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)

In conclusion, hematopoietic growth factors have been shown to enhance the recovery and function of circulating WBCs after standard-dose cancer therapy or high-dose cancer therapy with ABMT, and preliminary data strongly suggests that these agents may have the ability to restore leukocyte numbers and competence in AIDS, myelodysplastic syndromes, and other marrow failure states. Phase I and II trials of GM-CSF in patients with AIDS, cancer, marrow failure states, and following bone marrow transplantation have been published, and limited phase III randomized trial experiences have been reported as well. Overall, GM-CSF represents a fascinating molecule with which to modulate human hematopoiesis in vivo. The multilineage stimulatory effects of GM-CSF that are evident in vitro have not been striking or consistent in clinical trials. However, the effects of GM-CSF on the production and function of mature neutrophils, monocytes, and eosinophils have been noted in the vast majority of clinical scenarios in which this cytokine has been tested. The clinical benefits of GM-CSF have, to date, only been proven in large-scale randomized studies of recovery from ABMT for lymphoid neoplasms. However, further data regarding the use of GM-CSF in other clinical settings have been generated, and the final results are eagerly anticipated by the oncology community. The beneficial effects of GM-CSF following ABMT consisted not only of a shorter period of absolute neutropenia, but also fewer significant infections, a diminished requirement for intravenous antibiotic administration, and a shorter overall duration of inpatient hospitalization. The use of GM-CSF in clonal disorders of hematopoiesis, such as myelodysplasia or myeloid leukemias, requires caution before such applications can be routinely recommended, and the demonstration of safety in this setting from large randomized trials will be needed. Preliminary data from small randomized trials suggests that the incidence of evolution to leukemia in patients with myelodysplasia and the number of patients with regrowth of leukemia after induction treatment in relapsed patients with AML may not be significantly different than in patients who do not receive GM-CSF. Various neutropenic conditions (eg, idiopathic or congenital) may respond clinically to hematopoietic growth factors such as GM-CSF. Patients treated for 3 to 15 months continue to respond with significantly increased granulocytes and resolution of prior infection. The subcutaneous route of administration is convenient and patients seem to accept it readily. It is difficult to determine the extent to which adjunctive therapy with GM-CSF will be cost effective.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Granulocyte-macrophage colony-stimulating factor (GM-CSF): preclinical and clinical investigations. 150 75

The toxicity of autologous bone marrow transplantation (ABMT) is correlated to neutropenia. Although recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF) seems to hold promise in accelerating neutrophil recovery, few analyses from randomized studies are presently available. Ninety-one patients with non-Hodgkin's lymphoma receiving high-dose ablative chemotherapy followed by ABMT with unpurged or purged marrow were included in a randomized, double-blind, placebo-controlled trial. Forty-four patients received 250 micrograms rhu GM-CSF (Escherichia coli)/m2 and 47 patients received placebo. Treatment was administered daily as continuous infusion from day of ABMT until the absolute neutrophil count (ANC) reached 0.5 x 10(9)/L for 7 days or until day 30, whichever was first. With rhu GM-CSF, 50% of the patients reached an ANC count greater than 0.5 x 10(9)/L at day 14 as opposed to day 21 with placebo (P less than .0001). Patients transplanted with marrow purged by mafosfamide also recovered earlier when treated with rhu GM-CSF (16 v 20.5 days, P = .013). The hospitalization duration was shorter in the rhu GM-CSF group (median, 23 v 28 days, P less than .05). No difference was observed in fever, number of infections, and antibiotic administration between the two groups. The major adverse event ascribed to rhu GM-CSF was a capillary leak syndrome in three patients graded as severe in two patients, moderate in one, and reversible in all three patients. In addition, one patient in the rhu GM-CSF group died suddenly with no explanation. In long term follow-up, the relapse rate was identical in both groups and there was no significant difference in the number of deaths at 1 year (12 with rhu GM-CSF v 9 with placebo), although deaths seemed to occur slightly earlier in the rhu GM-CSF group. We conclude that after ABMT with purged or unpurged marrow, rhu GM-CSF (E coli) significantly reduces neutropenia duration and hospitalization stay. A positive causative relation between the study drug and/or its mode of application with an increased toxicity as compared with GM-CSF from other sources and/or other modes of application cannot be deduced from the experiences in this study. Additional randomized trials would be necessary for an appropriate answer.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor after high-dose chemotherapy and autologous bone marrow transplantation with unpurged and purged marrow in non-Hodgkin's lymphoma: a double-blind placebo-controlled trial. 151 37

We report a case of Felty's syndrome in which infectious complications due to severe neutropenia could be overcome by short-term treatment with recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF, 7 micrograms/kg/day s.c.). Leukocyte counts rose from 1,050/mm3 at presentation to 4,470/mm3 after 15 days of treatment. A flare-up of arthritis was not noted. Defects in granulocyte function and clinical improvement prior to leukocyte rise suggest that the beneficial effect of GM-CSF is mainly due to an improvement of granulocyte function.
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PMID:Felty's syndrome: favorable response to granulocyte-macrophage colony-stimulating factor in the acute phase. 151 33

The pharmacokinetics and pharmacodynamics of bacterially synthesized granulocyte-macrophage colony stimulating factor (GM-CSF) were studied in 33 patients. GM-CSF (0.3-30 micrograms/kg/d) was administered subcutaneously (s.c.) or intravenously (i.v.) by bolus or 2 h infusion for 10 d to three patients at each dose level, and serum levels measured by enzyme-linked immunosorbent assay (ELISA). Relationships between pharmacokinetic variables and GM-CSF efficacy and toxicity were investigated. GM-CSF appeared more effective s.c. than i.v. Correlations with response improved when patients with neutropenia or marrow infiltration by tumour were excluded. For the remaining patients, the correlation coefficients between the day 10 leucocyte count was highest with dose (R = 0.629, P less than 0.01), the duration GM-CSF concentrations exceeded 1 ng/ml (r = 0.524, P less than 0.05) and area under the concentration-time curve (R = 0.508, P less than 0.05). There was no correlation with peak serum GM-CSF (Cmax) (R = 0.188, P = NS). In contrast, the first dose reaction (characterized by hypoxaemia and hypotension) was associated with high Cmax (P less than 0.01) and i.v. administration. Fever, liver enzyme elevation and pericarditis occurred at 10-30 micrograms/kg and were not influenced by route. Since the variables correlating with response differed from those correlating with these toxicities, it appears that the therapeutic index for GM-CSF can be increased by modifying the method of administration.
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PMID:The dissociation of GM-CSF efficacy from toxicity according to route of administration: a pharmacodynamic study. 155 Jul 69

Seventeen patients with small cell lung cancer were entered into a dose ranging phase I-II study using rhGM-CSF (Glaxo). In the phase I study patients received 50, 150, 300 or 500 micrograms/m2 GM-CSF for 10 days by daily subcutaneous injection. Full blood counts were performed thrice weekly. After 4 days off all therapy patients then received chemotherapy with doxorubicin 50 mg/m2 i.v. bolus, day 1, ifosfamide 5 g/m2 with mesna 5 g/m2 over 24 h by continuous infusion followed by mesna 3 g/m2, and etoposide 120 mg/m2 i.v. on days 1-3. A total of six courses of chemotherapy were given. In the phase II study patients received the same dose of GM-CSF as in the phase I. GM-CSF was given 24 h after the last dose of chemotherapy for 14 days. Full blood counts were checked thrice weekly and the incidence of infections noted. Patients were randomised to receive GM-CSF with either odd or even courses of chemotherapy. The leucocyte count rose from a mean of 8.7 to 21.6 x 10(9)/l at the 50 micrograms/m2 GM-CSF dosage and from 11.4 to 39.4 x 10(9)/l at the 500 micrograms/m2 dosage during the phase I study. Phase I toxicity was: bone pain in 65% of patients, rash in 47%, fever in 24%, lethargy in 12% and diarrhoea in 12%. In the phase II study the duration of neutropenia was less during the chemotherapy courses with GM-CSF (p = 0.04) but the number of infections was similar.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Recombinant human GM-CSF in small cell lung cancer: a phase I/II study. 165 15

In three consecutive pilot studies the effect of recombinant human granulocyte/macrophage-colony-stimulating factor (rhGM-CSF) on haematopoetic recovery after chemotherapy in patients with small-cell lung cancer was investigated. In study I, 20 patients received AIO chemotherapy (A, Adriamycin 25 mg/m2 on days 1 + 2; I, ifosfamide 2 g/m2 on days 1-5; O, vincristine 2 mg on day 1) at 4-week intervals either with or without rhGM-CSF (250 micrograms/m2 sc) from day 8 until recovery of leucocytes. Neither the degree nor the duration of myelosuppression was markedly influenced by rhGM-CSF. Suggesting that these disappointing results were caused by the late onset of GM-CSF application, in the following study we shortened chemotherapy to 3 days and started with GM-CSF on day 4. The main objective of this study was to test whether the earlier administration of GM-CSF allowed treatment intervals to be reduced or the dose to be escalated. After 10 patients had received a starting dose of AIO (A, 50 mg/m2 on day 1; I, 2 g/m2 on days 1-3; 0,2 mg on day 1) alternating with cisplatin (90 mg/m2 on day 1) and etoposide (150 mg/m2 on days 1-3), the dose of ifosfamide and etoposide was escalated to 2.5 g/m2 on days 1-3 and 200 mg/m2 on days 1-3 in the next 10 patients. Treatment was given at 2-week intervals when leucocytes were greater than 3500/mm3 and thrombocytes were greater than 100,000 mm3 on day 14. At each dose level patients were randomized to receive either rhGM-CSF 250 micrograms/m2 s.c. on days 4-12 or no GM-CSF. In this study, rhGM-CSF markedly shortened the duration of leukopenia. Reinstitution of chemotherapy on day 15 was possible at dose level 1 in 1/4 patients without and in 3/4 patients with GM-CSF, and at dose level 2 in 0/5 patients without and in 5/5 patients with GM-CSF. However, the degree of myelosuppression was not improved by GM-CSF. In a third study we tried to apply rhGM-CSF simultaneously with chemotherapy. After 3 patients had received GM-CSF starting on day 1 concurrent to AIO chemotherapy, we noticed an increase of myelosuppression with prolonged neutropenia and thrombocytopenia and stopped this investigation. Considering all patients included in these three consecutive pilot studies, there is no difference in response rates and survival between patients with and without rhGM-CSF treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of rhGM-CSF on haematopoietic reconstitution after chemotherapy in small-cell lung cancer. 166 93

Because several human hematopoietic growth factors have been identified and shown to be effective for treatment of congenital or iatrogenic neutropenias, and cord blood contains stimulatory activities for blood-forming cells, we postulated that identification of these factors and analysis of their regulatory role in normal neonates would provide a rationale for their use in treating neonatal infections associated with neutropenia. We studied the plasma levels of granulocyte and granulocyte-macrophage colony-stimulating factors (G-CSF and GM-CSF, respectively) and the frequency of granulomonopoietic colony-forming cells (CFU-GM) in the umbilical cord blood of normal term neonates. Plasma growth factor levels were measured by a biologic assay. Circulating hematopoietic progenitors were assayed for colony formation with different recombinant growth factors used as exogenous growth stimulators. The cell cycle status of these progenitors was analyzed by the thymidine suicide technique. At birth the leukocyte count (mean +/- SD) was 11.0 +/- 3.9 x 10(9)L and the neutrophil count was 5.6 +/- 2.6 x 10(9)/L. The incidence of CFU-GM was significantly higher in umbilical cord blood than in normal adult peripheral blood (p less than 0.005) with up to 40% of the cells in S phase (less than 10% in normal adults). Plasma levels of G-CSF and GM-CSF at birth were 40.8 +/- 2.8 U/ml and 19.9 +/- 5.2 U/ml, respectively (normal adult plasma levels 2.5 +/- 1.5 U/ml for G-CSF and undetectable for GM-CSF). These high levels of G-CSF and GM-CSF in umbilical cord blood of normal neonates might play a role in maintaining adequate neutrophil production.
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PMID:High levels of granulocyte and granulocyte-macrophage colony-stimulating factors in cord blood of normal full-term neonates. 169 Jul 96

The number and growth factor requirements of committed progenitor cells (colony-forming units-granulocyte/macrophage and burst-forming units-erythroid) in three patients with cyclic neutropenia (two congenital, one acquired) were studied before and during therapy with recombinant human granulocyte colony-stimulating factor (G-CSF; 3 to 10 micrograms/kg/d). When the patients with congenital disease were treated with G-CSF, the cycling of blood cells persisted, but the cycle length was shortened from 21 days to 14 days, and the amplitude of variations in blood counts increased. There was a parallel shortening of the cycle and increase of the amplitude of variations (from two- to three-fold to 10- to 100-fold) in the number of both types of circulating progenitor cells in these two patients. In the patient with acquired cyclic neutropenia, cycling of both blood cells and progenitors could not be seen. In cultures deprived of fetal bovine serum, erythroid and myeloid bone marrow progenitor cells from untreated patients and from normals differed in growth factor responsiveness. As examples, maximal growth of granulocyte/macrophage (GM) colonies was induced by granulocyte/macrophage (GM)-CSF plus G-CSF in the patients, whereas a combination of GM-CSF, G-CSF and interleukin-3 (IL-3) was required in the normals, and erythropoietin alone induced fourfold more erythroid bursts from cyclic neutropenic patients than from normal donors (46% versus 11% of the maximal colony number, respectively). The growth factor responsiveness of marrow progenitor cells slightly changed during the treatment toward the values observed with normal progenitors. These results indicate that treatment with G-CSF not only ameliorated the neutropenia, but also increased the amplitude and the frequency of oscillation of circulating progenitor cell numbers. These data are consistent with the hypothesis that G-CSF therapy affects the proliferation of the hematopoietic stem cell.
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PMID:Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo. 169 89

Infantile genetic agranulocytosis (IGA) has a high morbidity and mortality rate due to severe neutropenia. The pathogenetic mechanisms of this syndrome have not been elucidated. However, a recent clinical trial with recombinant human granulocyte-colony-stimulating factor (rhG-CSF) has shown a dramatic increase in the absolute neutrophil count in patients with IGA. This suggests that these patients have either a lack of granulocyte-colony-stimulating factor (G-CSF) or have a defect in the G-CSF receptors. A clinical trial of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) in an infant with IGA is reported in this article. A marked eosinophilic response was observed without any increase in the absolute neutrophil count (ANC). In an effort to elucidate the pathogenetic mechanism underlying IGA, we examined (a) the in vitro response of patient's CFU-GM to rhGM-CSF and to rhG-CSF and (b) the ability of patient's monocytes to produce G-CSF. Our results tend to support the thesis that the defect in IGA is at the G-CSF receptor level. We also found a lack of correlation between in vivo and in vitro response to rhGM-CSF.
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PMID:Congenital neutropenia: a case study. 169 74

Patients with metastatic germ cell tumors undergoing five-day chemotherapy with etoposide, vinblastin, bleomycin and cisplatinum were given recombinant GM-CSF (mammalian glycosylated, Sandoz/Schering-Plough) at increasing dose levels of 75, 150, 300 or 600 micrograms protein/day in a double blind placebo controlled study. The drug was administered SC twice a day for 5 days starting 24 hours after completion of chemotherapy. Fourteen treatment courses, 10 with GM-CSF and 4 with placebo in 11 patients were evaluable for assessment of toxicity and hematological recovery, and 2 were not evaluable due to complications of progressive germ cell tumor. One patient receiving the highest dose level developed a delayed skin reaction at the site of injection. Fever under 38.5 degrees C and a flu-like syndrome were observed in 4/5 patients receiving the higher two dose levels, but not with lower dose levels or placebo. Two patients experienced mild bone pain. The neutrophil nadir was similar in the two groups, but the duration of neutropenia was significantly shorter in the GM-CSF group. At day 21 of chemotherapy the neutrophil count was 2.57 +/- 1.37 10(9)/l with GM-CSF, and 1.01 +/- 0.56 10(9)/l with placebo (p less than 0.05). Patients receiving GM-CSF could be retreated on day 21, whereas in patients given placebo, retreatment was delayed for an average of 7 days (p less than 0.05). Thus, a 5-day treatment with GM-CSF given subcutaneously resulted in a significant shortening of neutropenia and allowed for the timely administration of the subsequent cycle of chemotherapy.
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PMID:Placebo controlled phase I/II study of subcutaneous GM-CSF in patients with germ cell tumors undergoing chemotherapy. 170 98


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