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)

Hematopoietic growth factors are being used to accelerate the recovery of myelopoiesis following high-dose chemotherapy in cancer patients. G-CSF and GM-CSF reduce the duration of neutropenia following chemotherapy. Rapid restoration of neutrophils has been associated with reduced incidence of neutropenic fever and documented infections and fewer days of intravenous antibiotics and hospitalization. Recent studies suggest that combinations of cytokines may further expand the hematopoietic cell populations, which may be particularly useful following myeloablative chemotherapy, when thrombocytopenia may be a dose-limiting toxicity. For example, IL-3, which stimulates early progenitor cells, has definite but inconsistent effects on increasing neutrophil and platelet counts. However, in combination with later-acting cytokines (e.g., GM-CSF and IL-6), recovery from both thrombocytopenia and neutropenia is accelerated. As dose escalation of chemotherapy becomes more widely practiced, the role of cytokine combinations will become increasingly important.
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PMID:Clinical use of hematopoietic growth factors for control of infections after high-dose chemotherapy. 752 1

Colony-stimulating activity (CSA) was measured by the production of granulocyte-macrophage colony-forming units (GM-CFU) from normal donor bone marrow in the plasma of 29 patients with multiple myeloma (MM) after intensive treatment with high-dose melphalan (HDM) with or without autologous bone marrow rescue (ABMR). Although patients who received ABMR had an earlier recovery of circulating neutrophils compared with those who received HDM alone, the time at which CSA reached a maximum was similar in both groups (10 to 11 days) after therapy. The decline in CSA correlated with the recovery of the neutrophil count. In plasma from patients who received recombinant human granulocyte colony-stimulating factor (rhG-CSF), in addition to an autograft, CSA reached a maximum earlier (7 days). Furthermore, neutrophil recovery was earlier in these patients. Platelet recovery was not increased by rhG-CSF. The time at which CSA was maximum in four patients who were undergoing intensive therapy for the second time occurred 9 days after treatment with HDM. Although the period without neutrophils was longer in three (of four) patients who survived long term, one patient who received rhG-CSF had a shorter period of neutropenia than the two who had not had the cytokine. G-CSF was detected in plasma from seven of seven patients but not at all times after treatment. In plasma samples that contained G-CSF, colony numbers were increased by recombinant interleukin-4 (rIL-4) in vitro. Neither IL-3 nor GM-CSF was detected in plasma; however, antibody to GM-CSF reduced CSA in all samples after intensive therapy. The data suggest that CSA is a consistent physiologic response to intensive therapy, even in previously treated patients, but that hematologic recovery is dependent on the availability of viable progenitor cells.
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PMID:G-CSF is a major component of colony-stimulating activity (CSA) in the plasma of patients with multiple myeloma after treatment with high-dose melphalan (HDM). 753 16

Recombinant human granulocyte colony stimulating factor (rHuG-CSF) has an accepted use in reducing the severe neutropenia and associated complications in patients who undergo chemotherapy or bone marrow transplantation (BMT). It is valuable in mobilising peripheral blood progenitor cells (PBPCs) for stem cell rescue after myeloablative chemotherapy as an alternative to BMT. rHuG-CSF also allows chemotherapy dose/schedule optimisation and intensification, although a clear survival advantage has yet to be demonstrated. Recommendations for the focus and methodology of future studies with rHuG-CSF have been made, incorporating the endpoints of survival, quality of life and cost/benefit. Future studies need to address the questions of optimal dosing level and duration, cytokine combinations, the factors influencing patient survival, and the most cost-effective use of therapy. rHuG-CSF has potential for extended use in cancer therapy and in a variety of non-malignant indications.
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PMID:Future strategy for cancer treatment using recombinant human granulocyte colony stimulating factor. 753 72

The ifosfamide/carboplatin/etoposide (ICE) combination represents an active chemotherapy regimen across a wide variety of disease types. The most common limiting toxicity for all three of these agents individually and in combination is myelosuppression. Thus, this regimen represents an ideal model to evaluate the role of hematopoietic growth factor support in amelioration of hematologic toxicity, maintenance of dose intensity, and dose escalation. While chemotherapy strategies using colony-stimulating factors have abrogated neutropenia, cumulative thrombocytopenia is common with many chemotherapy regimens, including ICE chemotherapy. In preclinical and phase II trials, monotherapy with recombinant human interleukin-6 (IL-6) has demonstrated substantial thrombopoietic activity, but with little enhancement of neutrophil recovery. Thus, this study was designed to evaluate combination cytokine therapy with both recombinant IL-6 and granulocyte colony-stimulating factor (G-CSF) after ICE chemotherapy. Previously untreated patients with inoperable non-small cell lung cancer are eligible. Treatment includes two monthly cycles of ifosfamide 2,000 mg/m2 with mesna 1,600 mg/m2 intravenously on days 1, 2, and 3, carboplatin 350 mg/m2 intravenously on day 1 only, and etoposide 75 mg/m2 intravenously on days 1, 2, and 3. All patients then receive G-CSF at a dose of 5 micrograms/kg/d subcutaneously beginning on day 4 until a postnadir absolute neutrophil count of more than 10 x 10(9)/L. Cohorts of patients (n = 15) are randomized to receive 0, 1, 2.5, or 5 micrograms/kg/d of IL-6 subcutaneously on days 4 to 13 in successive cohorts. This study has now reached its target accrual in all cohorts. The final data analysis is in progress. It is hoped that this trial will define the safety and tolerability of the simultaneous administration of IL-6 and G-CSF following ICE chemotherapy in patients with non-small cell lung cancer. In addition, this trial should determine the biologic activity and hematopoietic recovery observed during the simultaneous administration of these two cytokines in this setting.
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PMID:The role of hematopoietic growth factors in support of ifosfamide/carboplatin/etoposide chemotherapy. 754 16

Cycling intensive chemotherapy currently used to treat pediatric solid tumors induces severe neutropenia. Prolonged neutropenia is a major risk factor for septic death which occurs in up to 5% of febrile or septic neutropenic episodes. We treated 18 neutropenic pediatric cancer patients (eight females, 10 males) during 30 febrile and/or septic episodes with single daily doses of E. coli-derived non-glycosylated recombinant human granulocyte-macrophage colony-stimulating factor (rh-GM-CSF, 5 micrograms per kg of body weight). The cytokine was administered for a median period of 6.5 days (2-12 days). Analysis of circulating hematopoietic progenitor cells was performed at day 1 (baseline) and day 5 of rh-GM-CSF treatment and included flow cytometric CD34 analysis as well as the methylcellulose-based clonogenic assay. Prompt hematopoietic recovery and resolution of septic problems was observed in all children. The counts of leukocytes (WBC), absolute neutrophils (ANC), and platelets (PLT) rose above 1,000/microL, 1,000/microL, and 50,000/microL within 4 days (0-9), 5.5 days (2-13), and 6 days (0-14), respectively. Faster granulocyte recovery and improved recruitment of circulating hemopoietic precursors was observed in children with detectable amounts (> 0.1%) of CD34-positive mononuclear cells prior to rh-GM-CSF treatment. We conclude that, to some extent, the efficacy of rh-GM-CSF treatment in neutropenic cancer patients is influenced by the hematopoietic recovery status on the progenitor cell level. Although they respond more slowly to the treatment, patients without circulating CD34-positive progenitor cells may gain most from growth factor therapy. Rh-GM-CSF can be safely administered to febrile and/or septic neutropenic children treated for cancer.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor in septic neutropenic pediatric cancer patients: detection of circulating hematopoietic precursor cells correlates with rapid granulocyte recovery. 754 80

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation. 761 44

B-cell chronic lymphocytic leukaemia (B-CLL) is often associated with peripheral blood cytopenias resulting, in most cases, from bone marrow infiltration, hypersplenism, or circulating autoantibodies. The present study was undertaken to investigate the possible involvement of a cell-mediated suppression of granulopoiesis in these patients. We studied two groups of patients, 8 neutropenic and 26 non-neutropenic, defined by the arbitrarily taken cutoff count of 2000 neutrophils/microliters. We found that neutropenic patients had higher numbers of peripheral blood CD3+, CD8+ and CD57+ cells, and higher numbers of activated CD8+/HLA-DR+ cells than the non-neutropenic ones. A negative correlation between CD8+ cells and circulating neutrophils, and a suggested negative correlation between CD8+/HLA-DR+ cells and circulating neutrophils were noted in the patients studied. Furthermore, we investigated the capacity of immunomagnetically isolated CD8+ cells to inhibit in vitro colony formation by normal granulocyte/macrophage colony-forming units (CFU-GM) and we found that inhibition was more pronounced when CD8+ cells, added in the culture, were derived from neutropenic than from non-neutropenic patients. The degree of colony inhibition correlated with the number of circulating neutrophils and the numbers of CD8+ and CD8+/HLA-DR+ cells in the patients studied. Since tumour necrosis factor-alpha (TNF-alpha) has been reported to be involved in myelosuppression, we also investigated the capacity of isolated CD8+ cells to release this cytokine into the culture supernatant fluids, and we found that comparable amounts of TNF-alpha were produced after stimulation in both neutropenic and non-neutropenic patients. Elevated serum TNF-alpha concentrations were noted only in a number of neutropenic and non-neutropenic patients. All these data taken together provide strong evidence that a T-cell subpopulation of activated CD8+/HLA-DR+ cells may be involved in the pathogenesis of neutropenia, at least in a subset of B-CLL patients, suppressing myelopoiesis by a TNF-alpha-unrelated mechanism. Efforts to isolate this cell subpopulation by flow cytometry for further analysis and a better understanding of its effect on myelopoiesis in patients with B-CLL are in progress in our laboratory.
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PMID:Evidence for involvement of activated CD8+/HLA-DR+ cells in the pathogenesis of neutropenia in patients with B-cell chronic lymphocytic leukaemia. 761 48

Studies were carried out to establish the temporal effects of abbreviated administrations of IL-1 and IL-1 plus M-CSF as rescue agents on multipotential and short-term repopulating hematopoietic stem cell (HSC) subpopulations in murine marrow treated with a myelosuppressive dose of 150 mg/kg 5-FU. The recovery kinetics for high-proliferative-potential colony-forming cells (HPP-CFC), CFU-S8 and -S12, and both CFU-M and CFU-G compartments were monitored over a 14-day interval in 5-FU-treated bone marrow (FUBM) following daily cytokine injections over a 4-day interval. Both IL-1 and the coadministration of IL-1 and M-CSF rapidly enhanced the recovery of the HPP-CFC in FUBM to supranormal levels and maintained these levels for extended intervals. Moreover, since M-CSF was unable to influence the recovery of the HSC subpopulations in FUBM by itself, the results of the two cytokines amounted to a synergistic effect on the recovery of the HPP-CFC in FUBM and a reduction of severe neutropenia in the myelosuppressed animal. Scheduling studies demonstrated that these synergistic effects were restricted to those schedules in which M-CSF was coadministered with IL-1 during the first 2 days of cytokine rescue. Finally, the recovery curves generated for the HSC and CFU-M subpopulations in response to IL-1 (with or without M-CSF) also suggest that these cytokines may conceivably alter the normal balance between proliferation and differentiation within CFU-S8 and -S12 during the accelerated recovery of hematopoiesis in FUBM.
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PMID:Temporal recovery of short-term repopulating HSC subpopulations in marrow following schedule-dependent administrations of IL-1 alpha and M-CSF. 763 81

Cyclic neutropenia is a rare hematological disorder characterized by periodical severe granulocytopenia. A stem cell defect and/or immunological abnormalities are considered to play a role in this disease. Here we describe the case of an adult woman who was diagnosed as having both cyclic neutropenia and severe hypogammaglobulinemia. Her clinical history revealed that one or both abnormalities had been present since childhood. Normal in vitro growth of the patient's bone marrow CFU-GM was observed, while immunological analysis revealed the presence of a persistent excess of activated (HLA-DR+) CD8+ T lymphocytes in both bone marrow and peripheral blood. These T lymphocytes have been shown to be polyclonal by DNA analysis, and their role in determining the clinical picture of our patient remain uncertain since they could not be shown to produce inhibitors of in vitro CFU-GM growth. Intermittent low doses of human recombinant G-CSF were able to improve neutropenia and completely prevent infectious symptoms, thus confirming the efficacy of this cytokine in cyclic neutropenia patients.
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PMID:Cyclic neutropenia and severe hypogammaglobulinemia in a patient with excess of CD8-positive T lymphocytes: response to G-CSF therapy. 768 13

The grade of neutropenia after chemotherapy seems to be correlated to the bone marrow cellularity as judged by biopsies. Prolonged blood neutropenia after sequential chemotherapy reduces dose intensity and increases the risk of severe infections. A predictive non-invasive test for marrow cellularity is needed in the attempt to predict chemotherapy-induced blood neutropenia. Thirty-one patients with haematological disorders were studied with measurements of blood absolute neutrophil counts (ANC) 24 h after a single subcutaneous injection of recombinant human granulocyte colony stimulating factor (rhG-CSF) or granulocyte-macrophage CSF (rhGM-CSF). Before cytokine administration all patients had bone marrow biopsies performed. The median increase in blood ANC 24 h after cytokine administration was 15.9 x 10(9)/l (range 3.7-34.2) in 18 patients with normo- or hypercellular marrows and only 0.4 x 10(9)/l (range 0.0-11.2) in 13 patients with hypocellular marrows (P < 0.00001). An increase in ANC or more than 5 x 10(9)/l was predictive for normo- or hypercellular bone marrows with a sensitivity and specificity of 94% and 84%, respectively. A subsequent pilot study in selected patients with prolonged neutropenia was performed. The ANC increment in 12 cases before chemotherapy correlated to the grade of neutropenia and may predict the risk of febrile neutropenia. It is suggested that blood responsiveness to myeloid growth factors correlates with marrow cellularity and may identify outpatients with risk for severe neutropenia after cyclic chemotherapy.
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PMID:Blood neutrophil increment after a single injection of rhG-CSF or rhGM-CSF correlates with marrow cellularity and may predict the grade of neutropenia after chemotherapy. 751 73


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