losartan-potassium and Neutropenia

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

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

Fever during neutropenia may be a symptom of severe life threatening infection, which must be treated immediately with antibiotics. If signs of infection persist, therapy must be modified. Diagnostic measures should not delay treatment. If the risk of febrile neutropenia after chemotherapy is ≥ 20%, then prophylactic therapy with G-CSF is standard of care. After protocols with a risk of febrile neutropenia of 10-20%, G-CSF is necessary, in patients older than 65 years or with severe comorbidity, open wounds, reduced general condition. Anemia in cancer patients must be diagnosed carefully, even preoperatively. Transfusions of red blood cells are indicated in Hb levels below 7-8 g/dl. Erythropoiesis stimulating agents (ESA) are recommended after chemotherapy only when hemoglobin levels are below 11 g/dl. The Hb-level must not be increased above 12 g/dl. Anemia with functional iron deficiency (transferrin saturation < 20%) should be treated with intravenous iron, as oral iron is ineffective being not absorbed. Therapy of pain must follow diagnostic and treatment standards. Nausea or emesis following chemotherapy can be classified as minimal, low, moderate and high. The antiemetic prophylaxis should be escalated accordingly. In chemotherapy with low emetogenic potential steroids are sufficient, in the moderate level 5-HT3 receptor antagonists (setrons) are added, and in the highest level Aprepitant as third drug.

Topics: Anemia; Anti-Bacterial Agents; Antineoplastic Agents; Diarrhea; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Nausea; Neutropenia; Opportunistic Infections; Otorhinolaryngologic Neoplasms; Pain Management; Palliative Care; Pneumonia; Vomiting

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

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

Chronic hepatitis C is one of the leading causes for chronic liver disease globally. The past two decades have seen many advances in hepatitis C treatment. Despite these advances, side effects of treatment are common. Haematological complications of treatment can result in treatment cessation and suboptimal results. Recent data have suggested a role for epoetin/granulocyte colony stimulating factor (G-CSF) in optimizing sustained virological response (SVR).. To investigate the nature, frequency and management of haematological side effects in the treatment of chronic hepatitis C infection.. The terms hepatitis C, hepatitis C virus (HCV), treatment, side effects, interferon, peginterferon, ribavirin, anaemia, haemoglobin, neutropenia, thrombocytopenia, haematological, growth factor, erythropoietin and G-CSF were searched on MEDLINE for the period 1991-2009. References from selected articles were also included.. Haematological side effects such as anaemia, neutropenia and thrombocytopenia are frequent in anti-HCV treatment. The off-label use of haematological growth factors is common and effective.. Erythropoietic agents are effective in treating anaemia, preventing ribavirin dose reduction, improving patients' quality of life, but the effect on SVR is not fully elucidated. G-CSF is effective in raising absolute neutrophil count; however, neutropenic HCV-infected patients on combination treatment may not experience increased bacterial infections. Eltrombopag, a new oral thrombopoietin mimetic, may allow combination treatment in patients with thrombocytopenia.

Topics: Anemia; Antiviral Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia; Viral Load

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

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

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

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

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

To review the hematologic adverse effects of hepatitis C virus (HCV) therapy and adjuvant treatment with epoetin alfa and granulocyte colony-stimulating factor (ie, filgrastim).. Medical literature indexed in MEDLINE (1966-January 2007) and EMBASE (1980-January 2007) was searched, and published conference abstracts were reviewed.. Peer-reviewed articles and relevant conference abstracts regarding the use of epoetin alfa and granulocyte colony-stimulating factor were reviewed.. Ribavirin induces a dose-dependent hemolytic anemia. Studies using epoetin alfa 40 000 units subcutaneously once weekly have demonstrated efficacy in maintaining hemoglobin, ribavirin dose, and quality of life scores, but clear benefit shown with sustained virologic response (SVR) is lacking. The hemoglobin threshold for initiation of epoetin alfa used in studies may not adequately reflect values used in clinical practice. Treatment-related neutropenia is caused primarily by interferon or peginterferon. Few studies have investigated the impact of granulocyte or granulocyte-macrophage colony-stimulating factor derivatives on neutropenia. Results of dose maintenance evaluation vary, and studies reporting data on SVR showed no effect from growth factor therapy. The frequency of bacterial infections was not reported.. The role and benefit of hematopoietic growth factors in HCV therapy have not been conclusively determined to date. However, the possibility of a benefit to individual patients seen on an outpatient basis remains, and an individualized treatment approach is recommended.

Topics: Anemia; Chemotherapy, Adjuvant; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Hepatitis C; Humans; Interferons; MEDLINE; Neutropenia; Recombinant Proteins; Ribavirin

The clinical availability of recombinant hematopoietic growth factors was initially thought to be breakthrough in the treatment of bone marrow failure syndromes. However, in most disorders of hematopoeisis, the clinical use was rather disappointing. Only in congenital neutropenias (CNs) has the long-term administration of granulocyte colony-stimulating factor (G-CSF) led to a maintained increase in absolute neutrophil count (ANC) and a reduction of severe bacterial infections. In other disorders of hematopoiesis, the use of lineage-specific growth factors is either not possible due to mutations in the growth factor receptor or leads to a transient benefit only. Initial clinical trials with multilineage hematopoietic growth factors, such as stem cell factor (SCF; c-kit ligand) were discontinued due to adverse events. It is well known that bone marrow failure syndromes are pre-leukemic disorders. So far, there is no evidence for induction of leukemia by hematopoietic growth factors. However, it has been shown in patients with CN and Fanconi anemia that hematopoietic growth factors might induce preferential outgrowth of already transformed cells. Thus, it is strongly recommended to monitor patients for clonal aberrations prior to and during long-term treatment with hematopoietic growth factors.

Topics: Anemia; Anemia, Diamond-Blackfan; Anemia, Dyserythropoietic, Congenital; Erythropoietin; Fanconi Anemia; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Stem Cell Factor; Thrombocytopenia

Pegylated interferon and ribavirin combination therapy represent the standard-of-care treatment for chronic hepatitis C, that allows to cure more than half of the patients. However, the success of this bitherapy is in balance with numerous side effects, especially hematologic and psychiatric. This review is focused on complementary treatments (erythropoietin, G-CSF, vitamin E, glutathion, ursodeoxycholic acid and antidepressants) likely to bring a benefit in maintaining adequate interferon and ribavirin dosages and in improving quality of life. This analysis has been performed by using the Medline(R) data base and with data from laboratories which commercialized these molecules. Erythropoietin, G-CSF and antidepressants are the best tools to optimize the bitherapy in its dose and its duration while privileging the quality of life of HCV-infected patients.

Topics: Anemia; Antidepressive Agents; Antioxidants; Antiviral Agents; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Hematopoietic growth factors are usually administered in autologous and allogeneic stem cell transplantation. RhuG-CSF and rhuEPO are the most frequently used, either for mobilization of peripheral stem cells or after transplantation for the improvement of hematologic recovery. G-CSF (filgrastim or lenograstim) can be administered alone or in combination with stem cell factor to enhance stem cells mobilization. IL-3 and sargramostim are not used anymore. The protocol of administration of rhuG-CSF is well established. Furthermore, stem cell transplantation with peripheral cells is less expensive than with bone marrow. RhuEPO (erythropoietin) is not effective in mobilization. After transplantation, filgrastim or lenograstim can shorten the neutropenic period and decrease infectious complications. The potential effect of these growth factors on the incidence and the severity of GvHD is still unknown and under debate. The use of rhuEPO after transplantation might be of interest to reduce the need of red blood cell transfusion. Some studies suggest that the administration of rhuEPO should start before delivering the conditioning regimen. The new long acting growth factors such as pegfilgrastim are still under evaluation and their use in mobilization seems promising.

Topics: Antineoplastic Agents; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Lenograstim; Leukapheresis; Neutropenia; Polyethylene Glycols; Recombinant Proteins

Febrile neutropenia and anemia are two major complications of chemotherapy. Human recombinant cytokines as G-CSF and erythropoietin allow efficient fight against these secondary effects but require iterative injections due to a short half life. The glycosylation of natural cytokines results in enhanced stability of these molecules of new generation and makes it possible to space the injections which become concomitant of chemotherapies. With regard to the erythropoietin, the prolonged half-life form shows a similar effectiveness with the natural molecule. For the G-CSF, the glycosylated form could still show itself more effective for the prevention of febrile neutropenias. Finally, these new molecules allow an improvement of the quality of life while ensuring an optimal dose-intensity of the treatment.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Delayed-Action Preparations; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Neutropenia; Polyethylene Glycols; Recombinant Proteins

Pegylated (PEG)-interferon and ribavirin combination therapy are the standard of care for the treatment of chronic hepatitis C and are associated with a high rate of sustained virologic response. However, there is a high incidence of hematologic side effects with this therapeutic regimen. Hematologic side effects are particularly common; bone marrow suppression caused by interferon may result in neutropenia and thrombocytopenia. Ribavirin is directly toxic to red blood cells and is associated with hemolysis, which is usually dose-related but self-limited. Historically, the traditional management of hematologic side effects of interferon therapy has been dose reduction. However, recent studies have shown that response to therapy is strongly influenced by adherence to optimal doses of interferon and particularly ribavirin. Therefore, there is increasing emphasis on the use of growth factors such as filgrastim and erythropoietin to stimulate bone marrow production of erythrocytes and leukocytes to allow patients to receive the optimal doses of interferon and ribavirin. The incidence, magnitude, and possible mechanisms of hematologic complications associated with interferon and ribavirin are described in this review.

Topics: Anemia, Hypochromic; Antiviral Agents; Clinical Trials as Topic; Drug Therapy, Combination; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Hematologic side effects (anemia, neutropenia, and thrombocytopenia) of combination therapy with pegylated (PEG)-interferon alfa and ribavirin are commonly encountered during antiviral therapy for chronic hepatitis C (HCV). An important consequence of these side effects is dose modification of PEG-interferon alfa, ribavirin, or both. Dose modification (including discontinuation) diminishes the efficacy of optimal treatment regimen for HCV and may have a negative impact on sustained virologic response. Additionally, fatigue associated with anemia may impair patients' quality of life. The clinical implications of neutropenia or thrombocytopenia are less clear than for anemia; nevertheless, severe infection and bleeding are uncommon. Dose adjustments effectively treat these hematologic side effects, but the resulting suboptimal dosing and potential impact on virologic response are major concerns. Recent attempts to maximize adherence to the optimal treatment regimen have used hematopoietic growth factors rather than dose adjustment to treat side effects. Research on growth factor support has focused on anemia and neutropenia. Epoetin alfa and darbepoetin alfa are erythropoietic growth factors that effectively increase hemoglobin while maintaining the optimal ribavirin dose and improving patients' quality of life. Preliminary work suggests that filgrastim, granulocyte colony stimulating factors, may be an effective treatment of interferon-induced neutropenia. Although this early work shows tremendous promise for managing hematologic side effects of combination therapy for HCV, and potentially enhancing adherence, further research is needed to clarify the efficacy, safety, and cost-effectiveness of growth factors in the management of patients with chronic HCV.

Topics: Anemia, Hypochromic; Antiviral Agents; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Growth Substances; Hematinics; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Topics: Anemia; Animals; Cytokines; Erythropoietin; Genetic Therapy; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Neutropenia; Receptors, Cytokine; Recombinant Proteins; Signal Transduction

Consensus guidelines are in place for treating chronic hepatitis C virus infection. This article highlights some of the hematologic complications of hepatitis C therapy. Management options are presented.

Topics: Anemia; Antiviral Agents; Bone Marrow; Epoetin Alfa; Erythropoietin; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon Type I; Neutropenia; Recombinant Proteins; Ribavirin; Thrombocytopenia

The purpose was to conduct an integrated analysis of the cumulative hematologic toxicity of topotecan in patients with relapsed ovarian cancer and small cell lung cancer (SCLC). Data were pooled from eight phase II and phase III clinical studies performed in patients with relapsed stage III/IV ovarian cancer or extensive SCLC treated with topotecan at a dose of 1.5 mg/m(2) per day on days 1-5 of a 21-day course. Quantitative hematologic toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. A total of 4,124 courses of therapy was administered to the 879 patients in the pooled population. Grade 4 neutropenia was experienced by 78% of patients. The lowest nadirs for neutrophils and platelets generally occurred after the first course of therapy, followed by improvement or stabilization in subsequent courses. Neutropenia was noncumulative. During the first course, significant risk factors were identified: renal impairment and advanced age (grade 3/4 thrombocytopenia and grade 4 neutropenia) and prior radiotherapy; performance status score > or =2; SCLC; and exposure to both cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb) (grade 3/4 thrombocytopenia only). The most frequent interventions for hematologic toxicities were RBC transfusions, treatment delays, G-CSF support, and dose reductions. Analysis of neutrophil and platelet nadirs and dosing for each course of therapy showed no apparent evidence of cumulative neutropenia or thrombocytopenia. The risk of grade 3 or 4 anemia was higher during the first four courses of therapy and may need to be more aggressively managed with erythropoietin therapy.

Topics: Antineoplastic Agents; Bone Marrow; Carcinoma, Small Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Ovarian Neoplasms; Topotecan

Neutropenia and anemia are important complications of cancer chemotherapy and can be prevented and treated with granulocyte colony-stimulating factor and erythropoietin.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Female; Filgrastim; Genital Neoplasms, Female; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia; Quality of Life; Recombinant Proteins

Hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia are common during combination therapy with pegylated (or standard) interferon and ribavirin for chronic hepatitis C. Ribavirin-induced hemolytic anemia is a common cause of dose reduction or discontinuation. Bone marrow suppression also contributes to the anemia and is the predominant mechanism for interferon-induced neutropenia and thrombocytopenia. Although dose reduction or discontinuation of combination therapy can reverse these abnormalities, they may reduce virologic response. Hematopoietic growth factors may provide a useful alternative for managing these hematologic side effects without reducing the optimal dose of the combination antiviral regimen. Treatment of anemia also may improve patients' health-related quality of life and their adherence to combination antiviral therapy. The impact of growth factors on sustained virologic response and their cost-effectiveness in patients with chronic hepatitis C need further assessment.

Topics: Anemia; Antiviral Agents; Clinical Trials as Topic; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Interleukin-11; Neutropenia; Patient Compliance; Polyethylene Glycols; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Ribavirin; Thrombocytopenia

Certain populations with chronic hepatitis C face special challenges in attaining optimal adherence to antiviral therapy, including patients coinfected with human immunodeficiency virus, patients undergoing dialysis for end-stage renal disease, and liver transplant recipients. These patient groups may stand to gain particular benefit from the expanding use of hematopoietic growth factors to manage the cytopenic effects of antiviral therapy for hepatitis C. This article reviews the rationale, current evidence, and future prospects for the adjunctive use of growth factors in these special populations with hepatitis C.

Topics: Anemia; Antiviral Agents; Clinical Trials as Topic; Comorbidity; Drug Therapy, Combination; Erythropoietin; Forecasting; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; HIV Infections; Humans; Interferons; Kidney Failure, Chronic; Liver Transplantation; Neutropenia; Patient Compliance; Recombinant Proteins; Recurrence; Renal Dialysis; Ribavirin

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

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

For previously untreated patients receiving most chemotherapy regimens, primary prophylactic administration of granulocyte colony-stimulating factor (G-CSF) cannot be recommended. Secondary prophylactic G-CSF administration can lessen incidence of febrile neutropenia (FN) in subsequent cycles of chemotherapy in patients with a prior episode of FN. Physicians should consider chemotherapy dose reduction after neutropenic fever or severe or prolonged neutropenia after the previous cycle of treatment. Intervention with G-CSF in afebrile neutropenic patients is not recommended. For the majority of patients with FN, the available data do not clearly support the routine initiation of G-CSF as an adjunct to antibiotic therapy. However, certain FN patients may have prognostic factors that are predictive of clinical deterioration, such as pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or fungal infection. The therapeutic use of G-CSF together with antibiotics may be reasonable in such high-risk patients. Empirical antifungal therapy is effective, especially for patients with neutropenia who were treated for seven days with empirical antibiotic therapy but remained febrile, or became afebrile but then had recurrent fever. The patient's overall clinical status and laboratory parameters are both considered when deciding to transfuse a patient. Epoetin may be available for use in the future as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dl. Giving prophylactic platelets at a threshold of 10,000/microliter compared with 20,000/microliter can decrease the total utilization of platelets with only a small adverse effect on bleeding, and no statistically significant effect on morbidity.

Topics: Anemia; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Guidelines as Topic; Humans; Neoplasms; Neutropenia; Platelet Transfusion; Recombinant Proteins; Risk

As the population ages, a dramatic increase in the number of cases of cancer is expected and the need for supportive-care agents, those used to ameliorate some of the side effects of cancer or its treatment, becomes more urgent. At present, supportive-care products are available and new agents are being developed with novel mechanisms of action or modifications of existing agents that improve performance. Because of the urgent need for such products, efficient development is required to deliver useful products to patients as rapidly as possible. This chapter uses actual examples to illustrate the stages of drug development, phase I through phase 3.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Drug Approval; Drug Design; Drug Evaluation; Erythropoietin; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Neutropenia; Palliative Care; Polyethylene Glycols; Quality of Life; Recombinant Proteins; Stomatitis; United States

Myelosuppression associated with cancer chemotherapy may lead to neutropenia, anemia, or both, resulting in an increased risk for infection, fatigue, diminished quality of life, and reduced survival. In addition, neutropenia specifically has been shown to result in dose reductions, treatment delays, or both in subsequent chemotherapy cycles. Hematopoietic growth factors have been used effectively as supportive therapy to reduce chemotherapy-associated neutropenia and anemia. New preparations have the potential to improve treatment outcome dramatically. Results from recently reported studies indicate that patients at risk for neutropenia can be safely and effectively treated with pegfilgrastim once per chemotherapy cycle, and that those with anemia can be managed with weekly or biweekly darbepoetin alfa therapy. These new treatments have the potential to reduce the morbidity and mortality associated with opportunistic infections, decrease the requirement for potentially dangerous blood transfusions, and improve the quality of life for patients undergoing cancer chemotherapy. The longer dosing intervals offered by these new preparations may decrease healthcare expenses and enhance patient adherence.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Neutropenia; Polyethylene Glycols; Recombinant Proteins

The recombinant human cytokines granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, and interleukin-2 (IL-2) have been manufactured and licensed. Studies have been carried out that investigate the use of G-CSF and GM-CSF to reverse leukopenia, as adjunctive therapy for HIV-associated infections and for novel approaches to treat HIV infection, including stem cell mobilization. In addition, studies that identified the role of erythropoietin in the management of anemia have been performed. Furthermore, the abilities of G-CSF and erythropoietin to permit the continued use of marrow suppressive agents that are key in managing HIV infection have been assessed. The aim of this review is to summarize these studies and to describe the reports that evaluate the use of IL-2 to enhance elevation of CD4 cell counts mediated by highly active antiretroviral therapy. This summary is important to the treating clinician in that it identifies the optimal use of these cytokines in current clinical practice as well as their potential future roles.

Topics: Anemia; Colony-Stimulating Factors; Erythropoietin; HIV Infections; Humans; Interleukin-2; Neutropenia; Recombinant Proteins

Recombinant hematopoietic growth factors were introduced into clinical practice a decade ago: erythropoietin in 1989, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 1991, and interleukin-11 in 1997. The role of these agents in supportive therapy for children with cancer is still under considerable evaluation. This pediatric-based review summarizes current clinical applications, practice guidelines, and practice patterns for hematopoietic growth factors in the supportive care of children with cancer. It also discusses ongoing controversies and unanswered questions.

Topics: Chemotherapy, Adjuvant; Child; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Neoplasms; Neutropenia

Bone marrow suppression is a substantial problem in patients infected with HIV. Contributing factors include the underlying HIV infection, alterations in the marrow microenvironment (resulting in abnormal cytokine regulation of hematopoiesis), and opportunistic infections and their associated medical treatments. Hematopoietic stimulants offer the promise of correcting peripheral blood cytopenias, augmenting host immune function, and permitting the continued use of potentially beneficial myelosuppressive therapies, which would otherwise result in dose-limiting side effects. The bone marrow abnormalities and mechanisms that contribute to alterations in hematopoiesis in HIV infection are briefly reviewed. Attention is then focused on the expanding clinical role of myeloid colony-stimulating factors (CSFs) and recombinant human erythropoietin (rHuEPO [Epogen, Procrit]) in the treatment of patients with AIDS.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Bone Marrow; Bone Marrow Diseases; Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Humans; Neutropenia; Neutrophils; Recombinant Proteins

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

Topics: Anemia; Animals; Antineoplastic Agents; Bone Marrow Transplantation; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Humans; Neoplasms; Neutropenia; Recombinant Proteins; Stomatitis

Topics: Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Macrophage Colony-Stimulating Factor; Neutropenia

Topics: Anemia; Bone Marrow Transplantation; Colony-Stimulating Factors; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neoplasms; Neutropenia; Radiotherapy; Thrombocytopenia

Neutropenia and anaemia are common problems in patients with HIV infection. Neutropenia can lead to a reduction in drug doses or to withdrawal of important myelosuppressive agents such as ganciclovir, zidovudine, cotrimoxazole and pyrimethamine, while anaemia may require the administration of blood transfusions.. Haematopoietic growth factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) are effective in the treatment of AIDS-related neutropenia. G-CSF appears to be better tolerated than GM-CSF. Moreover, GM-CSF can stimulate HIV replication in the absence of antiretroviral treatment. Thus G-CSF may offer a better treatment option in some patients. Doses of up to 300 micrograms G-CSF (filgrastim) per day rapidly reverse neutropenia in most HIV-infected patients. Subsequently, normal neutrophil counts can be maintained with intermittent doses (1-7 days a week). This allows greater use of myelosuppressive agents. Recombinant human erythropoietin is well tolerated and effective in the treatment of anaemia due to zidovudine when endogenous erythropoietin levels are < or = 500 IU/l. Recombinant human erythropoietin combined with CSF also appears to be well tolerated and effective in the treatment of combined cytopenias. Other haematopoietic growth factor combinations are currently being explored.. CSF and recombinant human erythropoietin, used alone or in combination, appear to be well tolerated and effective in the treatment of neutropenia and anaemia, respectively, in patients with HIV infection. G-CSF may be preferable to GM-CSF in some patients. However, the advantages of therapy with haematopoietic growth factors have to be balanced against the disadvantages of cost, inconvenience and discomfort associated with repeated subcutaneous injections. At present there is no clear evidence that CSF prolongs the survival of AIDS patients.

Topics: Anemia; Antiviral Agents; Drug Therapy, Combination; Erythropoietin; Filgrastim; Ganciclovir; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; HIV Infections; Humans; Immunosuppression Therapy; Neutropenia; Recombinant Proteins

Human immunodeficiency virus infection causes multilineage hematopoietic defects. Defects in the production and function of CD4+ helper cells have been the focus of the majority of HIV research, but anemia, neutropenia, and thrombocytopenia are significant clinical problems as well. Bone marrow suppression is the dose-limiting toxicity for a number of antiviral and prophylactic medications. Hematopoietic growth factors such as granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor are used to optimize the delivery of antiretroviral and prophylactic therapy. Because of the expense involved, the most appropriate use of these hematopoietic growth factors remains a subject of intense investigation. This review focuses on recent experimental results.

Topics: AIDS-Related Opportunistic Infections; Bone Marrow Diseases; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; HIV Infections; Humans; Neutropenia; Virus Replication

The use of the recombinant hematopoietic growth factors G-CSF and GM-CSF have shortened the period of neutropenia, or avoided this problem, in many cancer patients who have received cytotoxic therapy. Although these benefits have been particularly striking in the autologous bone marrow and/or autologous peripheral blood progenitor cell transplant setting, most data suggest that the use of G-CSF and GM-CSF only marginally enhance recovery of the neutrophil count when administered after allogeneic bone marrow infusion. Furthermore, in the allograft setting these expensive agents have not provided benefit in the form of enhanced platelet count recovery, lessening the incidence of graft-versus-host disease, or improvement in overall survival. These data do not justify routine widespread use of G-CSF and GM-CSF and suggest that these agents should be reserved for patients who experience delay in engraftment after allogeneic bone marrow infusion. Administration of erythropoietin, on the other hand, may reduce the need for homologous red blood cell transfusions, and may increase the safety margin for both the allogeneic bone marrow recipient and as well as the donor. Recombinant hematopoietic growth factors targetted specifically to enhance platelet recovery after transplantation (such as interleukin-3, interleukin-6, and interleukin-11) have shown promise after autotransplantation and after conventional dose chemotherapy, and likely will be evaluated in the allogeneic transplant patient.

Topics: Bone Marrow Transplantation; Clinical Trials as Topic; Erythropoietin; Graft Survival; Graft vs Host Disease; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoiesis; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Depletion; Macrophage Colony-Stimulating Factor; Neoplasms; Neutropenia; Recombinant Proteins; Transplantation, Homologous; Treatment Outcome

HIV-infected patients commonly experience haematological disturbances including anemia, neutropenia or thrombocytopenia. Bone marrow failure may be caused by HIV itself, or by secondary involvement by opportunistic pathogens and malignancy. The need for multiple concomitant suppressive treatments may increase the risk of cytopenias. Strategy to reduce both anemia and neutropenia as well as to improve the haematological tolerance to myelotoxic agents have been developed by using haematological growth factors. So far, erythropoietin and granulocyte(macrophage) colony-stimulating factors have been successfully used in clinical trials including HIV-patients with either zidovudine-associated anemia or severe HIV or drug-induced neutropenia. However, according to the cost of these palliative approaches, there is a need for more reliable data showing that these growth factors could really have a major impact on the patient's compliance to therapy, reduction of hospitalization and infection rate and improvement of the overall survival.

Topics: AIDS-Related Complex; Anemia; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; HIV-1; Humans; Neutropenia

Cytokines play key roles in the control of hemopoiesis and immunity. As they become available in increasing quantities and purity through improved recombinant technology, cytokines hold great clinical promise. This article focuses on recent clinical experience with a wide variety of cytokines. For example, newer uses of recombinant human erythropoietin include treatment of anemia of prematurity, AIDS, and some hemoglobinopathies. The myeloid-stimulating factors have established a niche in the treatment of chemotherapy-induced neutropenias and as an adjunct to bone marrow transplantation. Combinations of cytokines that act at different levels of hemopoietic proliferation are being evaluated for the treatment of other causes of neutropenia and thrombocytopenia and also as biologic response modifiers.

Topics: Anemia; Bone Marrow Transplantation; Child; Cytokines; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Neutropenia; Recombinant Proteins

Haematopoietic growth factors help patients with intense chemotherapy and patients after transplantation of bone marrow to overcome the critical stage of leucopenia. In the submitted paper the authors present more detailed data on the results of investigations evaluating G-CSF, GM-CSF and erythropoietin in patients with anti-tumourous treatment. Both leucocytic growth factors, G-CSF and GM-CSF shorten the period of leucopenia by approximately one week which means a substantial reduction of the number of infectious complications and also a reduction of the hospitalization period. The price of the mentioned growth factors which is still high as compared with the costs of intensive treatment of septicaemia in leukopenic patients. To the authors' surprise, comparing an equal period of time, treatment of septicaemia is associated with much higher costs than administration of G-CSF which can prevent sepsis or reduce its duration.

Topics: Czechoslovakia; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunocompromised Host; Neoplasms; Neutropenia

The human recombinant hematopoietic growth factors have attracted widespread interest because of their potential efficacy in a number of clinical settings. Recombinant human erythropoietin is now an established therapy to treat and prevent the anemia associated with chronic renal failure in children and adults. This agent also shows extraordinary promise to stimulate erythrocyte production and reduce transfusion requirements in premature infants. Granulocyte and granulocyte-macrophage colony-stimulating factors stimulate the production and function of myeloid cells and have provided major clinical benefit to children with congenital disorders of neutrophil production. The myeloid growth factors also show great promise in reducing the duration and severity of neutropenias associated with cytotoxic cancer treatment and in improving granulocyte production in patients with human immunodeficiency virus infections.

Topics: Anemia; Anemia, Aplastic; Antineoplastic Agents; Bone Marrow Transplantation; Child; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; HIV Infections; Humans; Infant, Newborn; Neutropenia; Recombinant Proteins; Stem Cell Factor

Clinical usefulness of cytokines in cancer treatment has been described. Cytokines presently used in clinical practice are IFNs, IL-2, and hematopoietic growth factors. IFNs and IL-2 used with an expectation of direct antitumor effect of these cytokines have been proven to be specifically effective against certain types of tumors. Hematopoietic growth factors have been used as the adjuvant drugs in cancer treatment and proven to be effective against neutropenia and associated infections after chemotherapy and bone marrow transplantation. Future development of new cytokines and trials on the combination among cytokines and cytokines with chemotherapeutic agents, will promote the usefulness of cytokines in cancer treatment.

Topics: Antineoplastic Agents; Bone Marrow Transplantation; Colony-Stimulating Factors; Erythropoietin; Humans; Infections; Interferons; Interleukin-2; Neoplasms; Neutropenia; Recombinant Proteins

Topics: Acquired Immunodeficiency Syndrome; Bone Marrow Transplantation; Colony-Stimulating Factors; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Neoplasms; Neutropenia; Tumor Necrosis Factor-alpha; Zidovudine

Hematopoietic growth factors may mitigate the cytopenias that frequently complicate HIV disease or its treatment. Clinical and in vitro studies have indicated the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO) to overcome the myelosuppression of HIV or many of the drug therapies used in the care of HIV-infected individuals. In addition, neutrophil or monocyte functional abnormalities observed in AIDS patients may be improved by the use of GM-CSF. Issues which may distinguish the use of hematopoietic growth factors in AIDS as compared with in other clinical settings include: 1) interaction of the growth factor with other cytokines which are aberrantly expressed, 2) direct effects of the growth factor on the replicative activity of HIV, and 3) potential interactions of the growth factor with other concurrently administered medications. This review focuses on the potential roles and limitations of growth factor use in AIDS and reviews the clinical studies using GM-CSF in HIV-infected individuals.

Topics: Acquired Immunodeficiency Syndrome; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV Infections; Humans; Leukocyte Count; Monocytes; Neutropenia; Neutrophils

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

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

The haemopoietic growth factors are a diverse group of hormones with effects on different haemopoietic cell lineages and at various points in their developmental differentiation. The biology of many of these factors is now well understood. They have entered clinical trials and have demonstrated benefits in particular clinical situations. The thrust of current phase II and III clinical investigations now is to use these factors, alone or in combinations, to modify various disease states and to ameliorate many of the side-effects of other therapeutic agents, particularly cytotoxic anticancer agents. Many other disease states also lend themselves to therapy with these growth factors. Other haemopoietic growth factors have not been as extensively studied in humans but hold great promise. In this chapter, the current status of the haemopoietic growth factors presently under clinical trial has been reviewed. In addition, several factors which have been recently described but which have not yet entered clinical trials have been discussed.

Topics: Acquired Immunodeficiency Syndrome; Animals; Antineoplastic Agents; Bone Marrow Diseases; Bone Marrow Transplantation; Clinical Trials as Topic; Drug Evaluation; Drug Evaluation, Preclinical; Erythropoietin; Haplorhini; Hematologic Diseases; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cells; Humans; Immunologic Factors; Leukemia, Myeloid, Acute; Mice; Neoplastic Stem Cells; Neutropenia; Recombinant Fusion Proteins

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

Myelosuppression is the main limiting factor in cancer chemotherapy. The development of recombinant hematopoietic growth factors which stimulate myeloid progenitors and mainly neutrophil precursor cells leads to the evaluation of their potential activity in numerous fields of oncology. The available clinical trials have demonstrated the ability of G-CSF (granulocyte colony-stimulating factor) and GM-CSF (granulocyte-macrophage colony-stimulating factor) to accelerate neutrophil recovery following cytotoxic chemotherapy, and therefore to reduce the incidence of neutropenic febrile episodes and thereby improve the quality of life of patients receiving chemotherapy. The main goals of the future studies will be to determine to what extent the increase of dose intensity may lead to higher response rates and survival at least in patients with chemosensitive tumors.

Topics: Animals; Antineoplastic Agents; Drug Administration Schedule; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Neoplasms; Neutropenia

Cellular proliferation and differentiation in the living organism are regulated, at least in part, by a complex network of interacting peptides, or growth factors. The purification and molecular cloning of these growth factors has now led to the exciting task of ascertaining their physiological role in vivo and to verify their value as therapeutic substances worthy of clinical use. Rigorous methods of drug evaluation are required to prove the efficacy and safety of these new biological agents, particularly now that so many of them are being produced by the new genetic engineering techniques. Haemopoietic growth factors and growth factors involved in the regulation of the immune response have been more extensively studied clinically and are discussed in this section.

Topics: Anemia; Colony-Stimulating Factors; Erythropoietin; Growth Inhibitors; Growth Substances; Humans; Neutropenia

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

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

We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787.. Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and /=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B].. This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Darbepoetin alfa; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Feasibility Studies; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Mesna; Middle Aged; Neoplasm Staging; Neutropenia; Polyethylene Glycols; Prognosis; Recombinant Proteins; Survival Rate; Taxoids

Dose reductions of pegylated interferon alpha and ribavirin may be avoided by using growth factors. This phase II clinical trial assesses the dose, efficacy and safety of darbepoetin alpha and filgrastim for treatment of anaemia and neutropenia associated with combination therapy for hepatitis C virus (HCV). Chronic hepatitis C patients (n = 101) received pegylated interferon alpha-2b (1.5 mug/kg once weekly) and ribavirin (800-1400 mg once daily). Patients with anaemia [haemoglobin (Hb) /= 0.75 x 10(9)/L and <10 x 10(9)/L. During antiviral therapy, 52% of patients required darbepoetin alpha, filgrastim or both. Hb at the time of darbepoetin alpha initiation was 10.2 +/- 0.4 g/dL. After 81 days of darbepoetin alpha, Hb increased by 1.9 +/- 1.0 g/dL to 12.1 +/- 1.1 g/dL (P < 0.0001). Filgrastim resulted in a significant increase in ANC [0.75 +/- 0.16 x 109/L to 8.28 +/- 5.67 x 10(9)/L (P < 0.0001)]. In treatment-naïve patients, 48% achieved sustained virological response (SVR), whereas 27% of patients previously treated with a course of pegylated interferon alpha achieved SVR. Low viral load, nongenotype 1 and treatment with growth factors were independently associated with SVR. Mild and severe anaemia were associated with quality of life impairments. Darbepoetin alpha resulted in an improvement in the Vitality domain of Short Form-36. No significant adverse events were related to growth factors. During anti-HCV therapy, filgrastim improved neutropenia and darbepoetin alpha improved both anaemia and quality of life. Future randomized clinical trials are needed to establish the impact of growth factors in improving sustained virological response.

Topics: Adult; Anemia; Antiviral Agents; Darbepoetin alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Hemoglobins; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Neutropenia; Polyethylene Glycols; Quality of Life; Recombinant Proteins; Ribavirin; Treatment Outcome; Viral Load

A phase II trial was performed to determine the efficacy and tolerance of docetaxel plus oxaliplatin with hematopoietic growth factor support in previously untreated patients with advanced gastroesophageal adenocarcinoma. Thirty-five patients were entered in this trial. Treatment consisted of 3-weekly docetaxel 80 mg/m2 and oxaliplatin 100 mg/m2 both infused on day 1. A prophylactic 5-day course of human granulocyte colony-stimulating factor 5 microg/kg/day was given subcutaneously, and erythropoietin (10,000 IU subcutaneously three times per week) was administered if hemoglobin was less than 12.0 mg/dl. The confirmed overall response rate was 34%, including two complete responses (6%) and 10 partial responses (28%). Fifteen patients (43%) had stable disease. The median time to response was 2.5 months (1-3.5), the median time to progression was 8.9 (4-42.5) months and the median overall survival time was 11.6 (2.5-51) months. Hematologic toxicity was common, though World Health Organization grade 3 or 4 neutropenia occurred only in six (17%) patients and anemia in six (17%) patients, respectively. Nonhematologic adverse reactions were usually mild-to-moderate. Our data suggest that the combination of docetaxel and oxaliplatin with granulocyte colony-stimulating factor and erythropoietin has a promising therapeutic index in patients with advanced gastroesophageal adenocarcinoma.

Topics: Adenocarcinoma; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Drug Administration Schedule; Erythropoietin; Esophageal Neoplasms; Female; Granulocyte Colony-Stimulating Factor; Humans; Infusions, Intravenous; Injections, Subcutaneous; Male; Middle Aged; Neutropenia; Organoplatinum Compounds; Oxaliplatin; Stomach Neoplasms; Survival Rate; Taxoids

We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor.. 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity.. The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting.. The schedule B daily cisplatin-topotecan x 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Infusions, Intravenous; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Neutropenia; Recombinant Proteins; Topotecan

We recruited 50 patients with T2-4 N0-2 M0 primary breast cancer into a phase I/II study to define the maximum tolerated dose (MTD), efficacy and tolerability of preoperative gemcitabine (1250 mg/m fixed dose) plus epirubicin (doses escalated from 90 mg/m) for 5 cycles followed by 4 cycles of docetaxel (scheduled fixed dose 100 mg/m) given on day 1 every 2 weeks (q2w) with pegfilgrastim support. The MTD for epirubicin was 100 mg/m, but the docetaxel dose had to be reduced to 80 mg/m. Dose-limiting toxicities included fatigue, stomatitis, diarrhea and dyspnea (all grade 3) during gemcitabine plus epirubicin, and fatigue (grade 3) and allergic reaction (grade 4) during docetaxel treatment, respectively. A pathologic complete response could be achieved in 13 patients (pT0+pTis, 26%), and in the breast and axilla in 12 patients [(pT0 or pTis)+pN0, 24%). Breast-conserving surgery (BCS) was possible in 35 patients (70%). Main grade 3/4 adverse events at MTD were fatigue (57/0%), leukopenia (27/8%), and liver (14/0%) and lung toxicity (14/0%). In conclusion, gemcitabine plus epirubicin 1250/100 mg/m q2w followed sequentially by docetaxel 80 mg/m q2w is highly effective as pre-operative chemotherapy with manageable toxicity. However, response and BCS rates could not be increased by administering gemcitabine plus epirubicin and docetaxel in a dose-dense fashion.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Darbepoetin alfa; Deoxycytidine; Docetaxel; Dose-Response Relationship, Drug; Epirubicin; Erythropoietin; Female; Filgrastim; Gemcitabine; Granulocyte Colony-Stimulating Factor; Humans; Ki-67 Antigen; Middle Aged; Neutropenia; Polyethylene Glycols; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Recombinant Proteins; Taxoids; Treatment Outcome

Dose-dense, every-2-week adjuvant chemotherapy using doxorubicin/cyclophosphamide (AC; 60/600 mg/m2 every 2 weeks x four cycles) followed by paclitaxel (175 mg/m2 every 2 weeks x four cycles), requiring filgrastim on days 3 through 10 of each cycle has been shown to improve survival compared with every-3-week treatment schedules but is associated with greater risk of RBC transfusion (13%). The role of long-acting hematopoietic growth factors in facilitating every-2-week chemotherapy and minimizing hematologic toxicity has not been established.. Women with stage I to III breast cancer received dose-dense AC --> paclitaxel as neoadjuvant or adjuvant chemotherapy. Patients received pegfilgrastim 6 mg subcutaneous (SQ) on day 2 of each cycle. Darbepoetin alfa was initiated at 200 microg SQ every 2 weeks for hemoglobin < or = 12 g/dL, and administered thereafter, according to a preplanned algorithm. The primary end points were to evaluate the percentage of patients with febrile neutropenia and the percentage of patients requiring RBC transfusion.. Among 135 women treated on this single arm study, there were two cases of febrile neutropenia (incidence 1.5%). No patients received RBC transfusion. Darbepoetin alfa therapy was initiated in 92% of patients. The modest leukocytosis seen during paclitaxel cycles was attributable, in part, to corticosteroid premedication. Other toxicity and dose-delivery were similar to dose-dense AC --> paclitaxel in Cancer and Leukemia Group B 9741.. Pegfilgrastim and darbepoetin alfa are effective and safe in facilitating every-2-week AC --> paclitaxel, minimizing rates of febrile neutropenia and RBC transfusion.

Topics: Adult; Aged; Algorithms; Anemia; Antineoplastic Combined Chemotherapy Protocols; Boston; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Darbepoetin alfa; Doxorubicin; Erythrocyte Transfusion; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Middle Aged; Neutropenia; Paclitaxel; Polyethylene Glycols; Recombinant Proteins; Treatment Outcome

Autologous stem-cell transplantation has been shown to be a curative procedure for a variety of leukemias and lymphomas. Most transplants require RBC and platelet support. We report the ability to perform autologous transplantation without blood-product support.. In this study, we treated 26 patients with religious objection to blood products with autologous stem-cell support without the use of any blood products. Patients received a combination of granulocyte colony-stimulating factor (G-CSF), erythropoietin, and interleukin-11 or G-CSF alone to mobilize stem cells. Post-transplant patients received intravenous iron, erythropoietin, G-CSF, and epsilon aminocaproic acid.. There were two major bleeding complications (8%), with two treatment-related deaths (8%). There were three minor bleeding complications (12%). The median fall in hemoglobin level was 4.7 g/dL; the median hemoglobin level 30 days after transplantation was 9.2 g/dL. The median total number of days with platelet count less than 10 x 10(9)/L was 4 days; the median days to platelet recovery greater than 20 x 10(9)/L was 12 days.. Autologous stem-cell transplantation can be performed safely without the use of any blood products.

Topics: Adult; Combined Modality Therapy; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemorrhage; Humans; Interleukin-11; Jehovah's Witnesses; Leukocyte Count; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Neutropenia; Peripheral Blood Stem Cell Transplantation; Platelet Count; Survival Rate; Transplantation, Autologous

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

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

The ability of granulocyte colony-stimulating factor (G-CSF) plus erythropoietin (EPO) treatment was compared in a randomized fashion with that of G-CSF treatment alone in promoting hematologic recovery and peripheral-blood progenitor-cell (PBPC) mobilization in previously untreated patients with advanced ovarian cancer who underwent their first course of epirubicin, paclitaxel, and cisplatin (ETP) chemotherapy during a phase II study of intensive outpatient ETP chemotherapy followed by high-dose carboplatin, etoposide, and melphalan (CEM) late intensification with PBPC support.. Comparative analysis of hematologic recovery of 50 randomized patients, after ETP chemotherapy, showed that life-threatening neutropenia occurred in 88% of the patients treated with G-CSF alone, whereas it occurred in only 4% of patients treated with G-CSF + EPO. Significantly different WBC and polymorphonuclear leukocyte (PMN) counts were observed in the two distinct arms on the day of WBC nadir (P <.0001 and P <.0001, respectively). Moreover, the addition of EPO to G-CSF increased PBPC mobilization and collection as compared with that in G-CSF-treated patients (P =.0009 and P =.0026, respectively), who required a significantly higher number of leukaphereses than G-CSF + EPO-treated patients (P =.0076) to obtain the planned minimum dose of PBPCs. Qualitative analysis by cloning assay of PBPCs collected in both arms revealed that G-CSF- and G-CSF + EPO-mobilized PBPCs have comparable in vitro functional properties.. This randomized comparison revealed that EPO significantly increases most of the hematologic effect produced by G-CSF administration after chemotherapy. This biologic property of EPO translated in vivo into a global improvement of patients' hematologic status.

Topics: Adult; Antigens, CD34; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Cisplatin; Combined Modality Therapy; Drug Synergism; Epirubicin; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Middle Aged; Neutropenia; Ovarian Neoplasms; Paclitaxel; Statistics, Nonparametric; Treatment Outcome

To evaluate safety and efficacy of recombinant human erythropoietin (r-HuEPO)in reducing the need for red cell transfusions in anemia of prematurity.. forty -two preterm infants (gestational age <32 weeks) were randomly assigned to a "treatment" group (r-HuEPO 400 units/kg every alternate day * 10 doses) or "no treatment" (control) group. All infants on enteral feeds received oral iron 3 mg/kg/day, graded up to 6 mg/kg/day.. Higher reticulocyte counts in week 2 and 3 and higher hemoglobin levels in week 4 were noted after treatment with r-HuEPO. Despite stumulated erythropoiesis, the frequency of transfusions could not be reduced with r-HuEPO therapy.Overall, Phlebotomy losses, frequency and volume of redcell transfusions were significantly more in neonates with birthweight <1000 grams compared with those with birthweight >1000 grams (p<0.05). Associated side effects of r-HuEPO such as neutropenia,sepsis, hypertension or increased risk of late death did not occur.. r-HuEPO therapy was safe without any side effects. Inability of r-HuEPO therapy to minimize red cell transfusions for anemia of prematurity may be explained by a relatively strict red-cell transfusion policy and the desired degree of treatment effect.

Topics: Administration, Oral; Anemia; Birth Weight; Enteral Nutrition; Erythrocyte Count; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Hypertension; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Iron; Male; Neutropenia; Phlebotomy; Recombinant Proteins; Reticulocytes; Safety; Sepsis; Survival Rate

The introduction of carboplatin as a replacement for cisplatin into treatment strategies against ovarian cancer has ameliorated major toxicities related to cisplatin, but carboplatin-evoked myelosuppression requires further study, especially since the addition of growth factors for bone marrow and hematologic support has been introduced into clinical practice. Since higher doses of platinating agents seem to be related to higher response rates, the protective effect of interleukin-3 on 800 mg carboplatin, a twofold increment over the usual dose, was studied. A modest myeloprotective potency was documented in the second treatment cycle of this aggressive chemotherapy program, but this effect tapered away in subsequent treatment courses, which occasionally included severe side effects (eg, headache, kidney function impairments). Another study addressed the anemia frequently observed with both cisplatin- and carboplatin-based treatment regimens in ovarian cancer, which is probably related to low erythropoietin levels. Very preliminary analysis of an ongoing phase III trial studying two erythropoietin doses given continuously subcutaneously versus a retrospective analysis of a "control group" (drawn from historical data on the occurrence of anemia in cisplatin- and/or carboplatin-treated patients) has shown beneficial effects of erythropoietin during treatment with these platinating agents.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Erythropoietin; Female; Humans; Interleukin-3; Middle Aged; Neutropenia; Ovarian Neoplasms; Recombinant Proteins; Thrombocytopenia

Hematopoietic growth factors may mitigate the cytopenias that frequently complicate HIV disease or its treatment. Clinical and in vitro studies have indicated the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) or erythropoietin (EPO) to overcome the myelosuppression of HIV or many of the drug therapies used in the care of HIV-infected individuals. In addition, neutrophil or monocyte functional abnormalities observed in AIDS patients may be improved by the use of GM-CSF. Issues which may distinguish the use of hematopoietic growth factors in AIDS as compared with in other clinical settings include: 1) interaction of the growth factor with other cytokines which are aberrantly expressed, 2) direct effects of the growth factor on the replicative activity of HIV, and 3) potential interactions of the growth factor with other concurrently administered medications. This review focuses on the potential roles and limitations of growth factor use in AIDS and reviews the clinical studies using GM-CSF in HIV-infected individuals.

Topics: Acquired Immunodeficiency Syndrome; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; HIV Infections; Humans; Leukocyte Count; Monocytes; Neutropenia; Neutrophils

To study the safety and efficacy of administering human recombinant erythropoietin (rHuEPO) to infants with anaemia of prematurity, a combined phase I/II trial of weekly intravenous injections for 4 weeks was undertaken. We treated 16 infants with 10, 25, 50, 100 or 200 units/kg body weight in groups of two to four patients per dose level. They were all born prematurely (mean gestational age: 29 weeks; range 27-32), had a mean post-natal age of 42 days (range: 25-59) and haemoglobin concentration of 87 g/l (range: 72-94) when treatment was started. Four patients (25%) needed a transfusion during the trial, one at day 7 treated with 10 units/kg and 3 at days 15, 25, 29 with 100 units/kg. In the others, a progressive rise in mean haemoglobin values was seen in each group after 21 days of treatment, without a dose-dependent effect. A positive change in absolute reticulocyte counts with a peak after 7-14 days of therapy was observed with low (25-50 units/kg) but not with higher doses, with a significant difference at day 14 between 25 and 100 units/kg (P less than 0.01). A dose-limiting severe neutropenia (absolute neutrophil count less than 0.5 x 10(9)/l) occurred transiently in five patients, with doses greater than 25 units/kg. No infectious complication and no sign of iron deficiency were observed. Weekly low doses of rHuEPO appear safe, convenient to administer and able to induce a reticulocytic response in infants with anaemia of prematurity. A phase III placebo-controlled trial is needed to confirm these results. Neutropenia associated with rHuEPO administration in infants might be related to their stage of human ontogeny.

Topics: Anemia, Neonatal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Injections, Intravenous; Iron; Neutropenia; Recombinant Proteins

In a prospective, controlled trial 26 anaemic, neutropenic children with newly diagnosed acute lymphocytic leukaemia were randomised in pairs to receive either transfusion to a haemoglobin of 10--12 g/dl where clinically indicated (group A) or hypertransfusion to a haemoglobin of 16--18 g/dl (group B). Compared with group A (11 of 13 transfused), group B (all transfused) had a significantly more rapid rise in neutrophils at 7 and 10 days post-transfusion, a lower incidence of infection, and less interruption to chemotherapy. Hypertransfusion restored the myeloid/erythroid ratio to normal in bone-marrow of 5 of 6 children and the proportion of early myeloid precursors was greater than in controls.

Topics: Adolescent; Agranulocytosis; Blood Transfusion; Cell Count; Child; Child, Preschool; Clinical Trials as Topic; Erythropoietin; Female; Hematopoietic Stem Cells; Hemoglobins; Humans; Infant; Infection Control; Leukemia, Lymphoid; Leukocyte Count; Male; Neutropenia; Neutrophils; Prospective Studies; Random Allocation; Remission, Spontaneous

To determine the effectiveness of erythropoietin-stimulating agent (ESA) and granulocyte colony-stimulating factor (CSF) in reducing blood transfusion needs and neutropenia incidence in community-dwelling elderly ovarian cancer patients.. The SEER (Surveillance Epidemiology and End Results)-Medicare database was used to identify 5572 women with stage III/IV ovarian cancer who received chemotherapy. To assess clinical effectiveness, we categorized patients based on the number of administrations of ESA (ie, epoetin-alfa and darbepoetin-alfa) and CSF (ie, filgrastim and pegfilgrastim). To evaluate effect on survival, patients were categorized as receiving ESA only, CSF only, ESA + CSF, and no ESA/CSF.. Two thirds of patients received growth factor support (24% ESA only, 13% CSF only, 30% ESA + CSF). Depending on the number of epoetin-alfa administrations, ESA was associated with 48% to 56% lower need for blood transfusion compared with no ESA (hazard ratio for 1-3 claims, 0.47; 4-6 claims, 0.52; 7-10 claims, 0.48; ≥11 claims, 0.44). Patients who received at least 3 prophylactic filgrastim administrations had 71% to 98% lower risk of developing neutropenia (hazard ratio for 3-4 claims, 0.29; ≥5 claims, 0.02) compared with those without CSF. Effectiveness was comparable for darbepoetin-alfa and pegfilgrastim use. Overall survival was longer in those who received CSF only; however, the risk of mortality after 24 months was higher in those who received ESA (P = 0.0005). All models were adjusted for relevant covariates.. Erythropoietin-stimulating agents were effective in reducing blood transfusion need. Granulocyte colony-stimulating factors were effective in lowering neutropenia incidence and also were associated with improved survival in elderly ovarian cancer patients. Findings are consistent with clinical trials and clinical guidelines.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Female; Filgrastim; Follow-Up Studies; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Middle Aged; Needs Assessment; Neoplasm Staging; Neutropenia; Ovarian Neoplasms; Polyethylene Glycols; Prognosis; Recombinant Proteins; Retrospective Studies; SEER Program; Survival Rate

To evaluate the incidence, onset, duration, characteristics and importance of late-onset neutropenia (defined as absolute neutrophil count<1500 μl(-1) at 3 weeks of age or later) in a group of very low birth weight (VLBW) infants.. Routine complete blood cell counts (CBCs) obtained from VLBW infants over a period of 7 years were gathered retrospectively, including those of newborns with weekly CBCs taken over a duration of at least 3 weeks. Data were obtained from between January 2003 and December 2009.. CBCs of 399 newborns were included. Values were obtained from birth to 36 weeks of postnatal age. Late-onset neutropenia was observed in 259 cases (65%). Neutropenic infants had a mean of 0.5 weeks lower gestational age. Late-onset neutropenia was more frequent in children with intraventricular hemorrhage but not in patients who received erythropoietin. The median age of neutropenia onset was 7 weeks in extremely low birth weight infants and 6 weeks in VLBW infants. The fifth percentile of neutrophils between weeks 3 and 4 was 1280 μl(-1) and between weeks 13 and 15 was 500 μl(-1). The average duration was 2 weeks with normalized values after 18 weeks.. A neutrophil count <1500 μl(-1) after the third week of life is frequently observed in VLBW infants and should not be used as a lower reference limit. The fifth percentile varies according to postnatal age from around 1300 μl(-1) in week 4 of life, decreasing to a nadir of 500 μl(-1) between 3 and 4 months of age. Values normalize in the first year of life.

Topics: Age of Onset; Cerebral Hemorrhage; Erythropoietin; Female; Humans; Incidence; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Leukocyte Count; Male; Neutropenia; Retrospective Studies

HCV infection is related to hepatic disease and mixed cryoglobulinaemia (MC). Renal involvement is reported in one third of cryoglobulinaemic patients. The combination of HCV related MC with renal involvement has been associated with poor survival and identified as Hepatitis C Virus Risk Syndrome (HCV RS). Here we describe antiviral treatment and management of side effects (anaemia and neutropenia) with RHuEpo and G CSF in a rare case of HCV RS.

Topics: Anemia; Antiviral Agents; Cryoglobulinemia; Drug Therapy, Combination; Erythropoietin; Glomerulonephritis, Membranoproliferative; Granulocyte Colony-Stimulating Factor; Hepatitis C; Humans; Interferons; Liver Cirrhosis; Male; Middle Aged; Neutropenia; Recombinant Proteins; Ribavirin; Risk Factors; Treatment Outcome

Chemotherapy induced neutropenia (CIN), febrile neutropenia (FN), chemotherapy induced anemia (CIA) frequently occur following myelosuppressive chemotherapy and are associated with morbidity, mortality, costs, and relative dose intensity (RDI), hence influencing overall survival (OS). Given prophylactically, granulocyte colony-stimulating factors (G-CSFs) can stimulate neutrophil production and depletion, they may thus reduce FN incidence when following chemotherapy. Erythropoietins are widely used to treat chemotherapy induced anemia. Several guidelines have been published to help onco-hematologists design their supportive therapy. The aim of our study was to assess the guidelines concerning everyday routine in supportive care. The final conclusion is that the Hungarian therapy support guidelines are up to date, are highly compliant with international standards [ASCO (1), EORTC (2), ESMO (3, 4), NCCN (5-7)], and that the clinicians have a deep understanding and comprehensive usage in their everyday practice.. A kemoterápia indukálta neutropénia (CIN - chemotherapy induced neutropenia), a lázas neutropénia (FN - febrile neutropenia) és a kemoterápia indukálta anémia (CIA - chemotherapy induced anemia) a mieloszuppresszív kemoterápia gyakran elõforduló mellékhatásai. Ezeknek a toxikus mellékhatásoknak súlyos következménye lehet a morbiditás, mortalitás, a költségek, a relatív dózisintenzitás (RDI - relative dose intensity) és így akár a túlélés szempontjából is. A profilaktikusan alkalmazott granulocita-kolóniastimuláló faktor sikeresen megelõzheti a lázas neutropénia kialakulását a neutrofiltermelõdés és -depléció fokozásával. A kemoterápia indukálta anémia kezelésére eritropoetint használunk. Számos terápiás ajánlás mellett magyar minisztériumi szakmai irányelv is segít az onkohematológiai kezelések szupportív terápiájának megtervezésében. Vizsgálatunk célja az volt, hogy összevessük a hazai gyakorlatot az ajánlásokkal. Megállapítottuk, hogy a magyar szakmai irányelv modern, összhangban van a nemzetközi ajánlásokkal, a klinikusok jól ismerik és megfelelõen alkalmazzák.

Topics: Administration, Oral; Anemia; Clinical Protocols; Drug Prescriptions; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Hematinics; Hematology; Humans; Hungary; International Cooperation; Iron Compounds; Medical Oncology; Neutropenia; Practice Guidelines as Topic; Surveys and Questionnaires

Topics: Anemia; Drug Approval; Erythropoietin; Granulocyte Colony-Stimulating Factor; Guidelines as Topic; Humans; Italy; Neoplasms; Neutropenia; Recombinant Proteins

Nilotinib (Tasigna) is a second-generation BCR-ABL kinase inhibitor, recently introduced and used for the treatment of chronic or accelerated phase CML patients, intolerant or resistant to imatinib. This treatment represents and important step forward for the disease control of such patients but can lead to side effects, sometimes serious, which can limit its optimal use. We propose here some guidelines that might be of help in daily practice, in order to manage properly these side effects.

Topics: Antineoplastic Agents; Benzamides; Drug Eruptions; Drug Interactions; Drug Resistance, Neoplasm; Erythropoietin; Fertility; Food-Drug Interactions; France; Granulocyte Colony-Stimulating Factor; Heart Diseases; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Metabolic Diseases; Neutropenia; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; Recombinant Proteins

To evaluate the frequency of chemotherapy-induced myelotoxicity in cancer patients, the related treatment (G-CSF, rHuEPO), and the occurrence of chemotherapy dose reductions, delays or discontinuations.. We retrospectively collected data from 1175 patients who completed at least four chemotherapy courses at 64 Italian Centres. Myelotoxicity was defined as anemia (Hb < 10 g/dL) and neutropenia (ANC < 1500/mm(3)). The study population was divided by age, in 664 adult patients aged < or =65 years and 511 elderly patients, aged > 65 years. The association between events during chemotherapy and myelotoxicity indices were assessed by logistic regression.. The median age of the patients was 64 years. Myelotoxicity was observed in 633 patients (53.9%), anemia (< 10 g/dL) in 263 (22.4%) and neutropenia in 530 (45.1%); 686 patients (58.5%) showed mild anemia (Hb < 12 g/dL). Dose reductions were observed in 199 patients (16.9%), dose delays in 338 (28.7%), and discontinuations in 157 (13.4%), with no significant difference between age groups. Myelotoxicity accounted for 20% of treatment withdrawals with no differences between age groups. G-CSF was administered to 53.4% of the neutropenic patients, and rHuEPO to 53.1% of the anemic patients. Logistic regression analyses showed a significant (P < 0.001) association between chemotherapy dose delays, dose reductions and myelotoxicity. Considering age strata, the association between dose reduction and myelotoxicity was significant. The risk of neutropenia in the adults was higher than in elderly (50.0% vs 38.7%).. Our results show that anemia and neutropenia occur in a substantial proportion of cancer patients receiving chemotherapy, and have an impact on chemotherapy dose delivery. G-CSF and rHuEPO are treatments widely used in about one half of neutropenic and anemic patients. Particular attention should be given to elderly patients, who are at high risk of myelotoxicity and should be carefully evaluated for the prophylactic use of G-CSF and monitored for the appropriate use of rHuEPO.

Topics: Aged; Anemia; Antineoplastic Agents; Bone Marrow; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Humans; Incidence; Male; Middle Aged; Neoplasms; Neutropenia; Prevalence; Recombinant Proteins; Retrospective Studies

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

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

Topics: Aged; Anemia; Copper; Diabetic Nephropathies; Drug Resistance; Enteral Nutrition; Erythropoietin; Female; Humans; Neutropenia; Renal Dialysis

Inpatient costs associated with different erythropoietic-stimulating therapy regimens have not been compared in an oncology setting.. To conduct a cost analysis of different regimens of epoetin alfa (EPO) and darbepoetin alfa (DARB) in an inpatient oncology setting.. A retrospective evaluation of oncology diagnosis-related group discharges during 2003, in 30 community hospitals, identified EPO treatment patterns. Wholesale acquisition costs were determined for patients who received EPO 40,000 units or more once weekly. Potential differences in costs were calculated using conversion ratios for an equivalent EPO dose 3 times weekly or DARB dose once weekly (EPO:DARB ratio 260:1, approximating DARB 150 microg once weekly). A sensitivity analysis was performed using an EPO:DARB ratio of 400:1, approximating DARB 100 microg once weekly (1.5 microg/kg).. Among the 1410 EPO doses administered (n = 677 pts.), a dose of 40,000 units or more was used 44% of the time (n = 311 pts.), with dosing initiated on average 5.6 days after admission. For these 311 evaluable patients, switching from EPO 40,000 units once weekly to EPO 10,000 units 3 times weekly reduced per-patient and total drug acquisition costs by approximately 50% (704 US dollars vs 359 US dollars and 218,938 US dollars vs 111,615 US dollars, respectively). Relative to EPO once weekly, switching patients to DARB resulted in increased drug acquisition costs at the 260:1 conversion and lower costs at the 400:1 conversion. However, EPO 3 times weekly remained the least costly option by 44-63%. The cost-savings realized with EPO 10,000 units 3 times weekly increased with longer duration of hospitalization.. In an inpatient setting, use of EPO 10,000 units 3 times weekly may minimize expenditures associated with treatment of cancer-related anemia using erythropoietic-stimulating therapies.

Topics: Algorithms; Costs and Cost Analysis; Darbepoetin alfa; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Neutropenia; Recombinant Proteins

We have encountered five hemodialysis patients who had received enteral nutrition and recovered from erythropoietin-resistant anemia with neutropenia after the correction of copper deficiency. We reduced the required doses of recombinant human erythropoietin (rHuEPO) to maintain the target hematocrit levels and three patients were finally weaned from the rHuEPO therapy. Thus, copper deficiency is involved in erythropoietin-resistant anemia in hemodialysis patients.

Topics: Anemia; Ceruloplasmin; Copper; Copper Sulfate; Deficiency Diseases; Enteral Nutrition; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Middle Aged; Neutropenia; Recombinant Proteins; Renal Dialysis; Treatment Failure

Topics: Anemia; Delayed-Action Preparations; Disease Progression; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Neoplasms; Neutropenia; Patient Selection

We examined whether women aged 60 years or older with ovarian cancer who were treated with surgery and postoperative chemotherapy are at higher risk of developing grade 4 hematological toxicity. Seventy-five patients were included: 34 patients aged < 60 years (group I) were compared with 41 patients aged > or =60 years (group II) after postoperative treatment with single-agent carboplatin or carboplatin/taxane combination chemotherapy. Secondary prophylaxis with granulocyte colony-stimulating factors was performed to avoid dose reduction and chemotherapy delay. A total of 450 chemotherapy cycles was completed. Anemia and thrombocytopenia were mild in both groups. Overall, grade 4 neutropenia developed in 41% (group I) and in 49% (group II) (p=0.51). Febrile neutropenia occurred in 12% and 2%, respectively (p=0.17). The carboplatin/taxane combination was associated with grade 4 neutropenia in 42% (group I) and 58% (group II) (p=0.21). Women > or =60 years are not at higher risk of developing severe myelotoxicity than their younger counterparts, particularly after treatment with carboplatin/taxane combination chemotherapy.

Topics: Adult; Age Factors; Aged; Anemia; Antineoplastic Agents; Carboplatin; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hematologic Diseases; Humans; Middle Aged; Neutropenia; Ovarian Neoplasms; Postoperative Complications; Recombinant Proteins; Retrospective Studies; Risk Factors; Taxoids; Thrombocytopenia

Results of CALGB 9741 demonstrated that administering standard doxorubicin/cyclophosphamide (AC)-paclitaxel therapy for adjuvant therapy of breast cancer in a dose-dense fashion with colony-stimulating factors increases efficacy, decreases severe neutropenia, but may increase the need for blood transfusions. A chart review was performed to evaluate the rates of anemia, neutropenia and skin toxicities with dose-dense and traditional AC-taxane chemotherapy.. A total of 112 patients received one of four treatments: non-dose-dense AC-paclitaxel (NDD Pac), dose-dense AC-paclitaxel (DD Pac), non dose-dense AC-docetaxel (NDD Doc), or dose-dense AC-docetaxel (DD Doc).. Transfusion rates were not increased in the dose-dense population; however, rates of grade 2-4 anemia (23% versus 0%, P=0.029), as well as erythropoietin use (58% versus 0%, P <0.0001), were significantly increased in the DD Pac group compared with the NDD Pac group. Grade 3 skin toxicities were significantly increased in the DD Doc group compared with the NDD Doc group (70% versus 11%, P <0.0001).. These results demonstrate that dose-dense AC-taxane therapy may increase rates of anemia and the need for erythropoietin, and decrease rates of neutropenia. The utility of DD Doc appears limited by skin toxicities and its use outside of a clinical study should not be recommended.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Breast Neoplasms; Chemotherapy, Adjuvant; Cyclophosphamide; Docetaxel; Dose-Response Relationship, Drug; Doxorubicin; Erythropoietin; Female; Humans; Incidence; Middle Aged; Neutropenia; Paclitaxel; Retrospective Studies; Skin Diseases; Taxoids

Many leukemia and cancer cells exhibit constitutive activation of STAT5, which was suggested to provide an anti-apoptotic advantage. Transformation of cytokine-dependent hematopoietic cells, such as Ba/F3 cells to autonomous growth and tumorigenicity equally results in selection for constitutive activation of STAT5. We compared STAT5 signaling between erythropoietin(Epo)-dependent cells and cells that were transformed by oncogenic activation of the erythropoietin receptor (EpoR) by coexpression of the gp55-P envelope protein of the spleen focus forming virus or by expression of the R129C constitutively active EpoR mutant. In transformed cells it was mainly STAT5B that was constitutively activated. In contrast, Epo stimulation activated both STAT5A and STAT5B. In transformed cells, chromatin immunoprecipitation (ChIP) showed STAT5 to be physically bound to promoters of STAT5 target genes, such as Bcl(XL), and to be able to promote transactivation of the Bcl(XL) promoter in a constitutive fashion. Sequencing of native sequences after ChIP with anti-STAT5 antibodies in Epo-dependent and -transformed cells indicated that in gp55-transformed cells, STAT5B bound in the chromatin not only to N3 high affinity, but also to low affinity N4 GAS sites. Transactivation for N3 GAS sites in luciferase reporters was specific to gp55 transformation. Because we also found preferential constitutive STAT5B activation after transformation of cells by a truncated form of the G-CSF-R that produces severe neutropenia (Kostmann syndrome) and favors leukemia in humans, we discuss the potential role of STAT5B in oncogenic transformation of hematopoietic cells.

Topics: Active Transport, Cell Nucleus; Animals; bcl-X Protein; Cell Line; Cell Transformation, Neoplastic; DNA-Binding Proteins; Erythropoietin; Growth Substances; Hematopoietic Stem Cells; Humans; Ligands; Mice; Milk Proteins; Neutropenia; Promoter Regions, Genetic; Proto-Oncogene Proteins c-bcl-2; Receptors, Cytokine; Receptors, Erythropoietin; Receptors, Granulocyte Colony-Stimulating Factor; Signal Transduction; STAT5 Transcription Factor; Trans-Activators; Transcription, Genetic; Tumor Suppressor Proteins; Viral Envelope Proteins

Copper deficiency has been reported to cause hematological disorders. However, its clinical and hematological characteristics are not fully understood. Therefore, we investigated bedridden patients suffering from copper deficiency and tried to clarify the clinical features of hematological disorders caused by this condition.. Five patients with typical copper deficiency who had been dependent upon enteral nutrition for a long period of time due to various diseases were investigated. We measured hematological parameters and observed the response to copper supplementation therapy and the recovery process of hematological disorders.. Their mean age was 82.6+/-10.4 years and the mean duration of enteral nutrition was 16.4+/-5.2 months. Their serum copper concentration was extremely decreased (range, 3 to 8 microg/dl). All five patients had anemia and neutropenia. On the other hand, platelet count remained within the normal range. After copper supplementation therapy, hemoglobin concentration increased from 6.8+/-0.7 g/dl to 9.9+/-0.7 g/dl within a few months (p<0.01). Neutrophil count also increased from 750+/-370/microl to 3,690+/-1,210/microl in a few weeks (p<0.01). Mean corpuscular volume (MCV) decreased from 94.3+/-7.3 fl to 86.0+/-4.8 fl (p<0.05). Elevated serum ferritin and erythropoietin (EPO) levels were normalized after the improvement of anemia.. Bicytopenia (anemia and neutropenia) with normal platelet count is a feature of hematological disorders caused by copper deficiency. MCV tends to indicate macrocytic anemia. Serum ferritin and EPO levels are elevated. These hematological abnormalities are improved within a few months after copper supplementation therapy.

Topics: Aged; Aged, 80 and over; Anemia; Blood Cell Count; Copper; Dietary Supplements; Enteral Nutrition; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Male; Neutropenia; Retrospective Studies; Risk Factors; Time Factors

To evaluate the benefits of haematopoietic growth factors (HGFs) during the treatment of chronic hepatitis C virus (HCV) infection with severe haematotoxicity.. This was a 1-year retrospective study of HCV-positive patients receiving pegylated interferon and ribavirin. Patients received different HGFs, depending on certain criteria: they received erythropoietin (EPO) when their haemoglobin (Hb) levels were less than 10 g/dl and granulocyte colony-stimulating factor (G-CSF) when their neutrophil count was less than 750 cells/mm3. Haematological data, adherence and virological response were analysed and compared according to HGF use.. In total, 132 patients were studied and 31 (23.5%) required HGF. Under multivariate analysis, baseline Hb levels of less than 13g/dl or a drop in Hb levels of over 2% per week predicted severe anaemia, and a baseline neutrophil count under 2900/mm3 predicted severe neutropaenia. HGF administration restored Hb values and the neutrophil count to above 10 g/dl and 1500 cells/mm3, respectively, in all 31 patients. Adherence to antiviral treatment was achieved in 25% of patients versus 58% of controls without severe haematotoxicity. The primary and sustained virological response did not differ statistically between HGF support and the control group (61% versus 57% and 32% versus 39%, respectively).. HGF administration counteracts the severe haematological adverse effects which occur during antiviral therapy and maintains the rate of sustained response.

Topics: Aged; Anemia; Antiviral Agents; Drug Therapy, Combination; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemoglobins; Hepacivirus; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Male; Middle Aged; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; RNA, Viral; Treatment Outcome

Topics: Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Cyclophosphamide; Doxorubicin; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Neutropenia; Polyethylene Glycols; Positron-Emission Tomography; Prednisone; Recombinant Proteins; Rituximab; Stomach Neoplasms; Vincristine

Current therapy for the treatment of hepatitis C virus (HCV) infection is standard interferon (IFN) or pegylated interferon (PEG-IFN) in combination with ribavirin (RBV). Hematologic side effects (neutropenia, thrombocytopenia, anemia) are a major reason for dose reduction of anti-HCV therapy. Because treatment adherence and maintenance of IFN or PEG-IFN and RBV doses have been shown to be important in achieving a sustained virologic response, appropriate management of hematologic side effects might play a substantial role in optimizing treatment outcomes. Neutropenia and thrombocytopenia are usually managed by IFN or PEG-IFN dose reduction; the role of hematopoietic growth factors to ameliorate these side effects needs further evaluation, but some studies suggest granulocyte colony-stimulating factor (G-CSF) may be useful in the management of IFN/PEG-IFN-associated neutropenia. Anemia is primarily due to RBV-induced hemolytic anemia, but IFN/PEG-IFN also suppresses bone marrow erythroid precursors. Treatment-induced anemia has usually been managed by RBV dose reduction or discontinuation. However, recent studies suggest that epoetin alfa can increase hemoglobin levels and facilitate maintenance of RBV dosage in patients with chronic hepatitis C who became anemic during standard combination therapy. Results of a randomized, randomized, double-blind, placebo-controlled trial suggest that epoetin alfa therapy can maintain RBV dosage, increase hemoglobin levels, and improve quality of life in this population. In patients who have chronic hepatitis C who experience hematologic toxicities during standard therapy, the use of hematopoietic growth factors such as epoetin alfa might have the potential to improve treatment adherence rates and allow optimal doses of IFN or PEG-IFN and RBV to be maintained, thereby leading to improved treatment outcomes.

Topics: Anemia; Antiviral Agents; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Hematinics; Hepatitis C; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

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

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

Strategies for managing antineoplastic therapy-associated hematopoietic toxicity (thrombocytopenia, neutropenia, and anemia) are discussed. Hemorrhage secondary to decreases in platelets is the major risk posed by chemotherapy-induced thrombocytopenia. Patients with < 20,000 platelets per microliter are at increased risk of bleeding, particularly if they have a history of bleeding associated with this condition. The risks of infection and complications are related to both the severity and duration of neutropenia. The rate of febrile neutropenia with most antineoplastic regimens is < 40%, and routine use of cytokine therapy is probably not cost-effective. The frequency of cancer-related anemia is dependent on the type, stage, and duration of disease. Chemotherapy-induced anemia is affected by the types of agents used, the schedule of drug administration, and the intensity of the regimen. Fatigue is the most common symptom of anemia, being reported by 80-100% of patients undergoing chemotherapy. Although fatigue is a major factor in patients' quality of life, it has often not been treated systematically and aggressively. Anemia used to be treated with transfusions, but therapy with epoetin alfa is showing promise as an alternative. The introduction of epoetin alfa has led to more aggressive treatment. Chemotherapy-induced hematopoietic toxicity is a multifactorial challenge that affects the treatment of oncology patients.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Fatigue; Hematinics; Humans; Neutropenia; Practice Guidelines as Topic; Recombinant Proteins; Severity of Illness Index; Thrombocytopenia

Myelosuppression is a common side effect in elderly patients undergoing chemotherapy. Neutropenia and anemia cause considerable morbidity, may increase mortality, and can result in a worse outcome of treatment in elderly patients compared to younger patients with comparable type and stage of disease. The availability and proven efficacy of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) have had a considerable impact on supportive care in cancer patients: Several randomized trials have demonstrated a reduction of neutropenia and the frequency of severe infections in elderly patients treated with G-CSF following myelotoxic chemotherapy compared with patients without growth factor support. Both for G-CSF and for recombinant human erythropoietin (rHu-EPO) several studies have demonstrated the safety and effectiveness of these molecules in elderly patients with regard to increasing hemoglobin concentrations, improving quality of life (rHu-EPO), and neutrophil recovery. Although a positive effect of the use of growth factors on overall survival in elderly cancer patients is not yet proven, a reduction of chemotherapy-induced side effects could clearly be shown. The National Comprehensive Cancer Network (NCCN) of cancer centers has recommended that all patients aged 70 years and older treated with CHOP or cytotoxic chemotherapy of comparable intensity should receive prophylactic G-CSF administration, and that the hemoglobin concentration be maintained at >or=12 g/dl in elderly patients undergoing chemotherapy.

Topics: Aged; Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Neoplasms; Neutropenia; Prednisone; Recombinant Proteins; Vincristine

To define the incidence, course, and etiology of hematologic abnormalities in children on tacrolimus-based immunosuppression, we reviewed records of 106 transplant patients (70 heart, 16 heart and lung, 20 double lung), 0-21 yr of age, who were transplanted at the Children's Hospital of Pittsburgh from 1989 to 1997. Fifty-four of the 106 patients (51%) developed 65 abnormal hematologic episodes (32 anemia, nine neutropenia, nine thrombocytopenia, 15 simultaneous anemia and neutropenia with or without thrombocytopenia). Common etiologies included: infections, post-transplant lymphoproliferative disease, and medications. Eleven episodes (seven anemia, one neutropenia, and three simultaneous anemia and neutropenia) had unclear etiologies and process of elimination suggested an association with tacrolimus. Interventions included filgrastim (effective in 15 of 15 patients, with resolution of neutropenia in a median of 5 days) and epoetin alfa (effective in five of 16 patients, including four of four patients with anemia possibly related to tacrolimus). Five patients (two with neutropenia and three with simultaneous neutropenia and anemia) were switched to cyclosporin A (CsA); rapid resolution occurred in four of the five patients, suggesting a possible association of the hematologic abnormalities with tacrolimus. In summary, hematologic abnormalities are common in children on tacrolimus-based immunosuppression. Most of these hematologic abnormalities are caused by common etiologies; however, a sub-population exists where tacrolimus may be the etiologic agent. Anemia and neutropenia respond to treatment with epoetin alfa and filgrastim. After thorough investigation, a trial switch to CsA may be warranted.

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Epoetin Alfa; Erythropoietin; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Heart Transplantation; Heart-Lung Transplantation; Hematologic Diseases; Humans; Immunosuppressive Agents; Infant; Lung Transplantation; Male; Neutropenia; Recombinant Proteins; Retrospective Studies; Tacrolimus; Thrombocytopenia

This study describes the frequency and the type of anemia seen in patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA). We found that NI-CINA patients had low hemoglobin levels and increased serum concentrations of erythropoietin (EPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). The hemoglobin levels correlated positively with the number of circulating neutrophils and inversely with the levels of EPO and TNF-alpha but not of IL-1beta. Anemia, defined as the reduction of the hemoglobin below 12.0 g/dl for women and 13.3 g/dl for men, was found in 23 out of 148 patients studied, a proportion of 15.5%. Two of the anemic patients had iron deficiency anemia (8.7%), 11 had anemia of chronic disease (ACD; 47.8%) presenting with normal or slightly reduced erythrocytic indices, low serum iron, and increased serum ferritin, and the remaining ten had anemia of undefined pathogenesis (AUP; 43.5%) with normal or slightly decreased erythrocytic indices, serum iron ranging from 43 to 88 microg/dl, and ferritin values ranging from 12 to 50 ng/ml. We conclude that ACD is the more frequent type of anemia seen in patients with NI-CINA, and that pro-inflammatory cytokines, notably TNF-alpha, may be involved in the pathogenesis of both ACD and AUP, given that serum levels of the cytokine were significantly increased and that the EPO response to anemia was blunted in these patients. These findings further support our previously reported suggestion for the possible existence, in NI-CINA patients, of an unrecognized low-grade chronic inflammatory process that may be involved in the pathogenesis of the disorder.

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Interleukin-1; Iron; Male; Middle Aged; Neutropenia; Reticulocyte Count; Tumor Necrosis Factor-alpha

Topics: Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature, Diseases; Neutropenia; Recombinant Proteins

Recombinant human GM-CSF (rhGM-CSF) and erythropoietin (rhEPO) were tested on chronically FIV-infected laboratory cats and uninfected specific-pathogen-free (SPF) cats. In Study 1, a total of eight cats (four cats per group of either infected or uninfected cats) received subcutaneous injection (twice a day) for 2 weeks with 5 microg/kg of rhGM-CSF, while seven cats (three SPF and four FIV-infected cats) served as the placebo-treated control cats. Four of eight rhGM-CSF-treated cats (two cats each from infected and uninfected groups) developed elevated WBC counts which peaked at Days 5-8 of treatment when compared to placebo-treated cats. The elevated WBC counts were attributed to the increase in either neutrophils, lymphocytes, eosinophils, monocytes, or their combinations. The RBC counts, platelet counts, and blood chemistry were not significantly affected by the treatment. Anti-rhGM-CSF antibodies were detected in six of eight rhGM-CSF-treated cats by Day 35 post-first treatment. All rhGM-CSF-treated infected cats but no placebo-treated infected cats had 1-2 log increase in FIV load in the PBMC during the treatment. In vitro studies suggest that rhGM-CSF has an effect on FIV replication in T cells but not in alveolar macrophages. Five of eight rhGM-CSF-treated cats had low-grade fever at 3-6 days of treatment. In Study 2, four cats per group of either infected or uninfected cats were treated (subcutaneously once a day) three times a week for 2 weeks with 100U/kg of rhEPO and monitored as before, while seven cats (three SPF and four FIV-infected cats) served as the placebo-treated control cats. All rhEPO-treated cats had a gradual increase in RBC, Hgb, and PCV counts which peaked at 2-4 weeks post-first rhEPO treatment, whereas none of the placebo-treated cats had significant increase in these parameters. The rhEPO-treated cats also developed elevated WBC counts consisting of either elevated neutrophils, lymphocytes, or their combination by 4 weeks post-first treatment but there was no statistical difference between rhEPO-treated and placebo-treated groups. None of the cats developed anti-rhEPO antibodies and no remarkable changes in blood chemistry, clinical signs, and FIV loads or FIV antibody titers were observed. Overall, rhEPO can be used safely on FIV-infected cats but the use of rhGM-CSF on FIV-infected cats should be performed with discretion.

Topics: Anemia; Animals; Blood Cell Count; Cat Diseases; Cats; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunodeficiency Virus, Feline; In Vitro Techniques; Lentivirus Infections; Male; Neutropenia; Recombinant Proteins; Virus Replication

Topics: Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Neutropenia; Recombinant Proteins; Risk

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

A 35-year-old man from Central America with a history of AIDS and numerous opportunistic infections presented with progressive neutropenia and thrombocytopenia despite having been stable for a period of 6 months. Cessation of antiviral medications did not stop his neutropenia, nor did use of folinic acid, G-CSF, or erythropoietin. The failure of these measures required repeated blood transfusions. Although the physical examination was relatively unremarkable, hematology and blood chemistries indicated that the patient needed urgent hospitalization due to fever and neutropenia. Neutropenia within HIV infection can be confusing, since it may be a result of the infection itself, an adverse effect of drug therapy, or from an opportunistic infection or malignancy. If the cause is not evident, it is wise to seek the etiology first rather than immediately use bone marrow stimulants, such as G-CSF. In this case, an infectious disease specialist made a diagnosis of disseminated histoplasmosis, after which the patient was treated with amphotericin B and released on itraconazole maintenance therapy.

Topics: Acquired Immunodeficiency Syndrome; Adult; Amphotericin B; Antifungal Agents; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Histoplasmosis; Humans; Male; Mucous Membrane; Neutropenia

In this study, we determined in vivo interactions between hemopoietic growth factors and etoposide (VP-16) to assess whether normal blood cell production could be maintained during chemotherapy if hemopoietic growth factors were simultaneously administered. Groups of mice were treated for 7 consecutive days with four different doses of VP-16 in combination with three different doses of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). In total, 12 combinations of VP-16 plus EPO and 12 combinations of VP-16 plus G-CSF were thus evaluated. Intricate dose-response surfaces of the effects of the different treatments on colony-forming units-erythroid, reticulocytes, hematocrit, colony-forming units-granulocyte/macrophage, and absolute neutrophil count were obtained, which revealed that: (a) simultaneous EPO administration was able to maintain reticulocyte production and to protect mice from VP-16 induced anemia; (b) simultaneous G-CSF administration was able to maintain granulocyte production and to protect mice from VP-16 induced neutropenia; (c) VP-16 dose escalation was feasible when EPO or G-CSF were simultaneously administered; and (d) no increased myelotoxicity on erythroid or granuloid progenitors was observed when EPO or G-CSF was simultaneously administered with VP-16. These results suggest that in vivo either individual hemopoietic progenitors can become resistant against VP-16-induced cell death by appropriate simultaneous growth factor administration or that the loss of overall cell amplification, induced by VP-16, can be compensated by extra amplification of surviving progenitors. Furthermore, these data indicate that a strict separation in time of cytostatic drug and growth factor treatment is not necessarily the optimal schedule with respect to the reduction of hemotoxicity.

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Cells; Dose-Response Relationship, Drug; Erythroid Precursor Cells; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Macrophages; Mice; Mice, Inbred C57BL; Neutropenia; Regression Analysis; Spleen

Topics: Anemia; Clinical Trials as Topic; Colony-Stimulating Factors; Drug Approval; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Multicenter Studies as Topic; Neutropenia; Randomized Controlled Trials as Topic

A preterm baby, whose mother received chemotherapy for acute leukaemia during pregnancy, required intensive care because of profound anaemia and neutropenia. Haemopoietic progenitor cell studies showed fetal marrow suppression. Those caring for such mothers and babies should know the possible serious effects chemotherapy for malignancies can have on a developing fetus. Long term follow up of the baby is imperative.

Topics: Acute Disease; Adult; Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Etoposide; Female; Granulocyte Colony-Stimulating Factor; Humans; Infant, Newborn; Infant, Premature, Diseases; Leukemia, Myeloid; Neutropenia; Pregnancy; Pregnancy Complications, Neoplastic; Prenatal Exposure Delayed Effects

The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT-treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy.

Topics: Anemia; Animals; Body Weight; Bone Marrow Cells; Cells, Cultured; Colony-Forming Units Assay; Drug Synergism; Erythropoietin; Female; Hematopoiesis; Hematopoietic Stem Cells; Heme; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Neutropenia; Thrombocytopenia; Weight Loss; Zidovudine

A transient hyporegenerative neutropenia has been reported in neonates, but not in older children or adults, undergoing treatment with recombinant erythropoietin (epo). Monocytopenia has not been reported. We postulated that epo might selectively reduce the responsiveness of neonatal progenitors to Granulocyte Colony-Stimulating Factor (G-CSF), while not similarly affecting their responsiveness to Macrophage Colony-Stimulating Factor (M-CSF). To test this hypothesis two types of experiments were performed. First, progenitors of adult or fetal origin were pre-incubated with epo (or control), then washed, and their responsiveness to G-CSF and M-CSF evaluated in clonogenic culture assays. Second, clonogenic maturation was initiated using either G-CSF or M-CSF, after which the effect of a late addition of epo to the developing clones was evaluated. Indeed, pre-incubation with epo resulted in production of fewer neutrophils from fetal progenitors grown in G-CSF (P less than 0.001), but it did not reduce the number of macrophages generated from progenitors grown in M-CSF. Adding epo to the already-developing G-CSF-responsive and M-CSF-responsive adult and fetal clones did not alter colony development. Thus, epo appears to have an action on G-CSF-responsive, but not-M-CSF-responsive fetal progenitors, resulting in reduced production of neutrophils. This effect is no longer apparent, however, when progenitors have matured to the 8-cell clone stage.

Topics: Adult; Cells, Cultured; Clone Cells; Erythropoietin; Fetus; Granulocyte Colony-Stimulating Factor; Humans; Infant, Newborn; Macrophage Colony-Stimulating Factor; Neutropenia; Neutrophils; Stem Cells

PURPOSE AND RATIONALE: There has been no previously published experience with granulocyte-macrophage colony-stimulating factor (GM-CSF) at doses less than 15 micrograms/m2/d in patients with aplastic anemia, and most observations have been made at doses of 100 to 500 micrograms/m2/d (2.5 to 12.5 micrograms/kg/d). The benefits of using considerably lower doses, if effective, should include a decrease in cost and in side effects. We have therefore used very low doses of GM-CSF to treat a group of patients with aplastic anemia. Additionally, since severe anemia is often a problem in these patients, we recently started administering erythropoietin along with the GM-CSF. Herein we report the results of very-low-dose GM-CSF therapy in patients with aplastic anemia and our preliminary findings in those individuals who received combination therapy.. We administered recombinant human GM-CSF subcutaneously at doses of 5 to 20 micrograms/m2/d ("very-low-dose GM-CSF") to 12 patients with aplastic anemia. In addition, a 13th patient received erythropoietin together with the GM-CSF regimen, and three of the 12 individuals who initially received 1 or more months of GM-CSF alone were later also given erythropoietin (4,000 U/d subcutaneously).. In five of 12 patients (42%) treated with very-low-dose GM-CSF, an increase in neutrophil counts (2.0- to 6.7-fold) was noted, and one of these subjects attained a bilineage response (neutrophil counts, 0.3 to 1.75 x 10(9)/L; platelet counts, 8 to 169 x 10(9)/L). Moreover, a sixth patient showed a rise in platelet counts (19 to 80 x 10(9)/L) without a concomitant increase in neutrophils. Constitutional side effects were minimal. Combining erythropoietin and very-low-dose GM-CSF produced a bilineage response (neutrophils, 1.0 to 3.0 x 10(9)/L; hemoglobin, 7.4 to 9.4 g/dL) in the one patient who received erythropoietin together with the GM-CSF from the time that GM-CSF was initiated. In one of the other patients who were given combination therapy, the addition of erythropoietin appeared to enhance the response; this patient demonstrated a neutrophil response to GM-CSF alone and a trilineage response (neutrophils, 0.8 to 3.75 x 10(9)/L; hemoglobin, 7.0 to 13.1 g/dL; and platelets, 10 to 34 x 10(9)/L) to the combination. No toxicity was associated with the addition of erythropoietin.. Our observations suggest that (1) very low doses of GM-CSF (5 to 20 micrograms/m2/d subcutaneously) may be used initially in neutropenic patients with aplastic anemia, and the dose subsequently increased only in patients who do not respond; and (2) the administration of erythropoietin together with GM-CSF is well tolerated, can augment responsiveness in some patients, and deserves further study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Aplastic; Bacterial Infections; Bone Marrow; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hemoglobins; Humans; Injections, Subcutaneous; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neutropenia; Neutrophils; Platelet Count; Recombinant Proteins; Thrombocytopenia; Time Factors

Twenty-two patients with acquired immunodeficiency syndrome (AIDS) or severe AIDS-related complex and multilineage hematopoietic defects were treated with recombinant granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) in a phase I/II trial. All patients were neutropenic and anemic after withdrawal of all bone marrow-suppressive drugs. Daily, G-CSF was subcutaneously self-administered until an absolute neutrophil count (ANC) greater than 6,000/microL was achieved and maintained for 2 weeks. Subcutaneous EPO was added to the regimen and the dose increased until an increase of 15 g/L of hemoglobin was observed. Groups of patients were administered increasing doses of zidovudine to determine their tolerance. G-CSF and EPO therapy was continued with dose modification to maintain an ANC greater than 1,500/microL and hemoglobin greater than 100 g/L. The dose of zidovudine was not altered. All 22 patients responded to G-CSF with a mean 10-fold increase in neutrophils occurring in less than 2 weeks. Significant increases in CD4 and CD8 cell number, lymphocyte proliferative response, and bone marrow cellularity were seen. EPO therapy increased hemoglobin in all 20 evaluable patients within 8 weeks. Sixteen patients received 1,000 mg and four patients received 1,500 mg of zidovudine per day. The reinstitution of zidovudine resulted in a decline in reticulocytes and hemoglobin and the reappearance of transfusion requirements in eight of the 20 patients, six of whom had the study medications stopped. No patient had the study medications stopped because of neutropenia or thrombocytopenia. Toxicities were mild and did not require dose modifications. Limiting dilution plasma and lymphocyte co-cultures for HIV as well as serum p24 antigen levels did not change significantly during G-CSF or combined G-CSF and EPO therapy. HIV p24 antigen decreased significantly with zidovudine therapy. Opportunistic infections occurred in 14 patients but were successfully treated with myelosuppressive antimicrobial agents, including ganciclovir, without the development of neutropenia. These results suggest that combined therapy with G-CSF and EPO may improve the neutropenia and anemia of AIDS. Combined therapy may allow the resumption of full-dose zidovudine in most patients intolerant of the hematologic effects of zidovudine without apparent alteration of HIV expression or the efficacy of zidovudine.

Topics: Acquired Immunodeficiency Syndrome; Blood Cell Count; Cell Survival; Dose-Response Relationship, Drug; Drug Evaluation; Drug Therapy, Combination; Erythropoietin; Ganciclovir; Gene Products, gag; Granulocyte Colony-Stimulating Factor; Hemoglobins; HIV; HIV Core Protein p24; Humans; Injections, Subcutaneous; Neutropenia; Opportunistic Infections; Recombinant Proteins; Viral Core Proteins; Virus Replication; Zidovudine

The neonatal neutropenia after pregnancy-induced hypertension is a function of diminished neutrophil production. These studies test the hypothesis that this diminution is due to decreased production of neutrophilic growth factors, reduced responsiveness of neutrophil progenitors to these factors, or the presence of an inhibitor. While the concentrations of placentally derived colony-stimulating factors were similar in normotensive and hypertensive gestations, bioassay demonstrated less colony-stimulating activity in placental conditioned media from hypertensive gestations. Evaluation of the responsiveness of progenitors to recombinant factors revealed no differences between those from normotensive and hypertensive gestations. However, neutrophilic colony formation in vitro was significantly inhibited after the addition of conditioned media or sera from hypertensive gestations, whereas the addition of these from normotensive gestations had no inhibitory effect. Thus this common maternal-fetal disorder is associated with an inhibitor of neutrophil production, which is elaborated by the placenta and present in cord blood serum.

Topics: Cells, Cultured; Erythropoietin; Female; Fetal Blood; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypertension; Infant; Interleukin-3; Neutropenia; Neutrophils; Placenta; Pregnancy; Pregnancy Complications, Cardiovascular; Umbilical Veins

Hematopoietic dysfunction with peripheral cytopenias is a common complication of human immunodeficiency virus (HIV) infection. Symptomatic anemia is the most common cytopenia and occurs in the presence and absence of myelosuppressive drug therapy such as zidovudine. Drug-induced neutropenia and immune thrombocytopenia are also frequent and occur in up to 50% of acquired immunodeficiency syndrome (AIDS) patients. Attempts to reduce the impact of bone marrow failure have focused on dose reduction of zidovudine, ganciclovir, and chemotherapy, and the use of recombinant hematopoietic hormones such as erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). Despite these maneuvers, approximately 30% of patients with AIDS receiving zidovudine will become transfusion-dependent. This has led to investigations of other cytokines that may increase blood cell formation. The recent identification of decreased number and proliferation of hematopoietic progenitors in patients with HIV infection suggests that agents which have activity on progenitor cell pools may have clinical utility. We demonstrate that human stem cell factor (HuSCF) increases burst-forming unit-erythroid (BFU-E), colony-forming unit-granulocyte-monocyte (CFU-GM), and CFU-Mix formation in vitro in normal and HIV-infected individuals. HuSCF also decreases the sensitivity of BFU-E to inhibition by zidovudine without altering HIV replication in lymphocytes or monocytes, altering peripheral blood mononuclear cell proliferation to phytohemagglutinin (PHA) and interleukin-2 (IL-2) or altering the effectiveness of zidovudine or dideoxyinosine in inhibiting HIV replication in lymphocytes or monocytes. These studies suggest that HuSCF may have clinical utility in HIV infection as an adjunctive treatment for HIV-related cytopenias.

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Complex; Anemia; Colony-Forming Units Assay; Erythroid Precursor Cells; Erythropoietin; Granulocytes; Hematopoietic Cell Growth Factors; HIV; HIV Infections; Humans; Lymphocytes; Macrophages; Monocytes; Neutropenia; Recombinant Proteins; Stem Cell Factor; Thrombocytopenia; Virus Replication; Zidovudine

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

Topics: Acquired Immunodeficiency Syndrome; Antiviral Agents; Colony-Stimulating Factors; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Growth Substances; Humans; Neutropenia; Recombinant Proteins; Zidovudine

The four existing animal models of cyclic hematopoiesis are briefly described. The unusual erythropoietin (Ep) responses of the W/Wv mouse, the Sl/Sld mouse, and cyclic hematopoietic dog are reviewed. The facts reviewed indicate that the bone marrow itself is capable of influencing regulatory events of hematopoiesis.

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Cells; Disease Models, Animal; Dog Diseases; Dogs; Erythropoiesis; Erythropoietin; Hematopoiesis; Humans; Hypoxia; Lithium; Mice; Mice, Inbred Strains; Mink; Neutropenia; Periodicity; Prednisolone; Strontium Radioisotopes

In addition to standard peripheral blood cell counts, sequential studies have been made of changes in the T-lymphocyte population and in the serum titres of the presumptive humoral regulators of haematopoiesis, Colony Stimulating Activity (CSA) and Erythroid Stimulating Activity (ESA), in a young woman with cyclic neutropenia (CN). In addition, serum immunoglobulins, C3 and total complement levels and serum protein concentrations were determined on several occasions during the study. Similar tests were done concomitantly on a haematologically normal, age and sex-matched control. Cell counts on peripheral blood from the subject with CN demonstrated a clearly defined periodicity in neutrophil and monocyte concentrations and equivocal fluctuations in reticulocyte numbers. There was no evidence of periodicity in the lymphocyte concentrations and the T-lymphocyte population appeared functionally normal. Spontaneous incorporation of tritiated thymidine into peripheral blood cells showed a highly significant correlation with the monocyte count, suggesting that these cells were responsible for the radioisotope uptake. CSA titres were elevated on all occasions tested and showed no evidence of periodicity. ESA showed some evidence of cycling with elevated levels being observed during the periods of neutropenia. Serum complement levels were within the normal range but all classes of immunoglobulins were elevated and albumin levels were depressed.

Topics: Adult; Agranulocytosis; Blood Proteins; Colony-Stimulating Factors; Complement C3; Complement System Proteins; Erythropoietin; Female; Hematopoiesis; Humans; Immunoglobulins; Leukocyte Count; Lymphocyte Activation; Neutropenia; Recurrence; Rosette Formation; T-Lymphocytes

Studies were done of cell production by marrow in diffusion chambers implanted in the peritoneal cavity of rabbits subjected to various stimuli to hematopoiesis. In chambers in neutropenic hosts and in hosts injected with endotoxin, animals presumed to have an increased stimulus to granulopoiesis, there was increased production of granulocytes but there was also increased production of red cells. Although red cell production was decreased in chambers in polycythemic hosts, granulocyte production was not different from that in controls. Stimulation of erythropoiesis by erythropoietin injections or by exposure to hypoxia increased red cell production by marrow in the implanted diffusion chambers without diminishing granulopoiesis. Only in chambers in hosts made anemic by bleeding was there an increase in red cell production accompanied by a decrease in granulocyte production. In these anemic hosts induction of neutropenia led to an increase in granulopoiesis without any depression of erythropoiesis.

Topics: Anemia; Animals; Bone Marrow Cells; Cells, Cultured; Endotoxins; Erythrocytes; Erythropoietin; Hematopoiesis; Hypoxia; Leukocytes; Male; Mechlorethamine; Neutropenia; Polycythemia; Rabbits

Following extensive bowel resection, a young woman experienced severe malnutrition; subsequent administration of parenteral nutrition precipitated the copper deficiency syndrome. This consisted of hypocupremia, subnormal ceruloplasmin levels, anemia, and severe neutropenia. The bone marrow was megaloblastic, vacuolated, and sideroblastic; granulocytic maturation was not observed beyond the myelocyte stage. Copper sulfate therapy was followed by a marked reticulocytosis, increase in hematocrit, and recovery of neutrophils. Additional studies indicated that both serum and urinary erythropoietin values were low; serum activity increased after copper supplementation. Abnormal granulopoiesis was demonstrated using the in vitro granulocyte colony assay. The patient's granulcoytic stem cells were normal on two occasions; however, mixing studies showed that culture of the patient's copper-deficient marrow with her copper-deficient serum yielded significantly reduced numbers of granulocyte colonies. Thus, copper appears to be a necessary element for normal hematopoiesis; lack of this trace element may result in ineffective erythropoiesis and granulopoiesis.

Topics: Adult; Agranulocytosis; Anemia; Bone Marrow Cells; Cells, Cultured; Colony-Stimulating Factors; Copper; Erythropoietin; Female; Hematopoiesis; Humans; Neutropenia

The results of erythropoietin (ESF) studies in dogs with cyclic haematopoiesis are presented. Even though the dogs were exposed to a constant stimulus of hypoxia, cycles in the plasma ESF levels occurred at 11 to 12 day intervals. In some dogs, minor midcycle peaks were observed and the amount of ESF produced varied with the different animals. The peaks of ESF characteristically appeared approximately five days after onset of neutropenia. A hypothesis is presented to explain the known facts concerning canine cyclic haematopoiesis. It suggests that a poietin controlling factor is produced and that this assumed factor then stimulates the production of specific factors leading to increases of reticulocytes, platelets, and monocytes. The monocytes in turn produce more colony stimulating factor (CSF) leading to the formation of granulocytes. Such a sequence of events would explain the apogee of reticulocyte, platelet, and monocyte counts at a time when the nadir of granulocyte counts is reached.

Topics: Animals; Dogs; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hematopoiesis; Hypoxia; Male; Neutropenia; Neutrophils; Reticulocytes; Time Factors

The marrow of a dog affected with cyclic neutropenia (CN) was transplanted into an unaffected supralethally irradiated litermate. Prompt engraftment occurred, and cyclic rises and falls in numbers of platelets, reticulocytes, and granulocytes were noted in the recipient soon after engraftment. Prior to transplantation and under hypoxic conditions, the donor had serum erythropoietin (ESF) peak levels at 11-12-day intervals. Following transplatation and under hypoxic conditions, cyclic peaks of ESF occurred in the transplanted dog.

Topics: Agranulocytosis; Ampicillin; Animals; Biological Assay; Blood Platelets; Bone Marrow Cells; Bone Marrow Transplantation; Dihydrostreptomycin Sulfate; Dog Diseases; Dogs; Drug Combinations; Erythrocytes; Erythropoietin; Hypoxia; Iron; Iron Radioisotopes; Leukocyte Count; Methotrexate; Neutropenia; Periodicity; Polymyxins; Radiation Chimera; Reticulocytes; Transplantation, Homologous