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Current Cancer Drug Targets


ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

Review Article

Mechanism and Treatment of Rituximab Resistance in Diffuse Large Bcell Lymphoma

Author(s): Linqing Zou, Guoqi Song, Siyu Gu, Lingling Kong, Shiqi Sun, Li Yang* and William C. Cho*

Volume 19 , Issue 9 , 2019

Page: [681 - 687] Pages: 7

DOI: 10.2174/1568009619666190126125251

Price: $65


Diffuse large B-cell lymphoma (DLBCL) is the most common subtype B non-Hodgkin lymphoma in adults. After rituximab being introduced to treat DLBCL, the current first-line treatment is R-CHOP regimen. This regimen greatly improves patient's prognosis, however, relapsed or refractory cases are commonly seen, mainly due to the resistance to rituximab. Although a large number of experiments have been conducted to investigate rituximab resistance, the exac mechanisms and solutions are still unclear. This review mainly explores the possible mechanisms oft rituximab resistance and current new effective treatments for rituximab resistance in DLBCL.

Keywords: Diffuse large B-cell lymphoma, CD20, rituximab resistance, biomarker, non-Hodgkin lymphoma, prognosis.

Martelli, M.; Ferreri, A.J.; Agostinelli, C.; Di Rocco, A.; Pfreundschuh, M.; Pileri, S.A. Diffuse large B-cell lymphoma. Crit. Rev. Oncol. Hematol., 2013, 87(2), 146-171.
Schneider, C.; Pasqualucci, L.; Dalla-Favera, R. Molecular pathogenesis of diffuse large B-cell lymphoma. Semin. Diagn. Pathol., 2011, 28(2), 167-177.
Shaffer, A.L., III; Young, R.M.; Staudt, L.M. Pathogenesis of human B cell lymphomas. Annu. Rev. Immunol., 2012, 30, 565-610.
Nastoupil, L.J.; Rose, A.C.; Flowers, C.R. Diffuse large B-cell lymphoma: current treatment approaches. Oncology (Williston Park), 2012, 26(5), 488-495.
Tedder, T.F.; Disteche, C.M.; Louie, E.; Adler, D.A.; Croce, C.M.; Schlossman, S.F.; Saito, H. The gene that encodes the human CD20 (B1) differentiation antigen is located on chromosome 11 near the t(11;14)(q13;q32) translocation site. J. Immunol., 1989, 142(7), 2555-2559.
Henry, C.; Deschamps, M.; Rohrlich, P.S.; Pallandre, J.R.; Rémy-Martin, J.P.; Callanan, M.; Traverse-Glehen, A.; GrandClément, C.; Garnache-Ottou, F.; Gressin, R.; Deconinck, E.; Salles, G.; Robinet, E.; Tiberghien, P.; Borg, C.; Ferrand, C. Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance. Blood, 2010, 115(12), 2420-2429.
Maeshima, A.M.; Taniguchi, H.; Fukuhara, S.; Morikawa, N.; Munakata, W.; Maruyama, D.; Kim, S.W.; Watanabe, T.; Kobayashi, Y.; Tobinai, K.; Tsuda, H. Follow-up data of 10 patients with B-cell non-Hodgkin lymphoma with a CD20-negative phenotypic change after rituximab-containing therapy. Am. J. Surg. Pathol., 2013, 37(4), 563-570.
Matsuda, I.; Hirota, S. Bone marrow infiltration of CD20-negative follicular lymphoma after rituximab therapy: A histological mimicker of hematogones and B-cell acute lymphoblastic leukemia/lymphoma. Int. J. Clin. Exp. Pathol., 2015, 8(8), 9737-9741.
Tsutsumi, Y.; Ohigashi, H.; Ito, S.; Shiratori, S.; Teshima, T. 5-Azacytidine partially restores CD20 expression in follicular lymphoma that lost CD20 expression after rituximab treatment: a case report. J. Med. Case Reports, 2016, 10, 27.
Small, G.W.; McLeod, H.L.; Richards, K.L. Analysis of innate and acquired resistance to anti-CD20 antibodies in malignant and nonmalignant B cells. Peer J, 2013. 1e31
Terui, Y.; Mishima, Y.; Sugimura, N.; Kojima, K.; Sakurai, T.; Mishima, Y.; Kuniyoshi, R.; Taniyama, A.; Yokoyama, M.; Sakajiri, S.; Takeuchi, K.; Watanabe, C.; Takahashi, S.; Ito, Y.; Hatake, K. Identification of CD20 C-terminal deletion mutations associated with loss of CD20 expression in non-Hodgkin’s lymphoma. Clin. Cancer Res., 2009, 15(7), 2523-2530.
Mishima, Y.; Terui, Y.; Takeuchi, K.; Matsumoto-Mishima, Y.; Matsusaka, S.; Utsubo-Kuniyoshi, R.; Hatake, K. The identification of irreversible rituximab-resistant lymphoma caused by CD20 gene mutations. Blood Cancer J., 2011, 1(4) e15
Johnson, N.A.; Leach, S.; Woolcock, B.; deLeeuw, R.J.; Bashashati, A.; Sehn, L.H.; Connors, J.M.; Chhanabhai, M.; Brooks-Wilson, A.; Gascoyne, R.D. 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, 2009, 94(3), 423-427.
Sar, A.; Perizzolo, M.; Stewart, D.; Mansoor, A.; Difrancesco, L.M.; Demetrick, D.J. Mutation or polymorphism of the CD20 gene is not associated with the response to R-CHOP in diffuse large B cell lymphoma patients. Leuk. Res., 2009, 33(6), 792-797.
Davis, T.A.; Czerwinski, D.K.; Levy, R. Therapy of B-cell lymphoma with anti-CD20 antibodies can result in the loss of CD20 antigen expression. Clin. Cancer Res., 1999, 5(3), 611-615.
Pedersen, A.E.; Jungersen, M.B.; Pedersen, C.D. Monocytes mediate shaving of B-cell-bound anti-CD20 antibodies. Immunology, 2011, 133(2), 239-245.
Czuczman, M.S.; Olejniczak, S.; Gowda, A.; Kotowski, A.; Binder, A.; Kaur, H.; Knight, J.; Starostik, P.; Deans, J.; Hernandez-Ilizaliturri, F.J. 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., 2008, 14(5), 1561-1570.
Ziepert, M.; Hasenclever, D.; Kuhnt, E.; Glass, B.; Schmitz, N.; Pfreundschuh, M.; Loeffler, M. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. J. Clin. Oncol., 2010, 28(14), 2373-2380.
Hatjiharissi, E.; Xu, L.; Santos, D.D.; Hunter, Z.R.; Ciccarelli, B.T.; Verselis, S.; Modica, M.; Cao, Y.; Manning, R.J.; Leleu, X.; Dimmock, E.A.; Kortsaris, A.; Mitsiades, C.; Anderson, K.C.; Fox, E.A.; Treon, S.P. Increased natural killer cell expression of CD16, augmented binding and ADCC activity to rituximab among individuals expressing the FcgammaRIIIa-158 V/V and V/F polymorphism. Blood, 2007, 110(7), 2561-2564.
Danielou-Lazareth, A.; Henry, G.; Geromin, D.; Khaznadar, Z.; Briere, J.; Tamouza, R.; Cayuela, J.M.; Thieblemont, C.; Toubert, A.; Dulphy, N. At diagnosis, diffuse large B-cell lymphoma patients show impaired rituximab-mediated NK-cell cytotoxicity. Eur. J. Immunol., 2013, 43(5), 1383-1388.
Weng, W.K.; Levy, R. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J. Clin. Oncol., 2003, 21(21), 3940-3947.
Vega, M.I.; Huerta-Yepez, S.; Martinez-Paniagua, M.; Martinez-Miguel, B.; Hernandez-Pando, R.; González-Bonilla, C.R.; Chinn, P.; Hanna, N.; Hariharan, K.; Jazirehi, A.R.; Bonavida, B. Rituximab-mediated cell signaling and chemo/immuno-sensitization of drug-resistant B-NHL is independent of its Fc functions. Clin. Cancer Res., 2009, 15(21), 6582-6594.
Rezvani, A.R.; Maloney, D.G. Rituximab resistance. Best Pract. Res. Clin. Haematol., 2011, 24(2), 203-216.
Takei, K.; Yamazaki, T.; Sawada, U.; Ishizuka, H.; Aizawa, S. Analysis of changes in CD20, CD55, and CD59 expression on established rituximab-resistant B-lymphoma cell lines. Leuk. Res., 2006, 30(5), 625-631.
Ziller, F.; Macor, P.; Bulla, R.; Sblattero, D.; Marzari, R.; Tedesco, F. Controlling complement resistance in cancer by using human monoclonal antibodies that neutralize complement-regulatory proteins CD55 and CD59. Eur. J. Immunol., 2005, 35(7), 2175-2183.
Macor, P.; Tripodo, C.; Zorzet, S.; Piovan, E.; Bossi, F.; Marzari, R.; Amadori, A.; Tedesco, F. In vivo targeting of human neutralizing antibodies against CD55 and CD59 to lymphoma cells increases the antitumor activity of rituximab. Cancer Res., 2007, 67(21), 10556-10563.
Hu, W.; Ge, X.; You, T.; Xu, T.; Zhang, J.; Wu, G. Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement-mediated cytolysis. Cancer Res., 2011, 71(6), 2298-2307.
Mamidi, S.; Höne, S.; Teufel, C.; Sellner, L.; Zenz, T.; Kirschfink, M. Neutralization of membrane complement regulators improves complement-dependent effector functions of therapeutic anticancer antibodies targeting leukemic cells. OncoImmunology, 2015, 4(3) e979688
Makou, E.; Herbert, A.P.; Barlow, P.N. Functional anatomy of complement factor H. Biochemistry, 2013, 52(23), 3949-3962.
Jazirehi, A.R.; Vega, M.I.; Bonavida, B. Development of rituximab-resistant lymphoma clones with altered cell signaling and cross-resistance to chemotherapy. Cancer Res., 2007, 67(3), 1270-1281.
Gomez-Gelvez, J.C.; Salama, M.E.; Perkins, S.L.; Leavitt, M.; Inamdar, K.V. Prognostic impact of tumor microenvironment in diffuse large B-cell lymphoma uniformly treated with R-CHOP chemotherapy. Am. J. Clin. Pathol., 2016, 145(4), 514-523.
Fridman, W.H.; Pagès, F.; Sautès-Fridman, C.; Galon, J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer, 2012, 12(4), 298-306.
Zhong, W.; Xu, X.; Zhu, Z.; Du, Q.; Du, H.; Yang, L.; Ling, Y.; Xiong, H.; Li, Q. Increased expression of IRF8 in tumor cells inhibits the generation of Th17 cells and predicts unfavorable survival of diffuse large B cell lymphoma patients. Oncotarget, 2017, 8(30), 49757-49772.
Lv, X.; Feng, L.; Ge, X.; Lu, K.; Wang, X. Interleukin-9 promotes cell survival and drug resistance in diffuse large B-cell lymphoma. J. Exp. Clin. Cancer Res., 2016, 35(1), 106.
Lykken, J.M.; Horikawa, M.; Minard-Colin, V.; Kamata, M.; Miyagaki, T.; Poe, J.C.; Tedder, T.F. Galectin-1 drives lymphoma CD20 immunotherapy resistance: validation of a preclinical system to identify resistance mechanisms. Blood, 2016, 127(15), 1886-1895.
Alas, S.; Emmanouilides, C.; Bonavida, B. Inhibition of interleukin 10 by rituximab results in down-regulation of bcl-2 and sensitization of B-cell non-Hodgkin’s lymphoma to apoptosis. Clin. Cancer Res., 2001, 7(3), 709-723.
Challa-Malladi, M.; Lieu, Y.K.; Califano, O.; Holmes, A.B.; Bhagat, G.; Murty, V.V.; Dominguez-Sola, D.; Pasqualucci, L.; Dalla-Favera, R. Combined genetic inactivation of β2-Microglobulin and CD58 reveals frequent escape from immune recognition in diffuse large B cell lymphoma. Cancer Cell, 2011, 20(6), 728-740.
Bittenbring, J.T.; Neumann, F.; Altmann, B.; Achenbach, M.; Reichrath, J.; Ziepert, M.; Geisel, J.; Regitz, E.; Held, G.; Pfreundschuh, M. Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab. J. Clin. Oncol., 2014, 32(29), 3242-3248.
Roschewski, M.; Staudt, L.M.; Wilson, W.H. Diffuse large B-cell lymphoma-treatment approaches in the molecular era. Nat. Rev. Clin. Oncol., 2014, 11(1), 12-23.
Bai, D.; Ueno, L.; Vogt, P.K. Akt-mediated regulation of NF kappaB and the essentialness of NF kappaB for the oncogenicity of PI3K and Akt. Int. J. Cancer, 2009, 125, 2863-2870.
Fan, Y.; Mao, R.; Yang, J. NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell, 2013, 4(3), 176-185.
Ma, Y.; Zhang, P.; Gao, Y.; Fan, H.; Zhang, M.; Wu, J. Evaluation of AKT phosphorylation and PTEN loss and their correlation with the resistance of rituximab in DLBCL. Int. J. Clin. Exp. Pathol., 2015, 8(11), 14875-14884.
Zhong, W.; Xu, X.; Zhu, Z.; Yang, L.; Du, H.; Xia, Z.; Yuan, Z.; Xiong, H.; Du, Q.; Wei, Y.; Li, Q. Increased interleukin-17A levels promote rituximab resistance by suppressing p53 expression and predict an unfavorable prognosis in patients with diffuse large B cell lymphoma. Int. J. Oncol., 2018, 4299.
Sarkozy, C.; Traverse-Glehen, A.; Coiffier, B. Double-hit and double-protein-expression lymphomas: Aggressive and refractory lymphomas. Lancet Oncol., 2015, 16(15), e555-e567.
Burotto, M.; Berkovits, A.; Dunleavy, K. Double hit lymphoma: from biology to therapeutic implications. Expert Rev. Hematol., 2016, 9(7), 669-678.
Juskevicius, D.; Jucker, D.; Klingbiel, D.; Mamot, C.; Dirnhofer, S.; Tzankov, A. Mutations of CREBBP and SOCS1 are independent prognostic factors in diffuse large B cell lymphoma: mutational analysis of the SAKK 38/07 prospective clinical trial cohort. J. Hematol. Oncol., 2017, 10(1), 70.
Knudsen, S.; Hother, C.; Grønbæk, K.; Jensen, T.; Hansen, A.; Mazin, W.; Dahlgaard, J.; Møller, M.B.; Ralfkiær, E. Brown, Pde. N. Development and blind clinical validation of a microRNA based predictor of response to treatment with R-CHO(E)P in DLBCL. PLoS One, 2015, 10(2)e0115538
Song, G.; Song, G.; Ni, H.; Gu, L.; Liu, H.; Chen, B.; He, B.; Pan, Y.; Wang, S.; Cho, W.C. Deregulated expression of miR-224 and its target gene: CD59 predicts outcome of diffuse large B-cell lymphoma patients treated with R-CHOP. Curr. Cancer Drug Targets, 2014, 14(7), 659-670.
Iqbal, J.; Shen, Y.; Huang, X.; Liu, Y.; Wake, L. Global microRNA expression profiling uncovers molecular markers for classification and prognosis in aggressive B-cell lymphoma. Blood, 2015, 125, 1137-1145.
Gu, J.J.; Hernandez-Ilizaliturri, F.J.; Mavis, C.; Czuczman, N.M.; Deeb, G.; Gibbs, J.; Skitzki, J.J.; Patil, R.; Czuczman, M.S. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models. Anticancer Drugs, 2013, 24(10), 1030-1038.
Olejniczak, S.H.; Blickwedehl, J.; Belicha-Villanueva, A.; Bangia, N.; Riaz, W.; Mavis, C.; Clements, J.L.; Gibbs, J.; Hernandez-Ilizaliturri, F.J.; Czuczman, M.S. Distinct molecular mechanisms responsible for bortezomib-induced death of therapy-resistant versus -sensitive B-NHL cells. Blood, 2010, 116(25), 5605-5614.
Barr, P.; Fisher, R.; Friedberg, J. The role of bortezomib in the treatment of lymphoma. Cancer Invest., 2007, 25(8), 766-775.
Bil, J.; Winiarska, M.; Nowis, D.; Bojarczuk, K.; Dabrowska-Iwanicka, A.; Basak, G.W.; Sułek, K.; Jakobisiak, M.; Golab, J. Bortezomib modulates surface CD20 in B-cell malignancies and affects rituximab-mediated complement-dependent cytotoxicity. Blood, 2010, 115(18), 3745-3755.
Advani, R.H.; Buggy, J.J.; Sharman, J.P.; Smith, S.M.; Boyd, T.E.; Grant, B.; Kolibaba, K.S.; Furman, R.R.; Rodriguez, S.; Chang, B.Y.; Sukbuntherng, J.; Izumi, R.; Hamdy, A.; Hedrick, E.; Fowler, N.H. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J. Clin. Oncol., 2013, 31(1), 88-94.
Johnston, P.B.; LaPlant, B.; McPhail, E.; Habermann, T.M.; Inwards, D.J.; Micallef, I.N. Everolimus combined with R-CHOP-21 for new, untreated, diffuse large B-cell lymphoma (NCCTG 1085 [Alliance]): Safety and efficacy results of a phase 1 and feasibility trial. Lancet Haematol., 2016, 3(7), e309-e316.
Galustian, C.; Meyer, B.; Labarthe, M.C.; Dredge, K.; Klaschka, D.; Henry, J.; Todryk, S.; Chen, R.; Muller, G.; Stirling, D.; Schafer, P.; Bartlett, J.B.; Dalgleish, A.G. The anti-cancer agents lenalidomide and pomalidomide inhibit the proliferation and function of T regulatory cells. Cancer Immunol. Immunother., 2009, 58(7), 1033-1045.
Nowakowski, G.S.; LaPlant, B.; Macon, W.R.; Reeder, C.B.; Foran, J.M.; Nelson, G.D.; Thompson, C.A.; Rivera, C.E.; Inwards, D.J.; Micallef, I.N.; Johnston, P.B.; Porrata, L.F.; Ansell, S.M.; Gascoyne, R.D.; Habermann, T.M.; Witzig, T.E. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell lymphoma: a phase II study. J. Clin. Oncol., 2015, 33(3), 251-257.
Chiappella, A.; Tucci, A.; Castellino, A.; Pavone, V.; Baldi, I.; Carella, A.M.; Orsucci, L.; Zanni, M.; Salvi, F.; Liberati, A.M.; Gaidano, G.; Bottelli, C.; Rossini, B.; Perticone, S.; De Masi, P.; Ladetto, M.; Ciccone, G.; Palumbo, A.; Rossi, G.; Vitolo, U. Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated, elderly patients with diffuse large B-cell lymphoma: A phase I study by the Fondazione Italiana Linfomi. Haematologica, 2013, 98(11), 1732-1738.
Kohrt, H.E.; Houot, R.; Goldstein, M.J.; Weiskopf, K.; Alizadeh, A.A.; Brody, J.; Müller, A.; Pachynski, R.; Czerwinski, D.; Coutre, S.; Chao, M.P.; Chen, L.; Tedder, T.F.; Levy, R. CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. Blood, 2011, 117(8), 2423-2432.
Kohrt, H.E.; Thielens, A.; Marabelle, A.; Sagiv-Barfi, I.; Sola, C.; Chanuc, F.; Fuseri, N.; Bonnafous, C.; Czerwinski, D.; Rajapaksa, A.; Waller, E.; Ugolini, S.; Vivier, E.; Romagné, F.; Levy, R.; Bléry, M.; André, P. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood, 2014, 123(5), 678-686.
Deguine, J.; Breart, B.; Lemaître, F.; Bousso, P. Cutting edge: tumor-targeting antibodies enhance NKG2D-mediated NK cell cytotoxicity by stabilizing NK cell-tumor cell interactions. J. Immunol., 2012, 189(12), 5493-5497.
Bhatt, S.; Parvin, S.; Zhang, Y.; Cho, H.M.; Kunkalla, K.; Vega, F.; Timmerman, J.M.; Shin, S.U.; Rosenblatt, J.D.; Lossos, I.S. Anti-CD20-Interleukin-21 fusokine targets malignant B-cells via direct apoptosis and NK-cell dependent cytotoxicity. Blood, 2017, 129(16), 2246-2256.
Jurczak, W.; Zinzani, P.L.; Gaidano, G.; Goy, A.; Provencio, M.; Nagy, Z.; Robak, T.; Maddocks, K.; Buske, C.; Ambarkhane, S.; Winderlich, M.; Dirnberger-Hertweck, M.; Korolkiewicz, R.; Blum, K.A. Phase IIa study of the CD19 antibody MOR208 in patients with relapsed or refractory B-cell non-Hodgkin’s lymphoma. Ann. Oncol., 2018, 29(5), 1266-1272.
Schuster, S.J.; Svoboda, J.; Chong, E.A.; Nasta, S.D.; Mato, A.R.; Anak, Ö.; Brogdon, J.L. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N. Engl. J. Med., 2017, 377(26), 2545-2554.
Lesokhin, A.M.; Ansell, S.M.; Armand, P.; Scott, E.C.; Halwani, A.; Gutierrez, M.; Millenson, M.M.; Cohen, A.D.; Schuster, S.J.; Lebovic, D.; Dhodapkar, M. Nivolumab in patients with relapsed or refractory hematologic malignancy: Preliminary results of a phase 1b study. J. Clin. Oncol., 2016, 34(23), 2698-2704.
Hayashi, K.; Nagasaki, E.; Kan, S.; Ito, M.; Kamata, Y.; Homma, S.; Aiba, K. Gemcitabine enhances rituximab-mediated complement-dependent cytotoxicity to B cell lymphoma by CD20 upregulation. Cancer Sci., 2016, 107(5), 682-689.
Vega, G.G.; Franco-Cea, L.A.; Huerta-Yepez, S.; Mayani, H.; Morrison, S.L.; Bonavida, B.; Vega, M.I. Overcoming rituximab drug-resistance by the genetically engineered anti-CD20-hIFN-α fusion protein: Direct cytotoxicity and synergy with chemotherapy. Int. J. Oncol., 2015, 47(5), 1735-1748.
Richter, M.; Yumul, R.; Saydaminova, K.; Wang, H.; Gough, M.; Baldessari, A.; Cattaneo, R.; Lee, F.; Wang, C.H.; Jang, H.; Astier, A.; Gopal, A.; Carter, D.; Lieber, A. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic. Mol. Ther. Methods Clin. Dev., 2016, 5, 16013.

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