Neutropenia, CSFs

GM-CSF, G-CSF, M-CSF, multi-CSF cytotoxic injury bone marrow transplantation myelodysplastic syndromes AIDS neutropenia rodent and human... 

Similar results have been reported in sublethaHy and lethaHy irradiated dogs, where G-CSF reduced the severity and duration of neutropenia and the duration of thrombocytopenia (161). G-CSF increases the survival of lethaHy irradiated animals by inducing eadier recovery of neutrophils and platelets. GM-CSF also decreases the severity and duration of neutropenia in dogs exposed to 2.4 Gy (2400 rad) TBI, but does not influence monocyte or lymphocyte recovery (162), indicating its expected selective action. 

Clinically, GM-CSF or G-CSF have been used to accelerate recovery after chemotherapy and total body or extended field irradiation, situations that cause neutropenia and decreased platelets, and possibly lead to fatal septic infection or diffuse hemorrhage, respectively. G-CSF and GM-CSF reproducibly decrease the period of granulocytopenia, the number of infectious episodes, and the length of hospitalization in such patients (152), although it is not clear that dose escalation of the cytotoxic agent and increased cure rate can be rehably achieved. One aspect of the effects of G-CSF and GM-CSF is that these agents can activate mature cells to function more efficiently. This may, however, also lead to the production of cytokines, such as TNF- a, that have some toxic side effects. In general, both cytokines are reasonably well tolerated. The side effect profile of G-CSF is more favorable than that of GM-CSF. Medullary bone pain is the only common toxicity. 

Neutropenia is a drop in the number of circulating leukocytes, especially neutrophils. It can be induced by a variety of drugs. Treatment with cytotoxic antineo-plastic drags usually results in severe neutropenia, which can be treated with colony-stimulating factors (G-CSF, GM-CSF). 

The CSFs should not be used routinely for treatment of febrile neutropenia in conjunction with antimicrobial therapy.5 However, the use of CSFs in certain high-risk patients with hypotension, documented fungal infection, pneumonia, or sepsis is reasonable. A recent meta-analysis demonstrated that hospitalization and neutrophil recovery are shortened and that infection-related mortality is marginally improved.14 As with prophylactic use of these agents, cost considerations limit their use to high-risk patients. 

Leukine Sargramostim (GM-CSF) Immunex Autologous bone marrow transplantation, neutropenia resulting from chemotherapy, peripheral blood progenitor cell mobilization, and transplantation... 

NEUPOGEN Filgrastim (G-CSF) Amgen Chemotherapy-induced neutropenia, bone marrow transplantation, chronic severe neutropenia, peripheral blood progenitor cell transplant... 

Topotecan—hold for ANC < 1500 or platelets < 100,000 decrease dose by 0.25 mg/M2/d for prior episode of severe neutropenia or administer G-CSF starting on day 6... 

Neupogen (filgrastim G-CSF) Neutropenia caused by chemotherapy Bone marrow transplants Amgen Inc. 

Several CSF preparations have gained regulatory approval (Table 10.2). G-CSF and GM-CSF have proven useful in the treatment of neutropenia. All three CSF types are (or are likely to be) useful also in the treatment of infectious diseases, some forms of cancer and the management of bone marrow transplants, as they stimulate the differentiation/activation of white blood cell types most affected by such conditions. 

Neutropenia is a condition characterized by a decrease in blood neutrophil count below 1.5 X 109 cells per litre a normal blood count is (2.0-7.5) X 109 cells per litre. Its clinical symptoms include the occurrence of frequent and usually serious infections, often requiring hospitalization. Neutropenia may be caused by a number of factors (Table 10.6), at least some of which are responsive to CSF treatment. Particularly noteworthy is neutropenia triggered by administration of chemotherapeutic drugs to cancer patients. Chemotherapeutic agents (e.g. cyclophosphamide, doxorubicin and methotrexate), when administered at therapeutically effective doses, often induce the destruction of stem cells and/or compromise stem cell differentiation. 

Neulasta, Pegfilgrastim, G-CSF-PEG Amgen, Inc. Infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelo-suppressive anti-cancer drugs Jan. 2002... 

GM-CSF was approved in 1991 by the United States Food and Drag Administration (FDA) to support transplant associated neutropenia and mobilize stem cells. In Europe, it is also approved for prophylactic treatment following dose intensive chemotherapy. However, the rate of absolute neutrophil count (ANC) recovery in response to treatment with GM-CSF in patients receiving myelosuppressive chemotherapy or in the... 

Recombinant GM-CSF (produced in Escherichia coli, yeast or COS cells) has been tested for its ability to affect haematopoiesis in primates and humans. Because of its relatively short half-life in the circulation, daily administration (usually via intravenous infusion) is required. Administration results in a transient neutropenia, monocytopenia and eosinopenia within 30 min of administration, presumably because of the ability of GM-CSF to stimulate the expression of adhesins and hence increase the numbers of leukocytes adhered to the capillary endothelium in the marginated pool. Additionally, these leukocytes may accumulate in the lungs after GM-CSF administration, which may contribute to the decrease in the observed numbers... 

There has been a great deal of interest in the use of colony-stimulating factors to treat MDS. GM-CSF and G-CSF, which have been used in clinical trials, offer a potential dual benefit. Firstly, they can affect neutrophil development in the bone marrow, and so can improve the neutropenia that is associated with these disorders. Secondly, they have the potential to increase or repair the function of circulating neutrophils. Indeed, there are some reports to indicate that these CSFs can result in enhanced function of peripheral blood neutrophils in these patients. Most patients show improvements in neutrophil counts after GM-CSF or G-CSF administration. In some cases, this has been associated with a decrease in the number of infective episodes. 

Despite G-CSF support, neutropenia was frequently encountered (70% in arm A, 78% arm B). Thirty-one percent of patients failed to complete their recommended treatment due to toxicity or patient refusal. Overall response rates in both arms were comparable (35% high-dose combination vs 36% low-dose combination) and were determined to be suboptimal not warranting further investigation. 

Filgrastim is a recombinant human G-CSF (produced in E. coli), approved for chemotherapy-induced neutropenia since 1991. Although the 18.8 kDa recombinant product is not glycosylated and contains an additional N-terminal methionine residue (due to expression in E. coli), it displays biological activity indistinguishable from native G-CSF. The product is presented in freeze-dried format and contains buffer elements as well as sorbitol and Tween as excipients. 

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