Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colony-stimulating factors (CSFs) have entered the clinical arena. Several investigators have explored, in first clinical phase I studies, different routes of administration to define the optimum biological dose, maximum tolerated dose, toxicity, and pharmacokinetics of these reagents. It has been demonstrated that recombinant human (rh) granulocyte-macrophage CSF (GM-CSF) and granulocyte CSF (G-CSF) can be safely administered over a broad dose range to increase number of circulating granulocytes in man. More recently, GM-CSF and G-CSF have been involved in phase Ib/II studies to assess the granulopoietic responses of patients with granulocytopenia due to various underlying disease states including myelodysplastic syndrome, aplastic anemia, cyclic neutropenia, Kostmann's syndrome, and the acquired immuno-deficiency syndrome. Both factors were also investigated with respect to their potential to prevent chemotherapy induced granulocytopenia or to accelerate recovery from that condition. The short-term effects of rh GM-CSF after autologous bone marrow transplantation for various solid tumors and lymphoid malignancies were assessed as well. In this article we will focus on recent results that have emerged from in vivo studies utilizing CSFs.
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PMID:Polypeptides controlling hematopoietic blood cell development and activation. II. Clinical results. 265 Jul 57

Congenital neutropenias include a heterogenous group of diseases characterized by a decrease in circulating neutrophils. In phase I/II/III studies in patients with severe congenital and cyclic neutropenia, treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) resulted in a rise in the absolute neutrophil counts (ANC) and a reduction in infections. We report the effects of long-term safety of subcutaneous r-metHuG-CSF administration in 54 patients (congenital n = 44. cyclic n = 10) treated for 4-6 years. A sustained ANC response was seen in 40/44 severe congenital neutropenia patients and 10/10 cyclic neutropenia patients. Two patients required an increase of > 25% in dose to maintain a clinical response; one patient became refractory to therapy. A significant decrease in the incidence of severe infections and the need for intravenous antibiotics was noted. Significant adverse events noted which may or may not be related to therapy included: osteopenia (n = 15), splenomegaly (n = 12), hypersplenism (n = 1), vasculitis (n = 2), glomerulonephritis (n = 1), BM fibrosis (n = 2), MDS/leukaemia (n = 3), and transient inverted chromosome 5q with excess blasts (n = 1). R-metHuG-CSF has been well tolerated in the majority of patients and resulted in a long-term improvement in their clinical status.
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PMID:Long-term safety of treatment with recombinant human granulocyte colony-stimulating factor (r-metHuG-CSF) in patients with severe congenital neutropenias. 1093 Oct 6

Myelodysplasia and acute myeloid leukaemia (MDS/AML) developed in three cases of severe aplastic anaemia (SAA) and one case of congenital neutropenia (CN, Kostmann's disease) who received recombinant human granulocyte colony-stimulating factor (G-CSF) are reported. In these four MDS/AML cases, age at diagnosis of SAA/CN was 0-13 years, the cumulative dose of G-CSF was 98 micrograms/kg to 10 mg/kg over 1-57 months, and the interval from initiation of G-CSF to MDS/AML was 25, 23, 31 and 57 months, respectively. These results suggest a link between SAA/CN and MDS/AML in relation to G-CSF administration; however, large studies are necessary to determine if such a risk is significant in patients with SAA/CN who are treated with G-CSF.
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PMID:Myelodysplasia and acute myeloid leukaemia in cases of aplastic anaemia and congenital neutropenia following G-CSF administration. 753 Apr 77

Monosomy 7 (Mo7) and leukaemia predisposition are associated with Kostmann's disease (KD). The recent introduction of long-term recombinant HuG-CSF treatment in patients with KD, whilst showing significant reductions in infectious complications and improved quality of life, might also be associated with an increased risk of developing karyotypic abnormalities, myelodysplasia (MDS) and acute myeloid leukaemia (AML). We describe a case of an identical twin with probable autosomal dominant KD who developed anaemia, Mo7/MDS and AML at 18, 30 and 50 months respectively from starting r-metHuG-CSF (filgrastim) treatment. Further patient analyses are required to establish the natural history of KD and to determine what role, if any, filgrastim plays in altering the pathobiology of this disorder.
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PMID:Kostmann's disease, recombinant HuG-CSF, monosomy 7 and MDS/AML. 757 23

The hematopoietic growth factors, granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been cloned, produced in bacteria and yeast, and approved for clinical use in the treatment of neutropenia. Both factors stimulate the proliferation and maturation of neutrophil progenitors and enhance the effector functions of mature cells by interaction with specific receptors on the cell surface. Serum levels of G-CSF correlate inversely with the neutrophil count, suggesting that G-CSF may be the normal homeostatic regulator of the neutrophil count, while GM-CSF is generally undetectable in the serum and appears under normal physiologic conditions to act locally at inflammatory sites. Phase I and II clinical trials with these factors demonstrated minimal toxicity for G-CSF and mild to moderate dose-dependent toxicity for GM-CSF. Recent clinical trials, including double-blind, randomized studies, support a role for these growth factors in the treatment of chronic neutropenias, such as Kostmann's syndrome, acquired immune deficiency syndrome (AIDS), aplastic anemia, and myelodysplasia, as well as in acute neutropenias, such as cyclic neutropenia, chemotherapy-induced neutropenia, and bone marrow transplantation.
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PMID:Southwestern Internal Medicine Conference: clinical use of hematopoietic growth factors. 768 52

Severe congenital neutropenia is a disorder of myelopoiesis characterized by severe neutropenia secondary to either a maturational arrest of myelopoiesis at the level of promyelocytes (Kostmann-Syndrome; SCN) or regular cyclic fluctuations in the number of blood neutrophils with a median ANC below 500/microliter (cyclic neutropenia). We have treated 32 patients with SCN and 4 patients with cyclic neutropenia. Thirty of 32 patients with SCN and all 4 patients with SCN responded to r-met HuG-CSF treatment with an increase of the median ANC to above 1000/microliter. The doses needed to achieve and maintain the response varied between 0.8 and 120 micrograms/kg/d. Long-term treatment did not exhaust the myelopoiesis: The mean ANC remained stable up to 5 years of treatment. The increase in ANC was associated with dramatic clinical responses: significant reduction of severe bacterial infections, reduction of intravenous antibiotic treatment episodes, and reduction of hospitalizations. No severe bacterial infections occurred in any of the r-met HuG-CSF responders during long-term treatment. Severe adverse event, most likely associated with the underlying disease, included the development of MDS/Leukemia in two patients, and osteopenia/osteoporosis in 12 patients. These results demonstrate the beneficial effects of r-met HuG-CSF treatment in severe congenital neutropenia patients.
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PMID:[Long-term treatment with recombinant human granulocyte colony stimulating factor in patients with severe congenital neutropenia]. 769 Aug 65

Severe chronic neutropenia (SCN) is a rare but important cause of recurrent fevers, oropharyngeal ulcerations and severe infections. In three forms of SCN, i.e., congenital neutropenia (Kostmann's syndrome and related syndromes), idiopathic neutropenia (both childhood and adult), and cyclic neutropenia, it is now established that long-term treatment with the hematopoietic growth factor, recombinant human granulocyte colony stimulating factor (rHuG-CSF or Filgrastim), can elevate blood neutrophil counts to the normal range in most patients, with a concomitant reduction in infection-related events including fever, oral ulcerations, antibiotic use and symptoms of inflammation. Treatment with this growth factor causes an increase in the number and maturity of marrow cells of the neutrophilic series; other cell lines are largely unaffected. Marrow stimulation and expansion are reflected by the occurrence of bone pain early in therapy, as well as some increase in spleen size in most cases. Adverse effects of therapy are infrequent in both children and adults, and long-term treatment with daily or every-other-day s.c. injections of rHuG-CSF are well accepted. Because of the risk that some patients with chronic neutropenia may have or develop myelodysplasia and/or leukemia, careful pretreatment evaluations (blood, bone marrow and cytogenetics) and long-term observations are extremely important. An international registry for patients with SCN has been established to maintain records and further investigate these conditions.
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PMID:Hematopoietic growth factors for the treatment of severe chronic neutropenia. 778 81

Cytokines are decisive for the regulation of the immune system as well as the renewal and maturation of the haematopoietic cells. The most important groups of substances, several of which are already produced by gentechnology, are the interferons, the interleukins and the haematopoietic growth factors. The main indications for the application of alpha-(less often beta-)Interferon in children are the juvenile larynx papillomatosis, chronic hepatitis B, viral encephalitis, and also chronic myeloic leukemia, extended haemangiomas, recurrent Langerhans cell histiocytosis and nasopharynx carcinomas. gamma-Interferon is administered successfully for chronic granulomatous disease and has recorded positive effects in therapy resistant rheumatoid arthritis, in kidney cell carcinoma and in osteopetrosis. G-CSF, GM-CSF and Interleukin 3 are the most effective haematopoietic growth factors currently in use. Through G-CSF congenital agranulocytosis (Kostmann syndrome) has become a treatable disease. Other proven applications are in the reduction of aplastic phases after chemotherapy and in critical situations of primary bone marrow failure as well as myelodysplastic syndromes, for prevention of transplant rejections after bone marrow transplantation and for mobilisation of stem cells into peripheral blood before apheresis. Erythropoietin is established in the treatment of chronic renal anaemia and is currently used in the treatment of anaemia in preterm infants. Finally, Interleukin 2 is also used for adoptive immunotherapy in children with minimal residual tumors. The future will show us, whether the spectrum of indications will expand and whether a definite benefit for sick children will result from a wider application of these substances. As long as the cost/benefit ratio for certain indications is not clear, the use of these drugs should be tested in prospective studies.
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PMID:[Clinical applications of cytokines in pediatrics]. 815 1

Cytogenetic analysis of bone marrow cells revealed an abnormal clone with monosomy 7 and trisomy 21 in a 12-year-old child with Kostmann disease (KD). The patient presented with anemia, thrombocytopenia, and splenomegaly after 5 years of treatment with granulocyte colony-stimulating factor (G-CSF). The bone marrow morphology was consistent with the diagnosis of myelodysplastic syndrome (MDS). Administration of G-CSF was discontinued at this point. Bone marrow studies 2 and 5 months later showed persistence of both myelodysplasia and the abnormal clone with monosomy 7 and trisomy 21. Monosomy 7 was also confirmed by fluorescence in situ hybridization (FISH). After 2 months of follow-up, the patient presented with acute basophilic leukemia, a very rare variant of acute myeloid leukemia (AML), expressing the same bone marrow chromosome abnormalities as observed earlier. This is a rare case of KD with prolonged survival and a cytogenetically abnormal clone evolving to MDS and acute basophilic leukemia. The significance of monosomy 7 and trisomy 21 in KD treated with G-CSF is discussed.
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PMID:An abnormal clone with monosomy 7 and trisomy 21 in the bone marrow of a child with congenital agranulocytosis (Kostmann disease) treated with granulocyte colony-stimulating factor. Evolution towards myelodysplastic syndrome and acute basophilic leukemia. 853 30

Severe congenital neutropenia (SCN) is a heterogeneous disease condition with a variable family history and a propensity to progress towards myelodysplastic syndrome (MDS) and acute myeloblastic leukemia (AML). In a subgroup of patients, point mutations in the G-CSF-R gene have been found. These nonsense mutations result in the truncation of the C-terminal cytoplasmic region, a subdomain that is crucial for G-CSF induced maturation. SCN patients with mutations in the G-CSF-R gene appear to be predisposed to develop AML. Here, we recapitulate our view of how defective G-CSF-R may contribute to neutropenia and leukemogenesis.
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PMID:Severe congenital neutropenia terminating in acute myeloid leukemia: disease progression associated with mutations in the granulocyte-colony stimulating factor receptor gene. 891 14


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