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      90Yttrium ibritumomab tiuxetan in the treatment of non-Hodgkin’s lymphoma: current status and future prospects

      Biologics : Targets & Therapy

      Dove Medical Press

      immunotherapy, radioimmunotherapy, ibritumomab, zevalin, non-Hodgkin lymphoma

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          Abstract

          After nearly three decades with little change in the treatment for B-cell non-Hodgkin’s lymphoma, the addition of immunotherapy has had a profound effect on the treatment of this group of diseases. A more subtle addition to the armentarium has been the radiolabeled monoclonal antibodies, 90yttrium ibritumomab tiuxetan and 131iodine tositumomab. Unfortunately these drugs have been underutilized. This is, in part, because of the need for coordination between specialties, concern about long-term effects, possible limitations on the tolerance of subsequent therapies and, in part, because of reimbursement factors. In this review, the studies in relapsed and refractory disease are discussed and the very promising results reported from phase II studies using radioimmunotherapy as first-line. Potential mechanisms of resistance to monoclonal antibodies are postulated based on alterations in cell signaling pathways that have been observed in lymphoma cell lines resistant to rituximab. It is anticipated that as mechanisms of resistance are better understood for both unlabeled and labeled monoclonal antibodies, biomarkers will not only predict their efficacy but also lead to the development of therapies to overcome resistance.

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          Most cited references 69

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          Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.

          Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.
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            Revised response criteria for malignant lymphoma.

            Standardized response criteria are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. The International Working Group response criteria (Cheson et al, J Clin Oncol 17:1244, 1999) were widely adopted, but required reassessment because of identified limitations and the increased use of [18F]fluorodeoxyglucose-positron emission tomography (PET), immunohistochemistry (IHC), and flow cytometry. The International Harmonization Project was convened to provide updated recommendations. New guidelines are presented incorporating PET, IHC, and flow cytometry for definitions of response in non-Hodgkin's and Hodgkin's lymphoma. Standardized definitions of end points are provided. We hope that these guidelines will be adopted widely by study groups, pharmaceutical and biotechnology companies, and regulatory agencies to facilitate the development of new and more effective therapies to improve the outcome of patients with lymphoma.
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              Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene.

              Given that the FcgammaRIIIa receptor 158V allotype displays a higher affinity for human immunoglobulin G1 and increased antibody-dependent cellular cytotoxicity, the aim of this study was to determine the influence of that FCGR3A polymorphism on the therapeutic response to rituximab, an anti-CD20 humanized immunoglobulin G1 increasingly used in the treatment of non-Hodgkin lymphomas. The FCGR3A-158V/F genotype was determined in 49 patients having received rituximab for a previously untreated follicular non-Hodgkin lymphoma. The clinical response and the disappearance of the BCL2-JH gene rearrangement in both peripheral blood and bone marrow were evaluated at 2 months (M2) and at 1 year (M12). The study population consisted of 20% FCGR3A-158V homozygous patients, 35% FCGR3A-158F homozygous patients, and 45% heterozygous patients (FCGR3A-158F carriers). The objective response rates at M2 and M12 were 100% and 90%, respectively, in FCGR3A-158V homozygous patients compared with 67% (P =.03) and 51% (P =.03), respectively, in FCGR3A-158F carriers. A disappearance of the BCL2-JH gene rearrangement in both peripheral blood and marrow was observed at M12 in 5 of 6 of homozygous FCGR3A-158V patients compared with 5 of 17 of FCGR3A-158F carriers (P =.03). The homozygous FCGR3A-158V genotype was confirmed to be the single parameter associated with clinical and molecular responses by multivariate analysis. This study showed an association between the FCGR3A genotype and clinical and molecular responses to rituximab. This finding will certainly give rise to new pharmacogenetic approaches to the management of patients with non-Hodgkin lymphomas.
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                Author and article information

                Journal
                Biologics
                Biologics: Targets & Therapy
                Biologics : Targets & Therapy
                Dove Medical Press
                1177-5475
                1177-5491
                September 2007
                September 2007
                : 1
                : 3
                : 215-227
                Affiliations
                University of Pittsburgh School of Medicine, 5150 Centre Avenue, Pittsburgh, PA, USA
                Author notes
                Correspondence: Samuel A Jacobs, University of Pittsburgh School of Medicine, 5150 Centre Avenue, Pittsburgh, PA 15232, USA, Tel +1 412 235 1278, Fax +1 412 623 4655, Email jacobssa@ 123456upmc.edu
                Article
                btt-1-215
                2721318
                19707332
                © 2007 Dove Medical Press Limited. All rights reserved
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