This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Davis, T. A. Articles by Levy, R. Search for Related Content PubMed PubMed Citation Articles by Davis, T. A. Articles by Levy, R.

Therapy of B-Cell Lymphoma with Anti-CD20 Antibodies Can Result in the Loss of CD20 Antigen Expression¹

National Cancer Institute, NIH, Rockville, Maryland 20852 [T. A. D.], and Division of Medical Oncology, Stanford University School of Medicine, Stanford, California 94305-5306 [D. K. C., R. L.]

Rituximab is a chimeric antibody with human -1 and constant regions and murine variable regions. It recognizes the CD20 antigen, a pan B-cell marker. Therapeutic trials in patients with B-cell non-Hodgkin’s lymphoma (NHL) have shown significant efficacy with a primary response rate of 50%, and a secondary response rate of 44% after repeat treatments in prior responders. The selection for proliferating tumor cells that no longer express CD20 may compromise repeated treatment. We have identified a patient who developed a transformed NHL that lost CD20 protein expression after two courses of therapy with rituximab. In a pretreatment lymph node biopsy, 83% of B cells (as defined by CD19 and surface immunoglobulin) expressed surface CD20. A biopsy from the recurrent tumor after two courses of rituximab revealed a diffuse large cell NHL where 0% of B cells expressed CD20 with no evidence of bound rituximab. Cytoplasmic staining showed no CD20 protein. Sequencing of immunoglobulin heavy chain cDNA identified identical variable sequences in the initial and recurrent lymphomas, confirming the association between the two tumors. Literature and database review suggests that approximately 98% of diffuse large cell lymphomas express CD20, which suggests that these tumors rarely survive without CD20. This is the first identified case of loss of CD20 expression in a lymphoma that has relapsed after rituximab therapy, although several other cases have since been identified. Considering the significant number of patients treated with anti-CD20 antibodies, this may occur only rarely and is unlikely to preclude recurrent therapy with anti-CD20 antibodies in the majority of patients. However, because many patients have relapsed after anti-CD20 antibody therapy and have not been biopsied to identify clones with down-regulated CD20 antigen, we do not currently know the true frequency of this phenomenon. When possible, patients should undergo evaluation for CD20 expression before repeated courses of anti-CD20 therapy.

This article has been cited by other articles:

				J. Hiraga, A. Tomita, T. Sugimoto, K. Shimada, M. Ito, S. Nakamura, H. Kiyoi, T. Kinoshita, and T. Naoe Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with rituximab-containing combination chemotherapies: its prevalence and clinical significance Blood, May 14, 2009; 113(20): 4885 - 4893. [Abstract] [Full Text] [PDF]

				N. A. Johnson, S. Leach, B. Woolcock, R. J. deLeeuw, A. Bashashati, L. H. Sehn, J. M. Connors, M. Chhanabhai, A. Brooks-Wilson, and R. D. Gascoyne CD20 mutations involving the rituximab epitope are rare in diffuse large B-cell lymphomas and are not a significant cause of R-CHOP failure Haematologica, March 1, 2009; 94(3): 423 - 427. [Abstract] [Full Text] [PDF]

				H. M. Horton, M. J. Bernett, E. Pong, M. Peipp, S. Karki, S. Y. Chu, J. O. Richards, I. Vostiar, P. F. Joyce, R. Repp, et al. Potent In vitro and In vivo Activity of an Fc-Engineered Anti-CD19 Monoclonal Antibody against Lymphoma and Leukemia Cancer Res., October 1, 2008; 68(19): 8049 - 8057. [Abstract] [Full Text] [PDF]

				M. S. Czuczman, S. Olejniczak, A. Gowda, A. Kotowski, A. Binder, H. Kaur, J. Knight, P. Starostik, J. Deans, and F. J. Hernandez-Ilizaliturri Acquirement of Rituximab Resistance in Lymphoma Cell Lines Is Associated with Both Global CD20 Gene and Protein Down-Regulation Regulated at the Pretranscriptional and Posttranscriptional Levels Clin. Cancer Res., March 1, 2008; 14(5): 1561 - 1570. [Abstract] [Full Text] [PDF]

				M. H.J. van Oers Rituximab maintenance therapy: a step forward in follicular lymphoma Haematologica, June 1, 2007; 92(6): 826 - 833. [Abstract] [Full Text] [PDF]

				A.J. Ferreri, G.P. Dognini, C. Verona, C. Patriarca, C. Doglioni, and M. Ponzoni Re-occurrence of the CD20 molecule expression subsequent to CD20-negative relapse in diffuse large B-cell lymphoma Haematologica, January 1, 2007; 92(1): e1 - e2. [Abstract] [Full Text] [PDF]

				K. Kawakami, M. Terabe, M. Kawakami, J. A. Berzofsky, and R. K. Puri Characterization of a Novel Human Tumor Antigen Interleukin-13 Receptor {alpha}2 Chain. Cancer Res., April 15, 2006; 66(8): 4434 - 4442. [Abstract] [Full Text] [PDF]

				E. Bremer, B. t. Cate, D. F. Samplonius, L. F. M. H. de Leij, and W. Helfrich CD7-restricted activation of Fas-mediated apoptosis: a novel therapeutic approach for acute T-cell leukemia Blood, April 1, 2006; 107(7): 2863 - 2870. [Abstract] [Full Text] [PDF]

				L. A. Emens and E. M. Jaffee Leveraging the Activity of Tumor Vaccines with Cytotoxic Chemotherapy Cancer Res., September 15, 2005; 65(18): 8059 - 8064. [Abstract] [Full Text] [PDF]

				D. G. Maloney Immunotherapy for Non-Hodgkin's Lymphoma: Monoclonal Antibodies and Vaccines J. Clin. Oncol., September 10, 2005; 23(26): 6421 - 6428. [Abstract] [Full Text] [PDF]

				W. Wojciechowski, H. Li, S. Marshall, C. Dell'Agnola, and I. Espinoza-Delgado Enhanced Expression of CD20 in Human Tumor B Cells Is Controlled through ERK-Dependent Mechanisms J. Immunol., June 15, 2005; 174(12): 7859 - 7868. [Abstract] [Full Text] [PDF]

				E. Bremer, D. F. Samplonius, M. Peipp, L. van Genne, B.-J. Kroesen, G. H. Fey, M. Gramatzki, L. F.M.H. de Leij, and W. Helfrich Target Cell-Restricted Apoptosis Induction of Acute Leukemic T Cells by a Recombinant Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Fusion Protein with Specificity for Human CD7 Cancer Res., April 15, 2005; 65(8): 3380 - 3388. [Abstract] [Full Text] [PDF]

				R. Niwa, M. Sakurada, Y. Kobayashi, A. Uehara, K. Matsushima, R. Ueda, K. Nakamura, and K. Shitara Enhanced Natural Killer Cell Binding and Activation by Low-Fucose IgG1 Antibody Results in Potent Antibody-Dependent Cellular Cytotoxicity Induction at Lower Antigen Density Clin. Cancer Res., March 15, 2005; 11(6): 2327 - 2336. [Abstract] [Full Text] [PDF]

				L A Emens, R T Reilly, and E M Jaffee Breast cancer vaccines: maximizing cancer treatment by tapping into host immunity Endocr. Relat. Cancer, March 1, 2005; 12(1): 1 - 17. [Abstract] [Full Text] [PDF]

				J. Bae, J. A. Martinson, and H. G. Klingemann Identification of CD19 and CD20 Peptides for Induction of Antigen-Specific CTLs against B-Cell Malignancies Clin. Cancer Res., February 15, 2005; 11(4): 1629 - 1638. [Abstract] [Full Text] [PDF]

				F. J. Hernandez-Ilizaliturri, V. Jupudy, J. Ostberg, E. Oflazoglu, A. Huberman, E. Repasky, and M. S. Czuczman Neutrophils Contribute to the Biological Antitumor Activity of Rituximab in a Non-Hodgkin's Lymphoma Severe Combined Immunodeficiency Mouse Model Clin. Cancer Res., December 1, 2003; 9(16): 5866 - 5873. [Abstract] [Full Text] [PDF]

				I. Jilani, S. O'Brien, T. Manshuri, D. A. Thomas, V. A. Thomazy, M. Imam, S. Naeem, S. Verstovsek, H. Kantarjian, F. Giles, et al. Transient down-modulation of CD20 by rituximab in patients with chronic lymphocytic leukemia Blood, November 15, 2003; 102(10): 3514 - 3520. [Abstract] [Full Text] [PDF]

				K. C.M. Straathof, C. M. Bollard, C. M. Rooney, and H. E. Heslop Immunotherapy for Epstein-Barr Virus-Associated Cancers in Children Oncologist, February 1, 2003; 8(1): 83 - 98. [Abstract] [Full Text] [PDF]

				V. A. Thomazy, R. Luthra, M. O. Uthman, P. J.A. Davies, and L. J. Medeiros Determination of Cyclin D1 and CD20 mRNA Levels by Real-Time Quantitative RT-PCR from Archival Tissue Sections of Mantle Cell Lymphoma and Other Non-Hodgkin's Lymphomas J. Mol. Diagn., November 1, 2002; 4(4): 201 - 208. [Abstract] [Full Text] [PDF]

				J. W. J. van Esser, H. G. M. Niesters, B. van der Holt, E. Meijer, A. D. M. E. Osterhaus, J. W. Gratama, L. F. Verdonck, B. Lowenberg, and J. J. Cornelissen Prevention of Epstein-Barr virus-lymphoproliferative disease by molecular monitoring and preemptive rituximab in high-risk patients after allogeneic stem cell transplantation Blood, May 29, 2002; 99(12): 4364 - 4369. [Abstract] [Full Text] [PDF]

				A. Countouriotis, T. B. Moore, and K. M. Sakamoto Cell Surface Antigen and Molecular Targeting in the Treatment of Hematologic Malignancies Stem Cells, May 1, 2002; 20(3): 215 - 229. [Abstract] [Full Text] [PDF]

				P. Comoli, M. Labirio, S. Basso, F. Baldanti, P. Grossi, M. Furione, M. Vigano, R. Fiocchi, G. Rossi, F. Ginevri, et al. Infusion of autologous Epstein-Barr virus (EBV)-specific cytotoxic T cells for prevention of EBV-related lymphoproliferative disorder in solid organ transplant recipients with evidence of active virus replication Blood, April 1, 2002; 99(7): 2592 - 2598. [Abstract] [Full Text] [PDF]

				B. Jahrsdörfer, G. Hartmann, E. Racila, W. Jackson, L. Mühlenhoff, G. Meinhardt, S. Endres, B. K. Link, A. M. Krieg, and G. J. Weiner CpG DNA increases primary malignant B cell expression of costimulatory molecules and target antigens J. Leukoc. Biol., January 1, 2001; 69(1): 81 - 88. [Abstract] [Full Text]

				O. W. Press, J. P. Leonard, B. Coiffier, R. Levy, and J. Timmerman Immunotherapy of Non-Hodgkin's Lymphomas Hematology, January 1, 2001; 2001(1): 221 - 240. [Abstract] [Full Text] [PDF]

				J. D. Hainsworth Monoclonal Antibody Therapy in Lymphoid Malignancies Oncologist, October 1, 2000; 5(5): 376 - 384. [Abstract] [Full Text]

				T. A. Davis, A. J. Grillo-Lopez, C. A. White, P. McLaughlin, M. S. Czuczman, B. K. Link, D. G. Maloney, R. L. Weaver, J. Rosenberg, and R. Levy Rituximab Anti-CD20 Monoclonal Antibody Therapy in Non-Hodgkin's Lymphoma: Safety and Efficacy of Re-Treatment J. Clin. Oncol., September 17, 2000; 18(17): 3135 - 3143. [Abstract] [Full Text] [PDF]

				I. Kuehnle, M. H. Huls, Z. Liu, M. Semmelmann, R. A. Krance, M. K. Brenner, C. M. Rooney, and H. E. Heslop CD20 monoclonal antibody (rituximab) for therapy of Epstein-Barr virus lymphoma after hemopoietic stem-cell transplantation Blood, February 15, 2000; 95(4): 1502 - 1505. [Abstract] [Full Text] [PDF]

				L. Kunkel and T. A. Davis Correspondence re: T. Davis et al., Therapy of B-Cell Lymphoma with Anti-CD20 Antibodies Can Result in Loss of CD20 Antigen Expression. Clin. Cancer Res., 5: 611-615, 1999. Clin. Cancer Res., January 1, 2000; 6(1): 317 - 318. [Full Text]