losartan-potassium and Leukemia--Lymphocytic--Chronic--B-Cell

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

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients often develop anemia due to the disease process and effects from disease therapy. Blood transfusion, the established treatment, has an immediate effect in improving patients' hemoglobin levels. However, this effect is transient and transfusion is associated with several risks, including infections and mild to life-threatening immunologic reactions. A newer option is recombinant human erythropoietin (epoetin); a biological treatment that leads to increased hemoglobin levels over an extended time without the risks of blood transfusion. Extensive evidence has shown that epoetin is effective in the treatment of cancer-associated anemia. An international expert panel met to develop treatment recommendations for the use of epoetin in MM and CLL patients. Based on the available data, it is recommended that treatment be initiated only after other possible causes of anemia are eliminated. Epoetin should be administered to any patient with hemoglobin < or=10 g/dl. Patients with hemoglobin 10-12 g/dl should receive epoetin if they suffer from significant symptoms of anemia and/or have progressively decreasing hemoglobin values. Dosage should be initiated at 10 000 IU three times/week or 40 000 IU once/week and be titrated to maintain hemoglobin at 12 g/dl. Nonresponsive patients (<1 g/dl increase over four weeks) may have their dose increased to 20 000 IU three times/week or 60 000 IU once/week, respectively. Epoetin treatment should be discontinued if there is no response to the increased dosage, or hemoglobin >14 g/dl. Treatment should resume for patients who exceed 14 g/dl, at a reduced dosage, if their hemoglobin falls below 12 g/dl.

Topics: Anemia; Disease Management; Epoetin Alfa; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Practice Guidelines as Topic; Recombinant Proteins

Anemia is prevalent among cancer patients with hematologic malignancies, with fatigue and weakness, major symptoms of anemia, contributing to diminished quality of life (QOL). Data from several randomized, placebo-controlled clinical trials and three large community-based studies in patients with hematologic malignancies indicate that recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct anemia, reduce transfusion requirements, and improve QOL. Moreover, a positive relationship has been found between increased hemoglobin (Hb) levels and improvements in QOL assessments, regardless of disease state, with the greatest incremental improvement occurring when Hb increases from 11 g/dL to 12 g/dL (range, 11 to 13 g/dL). This suggests that patients with mild-to-moderate anemia may achieve the greatest QOL benefit from epoetin alfa therapy. Evidence from community-based studies suggests that epoetin alfa administered once weekly has a similar safety and efficacy profile as three-times-weekly administration. Further research is ongoing with less frequent dosing regimens. The beneficial effects of epoetin alfa therapy have been reported in studies involving patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. Evidence also exists that epoetin alfa can benefit patients with myelodysplastic syndromes (MDS), although these results have not been as impressive. Combining epoetin alfa with other cytokine growth factors may confer some additional benefit in these patients, but more rigorous investigation is required.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Anemia is a frequent clinical feature with adverse prognostic effects in patients with chronic lymphocytic leukemia (CLL). It may complicate CLL at any time during the course of the disease. Different factors concur to the occurrence of anemia in CLL, as in other lymphoproliferative diseases: leukemic bone marrow infiltration, the myelosuppressive effect of chemotherapy and inhibiting cytokines, autoimmune phenomena, hypersplenism, a poor nutritional status that leads to folic acid, vitamin B12 and iron deficiency. In addition, a defective endogenous erythropoietin (EPO) production has also been described in patients with lymphoproliferative diseases. The severity of anemia, which may be worsened by an impaired cardiopulmonary function, may profoundly compromise the patients' quality of life and, indirectly, the outcome of cancer bearing patients. Several Authors have reported the clinical activity of recombinant human (rHu)EPO in anemic patients with lymphoproliferative diseases, including CLL. Low serum EPO levels at baseline and EPO levels inappropriately low for the degree of anemia help to identify patients who are likely to respond to EPO. A clear dose-dependent response to EPO has been reported by different Authors and it has been suggested that 5,000 IU should be considered as an appropriate initial dose for the majority of patients. rHuEPO represents a potentially effective and safe therapy for the management of anemia associated with lymphoproliferative diseases. The reduction of red blood cell transfusion requirement, the improvement of quality of life through the remission of fatigue-related anemia are two important results that should be considered in the management of patients with CLL. In prospect, the availability of new rHuEPO molecules with a more prolonged half-life may open new therapeutic avenues.

Topics: Anemia; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Bone Marrow; Cytokines; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypersplenism; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoproliferative Disorders; Multicenter Studies as Topic; Nutrition Disorders; Radiotherapy; Randomized Controlled Trials as Topic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

During the past 40 years substantial progress has been made in the treatment of hematologic malignancies, particularly in some subgroups of patients. Today, cure is attainable for patients with Hodgkin's disease and a considerable proportion of patients with high-grade non-Hodgkin's lymphoma. Prognosis is improving in patients with acute promyelocytic leukemia and, to some extent, those with acute lymphoblastic and myeloid leukemias. However, the majority of patients who suffer from a hematologic malignancy live with incurable disease. In CLL, outside the setting of a clinical trial, it is advisable to postpone treatment until the manifestation of clinical symptoms. It is yet to be determined whether treatment strategies based on new prognostic parameters such as cytogenetics can change the course of disease. In indolent lymphomas, cure is not attainable for the vast majority of patients; the median survival of 9 to 10 years has remained unchanged for several decades. Nevertheless, there has been a dramatic change in therapeutic paradigms in the past few years. For the first time, with the use of new cytostatic drugs and recombinant monoclonal antibodies, it is possible to achieve molecular remissions. Whether this will translate into cure or prolonged survival is still to be determined. In Hodgkin's disease, which is curable when treated with radiotherapy, chemotherapy, or combined therapy, depending on the stage of disease, the focus of future studies must be on prevention of early relapse and on primary resistant disease, both of which present a very poor prognosis. Finally, regardless of underlying malignancy and prognosis, the preservation of quality of life is of major consideration in the setting of hematologic malignancies.

Topics: Anemia; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Epoetin Alfa; Erythropoietin; Hematinics; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Prognosis; Quality of Life; Recombinant Proteins; Vidarabine

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

Immune-mediated acquired disorders of erythropoiesis can result in pure red cell aplasia or ineffective erythropoiesis. Erythropoiesis can be suppressed or impaired by humoral or cellular mechanisms. In vitro inhibition of erythroid colony growth by humoral factors or lymphocytes is a strong argument for the immune origin of the disease. Classical aetiologies are thymoma and hematological malignancies such as chronic lymphocytic leukaemia. Clonal proliferation of T cells has also been incriminated. Recently, acquired circulating autoantibodies directed against erythropoietin have been detected in a case of pure red cell aplasia. Autoimmune mechanisms have also been suggested in two dyserythropoietic syndromes recently described.

Topics: Anemia; Autoimmune Diseases; Cell Division; Erythropoiesis; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Red-Cell Aplasia, Pure; T-Lymphocytes; Thymoma

Theophylline, a drug that has been used for several decades, has several different actions at a cellular level, including inhibition of phosphodiesterase isoenzymes, antagonism of adenosine, enhancement of catecholamine secretion, and modulation of calcium fluxes. Recently, theophylline was found to have several immunomodulatory and anti-inflammatory properties, and thus interest in its use in patients with asthma has been renewed. The use of theophylline in the treatment of asthma and chronic obstructive pulmonary disease has diminished with the advent of new medications, but theophylline remains beneficial, especially in the patient with difficult refractory symptoms. In the future, theophylline may be used as treatment for bradyarrhythmias after cardiac transplantation, prophylactic medication to reduce the severity of nephropathy associated with intravenous administration of contrast material, therapy for breathing problems during sleep, and treatment for leukemias.

Topics: Apnea; Apoptosis; Asthma; Calcium Channels; Capillary Leak Syndrome; Catecholamines; Erythropoietin; Humans; Immunity; Kidney; Leukemia, Lymphocytic, Chronic, B-Cell; Lung Diseases, Obstructive; Phosphoric Diester Hydrolases; Receptors, Purinergic P1; Theophylline

The purpose of this study is to investigate the efficacy and safety of recombinant erythropoietin-beta in the treatment of anemic patients with multiple myeloma (MM), low-grade non-Hodgkin's lymphoma (NHL), and chronic lymphocytic leukemia (CLL). From December 2005 to November 2006, the patients with MM, low-grade NHL, and CLL were enrolled in this study, male or female, aged > or = 18 years, transfusion-dependant, and receiving anti-neoplasia chemotherapy. Recombinant human erythropoietin-beta was used in this study with the dose initiated at 150 IU/kg, thrice a week, subcutaneously. The total treatment duration was 12 weeks. The primary endpoint of the study is response rate (RR), which is defined as hemoglobin increasing > or = 2 g/dL comparing to baseline level, or returning to normal range, without any transfusion within 6 weeks of evaluation. Fifty out of 82 (64.6%) patients enrolled in this study responded to the treatment and 29 patients had no response. Hypertension (12.2%) is the most common adverse effect; however, all the adverse events were mild, categorized in NCI grade I or II. We conclude that recombinant erythropoietin-beta was effective in the treatment of anemia of the patients with MM, NHL, and CLL, as well as it is well-tolerated.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Asian People; Erythropoietin; Female; Ferritins; Humans; Iron; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Epoetin beta, three-times weekly (t.i.w.), is effective in reversing anaemia in lymphoproliferative disorders. The current study investigated whether an epoetin beta dose of 30,000 IU given subcutaneously once weekly (q.w.) was at least as effective as 10,000 t.i.w. administration in anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin (Epo) production. Overall, 241 anaemic patients with multiple myeloma, low-grade non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, all with serum Epo values

Topics: Adult; Aged; Aged, 80 and over; Anemia; Area Under Curve; Blood Transfusion; Disease-Free Survival; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Proportional Hazards Models; Recombinant Proteins; Time

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

To investigate the effectiveness of recombinant human erythropoietin (r-HuEPO) on disease-related anemia in patients with B-chronic lymphocytic leukemia (B-CLL) and to explore whether improvement of anemia could delay the initiation of cytotoxic therapy.. Twenty five B-CLL patients (12 males and 13 females; median age 70 years) with disease-related anemia were treated with r-HuEPO. Patients were either on no treatment or on a standard regimen, and had at least Rai stage III disease, with a hematocrit (Hct) <32%. Eleven were newly diagnosed, whereas 14 developed anemia during follow-up. Treatment induction lasted for a maximum of 3 months, during which patients were receiving 150 IU/kg of r-HuEPO s.c. t.i.w. with an escalation to 300 IU/kg t.i.w. if response was slow after one month. Responding patients were placed on maintenance r-HuEPO with 150 IU/kg s.c. once weekly, continuously. Complete response (CR) was defined as an increase of Hct to 38% or more and partial response (PR) as an increase of >6% from pretreatment level.. CR was observed in 18/25 (72%) and PR in 2/25 (8%) of the patients. Six patients were downstaged to stage Rai 0, 9 to Rai I and 4 to Rai II. Response was sustained with maintenance therapy. At a median follow-up of 32 months only 4 of the responders required antileukemic treatment. The median survival of responders has not been reached, and 3-year survival is 84%.. r-HuEPO was efficient in downstaging Rai stage III B-CLL patients, and delayed the initiation of antileukemic therapy. Whether this effect can be translated into better survival rates remains to be clarified in randomized trials.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Staging; Recombinant Proteins; Remission Induction; Treatment Outcome

To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM).. Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia-free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb > or = 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale.. Transfusion-free (P =.0012) survival and transfusion- and severe anemia-free survival (P =.0001) were significantly greater in the epoetin beta group versus placebo (Wald chi(2) test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P <.0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P <.05); this improvement correlated with an increase in Hb concentration (> or = 2 g/dL). A target Hb that could be generally recommended could not be identified.. Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Double-Blind Method; Erythropoietin; Female; Humans; Injections, Subcutaneous; Iron; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma; Quality of Life; Recombinant Proteins; Surveys and Questionnaires; Survival Rate; Treatment Outcome

The responsiveness of bone marrow erythroid progenitors (CFU-E and BFU-E) to various concentrations of recombinant human erythropoietin (rh-Epo) (2,5,20,40,100,200 and 500 U/ml) was investigated in vitro in 18 patients with B-chronic lymphocytic leukemia to assess the clinical usefulness of rh-Epo in this disease. Bone marrow mononuclear cells were cultured by methylcellulose methods for CFU-E and BFU-E assays. The B-chronic lymphocytic leukemia patients were divided into two groups according to the percentage of lymphocytes in the bone marrow (under 70% and over 70%). Among the patients with few lymphocytes, more than one third demonstrated some degree of response to rh-Epo. Among the patients with a high percentage of lymphocytes in the bone marrow, some revealed no response to rh-Epo, but there were patients who showed a good response to rh-Epo. Because erythroid progenitors from B-chronic lymphocytic leukemia appeared sensitive to rh-Epo in vitro, we propose that high doses of this drug may be clinically effective in some patients with this disease, regardless of the degree of lymphocytic inflitration of the bone marrow.

Topics: Aged; Bone Marrow; Bone Marrow Cells; Dose-Response Relationship, Drug; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Recombinant Proteins

Nine B-chronic lymphocytic leukaemia (B-CLL) patients suffering from anaemia, due to no obvious cause except their disease, were treated with recombinant human erythropoietin (r-HuEPO). The treatment protocol provided a closed label phase of 3 months duration, during which the patients received r-HuEPO or placebo in a ratio of 2:1, followed by an open label phase, also of 3 months duration, during which r-HuEPO was administered to all patients three times a week s.c. r-HuEPO was given a dose of 150 U/kg of body weight with an escalation of 50 U/kg up to a maximum of 300 U/kg three times a week. Complete response was achieved in 5/9 (55%) patients and partial response in 3/9 (33%). The response obtained was independent of the pretreatment serum EPO levels, the duration of anaemia, the concomitant administration of chemotherapy, the presence of splenomegaly, or the degree of bone marrow infiltration by lymphocytes. It appears that r-HuEPO is very effective in reversing the disease-related anaemia of B-CLL patients.

Topics: Aged; Anemia; Erythropoietin; Female; Hematocrit; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Multiple Myeloma; Prospective Studies

Aquaporin-1 (AQP1) is the membrane water channel responsible for changes in erythrocyte volume in response to the tonicity of the medium. As the aberrant distribution of proteins in hereditary spherocytosis (HS) generates deficiencies of proteins other than those codified by the mutated gene, we postulated that AQP1 expression might be impaired in spherocytes. AQP1 expression was evaluated through flow cytometry in 5 normal controls, 1 autoimmune hemolytic anemia, 10 HS (2 mild, 3 moderate, 2 severe, and 3 splenectomized), and 3 silent carriers. The effect of AQP1 inhibitors was evaluated through water flow-based tests: osmotic fragility and hypertonic cryohemolysis. Serum osmolality was measured in 20 normal controls and 13 HS. The effect of erythropoietin (Epo) on AQP1 expression was determined in cultures of erythroleukemia UT-7 cells, dependent on Epo to survive. Independent of erythrocyte size, HS patients showed a lower content of AQP1 in erythrocyte membranes which correlated with the severity of the disease. Accordingly, red blood cells from HS subjects were less sensitive to cryohemolysis than normal erythrocytes after inhibition of the AQP1 water channel. A lower serum osmolality in HS with respect to normal controls suggests alterations during reticulocyte remodeling. The decreased AQP1 expression could contribute to explain variable degrees of anemia in hereditary spherocytosis. The finding of AQP1 expression induced by Epo in a model of erythroid cells may be interpreted as a mechanism to restore the balance of red cell water fluxes.

Topics: Adolescent; Adult; Anemia, Hemolytic, Autoimmune; Aquaporin 1; Biological Transport; Body Water; Cell Line; Child; Child, Preschool; Erythrocyte Membrane; Erythrocytes; Erythropoietin; Gene Expression Regulation; Hemolysis; Heterozygote; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Osmolar Concentration; Osmotic Fragility; Spherocytosis, Hereditary; Splenectomy

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

Disease-related anemia in chronic lymphocytic leukemia (CLL) occurs when the obvious causes are excluded while its pathogenesis is still obscure. We investigated its underlying mechanisms in 56 untreated patients with CLL.. Bone marrow (BM) lymphocytic infiltration was estimated in trephine biopsies. Serum erythropoietin (EPO) and tumor necrosis factor-alpha (TNF-alpha) levels were measured by ELISA. The potential of BM CD34+ to differentiate into erythroid cells was evaluated by methylcellulose-based assays and in liquid cultures supplemented with EPO, SCF, IL-3 +/- TNF-alpha. The response of erythroid precursors to EPO +/- TNF-alpha was assessed by detecting activated key proteins of EPO-EPO receptor signalling pathway using Western Blot and EMSA.. Bone marrow lymphocytic infiltration was not exclusively responsible for disease-related anemia and CD34+ cells were intrinsically capable of generating erythroid precursors. Also, no deficiency of serum erythropoietin (EPO) or defective intracellular response of erythroid precursors to EPO +/- TNF-alpha stimulation was observed. Serum TNF-alpha levels were found increased in anemic CLL patients and TNF-alpha appeared to directly inhibit the erythroid development in early stages of erythropoiesis.. We concluded that CLL-related anemia was not due to intrinsic defects of erythroid precursors, but might result from the direct suppressive effect of TNF-alpha on the erythroid production.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Bone Marrow; Cells, Cultured; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Hematopoietic Cell Growth Factors; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemic Infiltration; Male; Middle Aged; Neoplasm Proteins; Tumor Necrosis Factor-alpha

Topics: Aged; Darbepoetin alfa; Drug Eruptions; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Recurrence; Treatment Outcome

Topics: Adolescent; Adult; Aged; Anemia; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Male; Middle Aged; Multiple Myeloma

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Paraneoplastic Syndromes; Phlebotomy; Polycythemia; Prednisone; Rituximab; Vincristine

Targeting BCR-ABL tyrosine kinase by treatment with the selective inhibitor imatinib (formerly STI571, Gleevec) has proved to be highly efficient for inhibiting leukemic growth in vitro. In addition, in clinical trials, imatinib has produced high response rates in patients with chronic myeloid leukemia (CML) in chronic phase and blastic crisis. However, episodes of severe cytopenia were also frequently observed, leading to discontinuation of therapy in some cases. Therefore, it is important to examine whether administration of cytokines overcomes the adverse effects of imatinib in in vitro systems. In this study, we examine the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) on TF-1/bcr-abl (which was generated by transduction of a bcr-abl fusion gene into the TF-1 cell line) as a model system for CML with blastic crisis. Imatinib induced apoptosis in TF-1/bcr-abl cells but not in the parental TF-1 cells. However, GM-CSF, a survival factor of the parental TF-1 cells, protected TF-1/bcr-abl cells from imatinib-induced apoptosis in a dose-dependent manner. Concomitantly, constitutive phosphorylation of Stat5 and FKHRL1 was significantly inhibited by imatinib, and the inhibition was canceled by the addition of GM-CSF, accompanied by upregulation of Bcl-xL and downregulation of p27/Kip1. In addition, although untreated TF-1/bcr-abl cells had lost responsiveness to both GM-CSF and EPO and showed autonomous growth, GM-CSF enhanced phosphorylation of Stat5 and FKHRL1 in these cells. Importantly, imatinib-treated TF-1/bcr-abl cells differentiated into hemoglobin-positive cells in the presence of EPO, as in the case for the parental TF-1 cells. Taken together, imatinib-treated CML cells may differentiate into mature cells in the presence of differentiation-inducing cytokines such as EPO.

Topics: Apoptosis; Apoptosis Regulatory Proteins; Benzamides; Cell Differentiation; Cell Line, Tumor; Erythropoietin; Fusion Proteins, bcr-abl; Granulocyte-Macrophage Colony-Stimulating Factor; Hemoglobins; Humans; Imatinib Mesylate; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm Proteins; Piperazines; Protein-Tyrosine Kinases; Pyrimidines

Topics: Anemia; Bone Marrow; Epoetin Alfa; Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Iron Deficiencies; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Recombinant Proteins

Serum levels of tumor necrosis factor-alpha (TNF-alpha) and of erythropoietin (Epo) have been evaluated in 100 patients with B-cell chronic lymphocytic leukemia (CLL) in order to determine whether these factors could be significant in the development of anemia, which was observed in some cases with advanced disease. In our series of patients, TNF-alpha serum levels had an inverse correlation with hemoglobin levels (r = -0.813). In patients with anemia, the serum levels of TNF-alpha were significantly higher (p = 0.022) than in those without anemia (186.7 +/- 84.7 vs. 39.8 +/- 20.7 pg/ml). Serum Epo levels were also significantly (p = 0.0003) increased in CLL patients with anemia compared to those without (134.1 +/- 225.9 vs. 12.3 +/- 4.8 mU/ml). The ratio of observed/predicted (O/P) serum Epo was adequate (>0.8) for the degree of anemia in 70% of patients with anemia and inadequate in the remaining 30%. In the latter, the mean serum TNF-alpha level was significantly higher (p = 0.005) than the mean for the anemic cases with an adequate O/P ratio of serum Epo (234.1 vs. 166.4 pg/ml). These data suggest that although CLL anemia is not characterized by inadequate Epo production, in some CLL patients this factor may be correlated. In these cases, the levels of TNF-alpha were significantly higher than in other anemic cases. Compared to other CLL patients with anemia, these CLL patients might better respond to therapy with recombinant human Epo in pharmacological doses.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Erythropoietin; Female; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Receptors, Transferrin; Solubility; Tumor Necrosis Factor-alpha

Topics: Anemia; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Thirty three B-chronic lymphoproliferative disorder (B-CLD) patients [22 with B-chronic lymphocytic leukemia (B-CLL), 5 with small lymphocytic lymphoma (SLL) and 6 with lymphoplasmacytic lymphoma (LPL)] with anaemia (Ht <32%) of no other cause but their disease, received recombinant human erythropoietin (r-HuEPO). The treatment protocol provided r-HuEPO in a dose of 150 U/kg s.c. thrice weekly for 3 mo. After 1.5 mo of r-HuEPO administration, if response was not satisfactory, r-HuEPO dose escalation was utilised by giving incremental doses of 50 U/kg more than the previous dose up to a maximum dose of 300 U/kg tiw. After maximal response, half of the responding patients discontinued therapy, while the other half received maintenance therapy at a dose of 150 U/kg s.c./w. Oral iron was given throughout the study. Pretreatment EPO levels were determined in all patients. A complete response (CR) was defined when Ht was >38% and a partial response (PR) when there was an increase of the Ht >6% from the initial value was achieved. Sixteen of the 22 B-CLL patients had Rai stage III disease and 6 stage IV, with a median duration of anaemia 27 months (6-38); twelve of them were receiving chlorambucil while the rest were on no treatment. Of the SLL and LPL group, 4 patients had Ann Arbor stage III disease and 7 stage IV with a median duration of anaemia 24 months (5-36); 8 patients were on chlorambucil. Complete response was achieved in 50% of the B-CLL group and 54% of the SLL and LPL group, with an overall response rate of 77% and 81% respectively. All patients on maintenance therapy had a continuous response, while all patients, in whom rHuEPO was discontinued, relapsed. No correlation was found between patients: with low or high pretreatment serum EPO levels; those receiving concomitant therapy or not; those with B-symptoms or not; those with a non-diffuse or diffuse bone marrow infiltration pattern; and with splenomegaly or not. Life quality was significantly improved and no major side effects were encountered. We conclude from our study that r-HuEPO is very effective in correcting disease-related anaemia in B-CLD, resulting in down-staging of Rai stage III patients and that maintenance therapy is necessary. Whether the correction of anaemia improves patients' overall survival, still remains to be seen.

Topics: Aged; Aged, 80 and over; Anemia; B-Lymphocytes; Erythropoietin; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoproliferative Disorders; Male; Middle Aged; Prognosis; Quality of Life; Recombinant Proteins; Severity of Illness Index; Splenomegaly; Treatment Outcome

Topics: Antigens, CD; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; CD4-CD8 Ratio; Cyclosporine; Erythropoietin; Hemoglobins; Humans; Immunoglobulins, Intravenous; Immunophenotyping; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Prednisone; Red-Cell Aplasia, Pure; Vidarabine

We report the use of a colony-stimulating granulocyte-macrophage factor (GM/CSF) and erythropoietin (EPO) combination as salvage treatment in four heavily-pretreated patients with refractory/ recurrent B-CLL. Induction therapy was subcutaneous GM-CSF 2.5 microg/ kg, and EPO, 150 units/kg both daily for the first 14 d. Maintenance therapy was GM-CSF on days 1, 3 and 5 and Epo on days 2, 4 and 6 at the same doses with weekly recycling. All the patients responded favourably. A significant reduction of lymphocytosis, lymphoadenomegaly, and organomegaly was obtained within one month of therapy. The number of infections and transfusional requirement decreased dramatically. The hemoglobin increased to over 11 g/dl in 3 out of 4 patients. With a median follow-up of 11 months (range 5-13) we observed 4 partial responses (NCI/IWCLL) and only one progression after a 10-month partial response. This combination regimen seems very active, safe and easy to administer. It may represent a promising therapeutical option in heavily pretreated patients. Further clinical and biological studies on a larger cohort of patients are needed to confirm these preliminary data, to clarify the hypothetical interactions between these cytokines and B-CLL cell proliferation pathways, and to establish if this therapy may have an impact on survival.

Topics: Administration, Cutaneous; Drug Resistance, Neoplasm; Drug Therapy, Combination; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Treatment Outcome

Anaemia is a frequent complication of advanced chronic lymphocytic leukaemia (CLL) and several cytokines known to inhibit erythropoietin (Epo) formation are produced by CLL B cells. Therefore we measured serum Epo levels in 47 CLL patients to determine whether Epo was a significant factor in the development of their anaemia. Epo levels were increased compared to normal individuals and this elevation appeared adequate for the degree of anaemia. The slope of the regression of Epo versus haemoglobin (Hb) was similar to that of a reference group. Serum transferrin receptor (sTfR) levels were also appropriately elevated for the degree of anaemia and correlated with serum Epo. Advanced stage was not associated with reduction of Epo production but diminished erythropoietic activity was observed in several patients. The results indicate that anaemia in CLL is not characterized by inadequate Epo production.

Topics: Adult; Aged; Aged, 80 and over; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Receptors, Transferrin

The etiology of anaemia associated with tumours is multifactorial. One of the mechanisms of development of anaemia in tumours are so-called chronic diseases anaemias, the main feature of which is inadequate production of endogenous erythropoietin (EPO). The objective of the investigation was to test the effect of recombinant human erythropoietin (rHuEPO) in the treatment of anaemia (rise of haematocrit, Hb) in patients with chronic lymphatic leukaemia (CLL) and multiple myeloma (MM) and the effect of this treatment on the quality of life. The authors evaluated at the same time the impact of the endogenous EPO level before treatment and its predictive value as regards the therapeutic response.. The investigation comprised a total of 14 patients (6 CLL, 8 MM). The basic criterion for inclusion in the group was a Ht value lower than 0.32 and Hb less than 105 g/l. The examination protocol was focused on elimination of other causes of anaemia. During the 12-week investigation the patients completed a questionnaire "Quality of life" which reflected their subjective evaluation of the effect of treatment. The patients themselves administered r-HuEPO three times a week by the s.c. route--an initial dose of 150 U/kg with the possibility to increase the dose to 300 U/kg.. A therapeutic response was obtained in four patients with CLL and eight patients with MM. Respondents with CLL had endogenous EPO values lower than 300 U/l, seven MM respondents lower than 200 U/l, one 400 U/l. The Hb level of the patients rose and the quality of life improved. All patients tolerated treatment very well and the authors did not observe any serious undesirable effects.. The investigation confirmed the therapeutic effect of r-HuEPO in patients with a lower baseline value of EPO. Subjective evaluation (questionnaire) correlated with objective evaluation (Ht, Hb). Assessment of the endogenous EPO level before treatment is according to the authors one of the important primary predictive parameters and EPO values between 200 and 300 U/l are the upper range where a therapeutic effect can be expected with the highest probability. The authors conclude also that a secondary predictive criterion of the response is evaluation of the therapeutic effect after 4-5 weeks treatment when a rise of Hb by at least 20 g/l is an argument for further treatment.

Topics: Aged; Anemia; Erythropoietin; Female; Hematocrit; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Multiple Myeloma; Quality of Life; Recombinant Proteins

Topics: Aged; Aged, 80 and over; Blood Transfusion; Chlorambucil; Cyclosporine; Erythropoietin; Follow-Up Studies; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Prednisone; Receptors, Transferrin; Recombinant Proteins; Red-Cell Aplasia, Pure; Reticulocyte Count

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

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Recombinant Proteins