Correction of iron-deficient erythropoiesis in the treatment of anemia of chronic disease with recombinant human erythropoietin.

Anemia of chronic disease (ACD) is a frequent complication of chronic inflammation in rheumatoid arthritis (RA). Recombinant human erythropoietin (rHuEpo) has been shown to be effective in correcting ACD, although with a variable rate of nonresponders. The first aim of this trial was to improve the response to rHuEpo by parenteral iron supplementation in cases of iron-deficient erythropoiesis (IDE). An additional goal was the evaluation of the zinc protoporphyrin content of erythrocytes (ZnPP), the soluble transferrin receptor (sTrfR) serum concentration, and the hemoglobin (Hb) content of reticulocytes (CHr) in stimulated erythropoiesis as diagnostic and prognostic parameters. Thirty RA patients with ACD were treated with subcutaneous 150 IU rHuEpo/kg body weight twice weekly. Intravenous iron supplementation (200 mg iron sucrose once weekly) was added in cases of IDE (n=23), which was defined by the presence of two of three criteria: saturation of transferrin (TrfS) < or =15%, hypochromic erythrocytes (HypoE) > or =10%, and a serum ferritin (Fn) concentration < or =50 microg/l. All 28 completers met the treatment goal, with an increase of the median Hb concentration from 10.3 g/dl to 13.3 g/dl. Epo treatment and iron supplementation was safe and well tolerated in all patients. Monitoring of Fn, TrfS, and HypoE every other week allowed a successful correction of anemia. Retrospective analysis of the evaluable parameters (CHr, sTrfR, and ZnPP) revealed no additional benefit for predicting or monitoring IDE in this setting, although the one or other may be advantageous in other therapeutic situations.

Memorial lecture. Megakaryocytic growth factors: is there a new approach for management of thrombocytopenia in patients with malignancies?

C-mpl ligand acts primarily as a lineage-specific hematopoietic growth factor by promoting proliferation of megakaryocyte precursors and their differentiation into megakaryocytes and platelets. In addition to the ability of c-mpl ligand to support megakaryocytic development from CD34+ precursor cells, several lines of evidence also point to a stimulatory effect on hematopoietic stem cells. When recombinant thrombopoietin or pegylated megakaryocyte growth and development factor is administered to normal animals or humans, there is a dose-dependent increase in the platelet count. When administered following chemotherapy in animal models or humans, c-mpl ligands reduce the duration and sometimes the degree of thrombocytopenia. The issue of whether clinically relevant thrombocytopenia can be ameliorated has so far been more difficult to resolve. Because severe thrombocytopenia is not commonly seen with standard chemotherapy regimens, clinical studies examining c-mpl ligands for their ability to ameliorate chemotherapy-induced thrombocytopenia will focus on treatment of acute leukemias and bone marrow transplantation. The potential utility of c-mpl ligands for treatment of myelodysplastic syndromes, aplastic anemias, or in HIV infection, will have to be evaluated in the future. Possibly the greatest potential of thrombopoietic growth factors in the near future may be in transfusion medicine, to collect and to store platelets from healthy donors or in autologous settings.

[Antibiotic therapy in leukopenia]. / Antibiotikatherapie bei Leukopenie.

Intensified chemotherapy-induced long-term neutropenia is the main cause for morbidity and mortality of patients with hematologic malignancies. The successful management of neutropenia is based on hygienic procedures antimicrobial prophylaxis and therapy, and diagnostics. Until today, Co-Trimoxazole or fluoroquinolenes and oral amphotericine B are the prophylactic standard. The initial therapy of febrile neutropenia has to be started empirically before identification of causative pathogens or infectious foci. The febrile episodes should be treated with broad spectrum antibiotics (combinations or monotherapy) due to the spectrum of microorganisms or resistance situation at hospital. In case of non-response after 3-4 days the initial therapy should be modified, in addition to further antibacterial therapy the start with an antifungal drug has to be recommended. In patients with pulmonary infiltrates the early treatment with amphotericine B has been shown to be more advantageous than delayed antifungal therapy. Furthermore, the antibiotic therapy is based on proven microorganisms, susceptibility testing and infectious foci. The value of interventional treatment with G-CSF or GM-CSF is controversely discussed. An uncompromising handling of febrile neutropenia is necessary to reduce the mortality due to infections in patients with hematologic malignancies.

In vitro improvement of bone marrow-derived hematopoietic colony formation in HIV-positive patients by alpha-D-tocopherol and erythropoietin.

The majority of patients with progressive HIV infection develop a severe hematopoietic failure which is aggravated by the hematotoxic effect of azidothymidine (AZT) treatment. Since it was shown in a mouse model that alpha-D-tocopherol (vitamin E derivative) antagonizes the inhibitory influence of AZT on the growth of burst-forming units-erythrocyte (BFU-E), it was the aim of this study to investigate whether alpha-D-tocopherol and high dosages of erythropoietin (EPO) increase the hematopoietic colony-forming capacity of bone marrow cells from patients with progressive HIV disease and especially if they reverse the inhibitory effects of AZT. The data demonstrate that tocopherol (1-100 mumol/l) significantly increases the growth of BFU-E and colony-forming units granulocyte-monocyte (CFU-GM) from HIV-infected patients. This stimulatory effect is dose-dependent (maximum at 30-100 mumol/l) and only occurs when the agent is present from the beginning of the cultures. EPO (5-10 U/ml) also augments the numbers of BFU-E from HIV-infected patients. Tocopherol equally ameliorates the growth of BFU-E and CFU-GM from the HIV-positive cohort in the presence of AZT (10-100 mumol/l). For healthy controls, no such increase was observed, either with tocopherol or with higher dosages of EPO. In conclusion, both tocopherol and EPO partially reverse the myelosuppressive action of AZT in HIV-positive patients.