Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In June 1992, we started a dose-escalated cytotoxic therapy with peripheral blood progenitor cell (PBPC) transplantation in patients with chemosensitive multiple myeloma (MM). At the time of best response to conventional treatment, 70 patients received high-dose cyclophosphamide (HD-CY) or, in case of pre-existing heart disease, dose-escalated ifosfamide/mitoxantrone followed by filgrastim (R-metHuG-CSF, 300 micrograms/day). PBPC collection was commenced when CD34+ cells were detectable using direct immunofluorescence analysis. Fifty-four out of 70 patients were successfully harvested (> or = 2.5 x 10(6) CD34+ cells/kg body weight [BW]) after the first cycle of HD chemotherapy. Conditioning therapy consisted of 140 mg/m2 melphalan plus TBI (14.4 Gy hyper-fractionated) or 200 mg/m2 melphalan in patients not eligible for TBI because of previous radiotherapy. To date, 56 patients have been transplanted. Autografts contained a median of 3.4 x 10(6) CD34+ cells/kg BW. Following reinfusion of PBPC, rapid engraftment was achieved in 54 out of 56 patients with a median of 14 days (range 9-23) to reach 0.5 x 10(9)/l neutrophils and 10 days (range 5-22) for an unsubstituted platelet count of > 20 x 10(9)/l. One patient died of transplantation-related complications. Sequential HD treatment improved the remission status (European Bone Marrow Transplantation criteria) in 19 out of 46 patients (9 patients too early). Of note, in 11 patients the immunofixation became negative and a polyclonal immunoglobulin reconstitution was achieved. Our protocol provides an effective treatment strategy for patients with advanced MM combined with low treatment-related toxicity.
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PMID:Sequential high-dose treatment with peripheral blood progenitor cell transplantation in patients with multiple myeloma. 874 87

Fifteen consecutive patients with multiple myeloma (MM) scheduled for peripheral blood progenitor cell (PBPC) transplantation, were randomly selected to receive cyclophosphamide (CY) (4 g/m2) alone (group I) or associated with recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) (5 micrograms/kg/day) (group II). The mean time of neutropenia after CY administration was 9.8 +/- 4.3 days in group I and 6.4 +/- 1.2 days in group II (P = 0.0228). One hundred and eight aphereses were performed (7.1 +/- 1.8 aphereses per patient in group I and 6.4 +/- 2.8 aphereses per patient in group II). rhGM-CSF administration after CY allowed a higher collection of CD34+ cells in apheresis products (1.42 +/- 1.68 x 10(6) CD34+ cells/kg) in comparison to without factor administration (0.47 +/- 0.52 x 10(6) CD34+ cells/kg) (P = 0.0165). The mean number of cells infused per patient was 6.56 +/- 4.02 x 10(8) MNC/kg and 7.64 +/- 3.00 x 10(4) CFU-GM/kg in group I and 6.25 +/- 4.03 x 10(8) MNC/kg and 8.16 +/- 9.73 x 10(4) CFU-GM/kg in group II. The mean time to recover 0.5 x 10(9) granulocytes/I, 20 and 50 x 10(9) platelets/I in peripheral blood (PB) was 17.2 +/- 7.4, 13.4 +/- 3.7 and 16.5 +/- 6.9 days respectively, in group I and 13.3 +/- 1.7, 11.6 +/- 1.6 and 15 +/- 6.3 days, in group II. rhGM-CSF administration after CY treatment for PBPC mobilization in MM patients reduces the neutropenic period after CY and enhances apheresis CD34+ cell collection.
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PMID:Mobilization of peripheral blood progenitor cells by cyclophosphamide and rhGM-CSF in multiple myeloma. 883 88

It has been reported that stroma-dependent cultures support proliferation of hematopoietic stem cells (HSC). In order to investigate the effect of soluble stromal factors, we developed short-term serum-low liquid cultures in which the effect of stroma-conditioned media (SCM) from the murine FBMD-1, and human L87/4 and L88/5 cell lines was studied on the maintenance and expansion of various human HSC subsets in CD34-positive selected mobilized peripheral blood stem cells (PBSC) from autologous transplants of lymphoma and multiple myeloma patients. The human cobblestone area forming cell (CAFC) assay was employed to determine the frequencies of both the CAFC weeks 2 to 4 as tentative indicators of progenitor and transiently repopulating HSC, and the more primitive CAFC weeks 6 to 8 as indicators of long-term repopulating HSC. In 7-day liquid cultures containing interleukin-3 (IL-3), stem cell factor (SCF) and IL-6, we recovered 3.0-fold more colony-forming cells (CFC) and 1.7- to 1.9-fold more CAFC weeks 2 and 4. The absolute number of primitive CAFC weeks 6 and 8 were only maintained (1.1- to 1.4-fold) in these liquid cultures. This modest expansion was significantly improved by the addition of SCM from the FBMD-1, L87/4 or L88/5 cell lines. Output CFC numbers were 6.8-, 5.8- and 9.9-fold higher, respectively, than the input values, while absolute CAFC week 2 to 4 numbers were 4.5-, 10.2- and 10.2-fold expanded, respectively. The addition of SCM also improved expansion of the more primitive CAFC week 6 to 8 stem cell subsets by 2.2-, 4.5- and 4.9-fold, respectively. The addition of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), IL-1beta, IL-11 or macrophage inflammatory protein-1alpha to cultures containing IL-3, SCF and IL-6 could not explain the SCM effect and in all these combinations SCM addition further increased the recovery of HSC subsets. Similarly, addition of anti-cytokine antibodies (ie alpha-G-CSF, alpha-GM-CSF, alpha-IL-11, alpha-leukemia inhibitory factor) to liquid cultures containing IL-3, SCF, IL-6 and SCM could not neutralize the SCM effect. These data indicate that SCM significantly enhances expansion of primitive HSC and progenitor cells from CD34-selected PBSC in 7-day cultures and in synergistic combination with multiple cytokines at optimal concentrations. As a result, SCM is a useful component of short-term liquid culture procedures for clinical expansion or manipulation of primitive HSC.
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PMID:Stroma-conditioned media improve expansion of human primitive hematopoietic stem cells and progenitor cells. 900 30

Increased numbers of eosinophilic granulocytes that exhibit an activated phenotype are found in bronchial tissue and bronchial alveolar lavage fluid of patients with allergic asthma. Little is known about the processes that lead to activation of eosinophils in vivo, but Igs might be important stimulants. In the present study we investigated the capacity of human eosinophils to interact with beads coated with human serum IgG or IgA. Binding of IgG/IgA-coated beads to eosinophils from normal donors appeared to be dependent on priming with Th2-derived cytokines. Priming with granulocyte-macrophage CSF, IL-4, or IL-5 is required for eosinophils to form rosettes with IgA-beads. IL-4 priming resulted in a fast and transient effect on binding of IgA-beads, whereas the effect of IL-5 priming was slower and longer lasting. The expression of Fc alphaR (CD89) was low compared with that on neutrophils, and experiments with the blocking mAb My43 (CD89) showed no inhibition of rosette formation between eosinophils and IgA-coated beads. However, polymeric myeloma IgA effectively inhibited the rosette formation of IgA-coated beads to eosinophils. Binding of IgG-beads could only be primed with granulocyte-macrophage CSF and IL-5, not with IL-4. These data are concurrent with the hypothesis that Th2-derived cytokines spatially produced at the side of an allergic inflammatory response can direct eosinophils to a rather restricted primed phenotype by IL-4 or to a more generalized primed phenotype by IL-5.
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PMID:Differential effects of the T helper cell type 2-derived cytokines IL-4 and IL-5 on ligand binding to IgG and IgA receptors expressed by human eosinophils. 923 44

Sera were obtained from two groups of patients. Group A included 7 patients with low-grade non-Hodgkin's lymphoma treated with three or more cycles of standard-dose chemotherapy and recombinant human granulocyte-colony stimulating factor (rhG-CSF). The cytokine was administered to half the patients after the first chemotherapy cycle and to the other half after the second according to a randomized design and then to all patients from the third chemotherapy cycle on, until documented hemopoietic reconstitution. Group B included 3 patients with high-grade non-Hodgkin's lymphoma, 1 patient with resistant Hodgkin's disease, and 1 patient with multiple myeloma who received high-dose chemotherapy and rhG-CSF. Anti-G-CSF antibodies were detected in the sera of 4 patients. Both immunoglobulin IgM and IgG antibodies were detected at low levels in pretreatment sera from one group A patient. IgG antibody titers increased markedly during the first and second periods of G-CSF administration. IgG class antibodies developed in 3 groups B patients during the first course of rhG-CSF administration. Circulating anti-G-CSF antibodies did not seem to affect hematological recovery. Low levels of anti-G-CSF antibodies were also detected in sera (15/135) from different healthy adults and in sera (5/40) from umbilical cord blood. Saturable antibody binding and competition enzyme-linked immunosorbent assay (ELISA) and immunoblotting confirmed antibody specificity.
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PMID:Naturally occurring and therapy-induced antibodies to human granulocyte colony-stimulating factor (G-CSF) in human serum. 936 26

We report on the RmetHuG-CSF (filgrastim)-related mobilization efficiency in 120 patients with multiple myeloma who received cytotoxic chemotherapy. Three schedules of G-CSF administration starting 24h after the end of chemotherapy were used: (1) a standard dose of 300 microg/d until the completion of PBSC collection; (2) dose escalation from 300 to 600-1200 microg/d during marrow recovery; (3) 600 or 1200 microg/d starting 24 h after cytotoxic chemotherapy. As a result, the individual dose per kg bodyweight varied between 2.83 and 23.08 microg. No relationship was found between the dose of G-CSF administered and the peak level of circulating CD34+ cells or the CD34+ cell counts recorded over the entire collection period.
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PMID:The dose of granulocyte colony-stimulating factor administered following cytotoxic chemotherapy is not related to the rebound level of circulating CD34+ haemopoietic progenitor cells during marrow recovery. 963 5

Discussion of the total costs and cost-effectiveness ratios of patients receiving high-dose chemotherapy (HDC) and peripheral blood stem cell support (PBSCS) is controversial. In Germany, no reliable data are available, whereas in other countries this issue has been extensively studied. We performed a pharmacoeconomic evaluation on all patients (n = 37) treated with HDC and PBSCS at our institution between July 1994 and June 1997. Patients suffered from high-risk or poor-prognosis breast cancer (n = 24), Hodgkin's disease (n = 3), high-grade non-Hodgkin's lymphoma (n = 4), multiple myeloma (n = 2), small-cell cervical cancer (n = 1), malignant hystiocytosis (n = 1) and testicular cancer (n = 2). For pharmacoeconomic evaluation, the period from initiation of induction chemotherapy (IC) until reconstitution after the last course of HDC and PBSCS was considered. A total of 18 patients received IC/HDC/PBSCS for locally advanced or systemic disease, and 19 patients received adjuvant or consolidation IC/HDC/PBSCS. Treatment protocols were heterogeneous. Patients were treated with two to five courses (median two) respectively of IC and sequential mono-HDC (n = 26), tandem-HDC (n = 10) or triple-HDC (n = 1). All patients received granulocyte/macrophage-colony-stimulating factor (G-CSF) for stem cell mobilisation and for amelioration of neutropenia after HDC. The relative costs (based on supplier prices) for the total amount of drugs prescribed during the in-patient period was 29.8% for G-CSF, 35.8% for blood products 18.5% for chemotherapy, 2.4% for antiemetics, 5.9% for antimicrobial drugs and 7.6% for other drugs. Contrary to expectations, antimicrobial drugs had only a minor pharmacoeconomic impact during IC/HDC/PBSCS in patients with high-risk or poor-prognosis malignancies, indicating that prolonged septic complications were uncommon in our institution. We conclude that pharmacoeconomic evaluations in IC/ HDC/PBSCS might be integrated into the effort to ensure quality control and monitoring.
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PMID:Pharmacoeconomic evaluation of high-dose chemotherapy and peripheral blood stem cell support in high-risk or poor-prognosis malignancies. 964 62

It has been shown that granulocyte/macrophage colony stimulating factor (GM-CSF) is able to support myeloma cell propagation in cooperation with interleukin (IL)-6, the major growth factor for malignant plasma cells, although the biological mechanisms involved remain unknown. Therefore we investigated (i) the expression levels of the GM-CSF receptor (GM-CSFR) constituents in three malignant plasma cell lines and in native malignant plasma cells, (ii) the ability of the receptor to mediate common signalling pathways regulating proliferation and cell survival in malignant plasma cell lines, and (iii) the effects of GM-CSF on tumour cell biology. The GM-CSFRalpha subunit was detected in the malignant plasma cell lines RPMI-8226, MC/CAR, IM-9 as well as 6/6 native myeloma cell samples derived from the bone marrow of patients with overt disease. Furthermore, GM-CSFR expression was also detected in the CD19+ fraction from 2/3 bone marrow samples and 5/8 peripheral blood samples derived from patients with malignant plasma cell disorders, but not in the CD19+ fraction of peripheral blood from healthy donors. The expressed cytokine receptor alpha-subunit was able to constitute a functional signalling complex with the ubiquitously expressed GM-CSFRbeta subunit, as demonstrated by the fact that GM-CSF induced the p21-ras/mitogen-activated protein kinase (MAPK) signalling cascade in malignant plasma cell lines. Since this signalling cascade plays an essential role in the mediation of both proliferation and cell survival, we investigated the impact of GM-CSF on these two events. Application of GM-CSF led to an increase of DNA-synthesis in MC/CAR, IM-9 and RPMI-8226 cells. Furthermore, it increased longevity of these malignant plasma cell lines by reducing the rates of spontaneous apoptosis. We conclude that (i) the functional GM-CSFR is commonly expressed on malignant plasma cells and that (ii) GM-CSF promotes the clonal expansion of myeloma cells by inhibiting spontaneous apoptosis and promoting DNA synthesis.
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PMID:Functional granulocyte/macrophage colony stimulating factor receptor is constitutively expressed on neoplastic plasma cells and mediates tumour cell longevity. 973 60

Engraftment in relation to infused CD34+ cell number was retrospectively analysed in 66 patients with hematological diseases: non-Hodgkin's lymphoma (n = 33), multiple myeloma (n = 21), acute myelogenous leukemia (n = 7), Hodgkin's disease (n = 4) and myelodysplastic syndrome (n = 1). Progenitor cells were mobilized with rhG-CSF, alone or in association with chemotherapy. The cells were harvested by leukapheresis until at least 2 x 10(6) CD34+/kg body weight were obtained. A total of 194 leukaphereses were performed (median = 3 per patient, range 1-9). A median of 3.40 x 10(8) nucleated cells/kg (range 0.31-27.59) and a median of 7.15 x 10(6) CD34+ cell/kg (range 1.31-115.70) were transplanted. Regardless of transfusional support or patient diagnosis, engraftment was rapid in patients who had received > or = 5 x 10(6) CD34+ cell/kg. In this case, absolute neutrophil blood count > or = 0.5 x 10(9)/l was obtained on day 12 post graft (range 7-19) and platelet count > or = 20 x 10(9)/l was also reached after the same median time interval (range 8-121). From the present results, a minimal threshold of 5 x 10(6) CD34+ cell/kg appears to be suitable for providing rapid and complete hematopoieitc reconstitution in patients exposed to high doses of chemotherapy with or without total body irradiation. Furthermore, administration of rhG-CSF during post-graft period significantly decreased the neutrophil time recovery (P = 0.002) but not that of platelets (P > 0.05).
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PMID:[Hematopoietic recovery as a function of the number of autografted CD34+ cells: a retrospective study of 66 patients with malignant hematologic diseases]. 1054 8

A randomized controlled study of patients with multiple myeloma was performed to evaluate the efficacy and safety of recombinant human granulocyte colony-stimulating factor (rhG-CSF:KW-2228) in treating neutropenia induced by chemotherapy, and its influence on the dose intensity of, and response rate to, chemotherapy. As a rule, 3 courses of chemotherapy at intervals of 4 weeks were administered both to the untreated and KW-2228-treated groups. Among 98 eligible patients evaluated for neutrophil recovery, a markedly reduced duration of neutropenia was observed during each course in the KW-2228 treated group. No significant difference distinguished the two groups in terms of incidence or duration of infection. However, febrile neutropenia appeared only in the untreated group. There was no significant difference in terms of response rate or dose intensity. However, only patients in the untreated group withdrew from the study due to protracted neutropenia. These results demonstrated that KW-2228 is effective and safe, and has a significant effect on the acceleration of neutrophil recovery in patients with neutropenia induced by chemotherapy for multiple myeloma, and is useful for the completion of chemotherapy regimens.
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PMID:[Clinical evaluation of rhG-CSF in patients with neutropenia induced by chemotherapy for multiple myeloma]. 1072 40


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