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

Interleukin-3 (IL-3) is a T-cell-derived colony-stimulating factor (CSF) whose primary targets include relatively early, multipotential, hematopoietic progenitor cells. In this trial, we treated 24 patients with recombinant human IL-3 given by a daily 4-hour intravenous infusion for 28 days. The dose levels were 30, 60, 125, 250, 500, 750, and 1,000 micrograms/m2/d. At least three patients were entered at every dose level. Each participant suffered from bone marrow failure, with the underlying diagnosis being myelodysplastic syndrome (13 patients), aplastic anemia (eight patients), or aplasia after prolonged high-dose chemotherapy (three patients) for multiple myeloma, breast cancer, or acute myelogenous leukemia. Most patients tolerated therapy well, with the most frequent side effects being low-grade fever and headaches. Hematopoietic changes included modest increases in neutrophil counts (eight patients), eosinophil counts (six patients), platelet counts (three patients), and reticulocyte counts (two patients). An increase in blasts occurred in one patient who had refractory anemia with excess blasts in transformation and was reversible once IL-3 was discontinued. In addition, one patient with chronic myelomonocytic leukemia showed an increase in monocytes (and granulocytes). Progression to acute leukemia did not occur. Pharmacokinetic analyses showed a rapid clearance with a mean half-life of 18.8 minutes at the 60 micrograms/m2/d dose, and 52.9 minutes at the 250 micrograms/m2/d dose. Serum concentrations of 10 to 20 ng/mL of IL-3 were achievable at the 250 micrograms/m2/d dose. Our observations indicate that recombinant human IL-3 can be given safely at doses of 1,000 micrograms/m2/d or less. In addition, on the basis of preclinical data and the biologic activity observed in this study, further trials of this molecule, alone and in combination with other growth factors, are warranted in patients with pancytopenia.
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PMID:Phase I study of recombinant human interleukin-3 in patients with bone marrow failure. 204 65

Since the first successful attempt in 1985, peripheral blood stem cell transplants are increasingly performed worldwide and should now be considered as an essential therapeutic weapon against onco-hematological diseases. Their development has benefited greatly from a rapid concomitant advance of experimental knowledge regarding the nature of hematopoietic progenitor cells. For this reason and also for technical ones, until now these transplants generally have been autotransplants. Although one of the main reasons to use blood rather than bone marrow-derived stem cells was that they might carry less risk of relapse than autologous bone marrow cells, the lack of clinical randomized trials and/or the short follow-up make conclusions difficult so far in terms of disease-free and overall survival. Probably the risk of relapse also depends on the type of disease, on prior chemotherapies, on the type of peripheral stem cell mobilization regimen and on the number of blood-derived cells transplanted. Nevertheless, there are several major clinical indications for autologous blood stem cell transplant: acute nonlymphoblastic leukemias (ANLL), low-grade non-Hodgkin's lymphomas, multiple myeloma, some solid tumors, and even chronic myeloid leukemia. Now well-demonstrated advantages add a socioeconomic interest to this technique. The speed of post-transplant hematopoietic recovery induces a briefer hospitalization and a lower cost of the procedure, which represents "per se" important progress. Furthermore, the increasing use of hematopoietic growth factor(s) at time of blood-derived cell mobilization should increase the safety of the procedure. Also new trends are currently being developed: autotransplants with purified peripheral CD34+ cells; addition of adjuvant immunotherapy to induce graft-versus-tumor effect, which is lacking in autotransplant; and transplants using allogenic umbilical cord blood progenitors. Allogenic blood cell transplants might also be developed, provided that blood cells would be less likely to cause graft-versus-host disease (GVHD) than bone marrow, which is still not verified. Finally, the use of blood-derived cells as a vehicle for gene therapy should develop greatly in the near future.
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PMID:Peripheral blood stem cell transplantations: past, present and future. 810 Apr 62

High-dose cyclophosphamide (HD-CY) has been shown to decrease the tumor mass in multiple myeloma (MM) patients and to be effective in the mobilization of PBPC. By administering hematopoietic growth factor the quantity of progenitor cells in the peripheral blood increased and the hematological toxicity of CY could be reduced. Thirty-two patients with stage II and stage III MM were treated to mobilize and harvest a sufficient amount of PBPC for autologous transplantation. Sixteen patients received 4 g/m2 CY and 16 patients 7 g/m2 CY in divided doses of 1 g/m2 every 2 h. Both patient groups were comparable for disease stages as well as previous therapies. Twenty-four hours after chemotherapy 300 micrograms GCSF were administered subcutaneously once daily until the last day of leukapheresis. Administration of 7 g/m2 HD-CY resulted in statistically significantly higher peak values for CD34+ progenitor cells (47.86/microliters vs 18.75/microliters, P = 0.0198) in the peripheral blood. PBPC autografts containing > 2.5 x 10(6) CD34+ cells/kg BW could be obtained at the first attempt from 14 of 16 patients treated with 7 g/m2 CY as compared to 10 of 16 patients treated with 4 g/m2 CY (P = 0.11). The analysis of potentially malignant CD19+ B cells showed a highly significant lower mean CD19+ cell content/kg BW per leukapheresis in the 7 g/m2 compared to the 4 g/m2 CY group (0.75 vs 1.81 x 10(6), P = 0.001). WHO grade IV treatment-related non-hematologic toxicity was not observed. We prefer the 7 g/m2 CY dosage followed by cytokine administration for the mobilization of PBPC in advanced state MM patients pretreated with alkylating agents.
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PMID:Mobilization of peripheral blood progenitor cells with high-dose cyclophosphamide (4 or 7 g/m2) and granulocyte colony-stimulating factor in patients with multiple myeloma. 873 83

Autologous peripheral blood stem cells (PBSC) are now widely used to support myeloablative therapy in patients with multiple myeloma (MM). The presence of malignant cells in these autografts has been demonstrated. Characteristic kinetics with differential and concomitant mobilization of CD34+ and malignant cells after high-dose (HD) chemotherapy and hematopoietic growth factor administration have been reported. We determined the amounts of tumor cells and PBSC in leukapheresis products (LP) collected on day 1 (LP1) and 2 (LP2) from 16 MM patients harvested after HD chemotherapy and G-CSF. Furthermore, LP from six patients collected on day 5 (LP5) could be examined. The content of clonotypic cells was quantitated by an allele-specific oligonucleotide (ASO)-PCR assay based on limiting dilutions. CD34+ PBSC were determined by flow cytometry. The percentages of malignant cells in the leukapheresis products were in the range of 0% to 0.713% (mean 0.047%). CD34+ cells ranged between 0.06% and 5.4% (mean 1.23%). Comparing LP1 with LP2, no differences in the quantity of tumor cells (mean 0.0538% vs 0.0448%; P = 0.96) and CD34+ cells (mean 1.49% vs 1.33%; P= 0.50) were seen. The calculated number of tumor cells per CD34+ cell did not differ significantly (mean 0.0420 vs 0.0249; P = 0.65). Analyzing LP5 revealed no changes in the number of tumor cells per CD34+ cell (0.0511 vs 0.1044; P = 0.46) indicating a relatively constant ratio of PBSC to tumor cells during the course of PBSC harvesting. These results offer the possibility of combining LP harvested over several days without increasing the tumor load per CD34+ cell.
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PMID:First and second apheresis in patients with multiple myeloma: no differences in tumor load and hematopoietic stem cell yield. 964 73

Despite considerable progress in recent years in the understanding of the biology of multiple myeloma (MM), this disease remains incurable, although many new therapeutic approaches are under evaluation. The rapid development of recombinant technologies has permitted the production of large amounts of cytokines and growth factors, favoring the use of biotherapies also in this disease. Among these products, the interferons have been the most extensively used in clinical trials, giving the most promising results especially in the setting of minimal residual disease, as maintenance therapy after response to conventional therapies, or to high dose chemotherapies followed by bone marrow (BM) or peripheral blood stem cell (PBSC) transplantation. However, more recently, a large number of cytokines and growth factors have been introduced in the clinical practice. Data of the use of erythropoietin have consistently demonstrated the role of this growth factor in ameliorating the grade of anemia as well as the quality of life of those MM patients whose disease is complicated by the presence of a severe or moderate anemia. Using hematopoietic growth factor in the mobilization of PBSC, the quantity of progenitor cells in the peripheral blood increased and the hematological toxicity of chemotherapy could be reduced. Despite the large amount of experimental data indicating a role for interleukins, as IL-2 and IL-6, in controlling tumor growth, there are only few clinical studies dealing with their use in MM. Results show that they arrest tumor progression rather than aid tumor regression, for this reason it appears that IL-2 and anti IL-6 antibodies should be investigated as maintenance therapy, in MM patients responding to chemotherapy. In the future it will be necessary to clarify for MM patients the role of other cytokines such as IL-1 beta and TNF alpha. A possible strategy to improve the clinical outcome of MM patients is to prevent the regrowth of residual tumor cells by establishing adoptive immunity at the stages of minimal residual disease previous obtained using chemotherapy. To this end a possible strategy is to induce an immune response against residual tumor cells by passive (using monoclonal antibodies) or active (using the idiotype expressed by malignant cells) immunotherapy.
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PMID:[The role of biotherapy in multiple myeloma]. 1107 35

Various chemotherapy regimens, combined with recombinant human granulocyte colony-stimulating factor(rhG-CSF) or recombinant granulocyte-macrophage CSF (rhGM-CSF) are used in cancer patients to mobilize and collect peripheral blood stem cells (PBSC). In this retrospective study, we evaluated and compared the efficacy of such regimens in 262 patients with different types of malignant diseases. The following chemotherapy regimens were applied: ifosfamide-etoposide-cisplatin or bleomycin (n = 96; mainly patients with testicular cancer); ifosfamide-etoposide plus or minus cytosine arabinoside (Ara-C) or vincristine (VCR)(n = 52; mainly patients with lymphoma); cyclophosphamide-anthracycline (n = 53; mainly patients with breast cancer); intermediate to high dose (ID-HD) cyclophosphamide (n = 37; mainly patients with breast or ovarian cancer. or multiple myeloma; and others (n = 24). rhG-CSF or rhGM-CSF, each at an average daily dose of 5 microg/kg body weight, were used in 166 and 96 patients, respectively. The study evaluated and compared the efficacy of these two cytokines. In patients receiving rhG-CSF, CD34+ cells could be collected earlier (median: day 14 versus day 16) and there was a significantly higher white blood cell count (WBC)(median 11,350 versus 5550/microl) and CD34+ cell count (median 88 versus 43/microl) at the start of apheresis, and a significantly higher CD34+ cell yield (median 7.4 x 10(6) versus 4.6 x 10(6)/kg) than in patients who receivedrhGM-CSF. Among the various chemotherapeutic regimens used, each combined with rhG-CSF, ifosfamide-etoposide plus or minus Ara-C or VCR mobilized a significantly higher number of CD34+ cells (median 119/microl) and produced a significantly higher harvest of these cells (median 13 x 10(6)/kg) than cyclophosphamide-anthracycline (median 87/microl and 7 x 10(6)/kg, respectively) or ID-HD cyclophosphamide (median 59/microl and 5 x I 0(6)/kg, respectively). Ifosfamide-etoposide plus or minus Ara-C or VCR was also superior to ifosfamide-etoposide-cisplatin or bleomycin (median 78/microl and 9 x 10(6)/kg, respectively), but at borderline significance. The outcome of PBSC mobilization and collection appeared to be negatively influenced by the number of relapses before the current salvage treatment. These data indicate that mobilization and collection of PBSCstrongly depend on the type of hematopoietic growth factor and chemotherapeutic regimen used. The data further show rhG-CSF is a more effective growth factor than rhGM-CSF and ifosfamide-etoposide-based regimens, particularly ifosfamide-etoposide plus or minus Ara-C or VCR, are highly effective regimens in mobilizing and collecting CD34+ cells.
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PMID:Impact of chemotherapy regimen and hematopoietic growth factor on mobilization and collection of peripheral blood stem cells in cancer patients. 1273 28

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) gene expression is abnormally regulated in multiple myeloma (MM) owing to imbalanced expression of the acute myeloid leukemia-1A (AML-1A) and AML-1B transcription factors. We hypothesized that the increased expression ratios of AML-1A to AML-1B also induced abnormal expression of other hematopoietic and bone-specific genes that contribute to the poor prognosis of MM patients with high levels of MIP-1 alpha. We found that interleukin-3 (IL-3) was also induced by the imbalanced AML-1A and AML-1B expression in myeloma. IL-3 mRNA levels were increased in CD138+ purified myeloma cells with increased AML-1A-to-AML-1B expression from MM patients, and IL-3 protein levels were significantly increased in freshly isolated bone marrow plasma from MM patients (66.4 +/- 12 versus 22.1 +/- 8.2 pg/mL; P = .038). IL-3 in combination with MIP-1 alpha or receptor activator of nuclear factor-kappa B ligand (RANKL) significantly enhanced human osteoclast (OCL) formation and bone resorption compared with MIP-1 alpha or RANKL alone. IL-3 stimulated the growth of interleukin-6 (IL-6)-dependent and IL-6-independent myeloma cells in the absence of IL-6, even though IL-3 did not induce IL-6 expression by myeloma cells. These data suggest that increased IL-3 levels in the bone marrow microenvironment of MM patients with imbalanced AML-1A and AML-1B expression can increase bone destruction and tumor cell growth.
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PMID:IL-3 expression by myeloma cells increases both osteoclast formation and growth of myeloma cells. 1461 78

Diarrhea is a major cause of morbidity and discomfort for patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation (APBSCT). There are multiple causes of diarrhea in patients undergoing transplantation including antineoplastic chemotherapy, antimicrobials and infection, including Clostridium difficile as the most common pathogen involved. The purpose of this study was to determine the incidence of C. difficile-associated diarrhea (CDAD) 1 week before and 30 days after APBSCT, and to identify risk factors for the development of CDAD including diagnosis. Two hundred and forty-two patients underwent APBSCT for multiple myeloma and lymphoma between October 1996 and October 2001 in two teaching hospitals. Diarrhea was reported in 157 (64.9%) subjects. One hundred and thirty-five out of the 157 subjects were tested for the presence of C. difficile toxin A. These subjects constitute the study group. The incidence of CDAD was 15%. Two thirds of the patients who developed CDAD had multiple myeloma and one third had lymphoma; this difference did not attain statistical significance. The use of cephalosporins (P = 0.03) and the use of intravenous vancomycin (P = 0.02) were the only identified risk factors associated with the development of CDAD. Patients treated with paclitaxel as part of the mobilization regimen had a lower incidence of CDAD than patients who received hematopoietic growth factor only (P = 0.01).
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PMID:Incidence of Clostridium difficile-associated diarrhea before and after autologous peripheral blood stem cell transplantation for lymphoma and multiple myeloma. 1643 18

Interleukin-3 (IL-3) is produced under various pathological conditions and is thought to be involved in the pathogenesis of inflammatory diseases; however, its function in bone homeostasis under normal conditions or nature of the downstream molecular targets remains unknown. Here we examined the effect of IL-3 on osteoclast differentiation from mouse and human bone marrow-derived macrophages (BMMs). Although IL-3 can induce osteoclast differentiation of multiple myeloma bone marrow cells, IL-3 greatly inhibited osteoclast differentiation of human BMMs isolated from healthy donors. These inhibitory effects of IL-3 were only observed at early time points (days 0 and 1). IL-3 inhibited the expression of c-Fos and NFATc1 in BMMs treated with RANKL. However, IL-3-mediated inhibition of osteoclast differentiation was not completely reversed by ectopic expression of c-Fos or NFATc1. Importantly, IL-3 induced inhibitor of DNA binding/differentiation (Id)1 in hBMMs, while Id2 were sustained during osteoclast differentiation of mBMMs treated with IL-3. Ectopic expression of NFATc1 in Id2-deficient BMMs completely reversed the inhibitory effect of IL-3 on osteoclast differentiation. Furthermore, inflammation-induced bone erosion was markedly inhibited by IL-3 administration. Taken together, our results suggest that IL-3 plays an inhibitory role in osteoclast differentiation by regulating c-Fos and Ids, and also exerts anti-bone erosion effects.
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PMID:Inhibitory regulation of osteoclast differentiation by interleukin-3 via regulation of c-Fos and Id protein expression. 2173 57