losartan-potassium and Lymphoma

The in vitro production of recombinant protein molecules has fostered a tremendous interest in their clinical application for treatment and support of cancer patients. Therapeutic proteins include monoclonal antibodies, interferons, and haematopoietic growth factors. Clinically established monoclonal antibodies include rituximab (targeting CD20-positive B-cell lymphomas), trastuzumab (active in HER-2 breast and gastric cancer), and bevacizumab (blocking tumor-induced angiogenesis through blockade of vascular-endothelial growth factor and its receptor). Interferons have lost much of their initial appeal, since equally or more effective treatments with more pleasant side effects have become available, for example in chronic myelogenous leukaemia or hairy cell leukaemia. The value of recombinant growth factors, notably granulocyte colony stimulating factor (G-CSF) and erythropoietin is rather in the field of supportive care than in targeted anti-cancer therapy. Adequately powered clinical phase III trials are essential to estimate the true therapeutic impact of these expensive compounds, with appropriate selection of clinically relevant endpoints and sufficient follow-up. Monoclonal antibodies, interferons, and growth factors must also, and increasingly so, be subjected to close scrutiny by appropriate cost-effectiveness analyses to ensure that their use results in good value for money. With these caveats and under the condition of their judicious clinical use, recombinant proteins have greatly enriched the therapeutic armamentarium in clinical oncology, and their importance is likely to grow even further.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Intercellular Signaling Peptides and Proteins; Interferons; Leukemia; Lymphoma; Neoplasms; Recombinant Proteins

Topics: Anemia, Hypochromic; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Small Cell; Clinical Protocols; Darbepoetin alfa; Data Interpretation, Statistical; Erythropoietin; Female; Filgrastim; Follow-Up Studies; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocytes; Hematinics; Hematologic Neoplasms; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulins, Intravenous; Lung Neoplasms; Lymphoma; Lymphoma, Non-Hodgkin; Male; Multicenter Studies as Topic; Neoplasms; Neutropenia; Platelet Aggregation Inhibitors; Polycythemia Vera; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Survival Analysis; Thrombocythemia, Essential; Treatment Outcome

The effectiveness of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with non-myeloid hematological malignancies needs to be assessed as the response to their administration is not uniform and their cost is high. We conducted a systematic review (SR) of the literature to identify reports of the effect of ESAs on survival, quality of life (QOL), transfusion requirements, and anemia. The entries to MEDLINE, EMBASE, and the Cochrane Library databases, and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology were searched. Seventeen reports and five abstracts of randomized trials fulfilled prospective criteria for inclusion. Five trials reported on survival; three failed to detect differences between groups and two demonstrated inferior survival in patients allocated to an ESA. Seven trials and three abstracts reported on QOL with four articles and three abstracts describing improvements in patients allocated to erythropoietin. However, important methodologic limitations were identified in these reports. Seven randomized controlled trials reported a reduction in the proportion of patients transfused. The absolute risk reduction in transfusions ranged from 15% to 24%. This is the only SR that assesses the use of erythropoiesis-stimulating agents specifically in patients with hematological malignancies. We conclude that available data evaluating ESAs in patients with hematologic malignancies demonstrate that these agents reduce transfusion requirements. Limitations of these data preclude conclusions that these agents improve QOL. More data are required to confirm the inferior survival associated with ESAs.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Lymphoma; Multiple Myeloma; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis

Patients with lymphoid malignancies frequently require repetitive and intensive anticancer treatments to induce and maintain disease remission. Anaemia (haemoglobin [Hb] <12 g/dL) is a common and debilitating problem associated with both the malignancy itself and its treatment burden. Anaemia negatively impacts on all aspects of patient quality of life (QOL) and treatment outcomes and survival, particularly in this disease setting. Widely acknowledged goals of anaemia treatment include Hb correction to approximately 12 g/dL, reduction in transfusion requirements and optimisation of patient QOL. Since the introduction of recombinant human erythropoietic therapy, transfusion (once the only anaemia treatment option available) is now primarily reserved for non-responders or those with severe or life-threatening anaemia. Data from randomised, double-blind, placebo-controlled studies, and large, non-randomised, open-label, community-based studies, along with almost 15 years of practical experience, support the assertion that epoetin alfa administered at a dosage of 150-300 U/kg three times weekly or 40,000-60,000U once weekly, both of which are US FDA-approved dose administration schedules, can effectively and safely achieve anaemia treatment goals for the majority of patients with lymphoid malignancies. Data and practical experience collected over the last 5 years on another erythropoietic agent with a slightly longer half-life but lower binding affinity, darbepoetin alfa, show that this agent when administered according to the FDA-approved dose administration schedules (2.25-4.5 microg/kg once weekly or 500microg once every 3 weeks) or according to a commonly-administered dose in clinical practice (3.0-5.0 microg/kg once every 2 weeks) can also effectively and safely correct anaemia, reduce transfusion requirements and improve QOL in many patients with lymphoid malignancies. One comparative head-to-head trial suggested that epoetin alfa might be superior to darbepoetin alfa in anaemic cancer patients receiving chemotherapy with respect to timing and magnitude of Hb correction, although further study is necessary, especially concerning optimal dose administration. Alternative dose administration schedules, such as epoetin alfa 80,000U every 2 weeks from initiation or 80,000U every 3 weeks following initiation with once weekly administration and darbepoetin alfa 4.5 microg/kg every 3 weeks following initiation with once weekly administration, are being actively

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Combined Modality Therapy; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Iron; Lymphoma; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Trace Elements

Anaemia is frequently associated with lymphoma. Many causes are implicated and can sometimes be associated to each other so that the level of haemoglobin is often very low. In follicular lymphoma, the level of haemoglobin remains an independent predictive prognostic factor. Likewise, anaemia seems correlated to survival for both Hodgkin's and non-Hodgkin's lymphomas. However, therapeutic strategies to control anaemia remain somewhat unsatisfactory. Thus, recombinant erythropoietin might be an effective drug to increase the haemoglobin rate, limit the transfusional risk and improve patients' quality of life.

Topics: Anemia; Blood Transfusion; Erythropoietin; Fatigue; Hemoglobin A; Humans; Lymphoma; Prognosis; Quality of Life; Recombinant Proteins

Eighty percent of children with cancer suffer from anemia at the time of diagnosis. The physiopathology of anemia is complex. Although anemia can be life threatening, its consequences on the physical, psychological and social state of the child are often minimized. Blood transfusion is the main treatment of anemia: its efficacy is immediate but shortlasting, and it involves infectious and hemolytic risks. The human recombinant erythropoietin has been used for more than 25-years, and is often prescribed to adults with cancer and anemia. The human recombinant erythropoietin rHuEPO is nowadays used when blood transfusion is contra-indicated because of religious or cultural considerations, although several promising studies have been conducted about rHuEPO and children with cancer since 1996: it might be soon the preferential alternative treatment to anemia in children with cancer.

Topics: Adolescent; Anemia; Blood Transfusion; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Leukemia; Lymphoma; Male; Neoplasms; Neuroblastoma; Recombinant Proteins

Although it is well established that the growth of solid tumors requires vigorous neovascularization, it has been assumed that leukemias and other hematological malignancies do not depend on angiogenesis. However, the role of angiogenesis in growth and survival of neoplastic cells of the hematopoietic system has recently been recognized, and provides a rationale for novel therapeutic approaches to hematological malignancy. This review summarizes the literature concerning the relationship between angiogenesis and disease progression of several hematological malignancies. It is becoming increasingly evident that agents that interfere with blood vessel formation also block tumor progression, and, accordingly, antiangiogenic therapy has gained much interest as a potential adjunct to conventional therapy of many hematological malignancies. Recent successful applications of antiangiogenic agents that interfere or block the progression of hematological malignancies are evaluated in light of recent demonstrations of potent angiogenic activity of several hematopoietic growth factors. A novel finding regarding the role of angiogenesis in hematological malignancies, which accounts for many clinical observations as well as the apparent independence of these tumors on marrow vascularity, is presented. The information presented in this review will facilitate the design of future clinical trials using antiangiogenic agents for the treatment of hematological malignancies and will provide a basis for the design of experiments undertaken to define the mechanisms involved, mechanisms that may shed new light on the pathology of hematological malignancies.

Topics: Angiogenesis Inhibitors; Animals; Chick Embryo; Clinical Trials as Topic; Disease Progression; Erythropoietin; Humans; Leukemia; Lymphoma; Matrix Metalloproteinases; Neoplasms; Neovascularization, Pathologic; Recombinant Proteins

Anaemia is a frequent finding in cancer and may be due to different causes. In untreated subjects, the most common type is the so-called anaemia of chronic disease, a condition characterised by excessive release of cytokines such as interleukin-1 and tumour necrosis factor. These peptides both inhibit erythroid marrow proliferation and blunt the normal exponential relationship between haematocrit and serum erythropoietin. Chemotherapy may cause or worsen anaemia in cancer patients. Cisplatin appears to be peculiar in that this drug can blunt erythropoietin production and cause prolonged anaemia. Controlled studies have demonstrated that recombinant human erythropoietin (rHuEPO) can ameliorate anaemia in patients with malignancy and prevent chemotherapy-induced anaemia. However, improvement of anaemia following rHuEPO treatment is seen in only a portion of cancer patients, and significant improvements of quality of life cannot be demonstrated in all responsive patients. Therefore, an important issue remains whom to treat.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Erythropoiesis; Erythropoietin; Humans; Leukemia; Lymphoma; Prognosis; Quality of Life; Recombinant Proteins; Treatment Outcome

Anaemia, manifesting as fatigue, dizziness, dyspnoea and anorexia, is common among patients with cancer. A host of factors, such as neoplastic bone marrow infiltration, impaired haematopoiesis, autoimmune haemolysis, impaired endogenous erthropoietin production and treatment with cytotoxic agents contribute to the underlying pathology. Traditionally, blood transfusions have formed the mainstay of therapy for the treatment of cancer-related anaemia. Numerous clinical trials have subsequently confirmed the safety and therapeutic utility of recombinant human erythropoietin (rHuEPO) in anaemic cancer patients, including those with haematological malignancies, such as multiple myeloma and non-Hodgkin's lymphoma. Indeed, well over 50% of unselected patients treated with rHuEPO can be expected to respond with increases in haemoglobin level and/or elimination of transfusion need. In addition, a low baseline serum erythropoietin level can identify those patients with haematological malignancies having a very high likelihood of responding to rHuEPO therapy. These findings, in combination with the possibility of titrating to a lower, maintenance dose, have improved the cost-benefit relationship and thus support the use of rHuEPO as an appropriate alternative to blood transfusions for the management of anaemic patients with lymphoma and myeloma.

Topics: Anemia; Blood Transfusion; Cost-Benefit Analysis; Drug Costs; Erythropoietin; Humans; Leukemia; Lymphoma; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Anaemia is a common disorder in patients with cancer, occurring in 10-40% of cases, depending upon the tumour type and chemotherapy used. It is present in nearly all patients with leukaemia at some time in the disease and in 50% of patients with lymphoma after chemotherapy. Cancer-related anaemia appears to result from a range of factors including chronic inflammation, blood loss, nutritional deficiencies, haemolysis, bone marrow infiltration by malignant cells, low serum erythropoietin (EPO) levels, and a decrease of bone marrow responsiveness to EPO. The consequences of anaemia, namely fatigue and cardiovascular symptoms, can adversely affect patients' quality of life and may even alter their response to cancer treatment. Moreover, anaemia is often associated with the presence of several adverse prognostic parameters and is also itself a predictor of poor prognosis. Furthermore, anaemia and its symptoms can be exacerbated by cancer treatment. Until recently, blood transfusions have been the mainstay of treatment for cancer-related anaemia, despite the associated risks of transfusion-related reactions and transmission of infection. By increasing haemoglobin levels and haematocrit, treatment with recombinant human erythropoietin (rHuEPO) has been shown to reduce the need for blood transfusion in patients with haematological malignancies. It is recommended that rHuEPO be administered when a patient's haemoglobin level is at risk of falling below 8g/dL, and that treatment is maintained until levels rise above 13g/dL. Consideration of the detrimental effects of anaemia on cancer patients' physical and emotional well-being and therapeutic outcome suggests that rHuEPO therapy has the potential to provide substantial clinical benefits.

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Leukemia; Lymphoma; Prognosis; Quality of Life; Recombinant Proteins

Anemia is a common complication of myelosuppressive chemotherapy that results in a decreased functional capacity and quality of life (QOL) for cancer patients. Severe anemia is treated with red blood cell transfusions, but mild-to-moderate anemia in patients receiving chemotherapy has traditionally been managed conservatively on the basis of the perception that it was clinically unimportant. This practice has been reflected in the relative inattention to standardized and complete reporting of all degrees of chemotherapy-induced anemia. We undertook a comprehensive review of published chemotherapy trials of the most common single agents and combination chemotherapy regimens, including the new generation of chemotherapeutic agents, used in the treatment of the major nonmyeloid malignancies in adults to characterize and to document the incidence and severity of chemotherapy-induced anemia. Despite identified limitations in the grading and reporting of treatment-related anemia, the results confirm a relatively high incidence of mild-to-moderate anemia. Recent advances in assessing the relationships of anemia, fatigue, and QOL in cancer patients are providing new insights into these closely related factors. Clinical data are emerging that suggest that mild-to-moderate chemotherapy-induced anemia results in a perceptible reduction in a patient's energy level and QOL. Future research may lead to new classifications of chemotherapy-induced anemia that can guide therapeutic interventions on the basis of outcomes and hemoglobin levels. Perceptions by oncologists and patients that lesser degrees of anemia must be endured without treatment may be overcome as greater emphasis is placed on the QOL of the oncology patient and as research provides further insights into the relationships between hemoglobin levels, patient well-being, and symptoms.

Topics: Adult; Aged; Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Clinical Trials as Topic; Colorectal Neoplasms; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Humans; Incidence; Lung Neoplasms; Lymphoma; Middle Aged; Neoplasms; Ovarian Neoplasms; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Topics: Biological Products; Deltaretrovirus; Erythropoietin; Genetic Engineering; Hematologic Diseases; HIV; Humans; Immunoglobulins; Leukemia; Lymphoma; Oncogenes; Receptors, Antigen, T-Cell; Transfection; Translocation, Genetic

T gamma lymphocytes are those lymphocytes that express receptors for both the Fc portion of IgG and sheep erythrocytes. A very high proportion of normal T gamma lymphocytes are large granular lymphocytes (LGL), the cell responsible for most, if not all, natural killer (NK) and antibody-dependent cell-mediated cytotoxicity (ADCC) in humans, rats, and mice. In general, these cells are large lymphocytes with prominent azurophilic granules in the cytoplasm. Recently, a group of lymphoproliferative disorders made up predominantly of T gamma lymphocytes has been described. The most common and best studied of these disorders we refer to as "chronic T gamma-lymphoproliferative disease" (T gamma-LPD). In most cases, this disease represents the abnormal expansion of LGL, which is reflected by an increase in functionally active NK or ADCC effector cells. The chronic T gamma-LPD lymphocytes are generally characterized as E- and EA-rosette positive, acid-phosphatase, and beta-glucuronidase positive and express the pan-T antigens OKT3/Leu-4, OKT11/Leu-5, the suppressor-associated antigens OKT5,8/Leu-2, and the NK-associated antigens Leu-7/HNK-1. Typically, the patients are older, predominantly males and characteristically have a lymphocytosis of predominantly T gamma lymphocytes with lymphocyte infiltration of the bone marrow and often the spleen. While chronic T gamma-LPD is not usually an aggressive disease, the patients are often neutropenic and have recurrent bacterial infections requiring antibiotic therapy. Some patients have benefited from cytotoxic chemotherapy., but most patients have not required chemotherapy. An experimental LGL leukemia in F344 rats appears morphologically, functionally, and clinically similar to the human chronic T gamma-LPD and serves as an experimental model for further examining the ontogeny and function of LGL and may be applicable for exploring new and more effective means for the treatment of patients with chronic T gamma-LPD.

Topics: Adult; Aged; Alkylating Agents; Anemia; Animals; Antibody-Dependent Cell Cytotoxicity; Antigens, Surface; Erythrocytes; Erythropoietin; Female; Humans; Immunologic Surveillance; Killer Cells, Natural; Lymphocyte Activation; Lymphoma; Lymphoproliferative Disorders; Male; Middle Aged; Phagocytosis; Rats; Receptors, Fc; Rosette Formation; Skin Neoplasms; Splenectomy; T-Lymphocytes; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

Topics: Adenocarcinoma; Adrenal Gland Neoplasms; Animals; Brain Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Cysts; Erythropoietin; Esophageal Neoplasms; Female; Growth Substances; Haplorhini; Humans; In Vitro Techniques; Kidney Neoplasms; Leiomyoma; Leukemia; Leukemia, Experimental; Liver Neoplasms; Lymphoma; Male; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Pheochromocytoma; Polycythemia; Rats; Sarcoma, Experimental; Skin Neoplasms; Time Factors; Wilms Tumor

We conducted a randomized study analyzing the impact of darbepoetin alfa (DA) administration with or without intravenous (i.v.) iron on erythroid recovery after autologous hematopoietic cell transplantation (HCT). Patients were randomized between no DA (Arm 1), DA 300 μg every 2 weeks starting on Day 28 after HCT (Arm 2), or DA plus i.v. iron 200 mg on Days 28, 42, and 56 (Arm 3). The proportion achieving complete hemoglobin (Hb) response within 18 weeks (primary end point) was 21% in Arm 1 (n = 24), 79% in Arm 2 (n = 25), and 100% in Arm 3 (n = 23; P < 0.0001). Erythropoietic response was shown to be significantly higher in Arm 3 (n = 46) than in Arm 2 (n = 50; P = 0.008), resulting in lower DA use, reduced drug costs, and improved quality of life scores, but the effect on transfusions was not significant. In multivariate analysis, DA administration (P < 0.0001), i.v. iron administration (P = 0.0010), high baseline Hb (P < 0.0001), and low baseline creatinine (P = 0.0458) were independently associated with faster achievement of complete Hb response. In conclusion, DA is highly effective to ensure full erythroid reconstitution after autologous HCT when started on Day 28 post-transplant. I.v. iron sucrose further improves erythroid recovery.

Topics: Aged; Anemia; Blood Transfusion; Combined Modality Therapy; Darbepoetin alfa; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematopoietic Stem Cell Transplantation; Humans; Infusions, Intravenous; Injections, Subcutaneous; Lymphoma; Male; Middle Aged; Multiple Myeloma; Postoperative Complications; Quality of Life; Transferrin; Transplantation Conditioning; Transplantation, Autologous

This study was aimed at investigating the effectiveness and safety of once-weekly epoetin beta for anaemic cancer patients receiving chemotherapy.. A total of 104 patients with a haemoglobin level of /=2.0 g/dL; the haemoglobin response rate. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Anaemia (FACT-An) questionnaire.. The haemoglobin response rate was 66.3% among the 98 patients (breast cancer: n = 25; malignant lymphoma: n = 21; ovarian cancer: n = 20; lung cancer: n = 15; other cancers: n = 17) assessable for a haemoglobin response. Thirty-nine patients (39.8%) required a dose escalation to 54 000 IU. At the end of the study, QOL assessable patients (n = 96) showed a mean improvement in the FACT-An total fatigue subscale score (FSS) of 0.3 points from baseline. Patients with a haemoglobin response had a mean change in the total FSS of +3.2, compared with -3.4 for patients without a haemoglobin response. No serious adverse event of epoetin beta was observed.. Epoetin beta administered at an initial dose of 36 000 IU once-weekly was well tolerated, with increased haemoglobin levels and improved QOL in anaemic cancer patients receiving myelosuppressive chemotherapy.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Ovarian Neoplasms; Patient Compliance; Quality of Life; Recombinant Proteins

The aim of the study was to evaluate the role of hypochromic erythrocytes (HYPO%) compared to "traditional" and novel markers of iron status and erythropoiesis in recognizing iron-restricted erythropoiesis (IRE) and predicting response to erythropoietin (rHuEPO) in anemic patients with myeloma and lymphoma. Forty-one newly diagnosed patients who received epoetin-beta at a subcutaneous weekly dose of 30,000 IU for 6 weeks were studied. Response to rHuEPO was observed in 27 patients (65.8%). Twelve non-responders received, additionally, 200 mg of IV iron sucrose, weekly, for 4 weeks. Evaluation of markers was performed at baseline and on weeks 1, 2 and 6 for all patients and also on weeks 7-10 for non-responders to rHuEPO. Baseline HYPO%, at a cut-off value of <5%, and an increment in reticulocyte absolute number (RETICS-AB) >or= 50,000/microl and reticulocyte hematocrit (RETICS-Hct) >or= 50%, between baseline and week 2, were independent predictive factors for response to rHuEPO. We found that these markers had superior predictive value for response to rHuEPO than four widely used predictive models. Furthermore, a baseline HYPO% count of above 5% proved superior over serum ferritin < 100 ng/ml and transferrin saturation < 20% in recognizing IRE. In conclusion, baseline HYPO% either alone or in combination with RETICS-AB or RETICS-Hct after 2 weeks of rHuEPO treatment could be reliably used in predicting response to rHuEPO. Additionally, HYPO% has proved a reliable marker for recognizing IRE before rHuEPO treatment and, thus, could be used for identifying patients who will benefit from IV iron supplementation.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Biomarkers; Erythrocyte Indices; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematinics; Hematocrit; Humans; Lymphoma; Male; Middle Aged; Multiple Myeloma; Predictive Value of Tests; Recombinant Proteins

Anemia-related fatigue in cancer patients reduces health-related quality of life (HRQOL). These analyses evaluate the effect of hemoglobin level on fatigue and examine the relationship between improved fatigue and HRQOL. Data were collected during a multicenter, randomized trial involving 344 anemic patients with lymphoproliferative malignancies receiving chemotherapy and darbepoetin alfa or placebo. At baseline, interim study visits, and end of treatment, patients completed an HRQOL questionnaire. Improved hemoglobin levels were significantly associated (P < 0.001) with improved fatigue. Mean change in the Functional Assessment of Cancer Therapy (FACT) Fatigue score was 5.9 points greater when hemoglobin improved > 2 g/dl than when it declined. Patients experiencing a clinically meaningful improvement in fatigue reported significantly (P < 0.001) greater improvements in all other scales, except the FACT Social subscale. Managing anemia-related fatigue appears to have a positive impact on HRQOL, enhancing cancer patients' activity levels, mood, and perceived overall health.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Fatigue; Female; Health Status; Hemoglobins; Humans; Leukemia, Lymphoid; Lymphoma; Male; Middle Aged; Quality of Life; Treatment Outcome

To determine a recommended dose of once-weekly epoetin-beta administration for anemic cancer patients receiving myelosuppressive chemotherapy, we conducted a multicenter, randomized, double-blind trial.. A total of 86 patients with malignant lymphoma or lung cancer who received chemotherapy containing platinum, taxanes or anthracyclines were enrolled in the study. Patients were randomly assigned into groups that received three dose levels of epoetin-beta (9000, 18,000 or 36,000 IU) administered subcutaneously once a week for 12 weeks. The primary endpoint was change in hemoglobin, while the secondary endpoints were quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and transfusion requirements.. Among the 69 patients (per protocol set population) assessable for efficacy, hemoglobin level change in the 36,000 IU group was significantly greater than that in the 9000 IU group (1.75 +/- 2.15 versus 0.04 +/- 1.98 g/dl; P = 0.009), and a significant dose-response relationship was observed for the change in hemoglobin level (P = 0.003). Although changes in FACT-An Total Fatigue subscale (Fatigue subscale) scores were similar for the three dosage groups, there was a statistically significant correlation (r = 0.435, P < 0.001) between the change in hemoglobin levels and the change in Fatigue subscale scores. The proportion of transfused patients was significantly smaller in the 36 000 IU group compared with that in the 9000 IU group (P = 0.022, not adjusted for pre-study transfusions). The incidence of adverse events was similar in the three dosage groups.. Once-weekly epoetin-beta 36,000 IU for 12 weeks was well tolerated and significantly increased hemoglobin levels in anemic cancer patients receiving chemotherapy.

Topics: Adult; Aged; Anemia; Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Bridged-Ring Compounds; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Leukopenia; Lung Neoplasms; Lymphoma; Male; Middle Aged; Platinum Compounds; Quality of Life; Recombinant Proteins; Taxoids

To determine the effect of darbepoetin alfa (DA) on progression-free survival (PFS) and overall survival (OS) in patients with chemotherapy-induced anemia (CIA).. Two 16-week randomized, double-blind, placebo-controlled phase III studies of weekly DA in anemic patients with lung cancer (n = 314) or lymphoproliferative malignancies (LPMs; n = 344) undergoing chemotherapy were analyzed with prospectively defined long-term PFS and OS end points. Short-term effects of DA on PFS and OS were analyzed by including two additional 16-week dose-finding, double-blind, placebo-controlled studies in anemic patients with multiple tumor types (n = 405) and LPMs (n = 66).. Median follow-up is 15.8 months (lung cancer) and 32.6 months (LPM). Median duration of PFS was comparable between DA and placebo: 5.1 months (95% CI, 4.1 to 6.9 months) versus 4.4 months (95% CI, 3.7 to 5.3 months) for lung cancer and 14.2 months (95% CI, 12.2 to 17.5 months) versus 15.9 months (95% CI, 13.1 to 19.0 months) for LPMs. The estimated hazard ratio (HR) of death related to DA use for lung cancer was 0.77 (95% CI, 0.59 to 1.01) and 1.26 (95% CI, 0.92 to 1.71) for LPMs. In the pooled analyses of all four studies (n = 1,129), no differences in PFS or OS were observed between DA and placebo (HR = 0.92; 95% CI, 0.78 to 1.07; and HR = 0.95; 95% CI, 0.78 to 1.16, respectively).. Treatment with DA does not seem to influence PFS or OS in patients with CIA. Prospective, randomized clinical trials will provide additional insights into the effects of DA on PFS and OS in specific tumor types.

Topics: Anemia; Darbepoetin alfa; Disease Progression; Disease-Free Survival; Double-Blind Method; Erythropoietin; Female; Humans; Lung Neoplasms; Lymphoma; Male; Placebos; Survival Analysis; Treatment Outcome

This phase 3, randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Patients (n = 344) with lymphoma or myeloma received darbepoetin alfa 2.25 microg/kg or placebo s.c., once weekly for 12 weeks. The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group (60%) than in the placebo group (18%) (P < 0.001), regardless of baseline endogenous erythropoietin level. However, increased responsiveness was observed in patients with lower baseline erythropoietin levels. Darbepoetin alfa also resulted in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase (1.80 g/dl vs 0.19 g/dl) and after 12 weeks of treatment (2.66 g/dl vs 0.69 g/dl). A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group (P < 0.001). The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma. Improvements in quality of life were also observed with darbepoetin alfa. The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population. Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy.

Topics: Aged; Analysis of Variance; Anemia; Blood Transfusion; Darbepoetin alfa; Diarrhea; Double-Blind Method; Erythropoietin; Fatigue; Female; Fever; Follow-Up Studies; Humans; Linear Models; Lymphoma; Lymphoproliferative Disorders; Male; Middle Aged; Multiple Myeloma; Nausea; Quality of Life

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

Previous studies have shown that, unlike in patients submitted to allogeneic BMT, administration of recombinant erythropoietin (Epo) after autologous BMT (ABMT) had no significant effect on erythroid recovery and transfusional requirements. On the other hand, it has also been shown that combining Epo with recombinant granulocyte colony-stimulating factor (G-CSF) in patients with the acquired immunodeficiency syndrome (AIDS) and with myelodysplastic syndromes resulted in additive effects on erythropoiesis. To test the effects of combined G-CSF + Epo therapy on erythroid recovery after autologous bone marrow transplantation a pilot randomized, three-arm trial was designed. Thirty patients suffering from lymphoid malignancies submitted to ABMT were randomly assigned to receive G-CSF alone (5 micrograms/kg, from day + 1 up to reaching an ANC > or = 10(9)/1), G-CSF + Epo (150 U/kg, from day +1 to +21), or neither of these (controls). Patients receiving G-CSF + Epo had significantly more reticulocytes on day +21 and reached 30 x 10(9)/1 reticulocytes earlier when compared to both G-CSF and control patients; however, the number of red blood cell (RBC) transfusions was not modified by the addition of Epo to G-CSF, although both groups had significantly fewer units transfused than controls. No effect on platelet recovery or platelet transfusional requirements was observed. Myeloid recovery was comparable in the G-CSF and G-CSF+Epo groups, and significantly accelerated as compared to controls. We conclude that the addition of Epo to G-CSF causes a slight acceleration of erythroid recovery after ABMT, but is not associated with transfusional benefits. Therefore, the present data do not support the use of Epo in association with G-CSF to hasten erythroid recovery after ABMT.

Topics: Anemia; Blood Transfusion; Bone Marrow Transplantation; Drug Synergism; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Humans; Lymphoma; Pilot Projects; Platelet Count; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reticulocyte Count; Safety; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Topics: Bone Marrow Transplantation; Busulfan; Costs and Cost Analysis; Double-Blind Method; Erythrocyte Transfusion; Erythropoietin; Follow-Up Studies; Humans; Leukemia; Lymphoma; Platelet Transfusion; Recombinant Proteins; Time Factors; Transplantation, Homologous; Whole-Body Irradiation

Autologous stem-cell transplantation (ASCT) has shown to provide curative benefit in patients with relapsed lymphoma and multiple myeloma (MM), often requiring hematopoietic support until marrow engraftment. Because of Jehovah's Witnesses' (JW) refusal of blood products, treatment challenges arise. This study represents 125 JWs with lymphoma (n = 55), MM (n = 68), or amyloidosis (n = 2), treated with high-dose chemotherapy (HDC) and ASCT without transfusions.. Priming with intravenous iron and erythropoietin occurred to increase hemoglobin (Hb) pretransplantation. Cytokine mobilization of stem-cells was used. Delay to HDC was done to allow Hb and platelets to approach 11 g/dL and 100 × 10(3)/μL, respectively. Patients with MM received a standard dose of melphalan 200 mg/m(2), with dose reduction for severe kidney dysfunction. Patients with lymphoma received carmustine 300 mg/m(2), cyclophosphamide 1,500 mg/m(2) on days 2 through 5 (total 6 g/m(2)), and etoposide 700 mg/m(2) per day on days 2 through 4 (total 2,100 mg/m(2)). Post-transplantation, a combination of granulocyte colony-stimulating factor, erythropoietin, aminocaproic acid, and phytonadione was administered.. There were two major and 15 minor bleeding complications, none occurring at platelets less than 5.0 × 10(3)/μL, with six (4.8%) treatment-related mortalities. The median decrease in Hb was 5.0 g/dL, with median Hb nadir of 7.0 g/dL. The median number of days with platelet count less than 10 × 10(3)/μL was 3, with median platelet nadir of 5.0 × 10(3)/μL. Cardiac complications occurred in 40 patients (32%).. ASCT can safely be performed without transfusion support. A platelet transfusion trigger of ≤ 5 × 10(3)/μL may be appropriate in select patients. Pharmacotherapy and cardiac monitoring are effective in the management of cardiac complications.

Topics: Adult; Aged; Aminocaproic Acid; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Carmustine; Combined Modality Therapy; Cyclophosphamide; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hemoglobins; Humans; Iron; Jehovah's Witnesses; Lymphoma; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Stem Cell Transplantation; Transplantation, Autologous; Vitamin K 1; Young Adult

In patients with CKD, anaemia mainly develops due to a decreased renal synthesis of erythropoietin. The anaemia, both normochromic and normocytic, becomes more severe as the glomerular filtration rate progressively decreases. Tumor markers are used to detect or monitor proliferative diseases. Carcinoembryonic antigen (CEA) is usually produced in the gastrointestinal tract, but its production is terminated before birth. The main application of this indicator is to monitor the treatment and the presence of metastases of colorectal cancer. We present a case of 86-year-old woman who was diagnosed with renal anaemia in stage 4 of chronic kidney disease (CKD), treated by periodic blood transfusions. This paper presents the difficulties in diagnosis and treatment of anemia with complex and different than renal origin anemia in patients with CKD. Patients require the detailed haematological diagnosis. Pointed out the usefulness of CEA in the diagnosis of lymphoma with co-existing renal failure. The use of erythropoietin in doses of nephrology allowed to avoid further blood transfusion.

Topics: Aged, 80 and over; Anemia; Biomarkers, Tumor; Blood Transfusion; Carcinoembryonic Antigen; Darbepoetin alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Lymphoma

This study was purposed to investigate the role of cytokines in pathogenesis of lymphoma-associated anemia. The levels of IFN-γ, IL-1β, IL-6, TNF-α and EPO in serum from 45 lymphoma patients and 12 normal controls were detected by using ELISA, the EPOR level on bone marrow cells were detected by flow cytometry, the CFU-E of bone marrow cultured in vitro was counted under inverted microscope. The results showed that 25 (55.6%) out of 45 newly diagnosed lymphoma patients had anemia before diagnosis, 13 (28.9%) had anemia during therapy, 7 (15.5%)never had anemia. The IFN-γ and TNF-α levels in serum of patients with moderate and severe anemia were significantly higher than those in patients with mild anemia and without anemia as well as normal controls. The EPO, IL-6 and IFN-γ levels correlated negatively with Hb concentration in patients, the EPOR level in patients without anemia significantly higher than that in patients with anemia and normal controls. The bone marrow CFU-E amount in patients showed positive correlation with Hb and EPOR levels. It is concluded that the increased IFN-γ, TNF-α and IL-6 may contribute to the anemia in lymphoma, and yet the EPO and EPOR levels are elevated to balance negative regulatory effects on hematopoiesis and maintain normal hematopoiesis.

Topics: Adult; Aged; Anemia; Case-Control Studies; Cytokines; Erythropoietin; Female; Humans; Interferon-gamma; Interleukin-1; Interleukin-6; Lymphoma; Male; Middle Aged; Receptors, Erythropoietin; Tumor Necrosis Factor-alpha

Topics: Cell Count; Cell Proliferation; Colony-Forming Units Assay; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cells; Herpesviridae Infections; Herpesvirus 8, Human; Humans; Interleukin-3; Lymphoma

Lymphomas are a heterogenous group of malignant diseases. 30-50% of patients, even before chemo- and radiotherapy are begun have anemia. The pathogenesis of this anemia is multifactorial and still not completely clear. Newer investigations refer to a causality between the anemia in patients with lymphoma and the inappropriate erythropoietin production for the degree of anemia. Based on this finding, the aim of the study was to evaluate the erythropoietin production in patients with malignant lymphoma in order to define the clinical conditions of Epo deficiency and thereby enable rational use of this expensive drug. 27 patients with malignant lymphoma were examined. The control group consisted of 25 patients with iron deficiency anemia. 14 healthy volunteers represented the so-called "normal" control. The adequacy of Epo production was estimated from the graphic representation of the linear regression between Epo and hemoglobin (Hb) in the control group, as well as from the O/PEpo ratio as a measure of the degree of adequacy of Epo production (O - observed Epo value, P-predicted Epo value from the regression equation of the control group). The erythropoietic activity was estimated from the graphic representation of the linear regression between soluble transferrin receptors (sTfR) and Hb in the control group, as well as from the O/PsTfR ratio, as a measure of the degree of adequacy of erythropoietic activity (O - observed sTfR value, P - predicted sTfR value from the regression equation of the control group). Significant inverse correlation between Epo and Hb was found in patients with malignant lymphoma (r= -0.76, p < 0.001). 33% of patients had inadequate Epo response to anemia. O/PEpo in patients with malignant lymphoma is significantly lower in comparison to the control group, which also points to the inadequacy of erythropoietin production. There was a significant negative correlation between sTfR and Hb in patients with malignant lymphoma (r= -0.056, p < 0.001). Inadequate sTfR response to anemia have 76% of patients. The positive correlation between O/PEpo and O/PsTfR (r=0.79, p < 0.001) points out to a causality between the inadequacy of erythropoietin production and the inadequate erythropoiesis. In conclusion, results from this study show unambiguously that anemia in patients with malignant lymphoma appears because of decreased erythropoiesis as a consequence of bone marrow infiltration with lymphoma cells as well as inadequate Epo production. Mo

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Humans; Lymphoma; Male; Middle Aged; Receptors, Transferrin

It is now well established that after conventional allogeneic hematopoietic stem-cell transplantation (HSCT), erythropoietic recovery is impaired because erythropoietin (Epo) production remains inadequate for prolonged periods of time. However, erythropoietic reconstitution after nonmyeloablative SCT (NMSCT) has never been characterized.. Twelve patients received a nonmyeloablative conditioning regimen consisting of 2 Gy total body irradiation (TBI) alone (n=6), 2 Gy TBI and fludarabine (n=3), or cyclophosphamide and fludarabine (n=3), followed by transplantation of allogeneic peripheral blood stem cells. Graft-versus-host-disease (GvHD) prophylaxis was carried out with mycophenolate mofetil (from day -1 to day 28) plus cyclosporine (from day -1 to day 120 or longer in case of chronic GvHD). Erythropoiesis was quantitated by soluble transferrin receptor (sTfR) levels, and the adequacy of Epo production was evaluated by the observed-to-predicted Epo ratio (O/P Epo).. Mean sTfR levels decreased following the conditioning regimen but remained well within the normal range throughout the posttransplant period. The O/P Epo ratio presented an initial surge quite similar to that observed after conventional conditioning. Thereafter, the O/P Epo ratio normalized rapidly, and Epo levels remained adequate during the whole observation period.. Contrarily to what is observed after myeloablative transplant, Epo levels remained adequate after NMSCT, resulting in normal erythropoiesis. These results suggest that the administration of erythropoietin therapy (rHuEpo) could be less effective after NMSCT than after conventional allogeneic transplant.

Topics: Adult; Cyclosporine; Erythropoiesis; Erythropoietin; Female; Graft Rejection; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Lymphoma; Male; Middle Aged; Mycophenolic Acid; Receptors, Transferrin; Recombinant Proteins; Transplantation Conditioning; Transplantation, Homologous

Warm autoimmune hemolytic anemia (AIHA) is a condition in which peripheral red blood cell (RBC) destruction is induced by the presence of an autoantibody. Pure red cell aplasia (PRCA) represents an isolated process of decreased erythropoiesis. The combination of both is quite rare, with a very poor prognosis. We describe a patient with isolated splenic lymphoma whose presentation was a combination of AIHA and PRCA. The patient was resistant to all treatment.. Erythroid colony assays were performed, in order to compare the effect of the patient's serum on colonies with that of a normal control.. The patient's serum significantly suppressed normal erythroid colony growth. A red cell eluate revealed the presence of a warm autoantibody.. The patient's serum contained warm autoantibody responsible for peripheral RBC destruction and a humoral factor, perhaps the warm autoantibody, which suppressed bone marrow erythropoiesis. Establishing an early diagnosis, and treatment of the underlying disease might result in a better prognosis.

Topics: Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Autoantibodies; Cell Division; Coombs Test; Diagnosis, Differential; Erythroid Precursor Cells; Erythropoietin; Female; Humans; Lymphoma; Middle Aged; Red-Cell Aplasia, Pure; Sepsis; Splenectomy; Splenic Neoplasms

Cytokines and growth factors regulate expression of their target genes via the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) signaling pathway. One of the best characterized targets of STAT is the interleukin-2 receptor-alpha (IL-2Ralpha) gene. Its transcription is controlled by interleukin 2 (IL-2) through STAT5 activation. Using the PC60 cell line, in which the role of STAT5 in the regulation of the murine IL-2Ralpha gene by IL-2 has been elucidated, we have compared the response of this gene to IL-2, interleukin-9 (IL-9) and erythropoietin (Epo). IL-2 and IL-9, but not Epo, stimulate cell surface expression of IL-2Ralpha. This correlates with the fact that IL-2 and IL-9 support long-term STAT5 activation whereas Epo only induces transient activation. In cells treated with vanadate, a protein tyrosine phosphatase (PTP) inhibitor, Epo induces prolonged STAT5 activation and strongly stimulates IL-2Ralpha expression. Our study suggests that by controlling the duration of the STAT activation signal, PTP influences the specificity of cytokine signaling.

Topics: Animals; Cytokines; DNA-Binding Proteins; Enzyme Activation; Erythropoietin; Gene Expression Regulation; Hybrid Cells; Interleukin-2; Interleukin-9; Lymphoma; Mice; Milk Proteins; Rats; Receptors, Erythropoietin; Receptors, Interleukin; Receptors, Interleukin-2; Receptors, Interleukin-9; Recombinant Proteins; STAT5 Transcription Factor; T-Lymphocytes, Cytotoxic; Thymus Neoplasms; Trans-Activators; Transfection; Vanadates

The plasma concentrations of erythropoietin (Ep), soluble transferrin receptors (sTfRs), iron, total iron binding capacity (TIBC) and ferritin were monitored in five leukaemia patients undergoing autologous bone marrow stem cell transplantation (BMSCT) and in 10 lymphoma and 21 ovarian cancer patients undergoing autologous peripheral blood SCT (PBSCT); 9/21 ovarian cancer patients received recombinant human G-CSF and Ep and six recombinant human GM-CSF and Ep following SCT. All parameters were evaluated in relation to the kinetics of erythroid reconstitution as evaluated by haemoglobin (Hb) and reticulocyte levels [including the fraction of immature reticulocytes, also called highly fluorescent reticulocytes (HFR)]. Leukaemia patients undergoing BMSCT showed only a delayed (occurring at days 35-50 after SCT) and partial RBC, neutrophil and platelet recovery, whereas all patients undergoing PBSCT exhibited a rapid (occurring at days 10-15 after SCT) and sustained haemopoietic recovery. The various levels of erythroid rescue observed among these patients markedly influenced the kinetics of the different parameters investigated: (i) in leukaemia BMSCT patients sTfRs declined following SCT and remained at low levels thereafter, whereas Ep, iron. TIBC and ferritin showed a progressive and significant increase; (ii) in the different groups of patients undergoing PBSCT: (a) sTfR levels first declined following SCT and then returned to pre-therapy values at days 12-16, this response preceded erythropoietic recovery; (b) Ep, total iron, TIBC and ferritin showed an initial increase in the first days following SCT and then returned to pre-therapy values. Altogether, these observations indicate that: (i) both sTfR levels and reticulocyte counts are predictive parameters of erythropoietic recovery; (ii) coordinated changes of biochemical parameters underlying iron metabolism (iron, TIBC and ferritin) accompany erythroid rescue following SCT.

Topics: Adolescent; Adult; Aged; Erythropoiesis; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Hemoglobins; Humans; Leukemia; Lymphoma; Male; Middle Aged; Ovarian Neoplasms; Receptors, Transferrin; Reticulocyte Count

Topics: Adolescent; Adult; Blood Donors; Busulfan; Child; Child, Preschool; Cyclosporine; Erythropoietin; Female; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Leukemia; Lymphoma; Lymphoproliferative Disorders; Male; Methotrexate; Middle Aged; Prednisolone; Whole-Body Irradiation

Administration of vanadium as ammonium monovanadate (0.005 microgram/0.1 ml/mouse/day) was found to reduce the tumor cell proliferation in the host mice bearing Dalton's lymphoma. The high activity of gamma-glutamyl transpeptidase (GGT), a neoplastic marker, was seen in the host cells bearing lymphoma. Vanadium effectively prevented an increase in activity of gamma-glutamyl transpeptidase and maintained a sustained low activity of this enzyme. In addition, an improvement of the hematological aspects of the mice and almost fourfold elevation of erythropoietin (Epo) was obtained following vanadium treatment. This increase in Epo activity may play a vital role in regulating the growth of cellular neoplasia. The present study further confirms the antitumorigenic potential of vanadium in the control of tumor progression in lymphoma via modulating several factors involving erythropoiesis and may emerge as a new chemopreventive agent for the future.

Topics: Animals; Cell Differentiation; Cell Division; Erythropoiesis; Erythropoietin; gamma-Glutamyltransferase; Lymphoma; Mice; Mice, Inbred DBA; Vanadium

To provide sufficient numbers of peripheral blood progenitor cells (PBPCs) for repetitive use after high-dose chemotherapy, we investigated the ability of hematopoietic growth factor combinations to expand the number of clonogenic PBPCs ex vivo. Chemotherapy plus granulocyte colony-stimulating factor (G-CSF) mobilized CD34+ cells from 18 patients with metastatic solid tumors or refractory lymphomas were cultured for up to 28 days in a liquid culture system. The effects of interleukin-1 beta (IL-1), IL-3, IL-6, granulocyte-macrophage-CSF (GM-CSF), G-CSF, macrophage-CSF (M-CSF), stem cell factor (SCF), erythropoietin (EPO), leukemia inhibitory factor (LIF), and interferon-gamma, as well as 36 combinations of these factors were tested. A combination of five hematopoietic growth factors, including SCF, EPO, IL-1, IL-3, and IL-6, was identified as the optimal combination of growth factors for both the expansion of total nucleated cells as well as the expansion of clonogenic progenitor cells. Proliferation peaked at days 12 to 14, with a median 190-fold increase (range, 46- to 930-fold) of total clonogenic progenitor cells. Expanded progenitor cells generated myeloid (colony-forming unit-granulocyte-macrophage), erythroid (burst-forming unit-erythroid), as well as multilineage (colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte) colony-forming units. The number of multilineage colonies increased 250-fold (range, 33- to 589-fold) as compared with pre-expansion values. Moreover, the absolute number of early hematopoietic progenitor cells (CD34+/HLA-DR-; CD34+/CD38-), as well as the number of 4-HC-resistant progenitors within expanded cells increased significantly. Interferon-gamma was shown to synergize with the 5-factor combination, whereas the addition of GM-CSF significantly decreased the number of total clonogenic progenitor cells. Large-scale expansion of PB CD34+ cells (starting cell number, 1.5 x 10(6) CD34+ cells) in autologous plasma supplemented with the same 5-factor combination resulted in an equivalent expansion of progenitor cells as compared with the microculture system. In summary, our data indicate that chemotherapy plus G-CSF-mobilized PBPCs from cancer patients can be effectively expanded ex vivo. Moreover, our data suggest the feasibility of large-scale expansion of PBPCs, starting from small numbers of PB CD34+ cells. The number of cells expanded ex vivo might be sufficient for repetitive use after high-dose chemotherapy an

Topics: Antigens, CD; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cell Division; Cells, Cultured; Colony-Forming Units Assay; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Inhibitors; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Ifosfamide; In Vitro Techniques; Interferon-gamma; Interleukin-1; Interleukin-3; Interleukin-6; Interleukins; Kinetics; Leukemia Inhibitory Factor; Lymphokines; Lymphoma; Macrophage Colony-Stimulating Factor; Neoplasms; Recombinant Proteins; Stem Cell Factor; Vincristine

Immunoreactive erythropoietin levels were measured in 42 patients with lymphoid malignancies with anaemia and bone marrow involvement. Results were compared to a control group of 16 patients suffering from anaemia due to other causes. Significant inverse correlations between serum erythropoietin level and haemoglobin concentration were shown for the patients with lymphoid malignancies and also for the control subjects. Overall, the erythropoietin levels of patients with lymphoid malignancies with bone marrow infiltration and with normal renal function did not differ significantly from erythropoietin levels of the anaemic controls. We conclude that anaemia in patients with lymphoproliferative disorders with bone marrow infiltration and normal renal function is caused primarily by a diminished/inadequate response to erythropoietin at the level of the target cell.

Topics: Anemia; Bone Marrow Diseases; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Lymphoma; Lymphoproliferative Disorders; Male; Multiple Myeloma; Neoplasm Metastasis

Serum immunoerythropoietin (SIE) levels were studied of 25 randomly chosen cancer patients undergoing cisplatin-based chemotherapy and ten head and neck cancer patients who were studied prospectively before and during cisplatin-based therapy. The SIE levels were determined by standard radioimmunoassay, and the results were interpreted relative to erythropoietin levels and hematocrits of 17 aplastic or nutritionally anemic patients who were believed to have a normal erythropoietin response. Of the 25 randomly chosen patients, SIE levels were inappropriately low in four patients. In this population, there was a greater likelihood of erythropoietin deficiency in the patients with a hematocrit less than 30% compared with those with higher values (P less than 0.001), although there was no correlation between SIE level and the amount of cisplatin these patients received or their degree of renal impairment. Of the ten head and neck cancer patients, five were found to have inappropriately low SIE levels before therapy, and two additional patients had a decrease of SIE levels during therapy, in one patient to an abnormally low level. The anemia associated with malignancy was concluded to be in part associated with a relative erythropoietin deficiency, and in certain individuals, cisplatin therapy may contribute to that deficiency.

Topics: Adult; Aged; Anemia; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cohort Studies; Erythropoietin; Female; Head and Neck Neoplasms; Hematocrit; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Prospective Studies

AKR/O mice were used as a model for studying the pathogenesis of the anaemia accompanying leukaemia/lymphoma. The leukaemia incidence was 87%. Median age at diagnosis was 11.3 months. At diagnosis most of the mice had normal leukocyte counts. Clinically the mice divided into subgroups depending on the relative organ involvement: 1) thymoma group (n = 98), 2) spleen group (n = 144), 3) combined group (n = 27) and 4) mice with moderate organ changes (n = 216). Mice of group 1 were younger than the others, had a rapidly progressive disease, normal to elevated packed cell volume (PCV), and plasma erythropoietin (Epo) was normal or increased. Mice of group 2 were usually anaemic with high plasma Epo estimates and often elevated reticulocyte counts. Group 4 was the oldest group. Some of these mice were severely affected haematologically. Overall there was an inverse relation between PCV and plasma Epo estimate, indicating a normal Epo response to anaemia. In all groups increasing spleen size was associated with increased severity of anaemia and increased reticulocyte counts. The association between anaemia, elevated reticulocyte counts and spleen enlargement suggests haemolysis as a mechanism for anaemia, and also raises the question of compensatory spleen erythropoiesis.

Topics: Age Factors; Anemia; Animals; Erythropoietin; Female; Hematologic Tests; Incidence; Leukemia, Experimental; Lymphoma; Male; Mice; Mice, Inbred AKR; Spleen; Statistics as Topic; Thymoma; Thymus Gland; Thymus Neoplasms

A 30-year-old female patient with malignant lymphoma was admitted to the hospital because of large mass in the left pelvic cavity and of severe anemia. Since she had refused blood transfusion (Jehovah's witness), recombinant human erythropoietin (Epo) was used together with both chemotherapy and irradiation; this led to rapid recovery of the anemia and marked reduction of the mass volume. These findings may suggest the possible application of Epo administration as a supportive therapy in treatment of malignancy.

Topics: Adult; Blood Transfusion; Christianity; Combined Modality Therapy; Erythropoietin; Female; Humans; Lymphoma; Recombinant Proteins

In order to investigate the pathogenesis of anemia in childhood malignancy, we studied erythroid cell proliferation responses with bone marrow erythroid cultures and serum erythropoietin (Ep) levels in 32 children with lymphomas and malignant tumors. The erythroid colony formation from 20 normal controls (mean 68.8 colony-forming-unit erythroid [CFU-E] and 32 burst-forming-unit erythroid [BFU-E] derived colonies/10(5) mononuclear cells), was higher than that seen in children with lymphomas (mean 45.9 CFU-E and 20.7 BFU-E/10(5) cells, p less than 0.01) but similar to the values obtained from children with tumors (mean 65.1 CFU-E and 28.1 BFU-E/10(5) mononuclear cells). The degree of anemia in children with lymphomas correlated negatively (r = -0.7, p less than 0.01) with serum Ep levels. In contrast, a weak positive correlation (r = 0.3, p greater than 0.1) was observed between the degree of anemia and Ep values in the group with tumors. We suggest that the decreased number of committed erythroid progenitors in lymphomas may be the main factor for anemia in these patients, while the abnormal response of Ep to the degree of the anemia suggests a defect in erythropoiesis in children with tumors.

Topics: Anemia; Bone Marrow; Child; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Female; Humans; Lymphoma; Male; Neoplasms

Tumor-induced changes in the pattern of erythropoiesis have been studied in A/RB mice bearing a transplantable ascites tumor, DBA lymphoma. The tumor growth was accompanied by diminished erythropoiesis, and the 51Cr-labeled red cell half-life was also decreased. Plasma iron turnover rate of the tumor bearing hosts, however, was increased and the level of erythropoietic stimulating factor (erythropoietin) in the plasma was not reduced. The existence of an inhibitor(s) to erythropoietic activity was unlikely. Comparative study of the erythropoietic activity revealed suppression in the marrow, but an increment in the spleen. The distribution of pluripotent hematopoietic stem cells (CFUs) also paralleled this alteration. However, the degree of ineffective erythropoiesis, determined by in vitro technique, was significantly elevated in the spleen. Possibly, this has reduced the effectiveness of splenic compensatory erythropoiesis.

Topics: Animals; Bone Neoplasms; Erythrocyte Aging; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Hemoglobins; Iron; Lymphoma; Male; Mice; Neoplasm Transplantation; Spleen

In order the investigate mechanisms of diminished red cell production in malignancy, we assayed erythroid progenitor cell proliferative responses to erythropoietin in plasma clot cultures of bone marrow cells from 34 cancer patients. Erythroid colony growth by marrow cells of 11 healthy donors (means of 58 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) was similar to that in cultures of cells from patients either with (means of 44 CFU-E and 22 BFU-E derived colonies/6 X 10(4) cells) or without (means of 50 CFU-E and 19 BFU-E derived colonies/6 X 10(4) cells) myelophthisis. Colony formation was normal at all erythropoietin concentrations tested, indicating that both the CFU-E and BFU-E retain normal erythropoietin sensitivity in vitro. CFU-E proliferation correlated negatively (r = -0.56; P less than 0.001) with the level of hemoglobin. In contrast to marrow cell proliferative responses to erythropoietin, serum erythropoietin levels were inappropriately reduced in all 19 patients in whom they were measured, a finding which may be important in the pathogenesis of anemia in patients with cancer.

Topics: Carcinoma, Squamous Cell; Cell Division; Cells, Cultured; Erythropoiesis; Erythropoietin; Female; Hematologic Diseases; Hematopoietic Stem Cells; Hemoglobins; Humans; Leukemia; Lymphoma; Male; Middle Aged

Eleven human T cell leukemia-lymphoma cell lines were tested to determine whether or not they released a product into their media which could stimulate erythroid colony formation by human peripheral blood mononuclear cells. None of the cell lines studied released erythroid burst-promoting activity detectable in our culture conditions.

Topics: Cell Line; Culture Media; Erythropoiesis; Erythropoietin; Humans; Leukemia; Lymphoma; T-Lymphocytes

Topics: Adolescent; Adult; Aged; Anemia, Aplastic; Anemia, Hemolytic; Anemia, Sickle Cell; Bone Marrow Diseases; Creatinine; Erythropoietin; Female; Hematocrit; Hemolysis; Humans; Iron; Leukemia; Lymphoma; Male; Middle Aged; Multiple Myeloma; Sex Factors

Topics: Adult; Aged; Alkaline Phosphatase; Anemia, Aplastic; Aspartate Aminotransferases; Bilirubin; Blood Transfusion; Bone Marrow Diseases; Chromium Isotopes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron; Iron Isotopes; Lymphoma; Male; Middle Aged; Multiple Myeloma; Oxymetholone; Primary Myelofibrosis

Topics: Anemia; Anemia, Aplastic; Anemia, Sickle Cell; Animals; Biological Assay; Breast Neoplasms; Cachexia; Erythrocytes; Erythropoiesis; Erythropoietin; Iron; Iron Isotopes; Leukemia; Lymphoma; Male; Mice; Plasma; Polycythemia; Prostatic Neoplasms

Topics: Androgens; Anemia; Diagnosis, Differential; Erythropoietin; Humans; Iron; Kidney; Lymphoma; Male; Middle Aged; Radiation Injuries; Stomach Neoplasms

Topics: Blood Cell Count; Blood Platelets; Blood Transfusion; Bone Marrow Examination; Cell Nucleus; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Exchange Transfusion, Whole Blood; Hematocrit; Humans; Iron; Iron Isotopes; Leukemia, Erythroblastic, Acute; Lymphoma; Mitosis; Reticulocytes

Topics: Adult; Aged; Androgens; Anemia; Bone Marrow Examination; Chromium Isotopes; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Hypogonadism; Iron; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Transaminases

Topics: Adenocarcinoma; Animals; Blood; Carcinoma; Carcinoma, Hepatocellular; Epoetin Alfa; Erythropoietin; Growth Substances; Humans; Iron; Iron Isotopes; Liver Extracts; Liver Neoplasms; Liver Neoplasms, Experimental; Lymphoma; Neoplasms; Neoplasms, Experimental; Radiometry; Rats