Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Research in chronic lymphocytic leukemia (CLL) has undergone a resurgence of interest in the last decade. While it is obvious that most patients with CLL have typical mature B cells, a number of variants such as splenic lymphoma villous lymphocytes, mantle cell leukemia, and prolymphocytic leukemia need to be considered in the differential diagnosis. This can be established by immunophenotype studies and morphology. Cytogenetic abnormalities are emerging as being of interest, with abnormalities in chromosomes 11 and 17 having major prognostic significance. Immune disregulation is complicated in that along with hypergammaglobulinemia and T-cell dysfunction, the emergence of antibodies directed against hematopoietic cells causes autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. A number of prognostic factors are emerging as being more influential in prognosis and stage, such as serum beta2-microglobulin and soluble CD23. Apoptosis dysregulation is a major feature of CLL, and while no clear pattern has emerged, abnormal levels of bcl2 are common in CLL and bcl2 to bax ratios are also commonly disturbed. Bcl1 levels are commonly increased. Treatment has changed radically. The purine analogs have been demonstrated to be the most active group of drugs in CLL. Combinations of purine analogs, such a fludarabine or 2-chlorodeoxyadenosine, with alkylating agents are emerging as new treatments. The most recent development has been the emergence of two monoclonal antibodies, rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA; directed against CD20) and Campath-1H (directed against CD52 in CLL). The activity of rituximab in lymphoma has been less prominent in small lymphocytic lymphoma (the lymphomatous counterpart of CLL) and this has led to dose escalation studies in CLL with a good level of response. Campath-1H is emerging as another major antibody with marked effect against disease, particularly in the blood and bone marrow. Autologous, allogeneic, and mini-transplant are also being explored extensively. The prognosis for patients with CLL is changing as these new treatments become available.
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PMID:Chronic lymphocytic leukemia. 1056 Oct 25

A retroviral vector has been constructed that contains the human CD20 cDNA under the control of the Moloney murine leukemia virus (Mo-MuLV) LTR. Freshly isolated mononuclear cells are infected for three consecutive days in the presence of PHA and hrlL-2, and a mean 15.9% of the cells (range, 6.5 to 31.7%) acquire a CD3+CD20+ phenotype. Transduced T lymphocytes grow and expand in vitro for up to 3 weeks like mock-infected cells and, as observed for the T lymphoblastoid CEM cell line, CD20 expression is maintained for several months with no change in the growth curve of the cells. CD20-expressing CEM and fresh T lymphocytes can be positively immunoselected on columns using different anti-CD20 antibodies. Exposure to monoclonal chimeric anti-CD20 IgG1(kappa) Rituximab antibody (Roche), in the presence of complement, results in effective and rapid killing of the transduced CD3+CD20+ human T cells in vitro. This approach represents a new and alternative method to gene manipulation with "suicide" genes for the production of drug-responsive T cell populations, a crucial step for the future management of graft-versus-host disease in bone marrow transplant patients.
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PMID:Genetic modification of human T cells with CD20: a strategy to purify and lyse transduced cells with anti-CD20 antibodies. 1072 39

With the FDA approval of Rituximab in 1998 for the treatment of lymphoma, and Trastuzumab in 1999 for the treatment of breast cancer, monoclonal antibodies were officially added to the therapeutic armamentarium against malignancy. Most of the side effects associated with these agents are due to antigen-antibody interactions on specific cells and tissues. One of the most predictable side effects of these products is a constellation of various systemic effects including flu-like symptoms such as headache, fever, sweats, skin rash, shortness of breath, hypotension, nausea, and asthenia that occurs with the first infusion of such products. Rarely severe hypotension, bronchospasm, and hypoxia and even death have occurred. The pathophysiology of these reactions appears to be secondary to the release of cytokines as the antibodies bind do circulating antigen-expressing cells that are then removed in the reticuloendothelial system of the lungs, spleen and liver. In patients with large numbers of antigen-dense cells that have a high mitotic index, such as prolymphocytic leukemia, mantle cell lymphoma, or lymphosarcoma cell leukemia, there is a risk of true tumor lysis syndrome. One should be particularly cautious when treating patients with high numbers of circulating antigen-expressing cells in the setting of underlying cardiovascular or respiratory disease.
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PMID:Infusion reactions associated with the therapeutic use of monoclonal antibodies in the treatment of malignancy. 1085 89

The recent clinical trial in lymphoma using tumor antigen-loaded DCs (Hsu et al, Nature Med 1996; 2: 52) demonstrates the efficiency of the use of professional antigen presenting cells (APCs) for taking up, processing and presenting tumor protein in a vaccine strategy in cancer. However, the production of large quantities of clinical grade APCs remains to be resolved. Here, we describe that both dendritic cells (DCs) and macrophages (MOs) can be efficiently differentiated in large numbers from lymphoma patients in spite of their disease and previous therapy. These cells were produced using the VAC and MAK cell processors according to standard operating procedures. DCs and MOs were differentiated from circulating monocytes in gas permeable hydrophobic bags, with 2% autologous serum and in the presence of GM-CSF and IL-13 or GM-CSF alone, respectively. DCs and MOs were then purified by counter flow centrifugation. Phenotypic, morphological and functional analysis showed that cells differentiated from patients with lymphoma present quite similar features to DCs and MOs produced from monocytes of healthy donors. Moreover, we show that MOs, when combined with CD20 antibody (Rituximab), can efficiently engulf tumor cells and propose that a such combination could be used for initiating a clinical trial in lymphoma. Thus, the possibility of producing functional DC and MOs in large amounts in conditions compatible with therapeutic application will allow the development of new immune strategies to eradicate lymphoma.
Leukemia 2000 Sep
PMID:Differentiation of antigen-presenting cells (dendritic cells and macrophages) for therapeutic application in patients with lymphoma. 1099 15

Idiopathic thrombocytopenic purpura is a disorder in which autoantibodies are made to platelets, resulting in accelerated platelet destruction. The diagnosis may be made in outpatients who are previously well or in patients with multiple medical conditions and medications. There are no unequivocal ways to distinguish immune thrombocytopenias from other thrombocytopenias, even with state-of-the-art tests including anti-platelet antibodies, thrombopoietin, glycocalicin, and platelet reticulocyte counts. Clinical evaluation includes ruling out a systemic process such as a viral infection or leukemia. Treatment of idiopathic thrombocytopenic purpura should be individualized. Substantial platelet increases are seen in more than 50% of patients who receive intravenous IgG, intravenous anti-D, steroids, or splenectomy. Two additional agents showing promising clinical trial experience are anti-CD40 ligand and rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA).
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PMID:Overview of idiopathic thrombocytopenic purpura: new approach to refractory patients. 1122 7

Conventional cytotoxic management of leukemia has less than optimal results, while it is associated with life-threatening toxic effects due to lack of specificity for hematopoietic cells. Therefore, novel therapeutic strategies with monoclonal antibodies (MAbs) are being explored for delivering chemotherapy or radiation directly to malignant cells. Recently, anti-CD33 antibodies have been engineered to target malignant myeloid and immature normal cells and have been used to deliver cytotoxic agents or radiation to leukemic cells. 131I-labeled anti-CD45 antibodies are used in combination with conventional chemotherapy in leukemic patients receiving marrow transplantation. Additionally, the emergence of Rituximab (against CD20) and Campath-1H (against CD52) for chronic lymphocytic leukemia (CLL) has provided encouraging clinical results for the prognosis of this disease. In conclusion, there has been ongoing research indicating that the approach of patients with leukemia through the application of MAbs might be safer and more effective than current treatment. Considering the preliminary data, MAb therapy appears to be a new, promising weapon in the oncologist's armentarium.
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PMID:The development of monoclonal antibody therapy in leukemias. 1146 62

C2B8 (Rituximab, MabThera) is a chimeric mouse/human monoclonal antibody (mAb) directed against the human B cell-restricted cell surface antigen CD20 which is used as an alternative medication in the treatment of B cell non-Hodgkin lymphomas (NHL). Treatment of CD20+ B cells with C2B8 triggers different cell damaging effects including complement-dependent lysis of tumor cells, antibody-dependent cellular cytotoxicity and induction of apoptosis. Dendritic cells (DC) have recently been shown to ingest cell debris and to present associated antigens even on MHC class I molecules, a mechanism called cross-presentation. In this study, we investigated whether C2B8 treatment of lymphoma promotes the induction of CD8+ T cell responses against lymphoma cell-associated antigens via, cross-presentation. We used Daudi lymphoma cells as a model system in our studies and could demonstrate, that C2B8-treated Daudi cells undergo apoptosis, are phagocytosed by DC and induce in DC typical features of maturation; among them, the induction of CD83 expression as well as the up-regulation of prominent accessory molecules (CD40, CD86) and MHC molecules. Importantly, upon co-culture of such lymphoma cell-pulsed DC with autologous T cells, we could induce efficient cytotoxic T cell (CTL) responses against Daudi cell-associated antigens. These findings suggest that antibody treatment of tumor cells can, in addition to its direct cell damaging effects, under certain conditions, contribute to an induction of potentially protective cytotoxic T cell responses.
Leukemia 2001 Oct
PMID:CD20 antibody (C2B8)-induced apoptosis of lymphoma cells promotes phagocytosis by dendritic cells and cross-priming of CD8+ cytotoxic T cells. 1158 21

The introduction of first alpha-interferon and later the purine analogues has revolutionized the treatment of hairy cell leukaemia (HCL). However, there are still some patients that initially or eventually fail to respond and, thus, there is a need for alternative treatment modalities. We have treated 11 HCL patients (eight relapsing and three newly diagnosed) with a chimaeric monoclonal antibody, rituximab, in a dose of 375 mg/m2 once a week for 4 weeks. The response rate was seven out of eleven (64%) with six complete remissions and one partial remission, all which have lasted between 0 and 34 months (median 14 months). Rituximab appears promising in the treatment of HCL and warrants further studies.
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PMID:Rituximab, a chimaeric anti-CD20 monoclonal antibody, in the treatment of hairy cell leukaemia. 1173 43

The aim of this study was to investigate feasibility, tolerability and efficacy of rituximab-supplemented high-dose sequential chemotherapy (R-HDS) with peripheral blood progenitor cell autografting as frontline or salvage treatment in patients with advanced non-Hodgkin's lymphoma (NHL). Thirty-two patients have been treated: 14 at disease onset and 18 with relapsed or progressive disease. R-HDS regimens included six courses of rituximab. Rituximab was delivered either concurrently with high-dose chemotherapy to exploit the in vivo purging properties of the drug as well as at the end of the treatment plan to target minimal residual disease. All patients treated at disease onset completed their treatment with no life-threatening toxicity, while two toxic deaths due to severe bilateral pneumonia were observed among patients treated due to relapsed or refractory disease. Thirteen of 14 patients treated up-front achieved CR. Among pre-treated patients 10 of 18 achieved CR with better results in patients with relapsed (seven of eight) compared to progressive disease (three of 10). PCR analysis was carried out in indolent lymphoma patients: nine of nine follicular lymphomas and three of six CD5-positive NHL collected PCR-negative peripheral blood progenitor cell harvests. The results of this pilot study show that R-HDS is feasible and effective with acceptable toxicity when used at disease onset. In pre-treated patients this treatment also showed promising results, although the risk of severe infections needs to be considered.
Leukemia 2001 Dec
PMID:Concurrent administration of high-dose chemotherapy and rituximab is a feasible and effective chemo/immunotherapy for patients with high-risk non-Hodgkin's lymphoma. 1175 16

Over the last decade, major advancements in our understanding of chronic lymphocytic leukemia (CLL) and its variants have occurred. It has become apparent that there is diversity in types of CLL including those patients that do or do not have hyper-mutation of their immunoglobulin genes. Mutated genes confer a favorable prognosis. One of the major advances in our therapy has been the discovery of the activity of purine analogs, which have been demonstrated to be more active than conventional therapy in achieving complete remission, prolonged remission duration, and a suggestion of improved survival. More recently, based on information that purine analogs inhibit DNA repair, rational combinations have been developed. In particular, fludarabine plus cyclophosphamide appeared to have added activity compared to either drug given alone or in sequence. This has led to a higher response rate, longer time to progression, and an improvement in survival in patients treated following prior alkylating agents. Two monoclonal antibodies, Rituximab and Campath-1H, have become available for clinical use and research. Rituximab has modest activity as a single agent, with higher response rates being noted in patients who receive more intensive regimens. Rituximab has been successfully combined with chemotherapy, and in association with fludarabine plus cyclophosphamide (FCR) has a very high response rate and the ability to obtain polymerase chain reaction (PCR) negativity for the immunoglobulin heavy chain region. Campath-1H is very active as a single agent and is being recommended for treatment for patients with fludarabine refractory disease and will receive increased attention as a research agent in earlier-stage patients. Autologous and allogeneic bone marrow transplantation have emerged as significant treatments in CLL. The ability to achieve responses in bone marrow and peripheral blood with newer regimens has given the opportunity to collect stem cells from patients. There is a suggestion that intensification of remissions with autologous transplant can lead to PCR negativity and prolonged remissions. Allogeneic transplantation has been demonstrated to be effective with a strong suggestion of graph versus leukemia effect. This has been utilized in the development of non-ablative marrow allogenaic bone marrow transplant programs. Non-ablative transplants appear to be as effective as ablative transplants in the most recent analysis. Thus, multiple modalities have been brought together to achieve high-quality complete remissions in CLL, giving the prospect of improved survival.
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PMID:Progress in CLL, chemotherapy, antibodies and transplantation. 1176 60


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