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)

This review has two objects: a brief recapitulation of the biological background of erythropoietin (EPO), and a review of its clinical utilization in hematology. EPO, both in its naturally occurring and recombinant form (rH-EPO), is a single chain glycoprotein with an approximate molecular weight of 30.000 to 34.000 kD. Its heavy glycosilation is essential for its activity in vivo, since asialoEPO is readily cleared by the heptic asialoglycoprotein receptor. This impedes the recombinant molecule's synthesis in biologic cultures other than mammalian cells (Chinese hamster's ovary cells), and inevitably increases costs. If in vitro glycosilation of E. coli-derived rH-EPO could be achieved, the clinical utilization of the product would be considerably enhanced, most especially when very high doses are necessary, as discussed later. There is no antigenic diversity between natural and recombinant EPO, so that out of the enormous clinical experience only one single case of immunization has been recorded. Almost paradoxically there are however three published cases of pure red cell aplasia (PRCA) caused by immunization against autologous EPO. It is now established that in adults EPO is synthetized in renal peritubular interstitial cells, although some residual activity remains in the liver. Hypoxia results in a rapid induction of EPO expression, although the role of the oxygen sensor system is still debated. Cellular targets are notoriously erythroid progenitors and precursors (BFU-E, CFU-E, early and intermediate erythroblasts). The global erythropoietic activity resulted in various effects (proliferation, differentiation, survival), but most probably each single effect is integrated with and complementary of the others. The utilization of rH-EPO in hematologic diseases came much later than its dramatic success in renal anemia. A variety of tools useful for assessing the possible beneficial effects of rH-EPO in clinical hematology has been proposed, among which a low level of endogenous EPO is a good predictor for therapeutic success. 'Hemopathic' anemia can be subdivided into three categories: patients with normal erythropoiesis due to inadequate EPO production (anemia of prematurity), patients with depressed but nonclonal erythropoiesis (chemotherapy, lymphoid malignancies such as multiple myeloma-MM and chronic lymphatic leukemia-CCL) and patients with at least partially clonal anemia, such as paroxysmal nocturnal hemoglobinuria (PNH), hemoglobinopaties, myelodysplastic syndromes (MDS) and others. Results in the first category of patients are, as expected, prompt and satisfactory with physiologic doses. Although therapeutic strategy for MM is moving fast to curative intents, the utilization of rH-EPO is indicated for the control of anemia in conservatively-treated patients. In the third category the most important and controversial area is MDS. Significant erythropoietic results are generally obtained in about 20% of patients; however, the association with G-CSF has considerably enhanced the response rate. In the field of bone marrow transplantation there is an inadequate production of endogenous EPO in the allogeneic setting, and randomized studies have shown the benefits of rH-EPO in this situation. However, the most important results have been obtained in post-major-ABO incompatible PRCA, when the removal of the recipient's isohemagglutinins does not resolve the anemia. High and very high doses of rH-EPO (even over 500 UI/kg/day for 2-4 weeks) may resolve this occasionally quite refractory condition. Although extremely expensive, this treatment may be life-saving when an otherwise successful allogeneic transplant is at the risk of failure because of this relatively uncommon but severe immunohematologic complication.
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PMID:[Erythropoietin: biochemical characteristics, biologic effects, indications and results of use in hematology]. 948 78

This second part of the review looks at change seen in the bone marrow haemostasis and malignancies found in HIV infection. Examination of bone marrow is requested in the presence of cytopaenias, splenomegaly, lymphomas and myelodysplasia. The findings include marrow hypocellularity, myelodysplasia and poor marrow recovery. Dysmegakaryocytpoiesis is found in 88% while dyserythropoeisis in 83% of cases. Mechanisms leading to these pertubations include direct HIV effect on marrow progenitor cells, effect of drugs and other infective diseases. Altered levels and functions of growth modifies IL6 and G-CSF are also to contribute. Haemostatic disorder frequently noted is bleeding due to thrombocytopaenia. Non-Hodgkin's lymphomas with aggressive characteristics and Kaposi's sarcoma are the commonly associated malignancies. Currently IL6 is being linked with the causation of KS and NHL. While standard approaches to the management of these malignancies tend to be the practices, adjustments are usually necessary in most patients.
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PMID:Haematological changes in human immunodeficiency virus infection. Part II. 955 50

In myelodysplastic syndromes (MDS), pancytopenia leads to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. While transfusions of red blood cells and platelets are still a cornerstone of the therapy, the clinical use of recombinant hematopoietic growth factors has enlarged the range of therapeutic applications in patients with MDS. It is possible to reverse neutropenia by administration of G-CSF (granulocyte colony stimulating factor) or GM-CSF (granulocyte-monocyte colony stimulating factor). In the case of a severe infection, therapeutic administration of G-CSF together with antibiotics might be justified in otherwise neutropenic MDS patients. Since especially patients with only slight impairment of erythropoiesis and no transfusion dependency have the highest response rates but need erythropoietin (EPO) the least, pharmacoeconomic analyses are urgently needed. Controlled randomized trials will have to ascertain wether combinations of EPO with G-CSF or GM-CSF are of benefit. Clinical studies with thrombopoietin (megakaryocyte growth and differentiation factor) have to be initiated to find out whether thrombocytopenia in MDS can be reversed.
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PMID:Treatment with growth factors in myelodysplastic syndromes. 956 32

Recent advances in the molecular genetics of myelodysplastic syndromes (MDS) have shed new light on the pathogenesis of MDS allowing a better understanding of the defects of differentiation of the transformed clone and suppression of normal hematopoiesis. The clinical hematologist, however, continues to be challenged with the treatment of patients with MDS. Pancytopenia and defective function of neutrophils and platelets lead to a high risk of infectious and hemorrhagic complications. The progression to acute myeloid leukemia adds to morbidity and mortality. Supportive care including red blood cell and platelet transfusions are still the cornerstone of therapeutic management. While prophylactic administration of G-CSF or GM-CSF cannot be recommended, treatment of febrile neutropenia might benefit from administration of G-CSF in addition to antibiotics. Administration of high-dose erythropoietin will improve erythropoiesis in around 20% of the patients, mainly in those with rather preserved erythroid function and no or low transfusion need. Coadministration of erythropoietin with either G-CSF or GM-CSF could increase the response rate. Allogeneic stem cell transplantation still is the only curative treatment and prolongs survival. Intensive chemotherapy for advanced MDS is possible with an acceptably low rate of early death and a complete remission rate between 45% to 60%, while initial results of autologous transplantation are promising.
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PMID:Clinical use of hematopoietic growth factors in the myelodysplastic syndromes. 957 Jun 76

To explore the feasibility and potential advantages of PBSC in allogeneic transplantation, we grafted 24 patients (age 16-57, median 37) with different hematologic diseases (ALL = 10, AML = 5, MM = 4, NHL = 2, CML = 1, MDS = 1, AA = 1), 23 HLA-identical to their siblings and 1 partially matched. Cells were collected from donors by apheresis after G-CSF 10 to 16 mg/kg/day for 4 to 5 days, and stored at 4 degrees C until infusion. The patients were conditioned with chemotherapy regimens including busulfan and cyclophosphamide in the majority of cases and received GVHD prophylaxis with CSA-MTX in all but two. The graft consisted of PBSC alone, with a median of 143.5 (range 18.1-358.9) x 10(4)/kg CFU-GM, 9.0 (range 3.3-18.0) x 10(6)/kg CD34+ cells and 2.8 (range 1.2 to 8.6) x 10(8)/kg CD3+ and cells. An ANC >0.0.5 x 10(9)/L was recovered on (median) day 13 (range 11-17), and a platelet count >50 x 10(9)/L on (median) day 13 (range 12-55) post graft. There was no correlation between CD34+ cells or CFU-GM number in the inoculum and time to hematologic reconstitution. Acute GVHD (grade II-IV) occurred in 10 out of 22 (45%), chronic GVHD in 10 out of 18 evaluable (55%) patients. We found no relationship between occurrence of acute or chronic GVHD and number of CD3+ cells in the graft. Four patients relapsed and 7 died after transplantation. Fifteen patients are currently alive and disease-free 67 to 710 (median 286) days from the graft. Allogeneic transplantation with unmanipulated PBSC ensures a fast and stable engraftment. Acute GVHD incidence and severity seems comparable to that of bone marrow transplantation, but there may be an increase in chronic GVHD, mainly of the extensive form.
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PMID:Transplantation of unmanipulated allogeneic PBSC: preliminary report on 24 patients. 957 Jun 80

We evaluated a combination chemotherapy with cytarabine ocfosfate (SPAC), low dose etoposide and G-CSF for the treatment of high-risk MDS (RAEB, RAEBt). Seven patients with high-risk MDS were treated with a daily combination, 200 mg/day SPAC p.o., 50 mg/day etoposide p.o. and 75 micrograms/day G-CSF s.c. One patient achieved complete response, 2 achieved good response and one patient minor response. Although all of the patients developed severe marrow hypoplasia after chemotherapy, the nonhematologic adverse effects were mild enough to be tolerated. This combination chemotherapy should be useful in the clinical management of patients with high-risk MDS.
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PMID:[A combination chemotherapy with cytarabine ocfosfate, low dose etoposide, and G-CSF for the treatment of high risk MDS (RAEB, RAEBt)--a pilot study]. 959

One hundred and five consecutive primary high-risk myelodysplastic syndromes (MDS) or secondary acute myeloid leukaemia (sAML) evolving from MDS (performance status 0-3, ECOG) entered this study. Induction chemotherapy (CT) consisted of idarubicine 12 mg/m2 i.v. on days 1 and 2, etoposide 60 mg/m2/12h i.v. for 5d, Ara-C 120 mg/ m2/12h i.v. for 5d (one or two courses). Patients were randomized to receive or not G-CSF (5 microg/kg/d subcutaneously 48 h after the end of CT). 52 cases underwent CT alone and 53 CT+G-CSF. The CT+ G-CSF patients had a significantly shorter duration of neutropenia (8 nu 16d) with a lower incidence of infections and significantly better responses (CR+PR: 74% v 52%, P<0.05). 40 patients entered CR: 17 with CT and 2 3 with CT+G-CSF. Responders underwent two consolidation courses with the same CT, followed by high-dose Ara-C (2 g/m2 every 12h for 3 d). Most CRs were clonal. At present 21 responders have relapsed (median relapse-free survival 4 5 months). Eight responders received an allo-BMT, six are alive in CR 7-57 months post-transplant. Therefore allo-BMT only increases the chance of a long survival and possible cure. In conclusion, CT+G-CSF did not prolong either CR duration or survival; the growth factor support, however, increased the number of allo-transplantable cases by inducing higher remission rates and improving clinical conditions.
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PMID:Randomized clinical study comparing aggressive chemotherapy with or without G-CSF support for high-risk myelodysplastic syndromes or secondary acute myeloid leukaemia evolving from MDS. 972 93

Since the introduction of combined immunosuppressive therapy (IST) into management of aplastic anemia (AA) in childhood response and probability of survival improved. In contrast to bone marrow transplantation (BMT), however, patients after IST are not considered cured as high rates of relapse and development of clonal disease demonstrate. From 11/93 to 9/97 114 children (65 m, 49 f; median age 9.5 y.) from 37 centers in Germany and Austria were registered in the SAA 94 study. 86 patients lacking a matched sibling donor received IST. Most of the patients suffered from very severe (VSAA: PMN < 200/microliter) or severe AA (SAA: PMN < 500/microliter). All patients were treated with combined IST consisting of ALG and Cyclosporin A (CSA). VSAA and SAA patients were additionally treated with G-CSF. Therapy response was evaluated at day 112, after 6, 12 and 18 months. 8/86 patients died, the probability of survival being 87% after 4 years. At d 112 61% of evaluable patients became independent of transfusions (IST response: CR + PR), 13% with normal blood counts (CR). After 6 months 33% showed CR. At 12 and 18 months response improved to 74% resp. 80%, 39% resp. 55% CR. The best response was achieved in the subgroup of VSAA with 90% (PR + CR) and 65% CR after 18 months. 4 patients developed AML 3-19 months after the beginning of IST. In 2/4 pts. an aberrant clone (-7; 5q-) could be detected retrospectively in BM at diagnosis of AA. 3 nonresponders developed chromosomal aberrations (+19; -7, +12; +8) after 4, 12 and 16 months without morphological signs of AML or MDS. Overall 11 relapses occurred at a median time of 12 months (range 5-27 months) after the beginning of IST. 2 of them relapsed under CSA therapy, 2 under tapering of CSA and 7 after cessation of CSA. 7 patients responded again to CSA monotherapy. Overall response rate is 77% with a probability of event free survival (EFS) of 54% after 4 years regarding all complications mentioned as events.
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PMID:Relapse and clonal disease in children with aplastic anemia (AA) after immunosuppressive therapy (IST): the SAA 94 experience. German/Austrian Pediatric Aplastic Anemia Working Group. 974 49

Supportive care in hematologic malignancies includes a wide range of topics. We have selected the following issues for a review of recently published developments: new insights into the benefits and risks of established hematopoietic growth factors (HGF), such as granulocyte- or granulocyte-macrophage colony-stimulating factor (G-CSF, GM-CSF); the emerging role of newly introduced HGFs such as keratinocyte-growth factor (KGF) and thrombopoietin; the prophylactic and therapeutic use of amifostine, a cytoprotective agent; the role of hematopoietic growth factors and the demethylating agent decitabine in myelodysplastic syndromes (MDS); infectious complications of anticancer therapy; and, recent improvements in and complications of transfusional therapy, including the renewed interest in granulocyte transfusions.
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PMID:Supportive care in hematologic malignancies. 974 34

There is an increasing incidence of the evolution of myelodysplastic syndrome (MDS) from aplastic anaemia (AA) with immunosuppressive treatment. In paediatric patients G-CSF is also reported to increase MDS evolution, but this process is not precisely understood in children or in adults. Therefore risk factors of MDS evolution in adults are evaluated here. Of 72 patients, five developed MDS. In 47 patients without cyclosporine (CyA) or antithymocyte globulin (ATG) therapy, only one developed MDS with trisomy 8, 242 months after diagnosis. But of 25 patients treated with either CyA or ATG, four developed monosomy 7 MDS within 3 years. Of these 25 patients, 18 were treated with G-CSF and the four patients (22.2%) who developed MDS were found in this group. The cumulative dose and the duration of G-CSF administration were significantly elevated in patients who developed MDS when compared with those who did not, 822.3 +/- 185.0 v 205.4 +/- 25.5 microg/kg (P<0.05) and 187.5 +/- 52.5 v 72.0 +/- 24.6 d (P<0.002), respectively. However these two values for CyA did not differ significantly. Statistically, treatment with CyA, G-CSF and combined G-CSF and CyA were significantly related to MDS evolution. The administration of G-CSF for more than a year was the most important factor (P=0.00). These results suggested that a close relationship exists between G-CSF and subsequent monosomy 7 MDS from AA in adults who receive immunosuppressive therapy. Long-term administration of G-CSF should be prohibited in order to prevent MDS evolution.
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PMID:Long-term administration of G-CSF for aplastic anaemia is closely related to the early evolution of monosomy 7 MDS in adults. 982 95


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