Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The problems of immunologic adaptation during the transitional period from intra- to extrauterine life are responsible for the physiologic immaturity of the immune function in newborn infants. In preterm neonates the immunodeficiency is more severe and prolonged and is associated with a higher incidence of infections and sepsis. Furthermore, due to immaturity of the hematologic system, anemia, thrombocytopenia, and neutropenia are frequently observed in very low birth weight infants. The dysregulation of cytokine and hematopoietic growth factor synthesis is an important contributory factor to the complex deficiency of immunologic and hematologic function in the neonate and may explain the reduced incidence of acute graft-versus-host disease observed after cord blood transplantation in children. Human milk is a rich source of most of the cytokines that are reduced in the neonate. Granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and erythropoietin are currently under evaluation in newborn infants with septic neutropenia or anemia of prematurity.
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PMID:Hematopoietic growth factor levels in term and preterm infants. 1022 41

The myelodysplastic syndrome (MDS) remains challenging to the clinician in terms of diagnosis and management. The diagnosis is essentially one of exclusion in first ruling out other disorders that can also cause peripheral blood/bone marrow cell dysplasia and cytopenias. The distinguishing biological characteristic of MDS is that it is a clonal disorder of the marrow with impaired differentiation. Recent studies implicate extensive apoptosis as the explanation of the paradoxical observation of marrow hyperplasia but peripheral blood cytopenia. Neutropenia and/or neutrophil dysfunction account for the primary clinical manifestation of MDS in terms of an increased risk for infection, which is the leading cause of death in MDS. The clonal nature of MDS places it also at continual risk for transformation to acute leukemia. Predicting overall survival as well as the risk of AML transformation has been improved by the recent development of a scoring system (International Prognostic Scoring System) that incorporates three laboratory variables: percent of marrow blasts, degree of cytopenias, and presence of chromosomal abnormalities. Based on these variables, four prognostic subgroups can be delineated ranging from low risk with a median survival of 5.7 years, to high risk with a median survival of 0.4 years. Management of MDS can now be based on the patient's respective prognostic subgrouping, with low-risk patients being considered for hematopoietic growth factor singly or in combination if at the point of red cell transfusion dependence and/or neutropenia with recurrent infections, while high-risk patients should be offered AML-induction therapy or novel agents such as topotecan. One must individualize further in patients in the remaining intermediate groups, I and II, in choosing the most appropriate therapy. Future advances upon understanding the molecular details of the MDS clone should ultimately improve the care of patients with MDS.
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PMID:Understanding the Myelodysplastic Syndromes. 1038 74

Encouraged by preclinical synergism between docetaxel and 5-fluorouracil (5FU), we conducted a Phase I study of docetaxel in combination with continuous i.v. infusion of 5FU in patients with advanced solid tumors to determine the maximum tolerated dose, the recommended dose for Phase II studies, and the safety and pharmacokinetic profiles of this combination. Forty-two patients with advanced solid tumors, most of whom had been previously treated, received docetaxel on day 1 as a 1-h i.v. infusion, immediately followed by a 5-day continuous i.v. infusion of 5FU, every 3 weeks without hematopoietic growth factor support. All patients were premedicated with methylprednisolone. Dose levels of docetaxel/SFU studied were (daily dose, in mg/m2) 60/300, 75/300, 75/500, 75/750, 85/750, 85/1000, and 75/1000. Forty-one patients were assessable for toxicity. The maximum tolerated dose determined during the first cycle was 1000 mg/m2/day for 5 days of 5FU with either 75 or 85 mg/m2 docetaxel. Dose-limiting toxicities at these dose levels were reversible secretory diarrhea (4 of 12 evaluable patients), stomatitis (2 patients), and febrile neutropenia (2 patients). Overall, grade 3/4 neutropenia and febrile neutropenia were seen in 63.4% and 9.8% of the patients, respectively. Four patients experienced grade 3/4 infection, which led to toxic death in one of them. There were five early deaths: (a) one was clearly treatment related; (b) two others were possibly treatment related or remotely treatment related; and (c) two deaths were not related to the study drugs. Partial responses were documented in 5 of 39 evaluable patients. Pharmacokinetic results of both drugs were consistent with those from single-agent studies. The recommended dose of this combination, which showed acceptable toxicity and antitumoral activity at various dose levels, is 85 mg/m2 docetaxel given as a 1-h i.v. infusion on day 1 immediately followed by a 5-day continuous i.v. infusion of 5FU (750 mg/m2/day). This study has been extended by adding cisplatin on day 1 of the combination of docetaxel and 5FU.
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PMID:A phase I and pharmacokinetic study of docetaxel administered in combination with continuous intravenous infusion of 5-fluorouracil in patients with advanced solid tumors. 1065 33

The activity and toxicity of topotecan in women with recurrent cervical cancer are described from a case series of women with recurrent cervical cancer who had measurable disease and were not amenable to cure by surgery or radiation. All patients had prior platinum-based chemotherapy and developed progressive disease. Topotecan was given as 1 mg/m2/day over 30 min for 5 days every 3 weeks until progression of disease or prohibitive toxicity. Between July 1998 and July 1999, 12 patients received a total of 20 cycles of topotecan. Median age was 41 years (range 21-62), and 11 (92%) patients had prior whole pelvic radiation. The mean number of topotecan cycles was 1.5 (median 1, range 1-3). There were two partial responses (16.7%; 95% CI, 2% to 48%), both in prior radiation fields. Five patients required red blood cell transfusions, four had grade II nausea and vomiting, two developed sepsis (one with neutropenia), one developed fever, and one reported hyperpigmentation. There were no treatment-related mortalities. Although topotecan appears to exhibit modest activity in recurrent cervical cancer after radiation and platinum-based therapy, bone marrow toxicity may limit the utility of this regimen without hematopoietic growth factor support.
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PMID:Topotecan for recurrent cervical cancer after platinum-based therapy. 1124 Jun 88

Erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage stimulating factor (GM-CSF) are currently licensed for use in cancer patients and play a significant role in the management of anemia and neutropenia following myeloblative chemotherapy. EPO was the first recombinant hematopoietic growth factor to be used clinically after a number of clinical trials which demonstrated its effectiveness in treating mild to moderate cancer-associated anemia with or without concomitant chemotherapy (particulary cisplatin). An extensive research has been made for the improvement of the quality of life with EPO therapy, however, when formally assessed, variable effects of this important treatment have been observed. Recently, EPO has been shown to significantly accelerate hematopoietic reconstitution after peripheral blood stem cell transplantation (PBSCT) resulting in reduced infection rates. Both, G-CSF and GM-CSF have been shown, in numerous trials, to shorten the period of chemotherapy-induced neutropenia, with reduction in attendant morbidity and to mobilize PBSC. In addition, administration of both cytokines after PBSCT significantly reduced the use of antibiotics and duration of hospitalization suggesting an economic benefit. The narrower therapeutic window of GM-CSF at higher doses accounts for the fact that it is used much less frequently than G-CSF. To date, none of the growth factors used clinically has been shown to stimulate thrombopoiesis. Although thrombopoietin (TPO) has been found to induce megakaryocyte differentiation in vitro, it is unlikely to enter routine clinical use for treatment of post-chemotherapy thrombocytopenia, since results of clinical trials are not very encouraging, mainly because TPO is difficult to schedule and platelet aggregation may occur. Recently, innovative chimeric growth factor receptor agonists have been synthesized. Synthokine (SC-55494) (a high-affinity human IL-3 receptor ligand analog), myelopoietin (MPO) (activates human IL-3 and G-CSF receptors) and promegapoietin (PMP) (stimulates the human IL-3 and c-mpl receptors) were found to be multilineage hematopoietic growth factors and are currently undergoing clinical trials. Preliminary results suggest that these compounds may have a major impact on the management of myeloablative chemotherapy because of their ability to enhance platelet recovery in addition to their neutrophil restorative activity.
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PMID:Human hematopoietic growth factors: old lessons and new perspectives. 1132 88

We report the first randomized study assessing the efficacy and safety of daunorubicin (DNR) continuous infusion (CI) compared to the more conventional 30-min infusion (i.v.) in newly diagnosed adult acute lymphoblastic leukemia (ALL). Seventy-seven patients were initially randomized to receive either a 24-h CI DNR (60 mg/m2 days 2-4) (40 patients) or bolus DNR at the same dosage (37 patients) with vincristine (2 mg i.v. days 1, 8, 15) and oral prednisone (60 mg/m2 days 1-15), without hematopoietic growth factor support, as an induction regimen. The distribution of adverse prognostic factors was comparable in the two-induction arm. Acute toxicity was more important in the CI arm. Gram negative infection (9 vs 1 gram negative septicemia, P = 0.01) and infection-related deaths (6 vs 1 deaths, P = NS) occurred more frequently in the CI arm during the induction treatment than in the i.v. arm, leading to the study interruption. Neutropenia but not thrombopenia duration was significantly longer in the CI arm than in the i.v. arm (18 days vs 14 days, P > 0.05 and 16 days vs 12 days, P > 0.05, respectively). Despite a similar CR rate according to the method of DNR administration (68% in the CI DNR arm vs 76% in the i.v. arm after the first course), there was a trend toward higher freedom from relapse (FFR) after DNR CI (48% vs 28% in the i.v. arm at 5 years, P = NS), suggesting that despite this high toxicity, DNR CI may improve the CR quality and decrease further the residual disease.
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PMID:Daunorubicin continuous infusion induces more toxicity than bolus infusion in acute lymphoblastic leukemia induction regimen: a randomized study. 1141 74

Mutations in the genes of hematopoietic growth factor receptors as a cause of congenital cytopenia, such as congenital amegakaryocytic thrombocytopenia (CAMT) or severe congenital neutropenia (CN), are discussed. There are striking differences in the relevance of receptor mutations in these diseases. CAMT is a rare disease characterized by severe hypomegakaryocytic thrombocytopenia during the first years of life that develops into pancytopenia in later childhood. In patients with CAMT, we found inherited mutations in c-mpl, the gene coding for the thrombopoietin receptor, in 8 out of 8 cases. The type of mutation seems to correlate with the clinical course seen in the patients. Functional studies demonstrated defective thrombopoietin (TPO) reactivity in hematopoietic progenitor cells and platelets in CAMT patients. CN is a group of hematopoietic disorders characterized by profound, absolute neutropenia due to a maturation arrest of myeloid progenitor cells. About 10% of all patients develop secondary MDS/leukemia. The malignant progression is associated with acquired nonsense mutations within the G-CSF receptor gene that lead to the truncation of the carboxy-terminal cytoplasmic domain of the receptor protein involved in maturation of myeloid progenitor cells. This seems to be one important step in leukemogenesis in CN patients. CAMT is caused by inherited mutations in c-mpl, the gene for the thrombopoietin receptor, which lead to reduced or absent reactivity to TPO. In contrast, mutations in the G-CSF receptor in CN are acquired and are most probably connected with progression of the neutropenia into MDS/leukemia as a result of a loss of differentiation signaling.
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PMID:Implications of mutations in hematopoietic growth factor receptor genes in congenital cytopenias. 1145 19

Hematopoietic colony-stimulating factors have been introduced into clinical practice as additional supportive measures to reduce infectious complications associated with congenital or acquired neutropenia. Over the past decade, we have begun to appreciate the subtler aspects of the proper use of G-CSF and GM-CSF, identifying appropriate indications and contraindications. In the course of evaluating the corpus of studies, a set of formal recommendations have been propagated for the judicious use of these expensive growth factors. To prevent serious infection, the use of G-CSF or GM-CSF is recommended in a subset of pediatric cancer patients shortly after having received chemotherapy or a form of a marrow transplant. Children with highly intensive chemotherapy (e.g., children with high risk ALL or NHL) seem to benefit from hematopoietic growth factors whereas this is still unclear for children undergoing therapy for solid tumors. An exciting development is the use of G-CSF and GM-CSF to mobilize peripheral-blood progenitor cells for autologous or allogeneic transplantation. In pediatric patients with hematological diseases, there are only few data on the use of hematopoietic growth factors in children with myelodysplastic syndrome. Experts recommend the early administration of G-CSF in children with very severe aplastic anemia. The use of G-CSF is also recommended in children with severe chronic neutropenia, but these patients have to be monitored regularly for cytogenetic abnormalities. No larger study has shown a clinical benefit of hematopoietic growth factor in preterm or term infants. Future studies in pediatric patients are clearly warranted to address several issues. Prospective clinical trials are still needed to define specific treatment groups who can benefit from growth factor support. In this regard, efforts must be directed at better defining the endpoints and in particular assigning value to reduction in treatment of possible infectious complications, such as days in hospital, antibiotic usage and costs. In addition, randomized studies are required to evaluate the proper dosage and duration of therapy, which most likely will vary between groups of patients. In addition, combinations of different growth factors have to be tested, particularly if ex vivo expansion and the storage of hematopoietic stem cells are to be utilized in a wider spectrum of patients.
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PMID:[Hematopoietic growth factors in prophylaxis and therapy of infections complications in children with neutropenia]. 1152 56

The myelodysplastic syndromes (MDS) are clonal hematological disorders characterized by ineffective hematopoiesis manifested by anemia, neutropenia, thrombocytopenia or a combination. Correction of these cytopenia is a priority in MDS without excess of blasts. Treatment of anemia depends mainly on erythrocyte transfusions. However with the ability of recombinant human hematopoietic growth factor many trials have been promoted. In vitro, erythroid progenitors from MDS patients are able to differentiate but they require much higher concentrations of erythropoietin than normal progenitors. Trials using rHu-Epo alone are disappointing. Combining rHu-Epo and rHu-G-CSF induces more encouraging results showing a synergistic effect particularly clear in sideroblastic anemia. Patients with low endogenous Epo level and low transfusion need are more likely to respond. Clinician should be able in the future to identify MDS patients with a chance of reversal of anemia or transfusion dependency.
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PMID:[The place of growth factors in the treatment of myelodysplastic syndromes]. 1208 72

Acute complications such as veno-occlusive disease of the liver, acute and chronic graft-vs-host disease (GVHD), and infectious conditions remain major obstacles for the success of allogeneic hematopoietic stem cell transplantation (HSCT). Progress in allogeneic HSCT depends on several factors, including the adequate prevention and management of associated complications, advances in the conventional management of diseases currently treated with allogeneic HSCT, expansion of the donor pool, selective control of GVHD, development of more effective preparative regimens to eradicate the neoplastic cell population, characterization of a new generation of hematopoietic growth factors and cytokines, and development of newer techniques for ex vivo manipulation of stem cells. Hematopoietic growth factor-mobilized donor progenitor cells collected from peripheral blood have been shown to be associated with rapid hematopoietic engraftment without an increase in the incidence of acute GVHD compared with allogeneic bone marrow transplantation. Implementation of this approach will enhance donor acceptance, eliminate the risk of general anesthesia, decrease cost, and reduce the risk of infectious complications by reducing the duration of neutropenia. Nonmyeloablative allogeneic stem cell transplantation represents a novel treatment approach that may lead to reduced toxic effects and extended use of this treatment in older patients and in those with malignant and nonmalignant disorders. However, GVHD and disease recurrence remain a challenge. Promising results have been reported in patients with refractory hematologic malignancies and in metastatic renal cell cancer. Because late complications are commonly encountered in patients receiving allogeneic HSCT, lifelong observation is needed.
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PMID:Allogeneic hematopoietic stem cell transplantation: complications and results. 1212 98


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