male; Myelodysplastic Syndromes; Polyethylene Glycols; Recombinant Proteins

Despite the clinical importance of health-related quality of life (QOL) in patients suffering from myelodysplastic syndromes (MDS), few data exist on the prevalence of key MDS-associated symptoms, or the correlation of those symptoms with specific disease features such as hemoglobin level. In order to better understand the burden of disease-associated symptoms in patients with MDS, we designed a 120-question Internet-based survey of QOL appropriate for patients with MDS, incorporating validated QOL measurement instruments and questions about specific therapies. The 359 survey respondents were typical of MDS patients in terms of demographics, blood counts, and disease subtype. Patients reported high levels of excessive fatigue and poor scores on QOL assessments such as the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Brief Fatigue Inventory (BFI). Patients' debilitating fatigue correlated poorly with hemoglobin level, and fatigue was associated with significant impairment of both health-related QOL and ability to work or participate in desired activities. Within the limitations of self-reported data, these results provide a benchmark for future interventions to improve QOL in patients with MDS.

Topics: Adult; Aged; Aged, 80 and over; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Exanthema; Fatigue; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins

Anemia in MDS with 5q deletion was generally considered, until the advent of lenalidomide, unresponsive to available treatments. We analyzed erythroid response to erythropoetin (EPO) or darbepoetin (DAR) and thalidomide in MDS with 5q deletion treated by French centers (GFM) and in whom karyotype was successfully performed. Of 345 patients treated with EPO or DAR+/-G-CSF, 48 had 5q deletion. The response rate was 46% (31% major, 15% minor) according to International Working Group (IWG) 2000 criteria versus 64% in patients without 5q deletion (p=0.03). According to IWG 2006 criteria, the response rate in patients with 5q deletion was 39% versus 52% in patients without 5q deletion (p=0.10). Mean duration of response was 14 months versus 25 months (IWG 2000) and 13 months versus 27 months (IWG 2006) in 5q deletion and non-5q deletion patients (p=0.019 and 0.003, respectively). Of 120 MDS treated with thalidomide, all of whom had successful cytogenetic analysis, 37% of the 24 patients with 5q deletion responded (IWG 2000 criteria, 20% major, 17% minor) with a mean duration of 9.5 months, versus 32% (18% major, 14% minor) in MDS without 5q deletion and a mean response duration of 9 months (p=NS). Our results confirm that response rates to EPO or DAR and thalidomide are clearly inferior to those obtained with lenalidomide.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 5; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Thalidomide

The main clinical problems of low-risk patients with myelodysplastic syndromes (MDS), as defined by the International Prognostic Scoring System, are infections and the need for frequent transfusions due to ineffective myelopoiesis and peripheral blood cytopenia. Promising results in treating MDS-related anemia have been obtained using high-dose recombinant human erythropoietin (rhEPO). To evaluate the molecular basis of the response to rhEPO, we used commercially available macro-arrays to investigate gene expression profiles in the glycophorin-expressing (Gly+) bone marrow (BM) erythroid cells of five responders (ERs) and five non-responders (ENRs) to rhEPO treatment. The cells were separated by means of positive selection using an immunomagnetic procedure, after which flow cytometry showed that their purity was more than 97% in all cases. The array data were validated by means of real time RT-PCR. The results showed that the genes responsible for proliferation/differentiation and DNA repair/stability were repressed in the BM Gly+ erythroid cells of the ENRs, but almost normally expressed in the ERs. Furthermore, the expression of genes involved in signal transduction suggested that the activity of the MAPK signaling pathway is inhibited in ERs. The different gene expression profiles of ERs and ENRs may provide a basis for early gene testing as a means of predicting the response to rhEPO of MDS patients with low endogenous EPO levels.

Topics: Aged; Aged, 80 and over; Bone Marrow Cells; Cluster Analysis; Down-Regulation; Erythroid Cells; Erythropoietin; Female; Gene Expression Profiling; Gene Expression Regulation; Glycophorins; Humans; Male; Myelodysplastic Syndromes; Recombinant Proteins; Up-Regulation

Little is known about factors contributing to disease-evolution in early-phase myelodysplastic syndromes (MDS). In this article, low erythropoietin (EPO) production is discussed as a 'non-oncogenic' co-factor responsible for disease-manifestation in a group of patients with low-risk MDS. The hypothesis is based on the observations that (i) individuals with bone marrow dysplasia and MDS-related karyotypes but relatively high EPO levels may present without anemia and thus without frank MDS over years, (ii) several elderly patients with idiopathic anemia are low EPO producers and their anemia can be corrected with EPO therapy, and (iii) the well-known fact that low-risk MDS patients typically respond to EPO therapy when they have low endogenous EPO levels.

Topics: Aged; Aged, 80 and over; Chromosome Deletion; Chromosomes, Human, Pair 4; Erythropoietin; Female; Humans; Karyotyping; Male; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins

Therapy with RBC transfusions and rHuEPO for management of anemia in patients with myelodysplastic syndromes causes recurrent fluctuations in hemoglobin levels. The purpose of this study was to elaborate a mathematical model for the interpretation of hemoglobin fluctuations and to correlate the resulting numerical parameter (Variaglobin Index) with quality of life and fatigue. In 32 myelodysplastic patients, lower amplitude of the Variaglobin Index was found significantly correlated with a better quality of life and less fatigue. The mathematical model proposed here makes it easy to monitor anemia in myelodysplastic patients and to adjust therapy accordingly.

Topics: Aged; Aged, 80 and over; Anemia; Erythrocyte Transfusion; Erythropoietin; Fatigue; Female; Hemoglobins; Humans; Male; Middle Aged; Models, Biological; Myelodysplastic Syndromes; Quality of Life; Recombinant Proteins; Software; Surveys and Questionnaires; Treatment Outcome

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Male; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

The study was aimed to investigate the curative effects and adverse effects of amifostine in the treatment of patients with myelodysplastic syndrome (MDS). Amifostine (AMF) was used alone (4/12) or combined with recombinant human erythropoietin (rh-EPO) (8/12) in 12 MDS patients. The therapeutic regimen was adopted with AMF 0.4 g/day for 5 days, then took a break of 2 days and then went on for 3 weeks consecutively, that was reputed as one treatment cycle. rh-EPO 6 000 U was used for 3 days per week. The results showed that 12 patients all attained hematological improvement in peripheral blood. 11 cases showed major effective response rate (91.7%), while 1 case showed minor response rate (8.3%). The effective response rate of hemoglobin, leukocytes and platelets was 100%, 75% and 58.3% respectively. The intervals of red cell transfusions (RCT) in 2 cases living on red cell transfusion before AMF treatment were prolonged after AMF treatments, and the amount of each RCT was decreased obviously. The side effect was usually discomfort of digestive system, but all patients can endure. In conclusion, Amifostine is a potential drug in the treatment of MDS patients with safety especially to those elder patients who often suffered from other multiple organ disfunctions, and the curative effect will be improved by more treatment cycles.

Topics: Adult; Aged; Aged, 80 and over; Amifostine; Drug Therapy, Combination; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Antineoplastic Agents; Erythropoietin; Female; Granulocyte Precursor Cells; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Male; Myelodysplastic Syndromes; Thalidomide

Topics: Aspartate Aminotransferases; Bone Marrow Transplantation; Child, Preschool; Combined Modality Therapy; Erythropoietin; Female; Ferritins; Graft vs Host Disease; Hemochromatosis; Humans; Leukemia, Myeloid, Acute; Liver Function Tests; Myelodysplastic Syndromes; Phlebotomy; Recombinant Proteins

Topics: Erythropoiesis; Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Anemia occurs as a comorbidity in from 80% to 85% of patients with myelodysplastic syndromes (MDS): It causes fatigue, increases transfusion needs, and reduces quality of life. Darbepoetin alpha (DA) is an erythropoiesis-stimulating protein (ESP) that is more highly glycosylated and has a longer half-life relative to recombinant human erythropoietin (rHuEPO), thus, allowing less frequent administration, increased convenience, and better compliance.. This retrospective analysis included 81 patients with MDS who were enrolled at 9 Spanish centers and who received once-weekly, subcutaneous DA (75-300 microg) for 16 weeks.. Fifty-five percent of all patients (38 of 69 evaluable patients) achieved responses; 30.4% of were major responses, and 24.6% were minor responses; 64.7% of rHuEPO-naive patients and 45.7% rHuEPO-treated patients responded; and 43.2% had received previous rHuEPO. Most responses (65.8%) occurred at or before Week 8. The median age at diagnosis was 70 years (range, 38-87 years), the median age at the initiation of DA treatment was 75 years (range, 39-91 years), and 56.8% of patients were women. The median time from last ESP dose to DA initiation was 16.8 weeks (range, 0.0-159.0 weeks; <1 week in 53.1% of patients). According to the French-American-British classification system (n = 81 patients), 39.5% had refractory anemia (RA), 46.9% had RA with ringed sideroblasts, 9.9% had RA with excess blasts (RAEB), 1.2% had RAEB in transformation, and 2.5% had chronic myelomonocytic leukemia. According to the International Prognostic Scoring System (n = 47 patients), 55.3% of patients were in the low-risk group, and 36.2% of patients were in the intermediate-1-risk group. The median baseline hemoglobin level was 8.9 g/dL (range, 8.4-9.1 g/dL). The Starting DA dose was 75 microg per week in 3.7% of patients, 150 microg per week in 65.4% of patients, and 300 microg per week in 29.6% of patients (the dose was increased in 18.5% of patients and reduced in 9.9% of patients; median time to dose adjustment, 8 weeks). Five patients received granulocyte colony-stimulating factors. No DA-related adverse reactions occurred.. In the current study, 55% of evaluable patients with MDS safely achieved an erythroid response.

Topics: Adolescent; Adult; Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Spain

Lenalidomide has been approved for the treatment of transfusion-dependent low- or intermediate-1-risk myelodysplastic syndromes (MDS) associated with a chromosome 5q deletion with or without additional cytogenetic abnormalities. We evaluated the cost effectiveness of lenalidomide versus best supportive care (BSC) in these patients. We developed a decision analytic model to compare costs and outcomes of lenalidomide with BSC without recombinant erythropoietin (EPO) versus BSC with EPO over 1 year. Outcome measures were transfusion independence and quality-adjusted life years (QALYs) gained. The model incorporated costs of medications, transfusions, chelation, laboratory tests, office visits, and other resources associated with each therapy. Lenalidomide therapy was associated with an estimated incremental 0.53 transfusion-free and 0.25 QALY gain compared to BSC at 1 year. The costs of lenalidomide therapy were substantially offset by reduced blood transfusion and EPO costs. One-year total treatment costs were estimated at $63,385 for lenalidomide and $54,940 for BSC. The incremental cost-effectiveness ratio for lenalidomide vs BSC was estimated at $16,066 per transfusion-free year and $35,050 per QALY gained, values within the acceptable cost-effectiveness ranges for a new therapy. Results suggest that oral lenalidomide is cost effective in the United States in the treatment of transfusion-dependent, low- or intermediate-1-risk MDS associated with a deletion 5q cytogenetic abnormality. Confirmation of these findings awaits results of an ongoing randomized phase III trial (MDS-004 study).

Topics: Antineoplastic Agents; Blood Transfusion; Chromosome Aberrations; Chromosome Deletion; Chromosomes, Human, Pair 5; Cost-Benefit Analysis; Decision Support Techniques; Erythropoietin; Humans; Lenalidomide; Medical Oncology; Models, Econometric; Myelodysplastic Syndromes; Outcome Assessment, Health Care; Quality-Adjusted Life Years; Recombinant Proteins; Risk Factors; Thalidomide; United States

Thirty-seven anaemic subjects with low-to-intermediate risk myelodysplastic syndrome (MDS) received the highly glycosylated, long-acting erythropoiesis-stimulating molecule darbepoetin-alpha (DPO) at the single, weekly dose of 150 microg s.c. for at least 12 weeks. Fifteen patients (40.5%) achieved an erythroid response (13 major and two minor improvements, respectively, according to International Working Group criteria). Such results are currently maintained after 7-22 months in 13 of the responders, one of whom required iron substitutive therapy during the treatment. One patient relapsed after 4 months. Another responder died after 5 months because of causes unrelated to the treatment. No relevant side-effects were recorded. At multivariate analysis, significant predictive factors of response were baseline serum levels of endogenous erythropoietin <100 IU/l, absent or limited transfusional needs, no excess of blasts and hypoplastic bone marrow. This study suggests that DPO, at the dose and schedule used, can be safely given in low-intermediate risk MDS and may be effective in a significant proportion of these patients.

Topics: Aged; Anemia; Darbepoetin alfa; Erythrocyte Count; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Multivariate Analysis; Myelodysplastic Syndromes; Pilot Projects

The association between myelodysplastic syndromes (MDS) and autoimmune manifestations is not uncommon. As a rule, autoimmune abnormalities follow the diagnosis of MDS. We describe here a patient with MDS who developed a striking spectrum of diverse autoimmune disorders, including dermatitis, polyarthritis, and vasculitis, which preceded the clinical appearance of MDS.

Topics: Aged; Aged, 80 and over; Arthritis; Autoimmune Diseases; Blood Transfusion; Combined Modality Therapy; Dermatitis; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Male; Methylprednisolone; Myelodysplastic Syndromes; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Treatment Outcome; Vasculitis

Myeloproliferative disorders (MPD) represent a subcategory of hematological malignancies and are characterized by a stem cell-derived clonal proliferation of myeloid cells including erythrocytes, platelets, and leucocytes. Traditionally, the term 'MPD' included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMM). At present, these four disorders are referred to as 'classic' MPD and are distinguished from a spectrum of other MPD-like clinicopathologic entities that are operationally classified as 'atypical' MPD. The oncogenic mutations(s) in classic MPD are unknown except for CML, which is associated with an activating mutation (Bcr/Abl) of the gene encoding for the Abl cytoplasmic protein kinase (PTK). In the last 3 months, a somatic point mutation of JAK2 (JAK2(V617F)), the gene encoding for another cytoplasmic PTK was reported in the majority of patients with PV and approximately half of those with either ET or MMM. The same mutation was also found in a small number of patients with either atypical MPD or the myelodysplastic syndrome but not in normal controls, germline tissue including T lymphocytes, and patients with secondary erythrocytosis. In vitro, JAK2(V617F) was associated with constitutive phosphorylation of JAK2 and its downstream effectors as well as induction of erythropoietin hypersensitivity in cell lines. In vivo, murine bone marrow transduced with a retrovirus containing JAK2(V617F) induced erythrocytosis in the transplanted mice. Taken together, these observations suggest that JAK2(V617F) is an acquired myeloid lineage-specific mutation that engenders a pathogenetic relevance for the PV phenotype in MPD.

Topics: Alleles; Animals; Bone Marrow Cells; Cell Lineage; Cell Proliferation; Cytoplasm; DNA; DNA Mutational Analysis; Erythrocytes; Erythropoietin; Homozygote; Humans; Janus Kinase 2; Mice; Mutation; Myelodysplastic Syndromes; Myeloproliferative Disorders; Phenotype; Phosphorylation; Phosphotransferases; Point Mutation; Polycythemia; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Sequence Analysis, DNA; T-Lymphocytes; Tyrosine; Up-Regulation

The aim of this study was to investigate the curative effect of amifostine (AMF) combined with recombinant human erythropoietin (rhEPO) on the aged patients with myelodysplastic syndrome. Two aged MDS patients (one aged 91; another 86) were treated with amifostine and rhEPO over a period of 4 weeks. The results showed that a short-term curative effect was observed and transfusion interval was prolonged in both patients after 4 week treatment with 5 x 0.4 g AMF plus 3 x 6,000 U rhEPO per week. The reticulocyte count in MDS-RA patient returned to normal at first week of treatment and still remained in normal level for 4 weeks; leukocyte, hemoglobin and platelet values in peripheral blood of MDS-RCMD patient obviousby increased, the abnormally increased reticulocyte value displayed a decrease trend after amifostine plus rh-EPO treatment. In conclusion, amifostine plus rhEPO may have a good therapeutic effect for aged MDS patients, and its clinical long-term curative effect still needs further evaluation.

Topics: Aged; Aged, 80 and over; Amifostine; Drug Therapy, Combination; Erythropoietin; Humans; Male; Myelodysplastic Syndromes; Recombinant Proteins; Time Factors; Treatment Outcome

To investigate the efficaciousness of recombinant human granulocyte colony-stimulating factor (G-CSF) combined with recombinant human erythropoietin (EPO) in the treatment of patients with myelodysplastic syndrome (MDS), the hematological changes in the blood and bone marrow along with clinical features after treatment with G-CSF and EPO in 15 patients were observed. Patients were subcutaneously injected with G-CSF 300 microg/d for 10 days, then injected with EPO 100 U/(kg x d) for 10 days. The results showed that the obvious improvements in granulocytes of blood were found in 10 patients with MDS, improvements in erythrocytes of blood were observed in 7 patients with MDS. No serious side effects occured is all treated patients. In conclusion, treatment of G-CSF in combination with EPO is effective for patients with MDS.

Topics: Adult; Aged; Drug Therapy, Combination; Erythrocyte Count; Erythropoietin; Female; Fever; Granulocyte Colony-Stimulating Factor; Headache; Humans; Injections, Subcutaneous; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

We report on a 53-year-old Japanese female on hemodialysis with myelodysplastic syndrome whose condition improved with recombinant human erythropoietin (epoetin) therapy. In 1992, based on a diagnosis of folic acid deficiency anemia, folate derivatives were administered. However, the anemia did not improve, and red blood cells had to be transfused subsequently. The transfusion volume was gradually increased afterward, as renal failure progressed, probably due to nephropathy by phenacetin. In 1998, when hemodialysis started, epoetin therapy was started with a dose of 3000 units three times per week. In July 2001, myelodysplastic syndrome (MDS) of a refractory anemia type was diagnosed through bone marrow aspiration. Myelodysplastic syndrome might cause an epoetin-resistant renal anemia. Afterwards the transfusion volume was gradually reduced, and transfusions were not performed after March 2002. Improvements of histological findings of MDS as well as anemia were confirmed by bone marrow aspiration in July 2003. This is an unusual case of a patient with a previously existing MDS, who subsequently develops end stage renal disease, and has an amelioration of her underlying MDS with the administration of epoetin over a long-term period, while being treated with chronic hemodialysis, even when not effective for a short-term.

Topics: Erythropoietin; Female; Humans; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Renal Dialysis

How to treat anemia in the myelodysplastic syndrome (MDS) is controversial. Many health care systems refuse to fund erythropoietin on grounds of health economics. A new paper on the effect of anemia in MDS on cardiac remodeling has suggested that a higher treatment threshold level for hemoglobin should be introduced. This would have an impact of the calculation of risk/benefits.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Myelodysplastic Syndromes

Treatment of myelodysplastic syndrome (MDS) with epoietin is costly. However, cardiac morbidity associated with anemia has not been investigated in MDS. We studied this aspect in 39 patients. Echocardiography detected cardiac remodeling in 11 of 12 transfusion-dependent versus 13 of 27 transfusion-free patients (P=0.017). Hemoglobin independently indicated cardiac hypertrophy (P=0.004); each unit increase predicted a 49% reduction in the risk of remodeling confirmed by the area under the ROC curve (0.84, P<0.0001). At Hb 10.7 g/dL, sensitivity was 96% and specificity 64%. Below this level quality of life was poorer. Our results suggest early treatment, to be confirmed by future trials.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cross-Sectional Studies; Echocardiography; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Quality of Life; Recombinant Proteins; Ventricular Remodeling

Topics: Anemia; Clinical Trials, Phase II as Topic; Darbepoetin alfa; Databases, Factual; Erythropoietin; Fatigue; Hemoglobins; Humans; Myelodysplastic Syndromes

To determine the efficacy and tolerance to cyclosporine A (CsA) based therapy in patients with myelodysplastic syndrome (MDS), 16 patients with MDS consisting of 10 refractory anemia (RA) and 6 refractory anemia with accessory blasts less than 10% (RAEB-1) were analyzed. Five patients had hypocellular bone marrows and 11 patients had normocellular or hypercellular marrows. The dose of CsA was 2.5-5.5 mg/(kg.d) for 2 weeks to 2 years (mean 8 months). Two out of 16 patients were treated with CsA alone, 14 patients were treated with CsA, recombinant human erythropoietin, androgens, 1, 25 dihydroxy vitamin D(3) or two or three of them combination with CsA. Treatment responses were classified according to the International Working Group (IWG) criteria as complete remission (CR), partial remission (PR), hematological improvement (HI) and no response (NR). Patients who obtained CR, PR or HI were defined as responders. The results showed that HI was observed in 12 patients, PR in 2 patients and NR in 2 patients. Total response rate was 87.5%. Response rates shown in neutrophil lineage, platelet and erythroid lineage were 83.3%, 66.7% and 60%, respectively; their shortest time required to obtain some hematologic improvement after initiation of CsA therapy was 2 weeks, 1 month and 1 month, respectively. Of 13 patients being transfusion-dependent before treatment, 3 patients did not need transfusion any more and 5 showed the reduced transfusion requirements after CsA therapy. In 10 patients with RA, 9 responded to CsA. Of 6 patients with RAEB, 1 patient had no response and died of RAEB-t and 5 patients had transient responses. One of the latter transformed to CMML and two relapsed. The total response rate decreased to 50% in the patients with CsA therapy lasting more than 3 months at the end of following-up. The adverse effects included hirsutism, hyperplastic gingiva, reversible hepatic and renal dysfunction. In conclusion, the usefulness of CsA based therapy for MDS-RA and RAEB-1 with any marrow cellularity is useful, the CsA dose of 3-5 mg/(kg.d) is safe and efficacious.

Topics: Adolescent; Adult; Aged; Androgens; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Calcitriol; Cyclosporine; Drug Therapy, Combination; Erythropoietin; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

The purpose of this study was to determine the facility and reliability of the World Health Organization (WHO) classification of myelodysplastic syndromes (MDSs) with several observers reviewing the same diagnostic specimens. We also wanted to determine if the WHO classification provided additional information about predictability of clinical response outcome. To accomplish these goals we reviewed 103 previously diagnosed cases of low-risk MDS. We found 92% interobserver agreement (P <.001). Sixty-four of these patients had been entered into clinical trials using growth factors by the Nordic MDS Study Group. The WHO classification reliably predicted therapeutic response to the combination of granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo). The response rate differed significantly between refractory anemia with ringed sideroblasts (RARS) and refractory anemia with multilineage dysplasia and ringed sideroblasts (RCMD/RS) with regard to therapeutic response (75% versus 9%; P =.003). Also, in the group of patients with less than 5% marrow blasts, there was a difference in median survival between patients with unilineage dysplasia (51% surviving at 67 months) and those with multilineage dysplasia (median survival, 28.5 months; P =.03).

Topics: Classification; Drug Therapy, Combination; Erythropoietin; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Observer Variation; Predictive Value of Tests; Prognosis; Retrospective Studies; Survival Rate; Treatment Outcome; World Health Organization

Myelodysplastic syndromes (MDS) are a heterogenous group of hematological clonal malignancies. Patients belonging to the refractory anemia (RA) subtype are usually treated with recombinant human erythropoietin (EPO). Not all patients respond to EPO administration and they are strictly dependent on supportive therapy with red cell blood (RBC) transfusions. The aim of this study was to investigate the efficacy of an alternative combination regimen containing EPO, low-dose methylprednisolone and nandrolone decanoate, in patients with RA unresponsive to EPO administration alone. Ten patients, 4 women and 6 men, median age: 70 years (range: 55-78 years) with refractory anemia unresponsive to EPO administration and RBC transfusion-dependent were included in the study. Median hematological data at baseline were Hb: 8.7 g/dl, (range 6.2-9.8), WBC: 3.35x10(9)/l (range 2.1-4), PLT: 82.5x10(9)/l (range 59-110). EPO 150 U/Kg three times/week subcutaneously, low-dose methylprednisolone 8 mg/day orally and nandrolone decanoate (Decadurabolin) 50 mg two-times/week intramuscularly were administered. As complete response (CR) to treatment was considered the normalization of the peripheral blood and bone marrow smears and biopsy. As partial response (PR) was considered increase in Hb level > or = 2 g/dl, or up to 10 g/dl and discontinuation of RBC transfusions. The response to therapy was evaluated on the 4th week after the initiation of the combination treatment. Bone marrow smear evaluation was carried out at baseline and every six months afterwards. After a 4-week treatment all patients achieved PR and discontinued RBC transfusions. Median and range hematological values on the 4th week after treatment initiation were Hb: 11.2 g/dl, (range: 9.8-12.8), WBC: 4.4x10(9)/l (3.5-6.6), PLT: 130x10(9)/l (95-160). The increase observed in hematological values was significant (p = 0.0001, 0.0004 and < 0.0001, respectively, for Hb, WBC and PLT counts). Treatment was well tolerated. Furthermore, two women, on treatment with the combination regimen, achieved CR one after six months and the second after 12 months. They are alive after 5 years from initiation of the combination treatment. After a median period of 18 months (range 12 to 20 months) in PR three men developed acute leukemia; they received intensive antileukemic chemotherapy without any response and died during the phase of pancytopenia. Three other men achieved CR, one after 6 and two after 12 months of therapy and they ar

Topics: Aged; Androgens; Anemia; Anemia, Refractory; Anti-Inflammatory Agents; Blood Transfusion; Bone Marrow Cells; Drug Therapy, Combination; Erythrocytes; Erythropoietin; Female; Humans; Male; Methylprednisolone; Middle Aged; Myelodysplastic Syndromes; Nandrolone; Recombinant Proteins; Time Factors

Topics: Anemia; Clinical Trials as Topic; Cost-Benefit Analysis; Drug Costs; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Placebos; Quality of Life; Recombinant Proteins; Risk; Treatment Outcome

During the last 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndromes (MDS). It is a clonal disorder, characterised by ineffective haematopoiesis, which can lead to either fatal cytopenias or acute myelogenous leukaemias. Risk-adapted treatment strategies were established, due to the high median age (60 - 75 years) of the MDS patients and the individual history of the disease (i.e. number of cytopenias, cytogenetic changes, transfusion requirements). Allogeneic bone marrow transplantation currently offers the only potentially curative treatment, but this form of therapy is not available for the 'typical' MDS patient, who is > 60 years of age. Therapy with erythropoietin and granulocyte colony-stimulating factor has improved the quality of life of selected patients. The development of target-specific therapies, including antibodies and small molecules directed against specific molecular alterations in MDS, with minimal adverse effects, is the hope for the future. Furthermore, the innovative use of immunomodulatory agents and the optimising of cytotoxic treatment should continue to help in the treatment of MDS.

Topics: Antineoplastic Agents; Arsenic Trioxide; Arsenicals; Erythropoietin; Forecasting; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Oxides; Transplantation, Autologous; Transplantation, Homologous

Glutathione S-transferases (GSTs) are a group of enzymes involved in the detoxification process of carcinogens and other substances. The genes encoding isoenzymes M1 and T1 have "null" alleles, which are polymorphic in humans. Our purpose was to examine whether the GSTM1 and GSTT1 homozygous null genotypes have an impact on the response to recombinant human erythropoietin (rhuEpo) treatment in MDS patients. We analyzed lymphocyte DNA samples from 27 patients with all types of myelodysplastic syndromes (MDS) at the time of diagnosis. All patients were scheduled to receive rHuEpo in doses of 150 u/Kg/day for a period of 12 weeks in order to obtain and maintain stable responses. A multiplex polymerase chain reaction (PCR) was used to genotype both GSTM1 and GSTT1 simultaneously, in responders and non-responders to rhuEpo with respect to various pretreatment parameters: haemoglobin, white blood cell count, platelets, serum erythropoietin, transfusion requirements and bone marrow blasts. The data obtained were evaluated by chi2 test and odds ratio were extracted. Twelve out of 27 evaluated patients demonstrated an erythroid response (44%). Nine out of the 12 patients (75%) responding after 12 weeks of treatment had GSTM1 null genotype (OR=3.4). In contrast, only 1 responder (8.3%) was homozygotes of GSTT1 null genotype. Furthermore, no statistically significant difference in the response rate of the different MDS subgroups was observed. Our results suggest that a treatment with rHuEpo may be effective in achieving a stable erythroid response in MDS patients who carry an homozygous deletion of the GSTM1 gene.

Topics: Aged; Aged, 80 and over; Alleles; Blood Platelets; Blood Transfusion; Bone Marrow Cells; DNA; Erythrocytes; Erythropoietin; Female; Gene Deletion; Genotype; Glutathione Transferase; Hemoglobins; Homozygote; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Odds Ratio; Polymerase Chain Reaction; Polymorphism, Genetic; Recombinant Proteins; Time Factors

The 5q- syndrome is a distinct hematological disorder with typical laboratory, morphological, cytogenetic, molecular, and prognostic features. It is defined as a myelodysplastic syndrome with a medullary blast count <5% and an isolated interstitial deletion of the long arm of chromosome 5, including bands q31-q33. The molecular basis of this disease has not yet been fully elucidated, but there is evidence that a commonly deleted region of 1.5 Mb harbors one or several tumor suppressor genes, the loss of which being the basic event leading to disease activity. The 5q- deletion has been demonstrated in very early hematopoietic precursors, including CD34+CD133+ and CD34+CD38-Thyl+ cells. Analysing data of 60 patients with the 5q- syndrome that were followed over a period of up to 28 years, we found a median age at diagnosis of 66.8 years and a female preponderance with a male to female ratio of 1:1.5. Anemia is usually macrocytic and combined with low reticulocyte counts and high erythropoetin levels. Three types of cytogenetic deletion are most prevalent: del(5)(q13q33), del(5)(q13q31) and del(5)(q22q33). The 5q- syndrome has a good prognosis with a median overall survival of 107 months at a median follow-up of 53 months, and a low probability of transformation to AML. An increase of the medullary blast count to > or =5% or the addition of one karyotypic anomaly severely reduces median overall survival. The most promising therapeutic approach is the novel thalidomide analogue CC5013 that is currently evaluated in an international phase II study.

Topics: Age Factors; Antigens, CD; Chromosome Deletion; Chromosomes, Human, Pair 5; Cytogenetics; Erythropoietin; Female; Gene Deletion; Genes, Tumor Suppressor; Humans; Immunosuppressive Agents; Lenalidomide; Male; Myelodysplastic Syndromes; Prognosis; Sex Factors; Thalidomide

Topics: Adult; Aged; Blood Cell Count; Blood Cells; Bone Marrow Examination; Cytogenetic Analysis; Erythrocyte Transfusion; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Iron Chelating Agents; Middle Aged; Myelodysplastic Syndromes; Patient Selection; Prognosis; Stem Cell Transplantation

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

Increasingly, the therapeutic use of hematopoietic growth factors and immunomodulatory agents is under investigation in patients with low-risk myelodysplastic syndrome (MDS). Studies on amifostine therapy-alone or in combination with erythropoietin (EPO)-indicate that long-term treatment is possibly a decisive factor for therapy success. Therefore, we treated an 81-year-old female, transfusion-dependent patient with MDS and refractory anemia (RA) with amifostine and EPO over a period of 2 years. Following a 4-week induction phase of 5 x 500 mg amifostine plus 3 x 10000 IU EPO per week and maintenance therapy of 1 x 500 mg amifostine plus 3 x 10000 IU EPO per week, normal hemoglobin values were reached in week 14. A long-lasting erythroid response could be observed with a reduction of EPO to 2 x 10000 IU and 1 x 10000 IU and, at present, once a week application of amifostine alone (1 x 500 mg). Apart from the 1st week, the treatment was carried out at the outpatient department and was well tolerated by the patient. The patient experienced a good general clinical condition without further need for hospitalization or blood transfusions.

Topics: Aged; Aged, 80 and over; Amifostine; Anemia; Anemia, Iron-Deficiency; Drug Therapy, Combination; Erythropoietin; Female; Humans; Myelodysplastic Syndromes; Radiation-Protective Agents; Treatment Outcome

Topics: Anemia; Autoimmune Diseases; Clinical Trials as Topic; Doping in Sports; Erythropoietin; Humans; Kidney Diseases; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome; Uremia

Topics: Aged; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Carcinoma, Hepatocellular; Cell Differentiation; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Hypersplenism; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Myelodysplastic Syndromes; Pancytopenia; Reticulocyte Count; Reticulocytes

IMPROVED QUALITY OF LIFE WITH EPOETIN BETA: In a study against a placebo, there was evidence that the quality of life scores were significantly improved in patients treated with epoetin beta, whether they exhibited a solid tumour or a malignant lymphoma. The same was noted in children with cancer exhibiting severe neoplasia and treated with chemotherapy. The efficacy and tolerance to treatment were equivalent, whatever the administration regimen. IN PATIENTS SUFFERING FROM MYELODYSPLASTIC SYNDROMES: A particular entity among malignant blood diseases, myelodysplastic syndromes are at the origin of anaemia against which repeated transfusions and growth factors are proposed with varying results and disadvantages, and against which erythropoietin may be moderately effective (a mean of 25% in non-selected cohorts of patients). DEPENDING ON THE PROTOCOLS OF ERYTHROPOIETIN ADMINISTRATION IN CASES OF MYELODYSPLASTIC SYNDROMES: Recombinant human erythropoietin, irrespective of its concentration in myelodysplastic cell culture, does not appear capable of restoring normal erythropoiesis. The influence of prolonged treatment is not admitted by all. The effects of the addition of growth factors (notably G-CSF) are obvious but some are controversial because of the costs and the prolonged duration of such treatments.

Topics: Adult; Anemia, Aplastic; Blood Transfusion; Child; Erythropoiesis; Erythropoietin; Hemoglobinometry; Humans; Myelodysplastic Syndromes; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

A 65-year-old man with refractory anaemia with an excess of blasts developed an erythematous papular eruption symmetrically distributed on the legs and trunk 3 months after initiation of erythropoietin therapy. The lesions showed a dense neutrophilic infiltrate in the absence of leucocytoclastic vasculitis, and did not fit the criteria of a well-defined neutrophilic dermatosis. Concomitant with the rapid resolution of these skin lesions following erythropoietin discontinuation, typical lesions of erythema elevatum diutinum arose on the extensor surface of the fingers, knees and elbows, which responded to a brief course of dapsone treatment. Although typical and atypical neutrophilic dermatoses have been reported in patients with haematological disorders, they have also been associated with the use of drugs, in particular granulocyte colony-stimulating factor. To our knowledge this is the first report of unclassified neutrophilic dermatosis and erythema elevatum diutinum occurring following the administration of erythropoietin.

Topics: Aged; Colony-Stimulating Factors; Erythema; Erythropoietin; Humans; Male; Myelodysplastic Syndromes; Neutrophil Infiltration

Topics: Aged; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; 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

Topics: Erythropoietin; Hematologic Neoplasms; Humans; Myelodysplastic Syndromes; Neovascularization, Pathologic; Receptors, Erythropoietin

Topics: Adult; Aged; Autoantibodies; Autoantigens; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Thrombopoietin

We present the case of a 71 year-old man with secondary acute myeloblastic leukemia, who was successfully treated with low dose melphalan plus Epo plus G-CSF. We treated the patient with 2 mg of melphalan once a day orally, G-CSF 5 mg/kg 3 times a week and Epo 10.000 ui subcutaneously 3 times a week until the maximum response was obtained. Complete remission was achieved after 16 weeks of continuous treatment. Treatment-related toxicity was not significant. We recommend the use of low dose melphalan in elderly patients with high risk MDS as a treatment option.

Topics: Aged; Anemia, Refractory, with Excess of Blasts; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid, Acute; Male; Melphalan; Myelodysplastic Syndromes; Remission Induction; Risk Assessment

The issue of whether, in patients affected by myelodysplastic syndromes (MDS), haematological response to cytokines, particularly to recombinant human erythropoietin (rHuEpo), is a phenomenon related to the stimulation of normal haemopoietic cells or to the differentiation of cells belonging to the abnormal clone remains an open question. To assess the pattern of response to rHuEpo treatment of bone marrow (BM) cells, we evaluated in 13 low-risk MDS patients with known cytogenetic abnormalities the number of cytogenetically normal and abnormal cells by conventional cytogenetic analysis (CCA) and by a fluorescence in situ hybridization (FISH) technique, enabling the simultaneous visualization of FISH chromosomal abnormalities in morphologically and immunophenotypically identifiable BM elements. Patients responding to rHuEpo presented a lower number of abnormal metaphases at diagnosis in comparison with patients who did not respond (22.74% vs 76.23%, P = < 0.001). This was confirmed by the combined morphological FISH analysis, showing that, before treatment, BM samples from patients responding to rHuEpo had a lower proportion of both FISH abnormal erythroid (36.48% vs 66.93%, P = 0.002) and myeloid (40.76% vs 67.70%, P = 0.014) elements than unresponsive patients. After rHuEpo treatment, responding patients presented a significantly lower proportion of FISH abnormal erythroid precursors than observed before treatment (16.93%vs 36.48%, P = 0.017). Likewise, in responding patients, a significantly lower proportion of FISH abnormal erythroid elements (16.93% vs 66.30%, P < 0.001) was detected in comparison with unresponsive patients. These findings provide evidence that, in low-risk MDS patients with known cytogenetic abnormalities, response to rHuEpo may be due to the proliferation of karyotypically normal erythroid precursors, possibly representing residual normal erythroid elements.

Topics: Adult; Aged; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Risk Factors

Serum soluble transferrin receptor (sTfR) has been reported to be higher in patients with iron deficiency or with elevated erythropoiesis. In the present study, serum sTfR was measured in various anemic diseases and their clinical significance was examined in a multi-institutional joint study. Serum sTfRs in patients with the following anemic diseases were markedly higher than those in normal healthy adults: non-treated iron deficiency anemia (IDA) (9.13 +/- 7.04 mg/l, n = 52, p < 0.0001), anemia of chronic disorders (ACD) (3.45 +/- 1.38 mg/l, n = 20, p < 0.0001), hemolytic anemia (HA) (5.57 +/- 3.26 mg/l, n = 17, p < 0.0001), and myelodysplastic syndrome (MDS) (4.03 +/- 2.83 mg/l, n = 20, p < 0.0001). There were significant differences between IDA and ACD (p < 0.0001), between aplastic anemia (AA) (1.58 +/- 1.26 mg/l, n = 16) and MDS (p < 0.001), and between AA and MDS with refractory anemia (MDS-RA) (4.16 +/- 3.40 mg/l, n = 9) (p < 0.02). In patients with chronic renal failure (CRF), serum sTfR levels and serum sTfR/log serum ferritin ratios (sTfR/F index) were compared in the two classified groups according to Muirhead's criteria, as IDA and non-IDA groups with or without recombinant human erythropoietin (rHuEPO) treatment. Significantly high levels of both serum sTfR (p < 0.0001) and the sTfR/F index (p < 0.0001) were observed in IDA without rHuEPO treatment. Especially in CRF with rHuEPO treatment, the sTfR/F index showed marked elevation in the IDA group (p < 0.0001) compared with serum sTfR (p < 0.001), indicating more diagnostic efficacy of the sTfR/F index for CRF with IDA. In conclusion, the serum sTfR concentration is a useful diagnostic tool for discrimination between IDA and ACD, and between AA and MDS-RA, and for the detection of iron deficiency in CRF patients in the Japanese population.

Topics: Adult; Age Factors; Anemia; Anemia, Hemolytic; Anemia, Iron-Deficiency; Erythropoietin; Female; Ferritins; Humans; Japan; Male; Middle Aged; Myelodysplastic Syndromes; Reagent Kits, Diagnostic; Receptors, Transferrin; Recombinant Proteins; Renal Insufficiency; Sex Factors; Solubility

A 9-year-old girl who had hepatitis-associated aplastic anemia was treated intermittently with methylprednisolone pulse therapy and growth factors (granulocyte-colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEpo) and cyclosporin A (CyA) for over two years. At this time, there was hematological improvement, but chromosome analysis revealed monosomy 7. After six months, there was progression to myelodysplastic syndrome (MDS) (stage in refractory anemia of excess blasts (RAEB)) with monosomy 7, monosomy 6, marker chromosome and with hematological deterioration. She received bone marrow (1.57 x 10(5) cells kg(-1) (patient body weight)) plus cord blood cell (0.3 x 10(7) cells kg(-1) (patient body weight)) transplantation from her brother, 2 years and 7 months after the diagnosis of hepatitis-associated aplastic anemia. Engraftment was achieved after two weeks, and acute graft-versus-host disease occurred in a mild form after four weeks. Hematological remission has been continuous for 20 months after bone marrow transplantation. Transformation of hepatitis-associated aplastic anemia to MDS with the monosomy 7, monosomy 6 and marker chromosome in this patient was considered to have been related to the administration of high doses of immunosuppressive drugs plus growth factors.

Topics: Anemia, Aplastic; Bone Marrow Transplantation; Child; Chromosomes, Human, Pair 6; Chromosomes, Human, Pair 7; Cord Blood Stem Cell Transplantation; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Growth Substances; Hepatitis; Humans; Immunosuppressive Agents; Monosomy; Myelodysplastic Syndromes; Recombinant Proteins; Transplantation, Homologous; Treatment Outcome

Tumour necrosis factor alpha (TNF-alpha) is believed to play a major role in apoptotic death of bone marrow cells in myelodysplastic syndromes (MDS). We explored the efficacy and safety profile of infliximab chimaeric anti-TNF-alpha monoclonal antibody treatment in two MDS patients. They both had low-/intermediate-risk MDS, isolated anaemia and elevated circulating levels of TNF-alpha. Infliximab produced no adverse side-effects and resulted in sustained erythroid responses, one major and one minor. Laboratory studies indicated a remarkable decrease in the percentage of apoptotic stem cells in the bone marrow. This preliminary report indicates that infliximab may have an application as MDS therapy and warrants further investigation.

Topics: Aged; Antibodies, Monoclonal; Apoptosis; Erythropoietin; Female; Hemoglobins; Humans; Infliximab; Leukocyte Count; Male; Myelodysplastic Syndromes; Neutrophils; Platelet Count; Reticulocyte Count; Tumor Necrosis Factor-alpha

Erythropoiesis results from the proliferation and differentiation of pluripotent stem cells into immature erythroid progenitors (ie, erythroid burst-forming units (BFU-Es), whose growth, survival, and terminal differentiation depends on erythropoietin (Epo). Ineffective erythropoiesis is a common feature of myelodysplastic syndromes (MDS). We used a 2-step liquid-culture procedure to study erythropoiesis in MDS. CD34(+) cells from the marrow of patients with MDS were cultured for 10 days in serum-containing medium with Epo, stem cell factor, insulin-like growth factor 1, and steroid hormones until they reached the proerythroblast stage. The cells were then placed in medium containing Epo and insulin for terminal erythroid differentiation. Numbers of both MDS and normal control cells increased 10(3) fold by day 15. However, in semisolid culture, cells from patients with refractory anemia (RA) with ringed sideroblasts and RA or RA with excess of blasts produced significantly fewer BFU-Es than cells from controls. Fluorescence in situ hybridization analysis of interphase nuclei from patients with chromosomal defects indicated that abnormal clones were expanded in vitro. Epo-signaling pathways (STAT5, Akt, and ERK 1/2) were normally activated in MDS erythroid progenitors. In contrast, apoptosis was significantly increased in MDS cells once they differentiated, whereas it remained low in normal cells. Fas was overexpressed on freshly isolated MDS CD34(+) cells and on MDS erythroid cells throughout the culture. Apoptosis coincided with overproduction of Fas ligand during the differentiation stage and was inhibited by Fas-Fc chimeric protein. Thus, MDS CD34(+)-derived erythroid progenitors proliferated normally in our 2-step liquid culture with Epo but underwent abnormal Fas-dependent apoptosis during differentiation that could be responsible for the impaired erythropoiesis.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD34; Apoptosis; Bone Marrow Cells; Cell Culture Techniques; Cell Differentiation; Cell Division; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Fas Ligand Protein; fas Receptor; Female; Humans; Male; Membrane Glycoproteins; Middle Aged; Myelodysplastic Syndromes; Neoplastic Stem Cells

Twelve patients with myelodysplasia were treated with amifostine plus recombinant human erythropoietin (rHuEpo) for 6 weeks. A complete erythroid response was obtained in 2/12(16.6%) and a partial response in 4/12 (33.3%). Two of 8 patients with a platelet count < 100 x 10(9)/L had a complete response, as did 3/9 with a neutrophil count < 1.5 x 10(9)/L. Compared to rHuEpo or amifostine used as single agents, their combination did not offer substantial advantages.

Topics: Aged; Aged, 80 and over; Amifostine; Drug Evaluation; Drug Therapy, Combination; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Treatment with recombinant erythropoietin (EPO) can alleviate anaemia in patients with myelodysplastic syndromes (MDS). The present study, based on a long-term follow-up of 68 MDS patients (26RA, 16 RAS, 26 RAEB) treated with EPO alone, pinpoints pre-treatment variables associated with response induction, response duration and overall survival. Response, defined as an increase in haemoglobin >15gL1 or eliminated erythrocyte transfusion requirements, was observed in 22 of 66 (33%) evaluable patients. The median response duration was 15 (range 3-64+) months. Using univariate logistic regression models, responders displayed significantly lower baseline serum EPO levels (S-EPO), more often normal bone marrow blast cell content (RA/RAS vs. RAEB), normal cytogenetics and no need for erythrocyte transfusion. In a multiple logistic regression model, S-EPO (P=0.009), marrow blast content (P=0.031) and erythrocyte transfusion need (P=0.024) remained associated with response induction. The probability of response for a patient with S-EPO >50UL1, RA/RAS and no transfusion need was 0.79 (0.53-0.93, 95% CI). The median overall survival time from start of EPO treatment was 26 months, significantly longer for responders than for non-responders (49 vs. 18 months, P=0.018). Survival was also predicted by baseline S-EPO; patients with S-EPO >50UL1 (n=50) had a median survival of 17 months, as compared to 65 months for those with S-EPO >50UL1 (n=14, P=0.024). The international prognostic scoring system (IPSS) for MDS predicted survival (P=0.003) and progression to acute leukemia (P<0.001) but not response to EPO treatment. Furthermore, in a logistic regression model with S-EPO and IPSS, S-EPO (but not IPSS) was again a significant predictor for response (P=0.007). Our data facilitate the optimal selection of MDS patients suitable for EPO treatment and pinpoint S-EPO as a powerful predictor of response and overall survival in MDS.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Bone Marrow Cells; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Logistic Models; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins; Survival Rate

Recombinant erythropoietin (r-EPO) induces erythroid responses in patients affected by myelodysplastic syndromes (MDS). However, the response rate declines to 10-15% in MDS with substantial transfusion needs. Both in vitro and in vivo studies have suggested that the addition of growth factors (G-CSF, GM-CSF) or interleukin-3 (IL-3) may potentiate the effect of r-EPO on dysplastic erythropoiesis. The aim of this study was to evaluate the effects of the combination of r-EPO with G-CSF, GM-CSF or IL-3 on the anemia of heavily transfusion-dependent MDS patients, previously unresponsive to r-EPO alone.. Sixty patients with transfusion-dependent MDS, already treated without significant erythroid response with r-EPO alone, were scheduled to receive, for at least 8 weeks, r-EPO subcutaneously at the dose of 300 U/kg t.i.w. in combination with G-CSF (300 microcg s.c. t.i.w., 27 patients), or GM-CSF (300 microcg s.c. t.i.w., 23 patients), or IL-3 (5 microcg/kg s.c. t.i.w., 10 patients), after a two-week pre-phase during which G-CSF, GM-CSF and IL-3 were administered daily at the same dose, as single drugs.. Ten patients were not evaluable for erythroid response because of relevant side effects related to GM-CSF or IL-3 administration. Overall, among 50 patients who completed the study, there were 3 erythroid responses (as determined by complete abolition of red-cell transfusions): 1 (4%) in the G-CSF + r-EPO and 2 (10.5%) in the GM-CSF + r-EPO treated groups. No patient responded to the combination of r-EPO + IL-3. All responders had inappropriate serum levels of endogenous EPO and a relatively short disease duration. Both responders to GM-CSF + r-EPO developed acute myeloid leukemia 2-9 months after the start of the combined therapy. A third elderly patient, treated with the same association, developed marrow hypoplasia. A significant increase in leukocyte count occurred in 96% of patients who received r-EPO + G-CSF, 78.9% of those treated with r-EPO + GM-CSF and 66% of subjects receiving r-EPO + IL-3. A significant increase in platelet count was observed in a single patient receiving r-EPO and GM-CSF, while a slight decrease in platelet count with respect to baseline levels occurred in about 20% of patients.. Our results suggest that the combination of r-EPO with G-CSF, GM-CSF or IL-3, at least at the doses and schedules employed in the present study, has limited efficacy on the anemia of heavily transfusion-dependent MDS patients previously unresponsive to r-EPO alone. However, in this setting of patients, the combination of G-CSF or GM-CSF + r-EPO may occasionally be effective in subjects with low circulating levels of serum EPO and short disease duration.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Transfusion; Colony-Stimulating Factors; Drug Evaluation; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

Ten anemic patients with favorable myelodysplastic syndrome (MDS) were first treated with two 5-week courses of amifostine alone (each course consisted of 200 mg/m(2) of the drug given intravenously three times a week for 3 weeks), followed by an additional two courses combined with subcutaneous erythropoietin (EPO) (150 U/kg, three times a week for 8 weeks). The study patients either had previously failed to respond to treatment with EPO or had pretreatment serum EPO levels of more than 100 mU/ml. None of the patients experienced a complete or partial response in anemia or other cytopenias. We conclude that amifostine alone or in combination with EPO has limited therapeutic activity in MDS.

Topics: Aged; Amifostine; Drug Therapy, Combination; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Recombinant human erythropoietin (rHuEpo) improves anemia in 25% of patients with myelodysplastic syndromes (MDS). The variable and sometimes low response rate to rHuEpo treatment raises the question whether the existence of autoantibodies against erythropoietin (epo) is partially responsible. In the present study we investigated the presence of anti-epo autoantibodies in MDS patients.. Forty-three patients with MDS were studied. Sixteen patients had refractory anemia (RA), 13 had RA with ringed sideroblasts, 3 had RA with excess of blasts (RAEB), 9 had RAEB in transformation and 2 patients had chronic myelomonocytic leukemia. They were divided in 3 groups according to rHuEpo treatment. Group A consisted of 10 patients who did not receive rHuEpo treatment. Group B included 13 patients who were on rHuEpo treatment (150 IU/kg subcutaneously, 3 times weekly) showing an increase of hemoglobin (Hb) values or reduction of transfusion requirements and Group C consisted of 20 patients who did not respond or stopped responding to rHuEpo treatment. Laboratory studies consisted of a complete blood cell count, measurement of serum epo and determination of anti-epo antibodies using ELISA.. There were no significant differences with regard to age and sex among the three groups. No autoantibodies against epo were found in the examined sera, apart from a female patient from group A who showed a low positive titer.. We suggest that anti-epo autoantibodies do not contribute to the development of MDS-related anemia and are not responsible for the modest response to rHuEpo treatment. Further investigation is needed to identify possible reasons for the low response rate to rHuEpo treatment.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Antibody Specificity; Autoantibodies; Autoantigens; Blood Cell Count; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Female; Hemoglobins; Humans; Isoantibodies; Isoantigens; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Failure

A 33 year-old female patient presented with apparent skin pigmentation, sustained liver dysfunction and impaired glucose tolerance. She had received blood transfusions totalling more than 40,000 ml for myelodysplastic syndrome and an allogeneic bone marrow transplant from her HLA-matched sister at the age of 31. Ferrokinetic data showed a significant iron overload. Magnetic resonance imaging suggested excessive iron deposition in the liver. The patient was diagnosed as having secondary hemochromatosis. She was given subcutaneous injections of 6,000 units of recombinant human erythropoietin initially twice a week and then weekly, and phlebotomies were performed to maintain her hemoglobin level above 10 g/dl. Three years later, the total volume of phlebotomized blood reached 24,000 ml, and her ferrokinetic data, serum transaminase levels, glucose tolerance and skin color were significantly improved.

Topics: Adult; Bone Marrow Transplantation; Erythropoietin; Female; Hemochromatosis; Humans; Myelodysplastic Syndromes; Phlebotomy; Recombinant Proteins; Transfusion Reaction; Transplantation, Homologous; Treatment Outcome

Myelodysplastic syndrome (MDS) is characterised by ineffective erythropoiesis and poor progenitor response to erythropoietin (Epo). The aim of this study was to determine the role of the Epo-R mediated signalling in the rise of MDS and whether alteration of signalling pathways contribute to the leukeamogenesis from MDS to acute leukaemia. We analysed Epo and GM-CSF induced ERK1/2 activation, c-Fos expression, STAT-5 and AP-1 DNA binding activities in mononuclear cells of umbilical cord blood (UCBMNC), normal marrow (NBMMNC) or marrow with MDS, AML with prior MDS and de novo AML. In UCBMNC and NBMMNC, Epo and GM-CSF induced the activation of STAT-5 DNA binding and ERK 1/2 activation (n = 6). In contrast, in MDS RA, both signalling pathways were activated only by GM-CSF but not by Epo (n = 7). In acute leukaemia, elevated basal activity of STAT-5 DNA binding appeared in 8/8 cases, which was independent of Epo or GM-CSF treatment. In normal and MDS samples, c-Fos and Egr-1 proteins were not detectable and the expression levels were not increased by Epo or GM-CSF treatment. In contrast, we found an elevated level of c-Fos expression in 5/8 acute leukemia cases, which was not further increased in the presence of Epo or GM-CSF. The elevated c-Fos expression was accompanied by an extremely high blast number in 5/5 cases. These results suggest that impaired ERK/MAPK activation, similarly to impaired STAT-5 activation in Epo-R signalling, may be responsible for the apoptotic process and the block of maturation in MDS RA. The results also suggest that the appearance of the constitutively activated STAT-5 DNA binding and c-Fos expression may be used as a predictor of the blastic transformation.

Topics: Acute Disease; Adolescent; Adult; Aged; Bone Marrow Cells; Case-Control Studies; DNA-Binding Proteins; Enzyme Activation; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia; Male; Middle Aged; Milk Proteins; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myelodysplastic Syndromes; Phenotype; Proto-Oncogene Proteins c-fos; Signal Transduction; STAT5 Transcription Factor; Trans-Activators

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

To determine the expression and function of the c-kit receptor in bone marrow mononuclear cells (BMMNC) of patients with myelodysplastic syndromes (MDS).. Direct immunofluorescence assay and reverse transcriptase-polymerase chain reaction (RT-PCR) were used to detect c-kit protein and c-kit mRNA expressions in the BMMNC of 29 MDS patients and 10 normal controls. Cell culture was used to detect the function of the c-kit receptor.. c-kit protein expression in the MDS group was significantly higher than that in the control group (8.58% +/- 5.28% vs 3.04% +/- 1.49%, P < 0.05). c-kit protein expression in the refractory anemia (RA) group was significantly lower than that in the RA with an excess of blasts (RAEB)/RAEB in transformation (RAEB-t) group (5.12% +/- 2.13% vs 10.01% +/- 5.07%, P < 0.05). The rate of c-kit protein expression was 32.43% in acute myeloblastic leukemia (AML) cases transformed from MDS (t-AML). c-kit mRNA expression in the MDS group was correlated with c-kit protein expression. Interleukin-3 (IL-3) and erythropoietin (Epo), with or without stem cell factor (SCF), upregulated c-kit protein and its mRNA expression. In the presence of IL-3 and Epo, SCF showed significant stimulating effects on the formation of CFU-GM and BFU-E in semi-solid cultures of normal BMMNC, but had no effects on those of the MDS patients.. The protein and mRNA expression of the c-kit receptor in the BMMNC of MDS patients were higher than those of normal controls, and the function of this receptor in MDS BMMNC was abnormal.

Topics: Bone Marrow Cells; Cells, Cultured; Erythropoietin; Hematopoietic Stem Cells; Humans; Interleukin-3; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-kit; RNA, Messenger; Stem Cell Factor

Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) can stimulate megakaryopoiesis in vitro in some myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) patients. We assessed PEG-rHuMGDF combined with granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), interleukin 3 (IL-3), IL6, stem cell factor (SCF) or erythropoietin in 40 MDS, 33 AML and 16 normal bone marrow samples. CD61-positive cells in suspension cultures increased with PEG-rHuMGDF alone in 20/25 RA + RAS, 11/14 RAEB + RAEBt and 29/33 AML cases. Further increases when IL-3 and/or SCF were added to PEG-rHuMGDF occurred in 14/20 RA + RAS, 8/13 RAEB + RAEBt and 18/26 AML cases. CFU-Mk growth was poor overall, but could be enhanced by PEG-rHuMGDF combinations in some patients. Stimulation of megakaryopoiesis by PEG-rHuMGDF can be augmented by IL-3 and SCF in many MDS and AML patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Case-Control Studies; Cell Division; Cells, Cultured; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Hematopoiesis; Humans; Interleukin-3; Interleukin-6; Leukemia, Myeloid, Acute; Male; Megakaryocytes; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Platelet Glycoprotein GPIIb-IIIa Complex; Polyethylene Glycols; Recombinant Proteins; Stem Cell Factor; Stimulation, Chemical; Thrombopoietin

Topics: Adult; Anemia, Aplastic; Antilymphocyte Serum; Bone Marrow Transplantation; Erythropoietin; Hemoglobinuria, Paroxysmal; Humans; Male; Myelodysplastic Syndromes; Splenectomy; Transplantation Conditioning

Myelodysplastic syndromes (MDS) are characterized by a clonal disorder of haemopoiesis with defective growth in vitro. The long-term culture system was used to examine aspects of stromal function in MDS patients. Primary long-term cultures of MDS bone marrow showed poor myelopoiesis with progenitors being detected for a median 3.5 weeks (n = 12) compared with 18 weeks in cultures of normal marrow (n = 10; P < 0.0001). The haemopoietic function of adherent layers was assessed in secondary co-cultures seeded with 5 x 10(6) cord blood mononuclear cells on irradiated normal (n = 27; aged 38-82 years) or MDS (n = 32; aged 41-86 years) adherent layers (> 60% confluent). The median myeloid progenitor number/cord blood co-culture was 135 in 5-week-old cultures with normal adherent layers and 22 in those with MDS layers (P < 0.0001). Myeloid colonies were detectable for a median 11 weeks with normal adherent layers and 6 weeks with MDS adherent layers (P < 0.0001); erythroid colonies were detectable for 7 weeks (normal) compared with 5 weeks (MDS) (P < 0.01). The differences in granulocyte-macrophage colony forming unit (CFU-GM) generation were not related to patient age. Cells from adherent layers of at least half of the primary normal (n = 48) and MDS (n = 26) long-term cultures expressed cytokines [interleukin (IL)-3, IL-1 beta, thrombopoietin (Tpo) and erythropoietin (Epo)] and receptors for retinoic acid (RAR alpha) [IL-2, IL-3, macrophage colony stimulating factor (M-CSF) (Fms) and Tpo (Mpl)]. Only IL-1 beta expression was reduced in week-5 MDS cultures compared with those from normal marrows (P < 0.05). There was also a highly significant decline in IL-1 beta expression in normal (but not MDS) adherent layers between week 5 and week 10. Thus, the adherent layers in cultures grown from MDS patients were haemopoietically defective and showed abnormal IL-1 beta expression.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Cell Adhesion; Coculture Techniques; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Interleukin-1; Interleukin-3; Linear Models; Middle Aged; Myelodysplastic Syndromes; Myeloid Progenitor Cells; Receptors, Cytokine; Reverse Transcriptase Polymerase Chain Reaction; Statistics, Nonparametric; Thrombopoietin; Time Factors

We isolated a human leukemic cell line UT-7/GM from UT-7, which can differentiate into mature erythroid cells with erythropoietin (EPO) treatment. Using this cell line, we examined the effect of a truncated human EPO receptor (EPOR-T) on EPO-induced erythroid differentiation. Transfection studies revealed that UT-7/GM cells expressing exogenous EPOR-T were likely to undergo apoptosis even in the presence of EPO. In addition, EPOR-T-transfected cells could not differentiate into hemoglobin-positive cells after administration of EPO. These results suggest that EPOR-T is a negative regulator of EPO-induced anti-apoptosis and EPO-induced erythroid differentiation. The EPOR-T form was expressed in seven of nine cases of myelodysplastic syndrome but not in normal controls. In patients with myelodysplastic syndrome, dysregulated expression of EPOR-T may cause apoptosis and blockage of erythroid differentiation, resulting in ineffective erythropoiesis.

Topics: Cell Differentiation; Erythropoiesis; Erythropoietin; Genes, Dominant; Humans; Myelodysplastic Syndromes; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; Transfection; Tumor Cells, Cultured

A 35-year-old female presented with isolated thrombocytopenia of autoimmune origin. One and a half years later, hypoplastic myelodysplastic (MDS) was diagnosed. Following treatment with cyclosporin A, erythropoietin and granulocyte colony-stimulating factor, the patient has achieved a sustained hematological remission which is still ongoing after 3 years. Furthermore, to the best of our knowledge, this is the third case described in the literature where treatment with cytokines alone or in combination with immunosuppressive agents has resulted in a long standing cytogenetic response in MDS.

Topics: Adult; Autoimmune Diseases; Cyclosporine; Disease Progression; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Platelet Count; Remission Induction; Thrombocytopenia

P39/Tsugane is a myelomonocytoid cell line derived from a patient with myelodysplastic syndrome (MDS). The cells readily undergo apoptosis in response to various agents, and the cell line has been suggested as a useful model to study apoptosis in MDS. The aims of the present study were to assess differentiation and apoptosis induced with all-trans retinoic acid (ATRA) and etoposide, to characterize the mode of apoptosis in these two model systems, and to assess the influence of granulocyte colony-stimulating factor (G-CSF), which in combination with erythropoietin has been shown to inhibit apoptosis in MDS. ATRA induced differentiation and apoptosis in a concentration- and time-dependent manner. Differentiated cells were partially rescued (by 50%) from apoptosis with G-CSF. Etoposide induced apoptosis in a concentration- and time-dependent manner, but no signs of preceding maturation or G-CSF rescue were detected. ATRA- and etoposide-induced apoptosis were both mediated through the caspase pathway and were partially blocked with the general caspase inhibitor zVAD-fmk. Simultaneous treatment with G-CSF and zVAD-fmk additively blocked ATRA-induced apoptosis. However, the two pathways differed in terms of substrate cleavage during apoptosis. ATRA-induced apoptosis caused actin cleavage, which was not affected by G-CSF, and Bcl-2 downregulation. Etoposide induced a caspase-dependent cleavage of Bcl-2, while actin remained intact. The Fas system did not seem to play a major role in any of these apoptotic pathways. Our results may provide new tools to study the mechanisms of apoptosis in MDS.

Topics: Actins; Acute Disease; Amino Acid Chloromethyl Ketones; Antibodies, Monoclonal; Apoptosis; Blast Crisis; Caspase Inhibitors; Caspases; Cell Differentiation; Cysteine Proteinase Inhibitors; Cytoskeleton; Erythropoietin; Etoposide; fas Receptor; Granulocyte Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Tretinoin; Tumor Cells, Cultured

Topics: Erythropoietin; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Thrombocytopenia is a substantial clinical problem for patients with myelodysplastic syndromes (MDS). Cytokine treatment for granulocytopenia and anaemia may further reduce the platelet counts. We studied serum thrombopoietin levels (S-TPO) in 52 patients with MDS and 96 healthy controls and related the results to clinical and morphological variables. S-TPO was also assessed after treatment with granulocyte-CSF (G-CSF) and erythropoietin (EPO) in 30 of these patients. S-TPO in MDS was not a normally distributed variable; mean value was 394 pg/ml, SD +/-831 and median value 123 (12-5000 pg/ml). The controls showed lower S-TPO levels than the patients (median 78 pg/ml, P = 0.003) whereas no differences between the MDS subgroups were observed (P = 0.86). Patients with ringed sideroblastic anaemia (RARS) showed the highest platelet counts and higher S-TPO levels than the controls (P = 0.005). No association between platelet counts and S-TPO levels was found in the patients (P = 0.67). TPO levels were generally low in patients with refractory anaemia with an excess of blasts (RAEB), but very high levels were found in five patients. Patients with a high transfusion need had higher S-TPO levels, whereas bone marrow blast counts, cellularity or megakaryocytes showed no correlation with S-TPO. Patients with 5q- showed lower TPO levels than the other patients, indicating that thrombopoietin is not a mediator of thrombocytosis in these cases. Treatment with G-CSF + EPO significantly reduced the platelet counts (P = 0.0002), but this change was not related to significant changes in S-TPO levels or morphology. Patients with RARS and thrombocytosis who normalized their platelet counts showed a concomitant reduction in S-TPO. This may suggest that the increased platelet counts observed in RARS may be caused by increased S-TPO levels. In conclusion, our study shows that platelet, megakaryocyte and thrombopoietin regulation is rather complex in myelodysplastic syndromes and that spontaneous or induced thrombocytopenia are not usually mirrored by increased S-TPO levels.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Recombinant Proteins; Thrombocytopenia; Thrombopoietin

Topics: Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Immunoreactive serum erythropoietin (EPO) was measured in anemic and non-anemic patients with acquired non-severe aplastic anemia (AA; n = 22) and myelodysplastic syndromes (MDS; n = 31) receiving or not androgens to examine the effect of androgen therapy and anemia on EPO levels in these disorders. Soluble transferrin receptor (TfR) and absolute reticulocyte count (ARC) were also assayed in order to evaluate erythropoietic activity. AA and MDS patients were stratified for anemia and androgen treatment as follows: 12 untreated anemic patients; 17 anemic patients during androgen therapy; 14 non-anemic patients without any treatment (> 1 year); and 10 non-anemic patients on androgen therapy. Although EPO levels in non-anemic patients were significantly higher than in healthy controls (n = 29) no statistically significant differences in Hb and EPO values were found between non-anemic patients receiving or not androgen therapy. In the linear regression analysis between Hb and log EPO concentration, no statistically significant differences in the slopes between untreated and androgen-treated anemic groups nor between both groups and patients with iron deficiency anemia (n = 23) were observed. However, the y intercept (log EPO) of regression line was significantly higher in androgen-treated anemic patients than in the androgen therapy-free anemic group. Serum TfR levels were higher in treated than in untreated anemic patients, whereas ARC was not different between both groups. These data seemingly indicate that (1) androgens at pharmacological doses do not increase serum EPO levels in non-anemic AA and MDS patients, and (2) in patients with AA and MDS, androgen-driven EPO stimulation is appreciably enhanced by anemia.

Topics: Adult; Androgens; Anemia, Aplastic; Erythropoietin; Humans; Myelodysplastic Syndromes

Epoetin alfa is being used to treat patients with symptomatic anemia of cancer and to prevent or postpone chemotherapy-induced anemia in cancer treatment. As only approximately 50% of unselected anemic cancer patients respond sufficiently to epoetin alfa treatment, careful patient selection according to reliable prediction criteria is of great importance. Predictions of response to epoetin alfa treatment are based either on the degree of blunted erythropoietin response to the anemic condition or on indicators of responsiveness during the early treatment phase. The most accurate predictions of responsiveness, however, are derived from combinations of predictive factors. Combinations of synergistically acting hematopoietic growth factors, particularly epoetin alfa and granulocyte colony-stimulating factor, are beneficial to selected patients with myelodysplastic syndrome and may prolong survival in certain cases. Correction of anemia in cancer patients is particularly important because highly significant correlations have been reported between hemoglobin levels and quality of life in these patients.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Myelodysplastic Syndromes; Neoplasms; Patient Selection; Quality of Life; Recombinant Proteins

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Cytokines; Daunorubicin; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Myelodysplastic Syndromes; Remission Induction; Thioguanine

A 7-year-old German Shepherd dog was referred for evaluation of severe nonregenerative anemia (PCV, 10%; reticulocyte fraction, 0.2%). Cytologic examination of a bone marrow aspirate indicated erythroid predominance and dyserythropoiesis, and a diagnosis of myelodysplastic syndrome (MDS) with erythroid predominance was made. The dog was given a single blood transfusion and was treated with prednisone and recombinant human erythropoietin (EPO). Eight weeks later, anemia had resolved. The dog remained clinically normal 30 months after treatment, with a PCV of 45%. Results suggest that EPO may be useful in the treatment of dogs with MDS with erythroid predominance or erythroleukemia. Additional studies are required to confirm the benefit of EPO to manage MDS-associated anemia in dogs.

Topics: Animals; Blood Transfusion; Dog Diseases; Dogs; Drug Therapy, Combination; Erythroid Precursor Cells; Erythropoietin; Follow-Up Studies; Glucocorticoids; Hematocrit; Humans; Male; Myelodysplastic Syndromes; Prednisone; Recombinant Proteins

To investigate the effects of hematopoietic growth factors (HGFs) on apoptosis of hematopoietic cells in myelodysplastic syndromes (MDS) patients.. CD34+ cells in bone marrow from 12 MDS patients were purified by an immunomagnetic beads sorting system. Apoptosis of hematopoietic precursors was assayed by propidium iodine staining and flow cytometric analysis.. High dose rhEpo partly suppressed apoptosis of hematopoietic cells in MDS patients. At the 7th, 10th, 14th, cultured day, the apoptotic percentages of the high dose Epo group (rhEpo 200 U/ml or 100 U/ml) were substantially lower than that of the low dose group (20 U/ml, 2 U/ml and 0.2 U/ml) and showed a dose-dependent effect with rhEpo. rhGM-CSF and rhIL-3 could also suppress hematopoietic cell apoptosis in vitro, the differences between the high dose group (rhIL-3 200 U/ml or rhGM-CSF 500 U/ml) and the low dose group (rhIL-3 50 U/ml or rhGM-CSF 50 U/ml) were significant. Extensive apoptosis of myelodysplastic hematopoietic cells were markely suppressed when rhEpo and rhIL-3 or rhEpo and rhGM-CSF were given together.

Topics: Adolescent; Adult; Aged; Apoptosis; Bone Marrow Cells; Cells, Cultured; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Patients with myelodysplastic syndrome (MDS) have ineffective in vivo and in vitro erythropoiesis, characterized by an impaired response to erythropoietin (Epo). We examined proliferation and maturation of MDS marrow cells in response to Epo in more detail. Epo-dependent DNA synthesis as well as induction of GATA-1 binding activity in marrow cells from 15 MDS cases were severely reduced as compared with normal bone marrow (NBM). Additionally, the appearance of morphologically identifiable erythroid cells was decreased in MDS cell cultures. These data indicate that both the Epo-dependent proliferation as well as the differentiation induction by Epo is suppressed. To study more upstream events of the Epo signal transduction route we investigated activation of the signal transducer and activator of transcription (STAT) 5. In all 15 MDS samples tested, STAT5 activation was absent or greatly suppressed in response to Epo. In contrast, interleukin-3 induced a normal STAT5 response in MDS cells. Further, in MDS the subset of CD71+ BM cells that is phenotypically similar to Epo-responsive cells in normal marrow, was present. We conclude that the Epo response in MDS is disturbed at an early point in the Epo-receptor (EpoR) signal transduction pathway.

Topics: Adult; Aged; Aged, 80 and over; Bone Marrow; Cell Differentiation; Cell Division; Cells, Cultured; DNA-Binding Proteins; Erythroid-Specific DNA-Binding Factors; Erythropoietin; Female; GATA1 Transcription Factor; Humans; Male; Middle Aged; Milk Proteins; Myelodysplastic Syndromes; Signal Transduction; STAT5 Transcription Factor; Trans-Activators; Transcription Factors

RAS mutations arise at high frequency (20-40%) in both acute myeloid leukemia and myelodysplastic syndrome (which is considered to be a manifestation of preleukemic disease). In each case, mutations arise predominantly at the N-RAS locus. These observations suggest a fundamental role for this oncogene in leukemogenesis. However, despite its obvious significance, little is known of how this key oncogene may subvert the process of hematopoiesis in human cells. Using CD34+ progenitor cells, we have modeled the preleukemic state by infecting these cells with amphotropic retrovirus expressing mutant N-RAS together with the selectable marker gene lacZ. Expression of the lacZ gene product, beta-galactosidase, allows direct identification and study of N-RAS-expressing cells by incubating infected cultures with a fluorogenic substrate for beta-galactosidase, which gives rise to a fluorescent signal within the infected cells. By using multiparameter flow cytometry, we have studied the ability of CD34+ cells expressing mutant N-RAS to undergo erythroid differentiation induced by erythropoietin. By this means, we have found that erythroid progenitor cells expressing mutant N-RAS exhibit a proliferative defect resulting in an increased cell doubling time and a decrease in the proportion of cells in S + G2M phase of the cell cycle. This is linked to a slowing in the rate of differentiation as determined by comparative cell-surface marker analysis and ultimate failure of the differentiation program at the late-erythroblast stage of development. The dyserythropoiesis was also linked to an increased tendency of the RAS-expressing cells to undergo programmed cell death during their differentiation program. This erythroid lineage dysplasia recapitulates one of the most common features of myelodysplastic syndrome, and for the first time provides a causative link between mutational activation of N-RAS and the pathogenesis of preleukemia.

Topics: Acute Disease; Antigens, CD34; Apoptosis; Cell Differentiation; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Genes, ras; Genes, Reporter; Humans; Leukemia, Myeloid; Mutation; Myelodysplastic Syndromes; Preleukemia

We report a case of hypoplastic myelodyplastic syndrome (MDS) (refractory anemia (RA)) in which sustained trilineage haematological response and persistent disappearance of an abnormal chromosome clone were achieved after treatment with combination therapy of cytokines (granulocyte colony-stimulating factor (G-CSF) and erythropoietin (Epo)) and methylprednisolone (mPSL) pulse dose. The patient's haematological recovery was rapid and maintained even after cessation of the therapy. In addition, the predominant chromosome clone 13q- in bone marrow cells disappeared in the fourth week. The patient's improved bone marrow haemopoiesis and disappearance of the abnormal chromosome has continued to the present, 13 months after treatment. The occurrence of both trilineage response and abnormal chromosome disappearance in MDS patients treated with cytokine(s) or steroids is rare. Combination therapy might therefore be advantageous in MDS.

Topics: Anti-Inflammatory Agents; Chromosome Deletion; Cytokines; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Karyotyping; Male; Methylprednisolone; Middle Aged; Myelodysplastic Syndromes

In the present study, we analyzed the capacity of CD34+/CD36- sorted bone marrow cells of myelodysplasia patients (n = 4) to differentiate along the erythroid lineage in the presence of erythropoietin (Epo) and mast cell growth factor (MGF). Two subgroups could be identified. In 6 patients, a normal number of burst-forming units-erythroid (BFU-Es) were cultured from CD34+/CD36- sorted cells. Cells from these patients did have the capacity to differentiate to colony-forming units-erythroid (CFU-Es) progenitors in cell suspension cultures with Epo plus MGF followed by Epo in the culture assay. Moreover, the cells became CD34-/CD36+/gly-cophorin A (GpA)+ after 7 days of culture with Epo plus MGF, a pattern comparable to that of normal progenitors. In contrast, in 8 patients, a different pattern was observed. No BFU-Es or a low number of BFU-Es were cultured from the CD34+/CD36- sorted cell fraction that was, in most of the cases, incapable of differentiating to CFU-E progenitors. Flow cytometry of the sorted population showed that, after 7 days of culture with Epo plus MGF, a high proportion of CD34+/CD36- cells persisted, whereas a low proportion of cells became CD34-/CD36+/GpA+. The unresponsiveness is not caused by the used growth factor combination, because the addition of interleukin-3 did not correct the defect. Evi-1 expression was studied in 9 cases to show whether an aberrant Evi-1 expression correlates with a disturbed erythroid development. Evi-1 expression was shown in 4 of 9 cases, whereas 3 of 9 cases did have a disturbed erythroid differentiation. In summary, the results show that the defects in the erythroid development in a subpopulation of patients with myelodysplasia is localized at an early stage of the erythroid differentiation and is associated with the persistent expression of the CD34 antigen and, in some cases, with the expression of Evi-1.

Topics: Antigens, CD34; Base Sequence; Bone Marrow; CD36 Antigens; Cell Differentiation; Cell Division; Cell Separation; DNA-Binding Proteins; Erythropoiesis; Erythropoietin; Flow Cytometry; Gene Expression Regulation; Hematopoietic Stem Cells; HL-60 Cells; Humans; MDS1 and EVI1 Complex Locus Protein; Molecular Sequence Data; Myelodysplastic Syndromes; Proto-Oncogenes; Stem Cell Factor; Transcription Factors

Topics: Acquired Immunodeficiency Syndrome; Anemia, Aplastic; Antineoplastic Agents; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Neutropenia; Transplantation

The human erythropoietin receptor (EpoR) gene has been cloned and characterized. Very few EpoR genetic abnormalities have been reported so far. Polycythemia vera (PV) is characterized by low/normal serum erythropoietin (Epo) levels with proposed Epo hypersensitivity. Myelodysplastic syndromes (MDS) are characterized by refractory anemia with variable serum Epo levels. Several reports have suggested EpoR abnormalities in both types of stem cell disorders. We analyzed DNA obtained from peripheral blood mononuclear cells of seven healthy controls, 20 patients with myeloproliferative disorders (MPD, 11 patients with PV, five agnogenic myeloid metaplasia with myelofibrosis, four essential thrombocytosis) and eight patients with refractory anemia with ringed sideroblasts (RARS), an MDS variant. The DNA was digested with four restriction enzymes (BamHI, Bgl II, Sacl and HindIII), followed by Southern blot, using a 32P radiolabeled probe, containing 1.5 kb of the human EpoR cDNA. All 20 MPD patients and seven out of the eight MDS patients demonstrated a restriction pattern which was identical to the seven normal controls, as well as to the erythroid cell line K562, and also consistent with the expected restriction map, for all four enzymes tested. One RARS patient had a normal pattern with three enzymes but a different one with HindIII. The HindIII 12 kb large band was replaced by a faint 12 kb band and a new (about 9 kb) band appeared. The EpoR restriction map and the normal pattern obtained with the other three enzymes suggest that this patient has a 3 kb upstream deletion in one allelic EpoR gene. The same molecular pattern was detected in the patient's sister, who suffers from anemia with mild bone marrow (BM) dyserythropoiesis and plasmacytosis. Northern blot analysis showed that the patient's BM RNA carried normal EpoR message. This familial pattern may represent polymorphism. However, the patient's very high serum Epo level, her resistance to treatment with recombinant Epo, and the abnormally low growth rate of in vitro erythroid cultures, suggesting poor response to Epo in this MDS patient as well as the hematological abnormalities in her sister, support the speculation that the different EpoR gene might serve as a genetic predisposing marker and potentially could be involved (probably via post-transcriptional mechanisms and by an interaction with other factors or cytokines) in the pathogenesis. Our data suggest that the EpoR is intact in MPD and in most

Topics: Aged; Blotting, Northern; DNA; DNA, Neoplasm; Erythroid Precursor Cells; Erythropoietin; Family Health; Female; Humans; Leukemia, Erythroblastic, Acute; Male; Myelodysplastic Syndromes; Myeloproliferative Disorders; Prognosis; Receptors, Erythropoietin; RNA; Tumor Cells, Cultured

Long-term follow-up data are presented on changes in peripheral blood counts and Hb requirements of 11 patients with myelodysplastic syndromes (MDS) during iron chelation treatment with desferrioxamine for up to 60 months. The erythroid marrow activity was indirectly evaluated by repeated determinations of the serum transferrin receptor concentration. The efficacy of iron chelation was evaluated by repeated quantitative determination of the liver iron concentration by magnetic resonance imaging. Reduction in the Hb requirement ( > or = 50%) was seen in 7/11 (64%) patients. Five patients (46%) became blood transfusion independent. Platelet counts increased in 7/11 (64%) patients and the neutrophil counts in 7/9 (78%) evaluable patients. All patients in whom iron chelation was highly effective showed improvement of erythropoietic output accompanied by an increase in the serum transferrin receptor concentration. It is concluded that reduction in cytopenia in MDS patients may be accomplished by treatment with desferrioxamine, if the iron chelation is efficient and the patients are treated for a sufficiently long period of time. Exactly how treatment with desferrioxamine works remains a challenge for further investigation.

Topics: Adolescent; Aged; Bone Marrow Diseases; Chromosome Aberrations; Deferoxamine; Erythropoietin; Female; Follow-Up Studies; Hematopoiesis; Hemoglobins; Hemosiderosis; Humans; Iron; Karyotyping; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Receptors, Transferrin; Transfusion Reaction; Treatment Outcome

Ineffective hematopoiesis with associated cytopenias and potential evolution to acute myeloid leukemia (AML) characterize patients with myelodysplastic syndrome (MDS). We evaluated levels of apoptosis and of apoptosis-related oncoproteins (c-Myc, which enhances, and Bcl-2, which diminishes apoptosis) expressed within CD34+ and CD34- marrow cell populations of MDS patients (n = 24) to determine their potential roles in the abnormal hematopoiesis of this disorder. Marrow cells were permeabilized and CD34+ and CD34- cells were separately analyzed by FACS to detect: (1) a subdiploid (sub-G1) DNA population, and (2) expression of Bcl-2 and c-Myc oncoproteins. Within the CD34+ subset, a significantly increased percentage of cells demonstrated apoptotic/sub-G1 DNA content in early (ie. refractory anemia) MDS patients compared with normal individuals and AML patients (mean values: 9.1% > 2.1% > 1.2%). Correlated with these findings, the ratio of expression of c-Myc to Bcl-2 oncoproteins among CD34+ cells was significantly increased for MDS patients compared to those from normal and AML individuals (mean values: 1.6 > 1.2 > 0.9). Bcl-2 and c-Myc oncoprotein levels were maturation stage-dependent, with high levels expressed within CD34+ marrow cells, decreasing markedly with myeloid maturation. Treatment of seven MDS patients with the cytokines granulocyte colony-stimulating factor plus erythropoietin was associated with decreased levels of apoptosis within CD34+ marrow cells and may contribute to the enhanced hematopoiesis in vivo that was shown. These findings are consistent with the hypothesis that altered balance between cell-death (eg, c-Myc) and cell-survival (eg, Bcl-2) programs were associated with the increased degrees of apoptosis present in MDS hematopoietic precursors and may contribute to the ineffective hematopoiesis in this disorder, in contrast to decreased apoptosis and enhanced leukemic cell survival in AML.

Topics: Acute Disease; Adult; Aged; Apoptosis; Bone Marrow; Cell Cycle; Cell Transformation, Neoplastic; Disease Progression; DNA, Neoplasm; Erythropoietin; Female; Gene Expression Regulation; Genes, bcl-2; Genes, myc; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Leukemia, Myeloid; Male; Middle Aged; Myelodysplastic Syndromes; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Recombinant Proteins

Six patients with myelodysplastic syndromes (MDS) and two patients with chronic lymphocytic leukemia, all with severe anemia entered the study. Before treatment reasons of secondary anemia were excluded. Concentration of erythropoietin, iron, transferrin, ferritin were measured before, and in the second and the third month of the trial. A r-HuEpo dosage of 80 U/kg was administered intravenously three times weekly for a minimum of three months. Four patients finished the study. The increase in hemoglobin concentration by 6 g% was observed in one patient with MDS subtype RA. In three other patients who apart from r-HuEpo received chemotherapy transfusion requirements decreased by 90%. Together with increase in hemoglobin decrease in ferritin was observed. The correlation between r-HuEpo and endogenous erythropoietin and ferritin was defined.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Drug Administration Schedule; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Intravenous; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Anemia remains a therapeutic problem in patients with myelodysplastic syndrome (MDS). In view of the recently reported potential of stem cell factor (SCF) in restoring erythropoiesis in combination with erythropoietin (Epo), we first aimed to define a correlation between SCF serum levels and anemia in MDS. Endogenous SCF levels in 50 MDS patients were determined by using a quantitative sandwich enzyme immunoassay. Broad interindividual variations were observed, but SCF serum levels were in the normal range with no correlation to peripheral blood count. A soft agar culture system was used to further define the role of SCF for stimulation of erythroid growth. Bone marrow mononucleated cells of 20 MDS patients (4 refractory anemia, 5 refractory anemia with excess of blasts, 7 refractory anemia with excess of blasts in transition, and 4 chronic myelomonocytic leukemia) were investigated, and SCF plus Epo was able to stimulate burst-forming unit-erythroid significantly more than SCF or Epo alone independent of French-American-British group. When mononucleated cells from six MDS patients (two refractory anemia, two refractory anemia with excess of blasts, and 2 refractory anemia with excess of blasts in transition) with elevated serum Epo levels were incubated in the presence of SCF and autologous serum, a significant dose-dependent stimulation of burst-forming unit-erythroid number and cells per colony was detected. Erythroid differentiation was further enhanced by adding serum with high colony-stimulating activity obtained from patients with severe aplastic anemia. Our data suggest that in MDS patients with high endogenous Epo serum levels SCF alone might be effective in stimulating erythropoiesis in vivo.

Topics: Adult; Aged; Aged, 80 and over; Blood Transfusion, Autologous; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Stem Cell Factor

Topics: Erythropoietin; Humans; Meta-Analysis as Topic; Myelodysplastic Syndromes; Recombinant Proteins

The role of erythropoietin in the pathogenesis of anaemia associated with inflammatory disorders is unclear. We studied serum erythropoietin levels in patients with inflammatory process of varying aetiologies. Serum erythropoietin levels and reticulocyte counts were prospectively measured in 40 patients with inflammatory syndromes and compared with values obtained in 20 patients with myelodysplastic syndromes. Significant inverse correlation between erythropoietin levels and haemoglobin concentration were noted in the 2 groups. The slope of the regression line for patients with inflammatory disorders was lower as compared with that for the myelodysplastic syndromes. In all cases, when the erythropoietin response in relation to degree of anaemia is compared with that which occurs in patients with myelodysplastic syndromes, the inadequate erythropoietin response in patients with chronic inflammatory process becomes evident. In patients with inflammatory process, a relationship between erythropoietin levels and reticulocyte counts were only noted in patients with mildly anaemia (haemoglobin concentration higher than 10.5 g/dl). This study suggests blunted erythropoietin production and impaired marrow response to this hormone in the anaemia which occurs in inflammatory syndromes and supports the hypothesis that these disorders may contribute to the development of the anaemia associated with inflammatory disorders.

Topics: Adult; Aged; Anemia; Chronic Disease; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Inflammation; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Reticulocyte Count

An inherent defect of erythroid differentiation at the colony-forming unit blast (CFU-blast) compartment and (or) an impaired response of early erythroid progenitors (BFU-E) to growth stimulation are both considered to contribute to anemia in myelodysplastic syndromes (MDS). With the intention of improving survival and growth of early erythroid progenitors we investigated the effect of stem-cell factor (SCF) and interleukin-3 (IL-3) alone and in combination with erythropoietin, on the in vitro erythropoiesis of 13 patients with MDS and of three normal controls. SCF and IL-3 alone did not promote erythroid colony growth in MDS, while 3 cases responded to erythropoietin alone. In each of these, BFU-E colony growth could be increased by SCF, which was also found in all normal bone marrows. Altogether 6 cases showed a significant enhancement of BFU-E colony numbers by the combination of SCF and erythropoietin as compared to erythropoietin alone (P = 0.036). Out of the 6 responding cases, 5 belonged to the FAB-classified subgroups refractory anemia (RA) and refractory anemia with ringed sideroblasts (RA/RS) (5/5), while 1 patient was classified as having refractory anemia with excess of blasts (RAEB) (1/4). No patient with refractory anemia with excess of blasts in transformation (RAEB-T) (0/4) responded. In spite of these positive effects, the absolute number of BFU-E colonies remained reduced in all MDS cases when compared to normal controls. IL-3 proved ineffective in increasing the response to erythropoietin in MDS although it increased erythropoietin-induced BFU-E formation in normal controls significantly. We conclude that the striking synergistic effect of SCF and erythropoietin on erythroid colony formation seen with normal bone marrow is conserved in most cases with RA and RA/RS. In RAEB and RAEB-T the intrinsic defect of the erythroid differentiation pathway cannot be overcome by SCF.

Topics: Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; In Vitro Techniques; Interleukin-3; Myelodysplastic Syndromes

A 19-year-old man was diagnosed as having severe aplastic anemia and received high-dose methylprednisolone treatment without hematological response. A second course of high-dose mPSL treatment together with granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) was then started and resulted in trilineage blood cell response. Ten months after the combination therapy thrombocytopenia developed and cytogenetic analysis showed 45,XX,-7, indicating an evolution to myelodysplastic syndrome (MDS) associated with monosomy 7.G-CSF and EPO treatment together with immunosuppression may be an effective therapy in SAA patients, but such a therapy may increase the risk of evolution to MDS.

Topics: Adult; Anemia, Aplastic; Chromosomes, Human, Pair 7; Drug Therapy, Combination; Erythropoietin; Glucocorticoids; Granulocyte Colony-Stimulating Factor; Humans; Male; Methylprednisolone; Monosomy; Myelodysplastic Syndromes

Stem cell factor (SCF), the ligand of the c-kit receptor, is a potent enhancing cytokine for haematopoietic cells in the presence of IL-3, GM-CSF and erythropoietin (Epo). In the clonogenic assays of 63 MDS patients, the addition of rh-SCF + GM-CSF and/or IL-3 induced a significant increase (p < 0.001) in the number and size of CFU-GM. Never reaching the levels of controls, this increase was seen in all FAB subtypes, but particularly in RA. There was no significant increase in cluster formation, even in RAEB or RAEBt. Rh-SCF (10 ng/ml) led to mean increases of up to 26 times in the number of Epo-dependent BFU-E colonies, particularly in RA (p < 0.001) and RAEB (p < 0.05). Individual responses varied widely (especially in RA) from no response to supranormal levels. Added to the weekly refeed of 37 MDS LTBMC, SCF (10 ng/ml) induced only a 7% mean increase in both cell output and the number of clonogenic cells recovered in the supernatant. Immunohistochemical examination of the supernatant showed significant increases in differentiating myeloid cells in all examined cases, and in erythroid cells in 3 cases; blast cells increased in only 3 cases. These data suggest that rh-SCF is capable of at least partially reversing defective MDS myeloid haematopoiesis, and leads no overt risk of leukaemic transformation. Its potent effect on erythroid cells is encouraging for future clinical applications in patients, particularly if they are selected by means of in vitro tests.

Topics: Bone Marrow Cells; Cells, Cultured; Colony-Forming Units Assay; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; In Vitro Techniques; Male; Myelodysplastic Syndromes; Recombinant Proteins; Stem Cell Factor

Human recombinant stem cell factor (rSCF) was tested for its capability of improving the defective growth of hemopoietic progenitors in 28 cases of myelodysplastic syndromes (MDS). In vitro growth and response to rSCF were quite variable. However, in most cases, rSCF stimulated CFU-GM growth induced by rG-CSF, rGM-CSF, rIL-3, 5637 conditioned medium (50-1400% enhancement). rSCF effect was slightly more evident on day 14 CFU-GM and in the presence of rIL-3. BFU-E growth induced by rEPO or rIL-3 + rEPO was enhanced by rSCF in about 50% of cases, in linear correlation with the levels of patients' hemoglobin. rSCF did not increase CFU-E growth, whereas it slightly stimulated CFU-Mk in 33% of the cases. EPO, SCF and, particularly, their combination, enhanced the recovery of normal CFU-E and BFU-E after 7 days of liquid culture. This was less evident in cultures of MDS patients. Conversely, CFU-GM generation in long term liquid cultures, although highly variable, was stimulated by rSCF and, above all, by rSCF + rG-CSF, similarly to what was observed with normal bone marrow samples. SCF seems to enhance in vitro erythropoiesis only in MDS cases presenting without severe anemia. It has little effect on megakaryocytopoiesis, while it seems to be more active on CFU-GM growth and maintenance.

Topics: Cell Division; Cells, Cultured; Drug Synergism; Erythroid Precursor Cells; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Interleukin-3; Macrophages; Megakaryocytes; Myelodysplastic Syndromes; Recombinant Proteins; Stem Cell Factor

The in vitro colony-forming capacities of marrow CD34-positive (CD34+) cells from 25 patients with myelodysplastic syndromes (MDS) were studied. In all patients this purified cell population showed erythroid (burst-forming unit erythroid; BFU-E) or non-erythroid colony growth, both of which were more restricted than non-purified mononuclear cell population under stimulation with erythropoietin (EPO) or granulocyte/macrophage colony-stimulating factor (GM-CSF) alone. MDS patients examined were put into two groups; refractory anemia (RA) or RA with ringed sideroblasts (RA/RARS) and RA with excess of blasts (RAEB) or RAEB in transformation (RAEB/RAEB-t). The CD34+ cells of both RA/RARS and RAEB/RAEB-t exhibited a similarity to the cells of normal individuals in their responsiveness to the addition of interleukin 6 (IL-6), IL-3 or stem cell factor (SCF). SCF caused powerful but highly variable responses in both erythroid and nonerythroid colony formation as compared with IL-6 or IL-3. We demonstrated that MDS marrow hematopoietic progenitor cells reactive to GM-CSF or EPO were additionally stimulated with early-acting hematopoietic growth factors including IL-6, IL-3 and SCF in a fashion similar to those of normal individuals.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Antigens, CD; Antigens, CD34; Bone Marrow; Cell Division; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Myelodysplastic Syndromes

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) and erythropoietin (rhE-PO) were used to treat ten patients with myelodysplastic syndromes (MDS). None of the patients showed a favorable response in erythrocyte and platelet counts following 10 weeks' treatment, although favorable responses in neutrophil counts were observed in eight of ten patients (80.0%) and in seven of eight patients (87.5%) following 2 weeks' and 10 weeks' treatment, respectively. However, one patient with refractory anemia had a delayed favorable response in erythrocyte and neutrophil counts at week 14 in spite of the cessation of combination therapy at week 10. These results indicate that combination therapy with rhG-CSF and rhEPO is not beneficial to patients with MDS, based on the presently used protocol.

Topics: Adult; Blood Cell Count; Drug Combinations; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Failure

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

Using clonogenic assay we investigated the effect of stem cell factor (SCF) on the in vitro growth of clonogenic precursor cells from acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in the presence or absence of recombinant human erythropoietin (rhEpo) or recombinant human granulocyte colony-stimulating factor (rhG-CSF). SCF as a single factor did not induce significant colony formation, and even in the presence of rhEPO or rhG-CSF it very weakly stimulated erythroid colony formation and was rarely capable of inducing myeloid colony formation by clonogenic leukemic cells. In culture dishes supplemented with SCF, both myeloid and erythroid colony formations were dramatically enhanced in MDS, regarding both colony number and size. Colony-formation abilities by MDS progenitors were improved following costimulation with SCF and rhEpo. These results suggest that SCF may have a therapeutic role in restoring hematopoiesis in patients with MDS.

Topics: Acute Disease; Bone Marrow Cells; Cell Division; Cells, Cultured; Drug Synergism; Erythropoietin; Hematopoiesis; Hematopoietic Cell Growth Factors; Humans; In Vitro Techniques; Leukemia, Myeloid; Myelodysplastic Syndromes; Neoplastic Stem Cells; Stem Cell Factor

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; Aged, 80 and over; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Recurrence; Treatment Outcome

To determine the efficacy of recombinant human erythropoietin at pharmacological doses in myelodysplastic syndromes (MDS) without excess of blasts, 20 patients with refractory anemias (RA) or refractory anemias with ring sideroblasts (RARS) were treated in an open study with escalating doses from 40 U/kg to 300 U/kg three times a week subcutaneously during a period of 3 months. Maintenance therapy at the lowest effective dose was continued in responders. A dose response of CFU-E and BFU-E to Epo was analysed at the entry. Bone marrow examination with an in vitro study of hematopoietic progenitors was performed before and after the first three months. Seven of 20 patients responded: a total recovery was observed in 3 patients; one became transfusion independent and a reduction of 50% of the transfusion requirement was achieved in 3 others. 3 patients are still receiving treatment for 2, 3 and 4 years. No significant correlation was found between the in vitro and clinical response. A non parametric analysis of responders and non responders emphasised the importance of a long delay between the diagnosis and the treatment, (p = 0.024) and an endogenous Epo level less than 100 mU/ml (p = 0.025) in order to predict the efficacy of rhEpo. This study offers evidence that patients with refractory anemias without excess of blasts in the bone marrow respond to rhEpo at pharmacological doses. Larger studies are required in order to define the patients who may respond and to elucidate the mechanism of the positive effect of rhEpo.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Bone Marrow; Colony-Forming Units Assay; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

The erythroid abnormality in patients with myelodysplasia (MDS) is multifactorial, with ineffective erythropoiesis and poor in vitro progenitor response to erythropoietin (EPO). Serum EPO concentration is variable among patients for a given haemoglobin concentration. We studied 19 non-transfusion-dependent patients with MDS, and 13 healthy elderly control subjects in an attempt to define the factors governing variability in serum EPO and to further characterise the anaemia of MDS. Serum EPO concentration was appropriate for the degree of anaemia in 15/19 MDS patients, and was positively related to mean cell volume (MCV), mean cell haemoglobin (MCH), and percentage highly fluorescent reticulocytes (% HFR), but not to absolute or percentage reticulocyte count. Although the observed/predicted ratio for serum transferrin receptor (TfR) concentration was low in 12 of 19 MDS subjects, no relationship to haemoglobin concentration, reticulocytes or serum EPO was seen. Serum TfR was positively correlated with WBC and platelet counts. Serum TfR was higher in patients with sideroblastic anaemia than refractory anaemia. Standardized in vivo p50 was positively correlated to red cell 2,3 diphosphoglycerate concentration, although this was not the only factor influencing the oxygen dissociation curve. We conclude that effective erythroid output responsive to endogenous EPO drive in MDS is positively related to MCV, MCH and % HFR. Serum TfR may not represent effective output as precisely as % HFR, but may be proportional to total marrow erythropoietic activity.

Topics: Adult; Aged; Aged, 80 and over; Biological Transport; Erythropoiesis; Erythropoietin; Humans; Middle Aged; Myelodysplastic Syndromes; Oxygen; Predictive Value of Tests; Prospective Studies; Receptors, Transferrin; Recombinant Proteins; Reticulocyte Count; Reticulocytes

The presence of serum or contaminant cells may alter clonal development of haematopoietic progenitor cells in vitro. To investigate the pathogenesis of myelodysplastic syndromes (MDS), marrow progenitor cells from 13 MDS patients were highly purified using monoclonal antibodies including CD34 and immunomagnetic microspheres. The cells positive for CD34 in the purified cells were in the range from 87% to 98%. These purified cells were cultured in serum-free medium with individual colony stimulating factors (CSFs) to investigate whether CD34+ cells from MDS patients have abnormal responses to individual CSFs. Dose response experiments with the purified CD34+ cells and recombinant human macrophage-CSF (rM-CSF), granulocyte-CSF (rG-CSF), granulocyte/macrophage-CSF (rGM-CSF), interleukin-3 (rIL-3) or erythropoietin (rEP) were performed in serum-free fibrin clots in 11 patients. Five patients showed a diminished response to rG-CSF and one patient to rEP. In the remaining six patients the purified CD34+ cells did not respond to a stimulation of any individual CSFs. The results indicate that the progenitor cell growth abnormalities in these disorders involve a defect in the capacity of progenitor cells to respond to stimulation with G-CSF, and present direct evidence for the manner in which myelodysplastic CD34+ cells are impaired.

Topics: Adult; Aged; Antigens, CD; Antigens, CD34; Bone Marrow; Cell Differentiation; Cell Division; Cells, Cultured; Colony-Forming Units Assay; Colony-Stimulating Factors; Culture Media, Serum-Free; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Immunophenotyping; Interleukin-3; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

A 70-year-old man was admitted to our hospital with pancytopenia. He was diagnosed as having MDS (RA), and therapy with subcutaneous S-CSF (100 micrograms/day) was started. His leukocyte count increased from 800/microliters to 1,400/microliters in two weeks. The dose of G-CSF was raised to 200 micrograms/day in the third week, and leukocytes increased to 2,00/microliters. At the fifth week, intravenous EPO (6,000 U x 3 times/week) was added. His leukocyte count increased to 4,000/microliters. EPO therapy was raised to 12,000 U x 3 times/week at the eighth week, his leukocyte count remained at the same level. G-CSF and EPO was stopped at the eleventh week, and leukocytes decreased to the same level as before administration. Throughout the course, his platelet count and reticulocyte count did not change. G-CSF and EPO are known as the stimulators of granuriod and erythroid progenitor, respectively. However, in this case, combination therapy with G-CSF and EPO induced marked increase of granulocytes only. This was an interesting case in relation to the roles of these cytokines in the hematopoietic system.

Topics: Aged; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocytes; Humans; Injections, Intravenous; Injections, Subcutaneous; Leukocyte Count; Male; Myelodysplastic Syndromes

Anemia is a common complication of patients with multiple myeloma (MM) and myelodysplastic syndrome (MDS). Most of these patients often require blood transfusion. 12 patients, including 7 cases of MM and 5 cases of MDS, were treated with rhEPO 10,000 micrograms three times a week for 15 weeks. The hemoglobin in 6 of 7 cases of MM steadily increased and eventually reached normal level without blood transfusion. The number of erythroid precursors in bone marrow was increased significantly and serum ferritin concentration was decreased gradually during EPO administration. However 5 patients with MDS did not show any response to EPO. The adverse side effects were hardly observed in any patients received EPO treatment. It is suggested that rhEPO is a promising preparation for treating MM-associated anemia rather than MDS-associated anemia.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes

The purpose of this study was to improve erythropoiesis in patients with anemia due to myelodysplastic syndromes (MDS). We treated 13 patients first with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) for 6 weeks, then with recombinant human erythropoietin (rhEpo) and rhGM-CSF for the next 12 weeks. Five patients had refractory anemia (RA), 3 refractory anemia with ringed sideroblasts (RAS), and 5 refractory anemia with excess of blasts (RAEB). Ten patients were transfusion-dependent at the time of inclusion. Eleven patients completed this phase II study. Five responded with an increase in hemoglobin level (3 patients) or a reduction in transfusion requirement (2 patients). We registered no response in the remaining 6 patients during treatment. Patients responding to combined treatment had relatively low concentrations of plasma Epo and plasma ferritin before treatment with rhEpo and a normal karyotype throughout the study. Long-term bone marrow cultures did not predict the response. Still, responders seemed to have a higher number of colony-forming progenitors than nonresponders. In conclusion, combined therapy with rhGM-CSF and rhEpo may stimulate hematopoiesis and correct or improve anemia in some patients with MDS.

Topics: Aged; Aged, 80 and over; Anemia; Bone Marrow; Cells, Cultured; Drug Therapy, Combination; Erythropoietin; Female; Ferritins; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Hemoglobins; Humans; Karyotyping; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Neutrophils; Platelet Count; Recombinant Proteins

Topics: Erythropoietin; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Recombinant human erythropoietin (rhEPO) was administered subcutaneously to 13 anemic (Hb < 10 g/dl) patients with myelodysplasia (MDS). rhEPO was given 3 times a week at doses of 75-250 U/kg body weight, over a maximum period of 24 weeks. Five patients (38%) showed a response to rhEPO treatment. rhEPO was well tolerated and without relevant side effects throughout the study. All responding patients had low but detectable pretreatment circulating erythroid progenitor cells (BFU-E) and the response to rhEPO was associated with a significant increase in BFU-E (p < 0.01); concentrations of serum transferrin receptor (TfR) also consistently rose in all responding patients. Baseline erythropoietin (EPO) concentrations did not significantly differ between responders and nonresponders, although 4 out of the 5 responders had relatively low levels of EPO. In conclusion, subcutaneous rhEPO administration appears to be an effective treatment of anemia in a substantial subset of patients with MDS. Relatively low baseline EPO concentrations, detectable pretreatment circulating BFU-E and an early increase in the serum concentrations of TfR seem to be criteria for predicting response to rhEPO in patients with MDS.

Topics: Aged; Aged, 80 and over; Anemia; Bone Marrow; Erythrocyte Count; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Myelodysplastic Syndromes; Receptors, Transferrin; Recombinant Proteins

In a dose titration study we tested the efficacy and tolerance of recombinant human erythropoietin (rhEPO) in 10 patients with myelodysplasia (MDS) and 2 patients with idiopathic myelofibrosis. Patients with a haemoglobin level < 100 g/l were treated as out-patients for 12 weeks with daily doses ranging from 30 U/kg body weight (BW) up to 240 U/kg BW in non-responders. Of the 10 patients with MDS, 6 were suffering from refractory anaemia with sideroblasts (RAS) and 4 from refractory anaemia with an excess of blasts. The median age was 73 years (range 41-81). Two patients with RAS responded with a rise in haemoglobin concentration to > 130 g/l. They had not been transfusion-dependent prior to treatment. Both patients had relatively low serum concentrations of immunoreactive EPO. There was neither a rise in haemoglobin nor a reduction in transfusion dependence in any of the other patients. It may be concluded that rhEPO is possibly effective in a subgroup of MDS patients where the disease is less advanced. None of the transfusion-dependent patients benefited.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Refractory; Anemia, Refractory, with Excess of Blasts; Blood Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Primary Myelofibrosis; Recombinant Proteins

The effect of human recombinant erythropoietin (rhEPO) was investigated in 29 anemic patients with myelodysplastic syndromes (MDS). A rhEPO dosage of 150 U/kg was administered subcutaneously three times weekly for a minimum of 6 weeks. Seven out of 27 evaluable patients (26%) had an effective clinical response to therapy by increasing hemoglobin concentrations by more than 15 g/l (reaching at least 105 g/l) or by eliminating transfusion requirements. Six out of the seven patients responded within four weeks. Three of the responders successfully continued rhEPO treatment 15 months or more. To determine whether it may be possible to predict response to rhEPO, various clinical parameters were examined. Responders were found to be significantly different from non-responders in five aspects: They had less elevated baseline serum EPO levels (92 +/- 33 versus 515 +/- 108 U/l, mean +/- SEM; p = 0.023) and were more often transfusion-independent (71% versus 20% of non-responders; p = 0.022). Furthermore, responders were more often females (71% versus 40% in the non-responding group; p = 0.025), of subtype RA rather than RAEB (four patients and one patient, respectively, compared to seven and nine patients in the non-responding group; p = 0.025), and they predominantly displayed normal karyotypes or a 5q- aberration (86% versus 47%; p = 0.005). We conclude, that rhEPO treatment can reduce anemia in MDS and that certain pre-treatment clinical parameters may be used to predict response.

Topics: Aged; Aged, 80 and over; Anemia, Refractory; Blood Transfusion; Chromosome Deletion; Chromosomes, Human, Pair 5; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Predictive Value of Tests; Prognosis; Recombinant Proteins; Sex Factors

Age-density fractionation, in-vitro erythrophagocytosis, and enumeration of membrane-bound antibodies were monitored for circulating red blood cells (RBC) from five anemic patients with myelodysplastic syndromes (MDS), in relation to administration of recombinant human erythropoietin (rhEPO). The density distribution patterns of erythrocytes from the patients prior to treatment were in accordance with their inability to produce compensating levels of circulating RBC. The complete response of one patient to rhEPO and partial responses of two other patients were accompanied by shifts to larger proportions of low density (young) RBC. In vitro phagocytosis of density-fractionated RBC from the complete responder was similar to those of age-matched non-anemic donors. Elevated erythrophagocytosis prior to rhEPO administration was observed for the partial responders and further increased during treatment in one, suggesting the stimulation of abnormal progenitors producing highly defective erythrocytes. There was no correlation between levels of erythrophagocytosis and RBC membrane-bound immunoglobulins in this group of patients. Our findings suggest that density distribution analysis of circulating RBC coupled with in vitro erythrophagocytosis may provide useful predictive tools for selecting potential responders to rhEPO administration among anemic MDS patients.

Topics: Aged; Aged, 80 and over; Erythrocyte Aging; Erythrocyte Count; Erythrocyte Membrane; Erythrocytes; Erythrocytes, Abnormal; Erythropoietin; Female; Humans; Immunoglobulin G; Male; Middle Aged; Myelodysplastic Syndromes; Phagocytosis; Predictive Value of Tests; Recombinant Proteins; Remission Induction

To evaluate its clinical efficacy as well as its biologic safety, human recombinant Erythropoietin (rh-Epo) was given to 19 patients with myelodysplastic syndromes (MDS) in an open non-randomized study. Among the seventeen evaluable patients only two showed an apparent hematologic response to rh-Epo treatment. In these patients hemoglobin levels increased from a mean pretreatment value of 8.5 and 8.4 g/dl up to 11.7 and 11.3 g/dl respectively and remained relatively stable for several weeks. In one of these patients the transfusion requirement decreased from 4 to 1.5 units per month whereas the other had no transfusion requirement during the whole period of rh-Epo treatment. Interestingly, when the responding patients, after a "wash-out" period of at least ten weeks, received an additional course of rh-Epo results were less impressive. Before treatment the serum level of endogenous Epo was 18 and 110 mU/ml in the two responding patients, whereas a mean value of 532 mU/ml (range 17-2797 mU/ml) was observed in non responders. The treatment of MDS patients with rh-Epo was clinically well tolerated since no relevant side effects were registered. Moreover, no evidence of harmful cytogenetic changes nor activation of myeloid growth factor genes, as determined by Northern blot analysis of GM-CSF and G-CSF gene expression, could be related to rh-Epo treatment. Overall, it appears that administration of rh-Epo is well tolerated but the therapeutic effects appear to be restricted to a minority of patients and a limited period of time.

Topics: Aged; Aged, 80 and over; Cytokines; Erythropoietin; Female; Gene Expression; Humans; Male; Middle Aged; Myelodysplastic Syndromes; 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

A favorable prognosis and a low rate of leukemic transformation has been attributed to the 5q- syndrome, a myelodysplastic syndrome (MDS) characterized by macrocytic anemia, hypolobulated micromegakaryocytic hyperplasia, and an interstitial deletion of chromosome 5. We examined the characteristics and outcome of 43 consecutive patients in our institution strictly defined by morphologic criteria and a solitary 5q- cytogenetic defect. The median age at diagnosis was 68 years, with a clear female predominance (7:3). Eighty percent of the patients were red blood cell transfusion-dependent at diagnosis and all untransfused patients had macrocytic indexes. In contrast, significant neutropenia or thrombocytopenia was rare. The French-American-British (FAB) class distributions were RA (72%), RARS (7%), RAEB (16%), and RAEB-IT (5%). At a median follow-up of 31 months, 56% of the patients survive, with a projected median survival of 63 months. The incidence of acute leukemia was 16% and was uniformly fatal. Clinical hemosiderosis occurred in 28% of the patients, resulting in two deaths. Neither survival nor the risk of leukemic transformation was predictable from initial clinical parameters, including FAB classification, Bournemouth score, and degree of aneuploidy. The lack of significant neutropenia and thrombocytopenia seemed to account for a very low incidence of infection and bleeding resulting in a prognosis equal or superior to historical patients with MDS. Therapeutic endeavors, including the use of corticosteroids, androgens, cis-retinoic acid, pyridoxine, and danazol, were largely unsuccessful.

Topics: Acute Disease; Adult; Aged; Aged, 80 and over; Blood Transfusion; Bone Marrow; Cell Transformation, Neoplastic; Chromosomes, Human, Pair 5; Erythropoietin; Female; Gene Deletion; Humans; Leukemia; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis

Neoplasias, especially in their more advanced stages, are often associated with chronic anemia of malignancy which impairs the patient's physical ability and quality of life.. Forty-two patients with chronic anemia associated with hematological malignancies (18 multiple myelomas, 10 myelodysplastic syndromes) or solid tumors (9 breast cancers, 5 colon cancers) were treated with 150-300 units/kg rHuEPO for a median time period of 16 weeks. Response was defined as an increase of the initial hemoglobin level by at least 2 g/dl.. The response rates for solid tumors were comparable (44.4% and 40% for breast cancer and colon cancer, respectively), whilst the response in patients with hematological malignancies depended strongly on the disease entity (77.8% for multiple myeloma, 10% for myelodysplastic syndrome). Pretreatment serum levels of endogenous erythropoietin (EPO) were significantly higher in non-responding patients than in responders. During rHuEPO therapy, EPO levels in non-responders increased even further, while they remained basically unchanged in responding patients. In responders, the WHO performance status before the start of rHuEPO therapy was more favorable and showed impressive improvement during the course of treatment. The median survival time of responders was 28.0 months as compared to only 9.2 months for non-responders. Clinical symptoms of anemia subsided or at least considerably improved under successful rHuEPO therapy. With the exception of occasional flu-like symptoms, no undesirable effects of rHuEPO treatment were observed.. In conclusion, rHuEPO treatment corrected anemia of malignancy both in patients with hematologic disease and in those with solid tumors, but responsiveness varied considerably amongst the different disease entities.

Topics: Aged; Aged, 80 and over; Anemia; Breast Neoplasms; Chronic Disease; Colonic Neoplasms; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Multiple Myeloma; Myelodysplastic Syndromes; Survival Rate; Treatment Outcome

It has been recently demonstrated that erythropoietin increases the haemoglobin levels in anemia secondary to chronic renal failure. Moreover some recent experiences also suggested a possible role in the treatment of MDS. From April 1990 to April 1992, 23 patients (16 males and 7 females, median age 63.5 years) affected with low risk myelodysplastic syndrome (MDS) were treated with recombinant human erythropoietin (rHuEPO) to ameliorate Hb levels and transfusional requirement. All patients received high doses of rHuEPO (800 U/Kg weekly s.c. in 2-3 divided doses, for 3 months). A complete remission, defined as stable normalization of Hb level, was achieved in 1/23 patients. This patient had refractory anemia, by FAB criteria. A partial response, defined as stable increase of Hb levels > or = 1 g/dl and/or reduction of transfusional requirement > or = 50% lasting at least 3 months, was achieved in 7/23 patients. Patients with a partial response received rHuEPO at increased dosages (1200 U/Kg weekly s.c. 2-3 times): 1/7 achieved a complete response, 4/7 remained stable and 2/7 decreased to pre-therapy Hb value. These results suggest that rHuEPO may be a promising therapeutic tool for some MDS patients.

Topics: Adult; Aged; Aged, 80 and over; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Female; Hemoglobins; Humans; Immunologic Factors; Male; Middle Aged; Myelodysplastic Syndromes; Pilot Projects; Recombinant Proteins; Remission Induction; Treatment Outcome

Serum erythropoietin (EP) concentration was measured by the recombinant EP-based radioimmunoassay and was examined to standardize the hemoglobin (Hb) related level of 144 normal control and 56 patients with iron deficiency anemia and hemolytic anemia excluding paroxysmal nocturnal hemoglobinuria. The standardization was achieved by logarithmic regression of the EP titier on Hb either by the two-phase linear form or by the third degree sigmoid form at a 95% confidence limit for each regression. The third degree regression was found to be preferable from the view point of both statistics and the negative feedback mechanism. The average and scattering of the deviation from the standard level thus determined of the disease groups indicated that the EP level is: (1) 12 fold higher than the standard level in 42 aplastic anemias (the most in excess and a few in standard). (2) three fold higher than that in 27 myelodysplastic syndromes (relatively higher dispersed state). (3) 29% of the standard level in 33 anemias associated with chronic renal failure (deficient state). (4) 105% of the extrapolated standard level in 22 polycythemia veras (standard state). The standardization of Hb-related Ep titer may provide new pathophysiological approaches in a variety of hematopoietic disorders.

Topics: Anemia, Hemolytic; Anemia, Hypochromic; Erythropoietin; Hemoglobins; Humans; Myelodysplastic Syndromes; Polycythemia Vera; Radioimmunoassay; Reference Standards

Sera of 25 healthy controls and 75 patients suffering from myelodysplastic syndromes (MDS) were investigated for serum concentration of interleukin-1 alpha (IL-1 alpha), IL-3, IL-6, granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), erythropoietin (Epo), and tumor necrosis factor-alpha (TNF-alpha). According to French-American-British (FAB) classification, 21 refractory anemia (RA), seven refractory anemia with ring sideroblasts (RARS), 15 chronic myelomonocytic leukemia (CMML), 12 refractory anemia with excess of blasts (RAEB), and 20 RAEB in transformation (RAEBt) were examined. TNF-alpha levels were inversely correlated with lower levels of hemoglobin concentration (r = -0.31, p = 0.005), irrespective of the requirements for transfusion in anemic MDS patients. Significant differences in TNF-alpha levels between CMML (26.2 +/- 5.9 pg/ml) and the FAB subgroups (16.1 +/- 1.6 pg/ml) were detected. There was an overall inverse relationship between the level of erythropoietin and the degree of anemia, but a wide range of Epo response between patients with similar hemoglobin concentrations. Serum levels of IL-1 alpha and GM-CSF were undetected in most of the patients. In 57% of the samples there were detectable levels of G-CSF, without a correlation of the serum levels with blood cell counts, nor with any of the FAB subcategories. Overall, 29% and 25% of the patient sera exhibited elevated IL-3 and IL-6 levels, respectively. There was no correlation of the serum levels with any of the blood counts, other cytokines, nor FAB subcategories. In conclusion, simple negative feedback mechanism between a specific cytokine and the production of blood cells seems not to be the case in MDS, except for red cell production and erythropoietin concentration. Our data may suggest the involvement of TNF-alpha in the pathogenesis of anemia in MDS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-1; Interleukin-3; Interleukin-6; Male; Middle Aged; Myelodysplastic Syndromes; Tumor Necrosis Factor-alpha

This paper summarizes results of rhuEPO--treatment obtained by different authors in 27 patients with a myelodysplastic syndrome (MDS). Only 1/3 of all patients with a MDS were responsive to rhuEPO treatment, while in 2/3 of these subjects no amelioration of anaemia was noticed, even after extremely high doses of this hormone. A detailed description of a patient with MDS, which was observed by the authors, is presented. In this patient the anaemia was refractive even after very high doses of rhuEPO administered for 10 weeks.

Topics: Anemia; Erythropoietin; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Effects of recombinant human erythropoietin (rhEpo) and the combination of recombinant human interleukin-3 (rhIL-3) or recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) with rhEpo on erythroid colony formation were examined in vitro in 13 patients with aplastic anemia and 16 with myelodysplastic syndromes (MDS). The methylcellulose cultures of marrow cells from normals and the patients yielded no erythroid colonies in the absence of rhEpo. In normals, CFU-E and BFU-E colony formation was significantly increased by adding either rhIL-3 or rhGM-CSF with rhEpo, compared with rhEpo alone, and rhIL-3 was more potent than rhGM-CSF to form colony-forming units and burst-forming units of erythroid (CFU-E) (BFU-E) colonies. By adding rhIL-3 with rhEpo, CFU-E colony formation was increased in half of patients with RA, compared with rhEpo alone, and by rhGM-CSF, in one third. Approximately one third or one fourth of the patients with MDS showed increased BFU-E colonies when rhIL-3 or rhGM-CSF were added to rhEpo. Cultures containing rhIL-3 or rhGM-CSF with rhEpo yielded larger numbers of BFU-E colonies in half of the patients with nonsevere aplastic anemia than those containing rhEpo alone. These observations suggest that the combination of these growth factors, especially rhIL-3 with rhEpo, is applicable to the treatment of anemia in some patients with aplastic anemia and MDS.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Bone Marrow; Bone Marrow Cells; Child; Child, Preschool; Colony-Forming Units Assay; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; In Vitro Techniques; Interleukin-3; Male; Middle Aged; Myelodysplastic Syndromes; Prospective Studies; Recombinant Proteins

In order to investigate, whether heme would induce a response in myelodysplastic syndromes (MDS), 14 symptomatic patients (4 RA, 3 RARS and 7 RAEB) were treated with infusions of heme arginate 3 mg/kg body weight on 4 consecutive days, mostly for six cycles at 2-week intervals. Three of 14 patients (21%) showed an improvement in anemia (97-152, 79-120 and 92-114 g/l) within a few weeks, and 1 showed a milder increase in hemoglobin level (102-118 g/l). Of the 2 responders with marked thrombocytopenia, 1 showed an improvement in the platelet count (7-37 x 10(9)/l) and her regular need for red cell and platelet transfusions ceased. Some regression in bone marrow (BM) cytology was seen in all 3 responders. One of the responders is still in remission 41 months after cessation of the treatment, while in the other 2 the response lasted for 26 and 5 months. Four patients progressed during the treatment: 1 RA to RAEB, 1 RAEB to RAEBt and 2 RAEB, both with very complex chromosomal abnormalities at the beginning of the therapy, to acute erythroleukemia (AML-M6). Pretreatment delta-aminolevulinic acid synthase and heme synthase activities were generally low. Five patients had mild thrombophlebitis, but not after the infusion procedure was changed. No other side-effects common to growth factors occurred. In conclusion, it is likely that heme arginate has a therapeutic effect on some MDS patients, obviously by stimulating erythropoiesis. The response may be long-lasting.

Topics: Adult; Aged; Alanine Transaminase; Arginine; Aspartate Aminotransferases; Bone Marrow; Creatinine; Erythropoietin; Female; Heme; Humans; Karyotyping; Male; Middle Aged; Myelodysplastic Syndromes

A delay in red cell recovery after ABO-incompatible bone marrow transplantation (BMT) is often observed. The authors experienced a case of prolonged anemia after a major ABO incompatible BMT for myelodysplastic syndrome which was successfully treated with recombinant human erythropoietin (Epo). Effects of Epo were confirmed by the recurrence of anemia after withdrawal of Epo as well as the rapid reincrease in reticulocytes on readministration. The patient received a dose of Epo which was similar to the amount used for renal anemia, however serum concentration of Epo after administration exceeded endogenous Epo levels. Epo may have a beneficial role in the treatment of prolonged anemia after BMT.

Topics: Anemia; Blood Group Incompatibility; Bone Marrow Transplantation; Erythropoietin; Humans; Male; Middle Aged; Myelodysplastic Syndromes

We treated a patient with therapy-related myelodysplastic syndrome (MDS) with human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo). The patient achieved a hematological remission which continued for more than 16 months despite discontinuation of the treatment. Before the treatment with GM-CSF and Epo the patient had severe pancytopenia, required frequent red cell transfusions, and experienced episodes of severe infection, but after the therapy he no longer needed transfusion and no longer had the infection. While the patient remained in hematological remission, bone marrow examination revealed trilineage dysplasia, and cytogenetic analysis showed an abnormal karyotype [48, XY, +8, +der(1q5p)] in 100% of the metaphases examined. These findings suggest that the hematological remission of this patient may not result from the recovery of the non-clonal hematopoiesis of a normal clone, but result from the monoclonal hematopoiesis of a neoplastic clone.

Topics: Blood Cell Count; Bone Marrow Cells; Chromosome Banding; Clone Cells; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Time Factors

Topics: Erythropoietin; Humans; Myelodysplastic Syndromes

In an attempt to determine predictors of response to recombinant human erythropoietin (r-HuEPO) therapy in 20 patients with various subtypes of myelodysplastic syndrome (MDS), plasma concentrations of transferrin receptor protein were measured before and after 4 doses of r-HuEPO. An r-HuEPO dosage of 150 U/kg was administered subcutaneously 3 times weekly and increased to 300 U/kg in patients who failed to raise plasma concentrations of transferrin receptor protein by at least one third. Ten (50%) patients had an effective clinical response to therapy by reducing (greater than 50%) or eliminating transfusion requirements, or by showing an improvement in haematocrit of greater than or equal to 6 percentage points. Changes in plasma transferrin receptor protein concentrations failed to predict which patients would eventually respond to r-HuEPO therapy. A subset of MDS patients demonstrated a delayed response to therapy in order to achieve a satisfactory clinical outcome. Precise predictors of response, either laboratory or clinical, remain to be determined. Continued research is warranted in this group of patients in order to specifically target r-HuEPO therapy. It is, however, likely that r-HuEPO therapy will have an effective and important role in this subset of MDS patients.

Topics: Anemia; Blood Transfusion; Erythropoietin; Hematocrit; Humans; Myelodysplastic Syndromes; Receptors, Transferrin; Recombinant Proteins

Topics: Aged; Erythrocyte Count; Erythropoietin; Humans; Leukocyte Count; Male; Myelodysplastic Syndromes; Neutrophils; Platelet Count; Recombinant Proteins; Reticulocytes

Four-stem-cell assays, which evaluate megakaryocytic (CFU-Meg), immature and mature erythropoietic (BFU-E, CFU-E), and granulocyte-macrophage (CFU-GM) colony formation, were performed in nine patients with myelodysplastic syndromes (MDS). The CFU-Meg, BFU-E, and CFU-E colony growths were disturbed more often than the CFU-GM colony formation. A CFU-E increase was not recognized in most MDS patients, but a dose-dependent increase of bone marrow CFU-Es in response to erythropoietin (EPO) was recognized only in two refractory anemia (RA) patients whose CFU-Es were more than one tenth of normal controls. One patient with RA and the other with chronic myelomonocytic leukemia (CMML), both of whose bone marrow CFU-Es did not increase at the higher dose of EPO in vitro, were treated with recombinant human EPO (rHuEPO), resulting in no effects. The responsiveness of patients with MDS to various recombinant hemopoietic factors might be predicted by both the residual degree of bone marrow hematopoietic precursor cells and the response of stem cells to the higher doses of each hemopoietic factor.

Topics: Adult; Aged; Anemia; Bone Marrow; Colony-Forming Units Assay; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Leukemia, Myelomonocytic, Chronic; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Nine patients with myelodysplastic syndromes and one patient with agnogenic myeloid metaplasia have been treated with recombinant human erythropoietin (rhEpo), at the dose of 150 U/kg/day. Although serum Epo levels were correlated with hemoglobin concentrations in the whole population of patients, they clearly appeared inadequate in some instances, if compared to those of a group of control subjects with iron deficiency anemia. Moreover, no correlation was found between serum Epo and reticulocytes. Six patients showed a partial or complete response to the treatment and the outcome was not correlated with the pre-therapy serum Epo levels; however, serum Epo was less than 100 mU/ml in three of four patients who achieved a complete response. The mechanism(s) by which Epo stimulated erythrocyte production in myelodysplastic patients is unclear, because the number of both the reticulocytes and erythroid progenitors remained unchanged during and at the conclusion of a three months' therapy. Further studies are needed to better define the optimal dosage required to correct anemia in myelodysplastic syndromes, and to clarify rhEpo mechanism of action in these diseases.

Topics: Aged; Bone Marrow; Erythrocyte Count; Erythroid Precursor Cells; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Primary Myelofibrosis; Recombinant Proteins; Remission Induction; Reticulocytes

Topics: Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoietin; Hematopoietic Stem Cells; Humans; Myelodysplastic Syndromes; Myeloproliferative Disorders; Thrombocytosis

Hemopoietic growth factors are used with increasing frequency in the treatment of patients with myelodysplastic syndromes (MDS). While a response occurs regularly, it has not been unequivocally resolved whether this effect is due to the stimulation of normal hemopoiesis or to induced maturation of the abnormal clone. To determine whether selective responses to colony-stimulating factors of normal versus abnormal clones occurred, cytogenetic analysis was performed on bone marrow cells of MDS patients before and during in vivo treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF) or recombinant human erythropoietin (rhEPO). A proliferation of additional clones could be demonstrated by karyotypic analysis in one patient during GM-CSF therapy and in two patients during rhEPO treatment. Two patients, initially with completely normal cytogenetics, developed a mixture of normal and abnormal metaphases during treatment. Two patients, initially with all abnormal metaphases, developed normal metaphases during treatment with GM-CSF. A mosaic of normal and abnormal metaphases was present in six patients. The percentage of abnormal metaphases increased in three patients during GM-CSF treatment, and in one patient during rhEPO therapy. The cytogenetic anomalies in one patient persisted after clinical response to treatment, suggesting that GM-CSF enhanced maturation of the abnormal clone. These data indicate that cytokine therapy in MDS may have diverse effects on hematopoiesis.

Topics: Adult; Aged; Aged, 80 and over; Bone Marrow; Cytogenetics; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

The clinical and ferrokinetic effects of escalating doses of subcutaneously administered recombinant human erythropoietin (rh-EPO) were studied in ten patients with myelodysplastic syndromes and severe transfusion-dependent anemia. Red blood cell transfusion requirements diminished in four patients, and one of the patients eventually became transfusion independent with an EPO-induced rise of Hb from 7.7 g/dl to 12.3 g/dl. Endogenous serum levels of EPO were significantly increased in all patients (100-5700 mU/ml), but three of four responders had a relatively low baseline level. The effective red cell iron turnover (RCIT) improved in two responding patients and even normalized in one patient. This increase in RCIT was accompanied with a decline in the ineffective red cell iron turnover (IIT). The other responding patients had a relatively preserved RCIT before EPO treatment. EPO therapy further increased the fraction of IIT in the latter patients. Red cell survival time did not increase during EPO therapy, even in the responding patients. One transient and one maintained increase in platelet count were observed. Disease progression with a sustained increase in blast cells in one patient and a transient elevation of blasts in another patient was seen. No other side effects of EPO therapy were observed. These results suggest that anemic MDS patients with low serum EPO levels and relatively spared effective erythropoiesis as measured by ferrokinetic studies may be the best candidates for treatment with recombinant human EPO.

Topics: Adult; Aged; Anemia; Bone Marrow Cells; Cytogenetics; Erythrocyte Aging; Erythropoietin; Female; Granulocytes; Hematopoiesis; Humans; Iron; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

The serum erythropoietin (EPO) concentration in patients with myelodysplasia (MDS) varies widely at similar hemoglobin concentrations, although the reasons for this variation are unclear. We have studied the pharmacokinetics of an i.v. bolus of recombinant human EPO in ten subjects with myelodysplasia. Basal serum EPO concentration varied from 210 to 5984 mU/ml. Plasma half-time clearance (t1/2) varied from 3.9 to 20.0 h. A significant positive correlation was found between t1/2 and basal EPO concentration. An increase in immature peripheral blood reticulocytes was found on days 1 and 2 after EPO treatment; this may represent either an effect on hemopoiesis or on reticulocyte release from the bone marrow.

Topics: Aged; Aged, 80 and over; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; RNA

12 patients with myelodysplastic syndromes were treated with recombinant human erythropoietin (r-epo). 5 patients had stable anemia, 78-92 g/l, and 7 were transfusion-dependent. In 11 patients, r-epo was given intravenously three times a week, with dose escalation after 4 and 8 wk if hemoglobin did not increase more than 15 g/l. The doses were 600, 1500 and 3000 U/kg bodyweight/wk. The 12th patient was treated subcutaneously with a dose of 560 U/kg/wk. 3 patients showed a significant response with an increase in hemoglobin of greater than or equal to 15 g/l. 2 of these had stable anemia before treatment and increased in hemoglobin from 87 to 116 g/l and from 80 to 99 g/l, respectively. The 3rd patient was transfusion-dependent and rose to a stable hemoglobin level between 76 and 80 g/l without transfusions. 2 patients showed a reduction of their transfusion need. Mean initial serum erythropoietin in the responding group was 366 U/l compared to 1049 among the non-responders (p = 0.367). Response was observed in 5/7 patients without bone marrow sideroblasts and in 0/5 patients with sideroblasts (p = 0.027). Erythropoietin seems to be an effective and well-tolerated treatment for a certain proportion of patients with MDS. A larger patient material might provide a model for predicting responses.

Topics: Adult; Aged; Aged, 80 and over; Drug Administration Schedule; Erythropoietin; Female; Fever; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Thrombocytopenia

The majority of patients with cancer become anemic during the course of their disease. This anemia appears to be due largely to a blunted erythropoietin (Epo) response and an impaired ability of the bone marrow to respond to endogenous Epo. Both are exacerbated by chemotherapy and radiation therapy. Recombinant human erythropoietin (rhEpo) ameliorates the anemia associated with malignancy. However, we do not yet know whether rhEpo will decrease the need for homologous blood transfusions and improve the quality of life of cancer patients. While rhEpo will greatly alter the treatment of anemia in the 1990s, its precise role in the treatment of oncology patients is still being elucidated.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

We have established a new nonlymphoid leukemic cell ine from a patient with myelodysplastic syndrome (MDS), which progressed to overt leukemia. The parental cell line and a subline derived from this line have absolute dependency on several cytokines for their long-term survival and growth. The parental line designated F-36P requires granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) for continuous growth, while a subline designated F-36E can be maintained in the presence of erythropoietin (Epo) alone. When these cytokines are depleted, both the parental and the subline cells die within several days, even in medium supplemented with fetal calf serum (FCS). F-36E, maintained in the presence of Epo, constitutively synthesizes hemoglobin at a significant level. F-36P, which is usually maintained in the presence of GM-CSF or IL-3, can be induced to synthesize hemoglobin when GM-CSF or IL-3 is substituted by Epo. The surface marker profile shows that the F-36P cells are positive for the leukocyte common antigen (CD45) and some common multilineage markers such as CD13, CD33, and CD34, and negative for T- and B-cell antigens and mature myelomonocytic antigens. However, some monoclonal antibodies recognizing erythroid and platelet glycoproteins react with these cells. Thus, this cell line has a multilineage phenotype, suggesting that the transformation event occurred in a multipotent stem cell. It is also evident that the F-36 cells can be induced to differentiate into the erythroid lineage in the presence of Epo. This, to our knowledge, is the first description of a human leukemic cell line that can be stimulated to synthesize hemoglobin by Epo.

Topics: Antigens, Surface; Cell Differentiation; Cell Division; Cell Survival; Erythrocytes; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Hemoglobins; Histocytochemistry; Humans; Interleukin-3; Karyotyping; Leukemia; Male; Microscopy, Electron; Myelodysplastic Syndromes; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Tumor Cells, Cultured

Medullary dyserythropoiesis with reduced production of erythrocytes is an early and consistent feature of myelodysplastic syndromes (MDS). The mechanism underlying the disturbed red cell proliferation and maturation is presently unknown. In order to study the role of erythropoietic growth factors, we determined by radioimmunoassay the serum concentrations of immunoreactive erythropoietin (Epo) in 42 non-transfused patients with primary and secondary MDS. Their median hemoglobin concentration at the time of Epo measurement was 9.1 g/dl (range, 5.7-14.6). Compared with the control group, 83% of the MDS patients had increased serum Epo levels, ranging from 26-4530 mU/ml. Although in the entire patient population an inverse relationship between serum Epo and hemoglobin concentrations was noted (r = -0.35; p = 0.02), Epo titers differed markedly between patients at comparable degrees of anemia. In 7 patients presenting with a hemoglobin concentration between 5.9 and 11.9 g/dl, excessive elevations of Epo levels (greater than 500 mU/ml) were found. In contrast to previous observations, serum Epo concentrations were not shown to correlate with the percentage of erythroblasts in the bone marrow. There was, however, a significant relationship between the Epo activity and the degree of medullary dyserythropoiesis, as assessed by morphological criteria (p less than 0.01). From these data we conclude that the anemia in MDS is not due to an endogenous Epo deficiency. The marked variability of Epo production in these disorders is not fully explained by the degree of anemia, but may also reflect inherent abnormalities of the myelodysplastic erythropoiesis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow Cells; Child; Erythroblasts; Erythrocyte Volume; Erythropoietin; Female; Humans; Male; Middle Aged; Myelodysplastic Syndromes

In a phase II study, 12 patients with a myelodysplastic syndrome (MDS) and anaemia (nine transfusion-dependent) were treated with recombinant human erythropoietin (rHuEpo) to assess the therapeutic effect on erythropoiesis and on transfusion requirement. Patients with a low risk of developing acute leukaemia were included, i.e. refractory anaemia (RA), RA with ringed sideroblasts (RARS) and RA with excess blasts (RAEB), providing the percentage of myeloblasts in the bone marrow did not exceed 10%. Recombinant HuEpo treatment was initiated at a dose of 50 units/kg body weight and administered subcutaneously three times weekly. At 3-week intervals the dose was increased with 50 units/kg per injection, until after 15 weeks a maximum dose of 250 units/kg three times weekly was reached. All patients completed the study. Recombinant HuEpo was well tolerated and no serious side effects were seen. There was no evidence of the emergence of a new malignant clone in response to rHuEpo as shown by sequential karyotyping. In none of the patients was an increase in haemoglobin level or a diminished red blood cell transfusion requirement seen. In four out of 10 evaluable sequential bone marrow smears, an increase in erythropoiesis was seen, suggesting stimulation of ineffective red cell production. One of these patients also showed a rise in reticulocyte count. The number of erythroid progenitor cells (BFU-E and CFU-E) in blood and bone marrow was not affected by rHuEpo treatment. Also no change in the number of myeloid progenitor cells (CFU-GM) in blood and bone marrow was noted. In conclusion, subcutaneous treatment with rHuEpo at dosages up to 250 units/kg body weight (three times weekly) fails to increase the haemoglobin level or to diminish the transfusion requirement in patients with MDS and anaemia. It is unclear whether higher doses of rHuEpo are effective or whether patients with less severe anaemia who are transfusion independent, have a higher likelihood of response.

Topics: Adult; Aged; Bone Marrow; Cells, Cultured; Drug Evaluation; Erythropoiesis; Erythropoietin; Female; Humans; Injections, Subcutaneous; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Hematological disorders are commonly complicated by anemia, and the symptoms of red cell deficiency adversely affect the quality of life. Erythropoietin is a glycoprotein which controls red blood cell production. Recombinant human erythropoietin, 50 U/kg/day, was given subcutaneously to 16 patients with myelodysplastic syndrome and anemia. All but one patient was transfusion dependent. Diverse pretreatment endogenous serum erythropoietin levels were noted and ranged from 17 to 3616 IU/l. Two patients (12.5%) demonstrated an improvement in hemoglobin levels obviating the need for transfusions. Their responses lasted 5+ and 7 months with maintenance erythropoietin treatment. The responders had endogenous serum erythropoietin levels of 44 and 170, respectively. Treatment was generally tolerated without constitutional side-effects. However, three patients developed thrombocytopenia and one developed joint pain and leukocytosis on treatment. Overall, six patients showed changes in non-erythroid cells: two patients had an increase in platelet counts; three patients, a decrease in platelet counts; and one patient, an increase in white blood cell counts. Most of these changes reversed rapidly once erythropoietin was stopped. It is concluded that (a) serum erythropoietin levels are extremely variable in anemia patients with myelodysplastic syndrome, (b) only a minority of patients benefit from treatment with recombinant human erythropoietin, and (c) erythropoietin can affect cells of the myeloid and megakaryocytic lineage in a small proportion of patients.

Topics: Aged; Aged, 80 and over; Anemia, Hypochromic; Erythropoiesis; Erythropoietin; Female; Humans; Leukocyte Count; Male; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Recombinant Proteins

Recombinant human erythropoietin was administered subcutaneously to 10 patients with myelodysplasia (MDS) who had haemoglobin concentrations less than 10 g/dl, in an attempt to relieve their anaemia. Doses of 60 units/kg/d rising to 90 units/kg/d were given over a maximum period of 16 weeks. Two out of 10 patients showed a steady rise in haemoglobin concentration during treatment. One patient with refractory anaemia had a sustained rise from 9.9 g/dl to 11.3 g/dl, and one patient with refractory anaemia with excess blasts (RAEB) had a rise from 9.5 g/dl to 11.4 g/dl but then relapsed with the development of an iron deficient state. Serum concentrations of immunoreactive EPO varied considerably between patients, but both responders had relatively low baseline levels. Both responders were also new diagnoses and had received no red cell transfusions. The criteria for response to recombinant human erythropoietin therapy, as well as the indications for therapy remain to be clarified.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Erythropoietin; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Metabolic Clearance Rate; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia, Refractory; Erythrocytes; Erythrocytes, Abnormal; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Ferritins; Humans; Iron; Myelodysplastic Syndromes

The growth factor requirements of granulocyte-macrophage (GM) and erythroid marrow progenitor cells from 12 myelodysplastic (MDS) patients have been analysed. GM progenitors from two of six patients who grew normal numbers of colonies in response to conditioned medium + erythropoietin (5637CM + Epo) showed defective responses to either GMCSF and/or IL-3. Of all the recombinant factors tested (IL-3, IL-1, GCSF, GMCSF, MCSF), GMCSF was the strongest stimulator of myeloid clonal growth, inducing normal numbers of GM colonies from marrow of six patients (two of whom were neutropenic). Erythroid colonies were low in 5637CM + Epo-supplemented cultures of marrow from all but one patient and remained poor in the presence of any of the haemopoietins. tested. Supraoptimal doses (for normal marrow) of these haemopoietins improved colony growth in only one patient (GM colonies in response to IL-3). Combinations of factors were also largely ineffective at raising myeloid or erythroid colony numbers. These data indicate that the defective response of MDS progenitor cells to growth factors is not amenable to experimental manipulation of recombinant factor levels or combinations. Clonal assays might suggest a role for GMCSF therapy in a subpopulation of neutropenic MDS patients but their potential now needs to be evaluated in association with clinical trials.

Topics: Adult; Aged; Bone Marrow; Cell Division; Cells, Cultured; Clone Cells; Colony-Stimulating Factors; Culture Media; Erythroblasts; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Growth Substances; Hematopoietic Stem Cells; Humans; Interleukin-1; Interleukin-3; Macrophage Colony-Stimulating Factor; Macrophages; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Chromosomes of bone marrow cells obtained from nine patients with myelodysplastic syndrome (MDS) were assessed after in vitro co-culture (48 hours culture) with recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), or recombinant human erythropoietin. Three of the nine MDS cases showed no cytogenetic abnormalities with or without any recombinant human hematopoietic growth factors; one MDS patient with a t(3;4) did not show any change in the proportion of cells with this cytogenetic change. The remaining five cases exhibited changes in the frequency of subclones after the treatment. An increasing number of metaphase cells with less complex chromosome abnormalities was observed in two of the five cases by treatment with rhG-CSF; one of them also showed an increasing number of cells with normal karyotypes. After rhGM-CSF treatment, cells with nonclonal hyperdiploid abnormalities appeared in one MDS patient. After erythropoietin treatment, an increasing number of cells with a prototypic change was observed in one MDS patient, whereas one patient showed an increasing number of cells with an additional chromosome abnormality. These observations indicate that hematopoietic growth factors possibly modify the constitution of marrow cells with multiple chromosome abnormalities and the degree is different in each MDS patient. Furthermore, a chromosome analysis using an in vitro culture system with human recombinant hematopoietic growth factors may be able to detect metaphase cells with additional chromosome abnormalities in some MDS patients.

Topics: Cells, Cultured; Chromosome Aberrations; Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Lymphoma, Non-Hodgkin; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia; Colony-Stimulating Factors; Erythropoietin; Graft Rejection; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Myelodysplastic Syndromes

In a dose escalation study we tested the feasibility and tolerance of high-dose recombinant human erythropoietin (r-HuEPO) therapy in four patients with ineffective erythropoiesis due to myelodysplastic syndromes (MDS) or paroxysmal nocturnal hemoglobinuria (PNH). Recombinant human EPO was administered i.v. with an initial dose of 50 U/kg body weight (BW) three times per week. The dose was increased by steps of 25 or 50 U/kg bW with intervals of 1-4 weeks up to a maximum dose of 500 U/kg BW three times per week. All patients were treated as outpatients. Pre-study treatment with cyclosporin A and/or Danazol was continued in three patients. In one patient r-HuEPO was discontinued after 20 weeks because of relapse of severe aplastic anemia. No major side effects were observed even at the maximum dose. One patient with PNH showed an increase of hemoglobin from 89 to 139 g/liter that permitted monthly phlebotomies to reduce his iron overload. In one patient with MDS the reticulocyte count increased from 2.5 to 50 x 10(9)/liter, and the transfusion requirement decreased to 2 U every 3-4 weeks instead of every 2 weeks. Two patients did not complete the whole treatment period and showed no rise in reticulocyte count. We conclude that high dose r-HuEPO therapy is feasible in patients with anemia due to MDS or PNH. High-dose r-HuEPO appears to have some effect on anemia due to ineffective erythropoiesis in a subgroup of patients. Further studies are needed to identify potential responders and to define the optimal administration of r-HuEPO.

Topics: Adult; Anemia; Blood Transfusion; Erythrocyte Count; Erythropoietin; Female; Hemoglobins; Hemoglobinuria, Paroxysmal; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins; Reticulocytes

Erythropoietin-dependent regulation of erythropoiesis in myelodysplastic syndromes (MDS) was evaluated by measuring the in vitro response of primitive (BFU-E) and relatively mature (CFU-E) erythroid progenitors from 12 patients and from eight healthy donors to recombinant human erythropoietin (rhEPO), and by quantifying relationships between circulating EPO levels and progenitor cell frequencies in MDS marrow. Half-maximal growth of MDS CFU-E and BFU-E was detected at a 4-fold higher rhEPO concentration than required by control erythroid progenitors. Nine of the patients evaluated exhibited maximal growth of erythroid colonies at 5- to 20-fold higher than control saturating rhEPO concentrations. Circulating EPO levels in MDS patients were elevated, with a mean value approximately 35-fold higher than that of controls. The frequency of MDS marrow CFU-E and BFU-E was 57 +/- 42% and 18 +/- 9% of the mean control values, respectively. Correlation analysis of the relationships between MDS EPO levels and erythroid progenitors indicated that the anemia in MDS is not attributable to an abnormality in the capacity of EPO to induce the generation of CFU-E, but may be influenced by the BFU-E population, whose severe deficiency results in insufficient influx of EPO-responsive cells. Our findings therefore suggest that treatment of MDS patients with rhEPO may be of limited benefit, since the generation of BFU-E from more primitive ancestors and the initial growth requirements of these cells are not under the regulatory influence of this hormone.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Bone Marrow; Cell Count; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Granulocytes; Hematopoietic Stem Cells; Humans; Macrophages; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Eight patients with myelodysplastic syndromes (MDS) and four patients with aplastic anemia (AA) were treated with recombinant erythropoietin (rEpo) to investigate its effect on the anemia of these patients. rEpo was administered by i.v. injection three times a week for at least four weeks. The doses were 3,000, 6,000, or 12,000 U/day. Despite an elevated "endogenous" Epo level, a greater than 1.5 g/dl increase in hemoglobin (Hb) concentration was observed in one patient with refractory anemia (RA), one patient with refractory anemia with excess of blasts (RAEB), and one patient with AA. A greater than 50% decrease in red cell transfusion requirement was observed in one patient with RA and one patient with AA. One RA patient and one AA patient have received rEpo as maintenance therapy for more than 64 and 100 weeks, respectively. They no longer need red cell transfusions and have had a normal Hb concentration and normal ferrokinetics. No side effect was seen. These results indicate that rEpo may benefit some patients with MDS and AA who are dependent on red cell transfusions while further studies will be necessary to elucidate the mechanism by which rEpo stimulates erythropoiesis and improves anemia in patients with these diseases.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Erythropoietin; Female; Humans; Iron; Male; Middle Aged; Myelodysplastic Syndromes; Recombinant Proteins

Ineffective erythropoiesis is an early feature of the myelodysplastic syndromes (MDS), usually accompanying an hypercellular marrow. In a previous study, concentrations of serum erythropoietin (EPO) in MDS have been shown to correlate inversely both with haemoglobin concentration and with % bone marrow erythroblasts. We have measured erythroid production using a radioisotopic technique in 20 patients with MDS. Although haemoglobin concentration shows a weak inverse relationship with serum EPO concentration there is considerable variation in EPO concentration at a given haemoglobin level. There is no correlation between serum EPO and total erythroid production, though there is a weak correlation with effective erythropoiesis. The data suggests that control mechanisms of erythropoiesis in patients with MDS are complex.

Topics: Bone Marrow; Erythroblasts; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron; Myelodysplastic Syndromes

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: Colony-Stimulating Factors; Congenital Abnormalities; DNA; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Leukemia; Myelodysplastic Syndromes; Oncogenes

The ability of plasma from myelodysplastic patients to support the clonal growth of normal megakaryocyte progenitors (CFU-Mk) was compared with that of plasma from normal subjects. The resultant megakaryocyte colonies were expressed as a plasma factor index megakaryocyte (PFI-Mk). All cultures included PHA-LCM and medium conditioned by the human bladder carcinoma cell line 5637, and some of them had EPO. PFI-Mk (MDS) was significantly lower than PFI-Mk (normal), both with and without EPO. A positive correlation was found between megakaryocyte and platelet count in normal subjects, but was not present in MDS patients. There was no correlation between platelet count and PFI-Mk in neither group. In MDS there was a negative correlation between megakaryocyte number and PFI-Mk, both with and without EPO. Although, the mean megakaryocyte number in MDS and in normal bone marrow was similar, the proportion of immature megakaryocytes was much higher in MDS. Previous work indicates an abnormal clonal origin of megakaryocytes in MDS. The present study suggests that abnormal plasma factors affects megakaryocytopoiesis in this condition.

Topics: Adult; Aged; Aged, 80 and over; Cell Count; Cell Division; Cells, Cultured; Erythropoietin; Female; Humans; Male; Megakaryocytes; Middle Aged; Myelodysplastic Syndromes; Platelet Count; Stem Cells

Serum concentration of erythropoietin (Epo) has been measured by radioimmunoassay in 46 patients with myelodysplastic syndromes. There is an overall inverse relationship between the level of Epo and the degree of anaemia but a wide range of Epo response between patients with similar haemoglobin concentrations. No differences were found between the different FAB groups, but the highest Epo levels were found in those patients with erythroid hypoplasia in the bone marrow. It is suggested that the intensity of erythroid activity in the marrow, as well as the degree of anaemia, may be a factor determining serum Epo concentration.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Bone Marrow; Erythroblasts; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Myelodysplastic Syndromes

The accurate radioimmunological measurement of serum erythropoietin (EPO) levels has only been possible since the development of highly specific antibodies directed against recombinant human EPO. In the present study, we determined the serum EPO levels in 100 healthy volunteers and in over 300 patients with anemias and hyperglobulinemia of various causes. In the healthy group, the females had levels of 11.3 +/- 3.4 mU/ml, while the males had levels of 8 +/- 3.2 mU/ml. The serum EPO concentrations were inversely related to the degree of anemia in patients with nonrenal anemias, while predialysis patients with renal anemias showed only partially such a tendency. Hemodialysis patients exhibited EPO-levels that were inadequately low relative to the degree of anemia. Patients with hyperglobulinemia had significantly higher serum EPO-levels than healthy individuals and polycythemia vera patients, the latter having particularly low serum EPO levels. Our results show that the determination of serum EPO levels can be of value in the differential diagnosis of hyperglobulinemia. Finally, sequential measurements document fluctuating serum EPO-levels after gastrointestinal hemorrhages and in patients with iron deficiency anemias receiving iron substitution. The probable reason for this phenomenon seems to be the intermittent utilisation of the hormone by EPO-sensitive erythropoietic precursor cells.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Anemia, Hypochromic; Erythropoietin; Female; Gastrointestinal Diseases; Hemoglobins; Humans; Hypergammaglobulinemia; Kidney Diseases; Male; Myelodysplastic Syndromes; Polycythemia Vera; Renal Dialysis

Topics: Adult; Aged; Aged, 80 and over; Colony-Forming Units Assay; Colony-Stimulating Factors; Erythropoietin; Female; Growth; Hematopoietic Stem Cells; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Myeloproliferative Disorders