Rituximab therapy of patients with B-cell chronic lymphocytic leukemia

Huhn, D.; Schilling, Christoph von; Wilhelm, Martin; Ho, Anthony D.; Hallek, Michael; Kuse, R.; Knauf, Wolfgang; Riedel, U.; Hinke, Axel; Srock, Stefanie; Serke, Stefan; Peschel, Christian; Emmerich, Bertold

doi:10.1182/blood.v98.5.1326

Cited by 328 publications

(179 citation statements)

References 21 publications

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“…While the efficacy of rituximab monotherapy in relapsed CLL is limited, with virtually no complete responses, the finding of similar outcome in the concurrent and sequential treatment arm raises the possibility that attaining an early CR (ie, 2 months after treatment) may not be important to predicting long-term outcome. 8,9,18 As responses to rituximab can often improve following completion of therapy, future studies examining the bone marrow later in treatment will be required to accurately estimate the importance of CR as a surrogate end point to prolonged PFS and OS. All of these limitations mandate caution in overinterpreting the results reported herein beyond strong consideration of fludarabine and rituximab-based combinations in future randomized phase 3 trials.…”

Section: Discussionmentioning

confidence: 99%

Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011

Byrd

Rai

Peterson

et al. 2005

Blood

371

190

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Section: Discussionmentioning

confidence: 99%

Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011

Byrd

Rai

Peterson

et al. 2005

Blood

371

190

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“…However, RTX and CD20 are not internalized by the opsonized CD20 ϩ cells; rather, the RTX-CD20 complexes are removed from the opsonized cells and are taken up by the THP-1 cells, in an Fc␥R-mediated process we term shaving. This shaving process may explain the enhanced antigenic modulation seen earlier in the presence of monocytes, and may explain why RTX as a single agent has had limited success in CLL treatment (27,28,38).…”

Section: T Argeting Of Ags On Cancer Cells By Mabs Has Been a Key Strmentioning

confidence: 99%

The Shaving Reaction: Rituximab/CD20 Complexes Are Removed from Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Cells by THP-1 Monocytes

Beum

Kennedy

Williams

et al. 2006

The Journal of Immunology

209

226

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Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by FcγR. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20+ cells with acceptor THP-1 monocytes. After 45 min at 37°C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab′)2 of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by FcγR. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.

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“…However, there is general agreement that diseases such as chronic lymphocytic leukemia may display the CD20 cell-surface molecule in fairly low titer and may respond proportionally less well to Rituximab compared to other low-grade B cell malignancies [5][6][7].…”

mentioning

confidence: 99%

Regulation of CD20 expression by radiation-induced changes in intracellular redox status

Gupta

Crosby

Almasan

et al. 2008

Free Radical Biology and Medicine

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Increasing the levels of CD20 expression in cells that harbor low CD20 levels may enhance their responsiveness to CD20-specific antibody therapies. Here, we examined the regulation of CD20 expression after treatment with 0.5-2.0 Gy X-irradiation and hydrogen peroxide (H 2 O 2 ), in the presence or absence of known antioxidants, in the Burkitt lymphoma cell lines Daudi and Raji. Irradiation of cells enhanced cell-surface CD20 expression; the kinetics and extent of this change were cell-type specific and time-dependent. The kinetics of reactive oxygen species generation and changes in mitochondrial membrane potential after irradiation were also correlated with changes in CD20 expression. Raji and Daudi cells treated with H 2 O 2 showed a 2-to 2.5-fold increase in CD20 expression at 12 and 20 h, respectively. Buthionine sulfoximine, which depletes glutathione, also increased surface CD20, whereas antioxidants, such as PEG-catalase, PEG-SOD, vitamin C, and amifostine, decreased CD20 expression induced by radiation or H 2 O 2 . The antioxidant-mediated decrease in CD20 expression induced by radiation or H 2 O 2 suggests a mechanism involving redox regulation. These results demonstrate the critical role of radiationinduced oxidative stress in CD20 expression and may have implications for defining and improving the efficacy of CD20-targeted antibody therapy and radioimmunotherapy. Keywords CD20; Ionizing radiation; Reactive oxygen species; Antioxidants; Mitochondria; Mitochondrial membrane potential; Free radicals The CD20 transmembrane protein is exclusively expressed on B cells. It appears during the pre-B-cell stage, but is absent during the earlier or later stages of B cell differentiation, such as in antibody-secreting plasma cells [1,2]. CD20 has received extensive evaluation as an ideal target for immunotherapy and radioimmunotherapy, in part because of its ubiquitous expression on target cells, stable localization within the cell membrane, and absence from normal stem cells [3]. Rituximab, a chimeric monoclonal anti-CD20 antibody, has been used extensively in the treatment of low-grade B cell lymphomas, such as non-Hodgkin lymphoma (NHL) and other related pathologies. In clinical applications, the efficacy of Rituximab seems to fade after a period of months, leading to Rituximab resistance. The Recent studies have reported that bryostatin-1, interleukin-4, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-α, and interferon-α are all able to induce CD20 surface expression [8][9][10][11][12][13]. However, the mechanisms regulating the expression of CD20 remain poorly understood, even though these cytokines are well known to cause robust intracellular oxidative bursts [14,15]. Recently, it was shown that the bryostatin-1-induced increase of CD20 was regulated at the transcriptional level. The effect of bryostatin-1 on CD20 expression in NHL-derived cells was apparently mediated through the MAPK/ERK signal transduction pathway and involved protein kinase C [13]. Our group has previous...

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Rituximab therapy of patients with B-cell chronic lymphocytic leukemia

Abstract: Rituximab (IDEC-C2B8

Cited by 328 publications

References 21 publications

Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011

Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011

The Shaving Reaction: Rituximab/CD20 Complexes Are Removed from Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia Cells by THP-1 Monocytes

Regulation of CD20 expression by radiation-induced changes in intracellular redox status

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