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      Multiple Myeloma Includes Phenotypically Defined Subsets of Clonotypic CD20+ B Cells that Persist During Treatment with Rituximab

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          Abstract

          Potential progenitor B cell compartments in multiple myeloma (MM) are clinically important. MM B cells and some circulating MM plasma cells express CD20, predicting their clearance by treatment with anti-CD20. Here we describe two types of clonotypic CD20+ B cell in peripheral blood of myeloma patients, identified by their expression of CD19 and CD20 epitopes, their expression of CD45RA and their light scatter properties. Thus, the circulating component of the MM clone includes at least two distinct CD19+ CD20+ B cell compartments, as well as CD138+ CD20+ plasma cells. To determine whether either or both B cell subsets and the CD20+ plasma cell subset were depleted by anti-CD20 therapy, they were evaluated before, during and after treatment of patients with rituximab (anti-CD20), followed by quantifying B cell subsets over a 5 month period during and after treatment. Overall, all three types of circulating B lineage cells persist despite treatment with rituximab. The inability of rituximab to prolong survival in MM may result from this failure to deplete CD20+ B and plasma cells in MM.

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          Characterization of clonogenic multiple myeloma cells.

          The identity of the cells responsible for the initiation and maintenance of multiple myeloma (MM) remains unclear largely because of the difficulty growing MM cells in vitro and in vivo. MM cell lines and clinical specimens are characterized by malignant plasma cells that express the cell surface antigen syndecan-1 (CD138); however, CD138 expression is limited to terminally differentiated plasma cells during B-cell development. Moreover, circulating B cells that are clonally related to MM plasma cells have been reported in some patients with MM. We found that human MM cell lines contained small (< 5%) subpopulations that lacked CD138 expression and had greater clonogenic potential in vitro than corresponding CD138+ plasma cells. CD138- cells from clinical MM samples were similarly clonogenic both in vitro and in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice, whereas CD138+ cells were not. Furthermore, CD138- cells from both cell lines and clinical samples phenotypically resembled postgerminal center B cells, and their clonogenic growth was inhibited by the anti-CD20 monoclonal antibody rituximab. These data suggest that MM "stem cells" are CD138- B cells with the ability to replicate and subsequently differentiate into malignant CD138+ plasma cells.
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            CD20 levels determine the in vitro susceptibility to rituximab and complement of B-cell chronic lymphocytic leukemia: further regulation by CD55 and CD59.

            Complement-dependent cytotoxicity is thought to be an important mechanism of action of the anti-CD20 monoclonal antibody rituximab. This study investigates the sensitivity of freshly isolated cells obtained from 33 patients with B-cell chronic lymphocytic leukemia (B-CLL), 5 patients with prolymphocytic leukemia (PLL), and 6 patients with mantle cell lymphoma (MCL) to be lysed by rituximab and complement in vitro. The results showed that in B-CLL and PLL, the levels of CD20, measured by standard immunofluorescence or using calibrated beads, correlated linearly with the lytic response (coefficient greater than or equal to 0.9; P <.0001). Furthermore, the correlation remained highly significant when the 6 patients with MCL were included in the analysis (coefficient 0.91; P <.0001), which suggests that CD20 levels primarily determine lysis regardless of diagnostic group. The role of the complement inhibitors CD46, CD55, and CD59 was also investigated. All B-CLL and PLL cells expressed these molecules, but at different levels. CD46 was relatively weak on all samples (mean fluorescence intensity less than 100), whereas CD55 and CD59 showed variability of expression (mean fluorescence intensity 20-1200 and 20-250, respectively). Although CD55 and CD59 levels did not permit prediction of complement susceptibility, the functional block of these inhibitors demonstrated that they play an important role in regulating complement-dependent cytotoxicity. Thus, lysis of poorly responding B-CLL samples was increased 5- to 6-fold after blocking both CD55 and CD59, whereas that of high responders was essentially complete in the presence of a single blocking antibody. These data demonstrate that CD20, CD55, and CD59 are important factors determining the in vitro response to rituximab and complement and indicate potential strategies to improve the clinical response to this biologic therapy.
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              The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction.

              Rituximab is a chimeric monoclonal antibody directed at CD20 with significant activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). A variety of pathways of tumor cytotoxicity different from cytotoxic chemotherapy have been proposed for this therapeutic antibody including antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. This report describes that a proportion of patients with CLL receiving rituximab treatment have in vivo activation of caspase-9, caspase-3, and poly(ADP-ribose) polymerase (PARP) cleavage in blood leukemia cells immediately following infusion of rituximab. This suggests that apoptosis using a pathway similar to fludarabine and other chemotherapeutic agents is intricately involved in the blood elimination of tumor cells after rituximab treatment. Patients having caspase-3 activation and PARP cleavage in vivo had a significantly lower blood leukemia cell count after treatment as compared to those without caspase activation. Significant down-modulation of the antiapoptotic proteins XIAP and Mcl-1 was also noted, possibly explaining in part how rituximab sensitizes CLL cells to the cytotoxic effect of chemotherapy in vivo. These findings suggest that the therapeutic benefit of antibody-based therapy in vivo for patients with CLL depends in part on induction of apoptosis and provides another area of focus for studying mechanisms of antibody-resistance in neoplastic cells.
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                Author and article information

                Journal
                Clin Med Oncol
                101467911
                Clinical Medicine. Oncology
                Libertas Academica
                1177-9314
                2008
                27 March 2008
                : 2
                : 275-287
                Affiliations
                [1 ]Department of Oncology, University of Alberta and Cross Cancer Institute, 11560 University Avenue, Edmonton AB T6G1Z2, Canada
                [2 ]Department of Medicine, University of Alberta, Edmonton AB, T6G2R7, Canada
                [3 ]Department of Electrical and Computer Engineering, University of Alberta, Edmonton AB T6G2V4, Canada
                [4 ]Child Health Research Institute, 72 King William Road, North Adelaide SA 5006, Australia
                Author notes
                Correspondence: Linda M. Pilarski, Cross Cancer Institute, 11560 University Ave., Edmonton AB T6G1Z2, Canada. Tel: 01 780 432 8925; Email: lpilarsk@ 123456ualberta.ca
                Article
                cmo-2-2008-275
                10.4137/CMO.S615
                3161648
                21892289
                16aa52fc-33e2-47d3-a998-00ed264c7100
                © 2008 the author(s), publisher and licensee Libertas Academica Ltd.

                This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license http://creativecommons.org/licenses/by/3.0/).

                History
                Categories
                Original Research

                Oncology & Radiotherapy
                cd19 epitopes,b cell depletion by rituximab,multiple myeloma,cd20 epitopes,b lineage cells

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