Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Radiolabeled antibodies have shown promise for the treatment of lymphoma and for solid tumor targeting. Campath-1H is a humanized monoclonal antibody that reacts with the CD52 antigen present on human lymphoid and myeloid cells. Campath-1H is a gamma1 (G1) isotype that induces lymphopenia via an Fc-mediated mechanism(s). Isotype switches were engineered, and the resulting antibodies were expressed in NS0 mouse myeloma cells and biosynthetically radiolabeled with [35S]methionine. The forms included G1, G4, and a G4 variant that contained alanine substitutions at (EU numbering) Leu-235, Gly-237, and Glu-318. All isotypes bound antigen equivalently as assessed by target cell binding in vitro. The G4 variant had a greatly reduced capacity to interact with Fc receptor by virtue of reduced binding to THP-1 human myeloid cells and by a 1000-fold increase in EC50 to intermediate antibody-dependent cellular cytotoxicity. The pharmacokinetics of the isotypes were compared in CD-1 (nu/nu) mice bearing an experimental antigen-expressing tumor. The plasma half-life and tumor uptake were increased for the G4 variant. The G4 variant showed significantly less spleen, liver, and bone uptake but similar uptake in the lung, kidney, and stomach and lower tissue-to-blood ratios. Immunogenicity was assessed after repeated monthly administrations of unlabeled antibody in BALB/c mice. A 50% reduction in the incidence of anti-globulin response was observed for the G4 variant. These properties suggest that antibodies with reduced Fc receptor interaction merit additional study as potential targeting vehicles relative to other isotypes for radioimmunotherapy or situations where diminished normal tissue binding contributes to efficacy.
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PMID:Improved biodistribution, tumor targeting, and reduced immunogenicity in mice with a gamma 4 variant of Campath-1H. 861 27

We report the course of a patient with severe autoimmune neutropenia in whom only transient responses occurred with corticosteroids, antilymphocyte globulin and granulocyte-colony stimulating factor, and who was resistant to treatment with azathioprine, cyclosporin and intravenous immunoglobulin. A 10 d course of intravenous Campath-1H monoclonal resulted in a sustained haematological response. The long-lasting effect of Campath-1H may be due to its remarkable ability to induce a profound and prolonged peripheral blood T lymphopenia.
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PMID:Sustained remission of severe resistant autoimmune neutropenia with Campath-1H. 916 93

Antibody-based treatment is a novel, effective management strategy for a variety of diseases. Alemtuzumab (CAMPATH) is an example of a monoclonal antibody (mAb) that was initially developed in the laboratory and has completed its journey by being approved for therapeutic use in humans. The main clinical applications of alemtuzumab include treatment of lymphoid malignancies, particularly chronic lymphocytic leukaemia (CLL) and T-cell prolymphocytic leukaemia (T-PLL) and prevention of graft versus host disease (GVHD) and graft rejection in bone marrow and solid organ transplant recipients. Alemtuzumab administration is accompanied by a characteristic first-dose reaction due to cytokine release that consists of fever, rigors, rash and, at times, dyspnea and hypotension. The most significant toxic effect is profound, prolonged lymphopenia and the subsequent increased risk of opportunistic infections; antibiotic prophylaxis is recommended for patients undergoing alemtuzumab treatment. Alemtuzumab has demonstrated clinical activity as a single agent and has an acceptable toxicity profile. It has significant therapeutic potential, especially against lymphoid malignancies.
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PMID:Alemtuzumab: a novel monoclonal antibody. 1172 36

Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen, which is abundantly expressed on all normal and most malignant T-lymphocytes. We summarize the results of our experience using alemtuzumab to treat a range of clinically aggressive, mature, post-thymic, T-cell malignancies, including T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), T-cell large granular lymphocyte (T-LGL) leukemia, and human T-cell lymphotropic virus I (HTLV-I) associated adult T-cell leukemia-lymphoma (ATLL). Alemtuzumab was administered at a dose of 30 mg, three times a week until maximum response. Apart from first-dose reactions, which were common, treatment was well tolerated, the main complication being infection and viral reactivation associated with the prolonged lymphopenia. Overall response rates were 76% (60% complete response) in 39 patients with T-PLL and 100% in 3 patients with CTCL, of duration up to 4 yr. Experience in T-LGL and ATLL is limited to single cases only and further studies are required to better define the role of alemtuzumab in these subgroups. Our results indicate that alemtuzumab has activity in T-cell malignancies, particularly in T-PLL and in patients with predominantly blood and bone marrow disease. It may be possible to prolong response duration by the use of high-dose therapy and stem cell transplantation. Alemtuzumab may also have a role in purging minimal residual disease following other chemotherapy and prior to transplantation. We conclude that treatment with alemtuzumab may offer new hope to patients who otherwise have a bleak prognosis.
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PMID:Alemtuzumab in T-cell malignancies. 1218 Apr 89

Campath-1H is effective therapy for patients with relapsed and refractory chronic lymphocytic leukemia (CLL) and prolymphocytic leukemia (PLL), but it is associated with profound lymphopenia and deficiencies in cell-mediated immunity. We report the incidence of cytomegalovirus (CMV) viremia in 34 patients treated with Campath-1H for relapsed or refractory CLL and PLL. All patients received infection prophylaxis during therapy and continuing for at least 2 months following Campath-1H. Five patients (15%) developed CMV viremia at a median of 28 days (range, 20-30 days) after the first dose of Campath-1H. The median CMV viral load was 860/mL (range, 420-2100/mL), as determined by quantitative plasma polymerase chain reaction (PCR). All 5 patients had a temperature > 38.5 degrees C, normal chest radiographs, normal liver function tests, and negative bacterial blood cultures with no clinical evidence of CMV disease at the time of presentation with CMV viremia. The median absolute neutrophil count (ANC) was 740/ microL (range, 340-1600/ microL), and the median absolute lymphocyte count (ALC) was 16/microL (range, 11-169/ microL) for the 5 patients at the time of CMV viremia. All 5 patients received ganciclovir therapy followed by prompt fever resolution and clearance of CMV viremia by plasma PCR. By univariate regression analysis, the following were not risk factors for CMV viremia: age, number of prior regimens, prior rituximab therapy, prior splenectomy, modified Rai stage at Campath-1H therapy (low/intermediate vs. high), ANC, and ALC; although, there was a trend towards significance for prior rituximab therapy (P = 0.07). Cytomegalovirus viremia may be a significant infectious complication during Campath-1H therapy and should be investigated further in future studies.
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PMID:Cytomegalovirus viremia during Campath-1H therapy for relapsed and refractory chronic lymphocytic leukemia and prolymphocytic leukemia. 1243 78

Immunosuppressants have been proposed as disease-modifying treatments in multiple sclerosis (MS) for almost 40 years, but only one, mitoxantrone, has recently been approved, whereas beta-interferons and glatiramer acetate have been licensed since the mid-90s. Recent therapeutic trials of potent immunosuppressive agents such as Campath-1H, mitoxantrone and cyclophosphamide of MS patients with high relapse rates, rapid accumulation of disability and high degree of MRI activity, have resulted in strong suppression of clinical and MRI inflammatory activity, provided that profound and prolonged lymphopenia was achieved. Clinical experience during the past decades has amply demonstrated that some patients with MS respond to immunosuppressants. The odds ratios of relapsing-remitting MS patients to remain relapse-free after a 2-year period of treatment are similar for Betaseron, Avonex, Rebif, Copaxone, intravenous immunoglobulins or azathioprine compared to placebo. The risk of cancer induction is not significant for up to 10 years of daily usage of azathioprine. Currently available non-specific immunosuppressants are able to control inflammation and reduce relapses in MS, but cannot prevent neurodegeneration and the progression of irreversible disability; specific tools need to be developed for that purpose.
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PMID:Non-specific immunosuppressants in the treatment of multiple sclerosis. 1517 81

The humanized monoclonal antibody CAMPATH-1H (alemtuzumab) binds to the CD52 antigen, a glycoprotein that is widely expressed on normal and malignant B- and T-lymphocytes. Over the past 5 years, a number of trials have demonstrated that alemtuzumab has clinical activity in mature T-cell diseases such as T-cell prolymphocytic leukemia (T-PLL) and cutaneous T-cell lymphoma (CTCL). In heavily pretreated relapsed/refractory patients alemtuzumab induced responses in more than two thirds of T-PLL and more than 50% of CTCL patients. Responding patients had improved survival compared to nonresponders. Alemtuzumab is particularly effective in clearing malignant lymphocytes from peripheral blood and bone marrow and may therefore facilitate stem-cell transplantation (SCT) in selected patients. The toxicity profile for the antibody is acceptable; the major complications are infusional reactions, which generally subside after the first 1-2 weeks of therapy, and prolonged lymphopenia associated with reactivation of viruses. These can be minimized by careful monitoring and the use of prophylactic therapy. Future studies will be directed toward: alternative routes (subcutaneous) and schedules of administration; use as first-line therapy; combination strategies with conventional chemotherapy; and use of alemtuzumab to purge minimal residual bone-marrow disease prior to SCT.
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PMID:Alemtuzumab in peripheral T-cell malignancies. 1545 53

Traditional therapy for chronic lymphocytic leukemia (CLL) has consisted of alkylating agents, purine analogs, or a combination of these drugs. These agents are effective at producing remissions but are not curative.Thus, new drugs are still needed to improve the outcome of patients with CLL. The introduction of monoclonal antibodies, such as rituximab and alemtuzumab, provides a novel therapeutic modality.Rituximab is an active agent in CLL. Standard doses of rituximab result in higher response rates in previously untreated than in relapsed patients but low complete response (CR) rates. Rituximab is most effective in combination with chemotherapy, especially fludarabine-based regimens in the first-line and salvage setting. Rituximab is also useful in the treatment of complications of CLL, such as pure red cell aplasia, autoimmune thrombocytopenia, and autoimmune hemolytic anemia. Alemtuzumab has impressive activity in patients with refractory CLL and may play an important role in the consolidation treatment of CLL. Alemtuzumab is most efficacious at clearing disease in the peripheral blood and bone marrow. Bulky lymphadenopathy is less sensitive to therapy. Because of the significant lymphopenia associated with alemtuzumab, antibacterial and antiviral prophylaxis should always be used.
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PMID:Monoclonal antibodies in the treatment of chronic lymphocytic leukemia. 1557 12

Bone marrow transplantation (BMT) benefits nonmalignant diseases but is limited by regimen-related toxicity, graft-versus-host disease (GVHD), donor availability, and graft rejection (GR). To overcome some of these barriers, we developed a new conditioning strategy for these patients. In total, 16 patients received Campath-1H (33/48 mg; days -21 to -19), fludarabine (150 mg/m(2); days -8 to -4), melphalan (140/70 mg/m(2); day -3), and transplant using related/unrelated stem cells. GVHD prophylaxis included cyclosporine/methylprednisolone for cord cells. Other recipients also received methotrexate. Risk factors for GR included multiple transfusions (6), low stem cell numbers (1), and immunologic/metabolic disorders (3). Donor engraftment was present in 14/16 recipients. Neutrophils (ANC>0.5 x 10(9)/l) and platelets (>50 x 10(9)/l) engrafted at a median of 13 and 24 days. Two patients died of Pseudomonas sepsis prior to engraftment, one of CMV disease, and another of intracranial hemorrhage. With median follow-up of 281 days (78-907), 12/16 are stable/improved, or cured. Acute GVHD was absent (n=10) or mild and transient (grade1-2 skin) (n=4). There was no chronic GVHD. Toxicities were predominantly early infections within 100 days, and correlated with lymphopenia (CD4+ T and B cells). Stable engraftment and low incidence of significant GVHD, irrespective of age or stem cell source, make this reduced-intensity regimen attractive for nonmalignant disorders.
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PMID:A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders. 1559 91

Alemtuzumab is a humanized monoclonal antibody against CD52, a small glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on normal T- and B-lymphocytes, and on a large proportion of malignant lymphoid cells, but not on hematopoietic progenitor cells. Over the past several years, a number of clinical trials have demonstrated the clinical activity of alemtuzumab in treating patients with chronic lymphocytic leukemia, T-cell malignancies such as T-prolymphocytic leukemia and cutaneous T-cell lymphoma, as well as in the prevention and therapy of graft-versus-host disease in the setting of allogeneic stem cell transplantation. Its application in a number of autoimmune disorders is currently under investigation. The most significant side effect of alemtuzumab is predisposition to infections related to the associated profound lymphopenia. Despite this, and with appropriate and more effective antibiotic prophylaxis, it is likely that we will witness an expansion of the role of alemtuzumab in the future.
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PMID:Alemtuzumab. 1575 37


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