634
Views
44
CrossRef citations to date
0
Altmetric
Reviews

Molecular mechanisms of resistance to Rituximab and pharmacologic strategies for its circumvention

& , M.D.
Pages 873-885 | Received 03 Mar 2009, Accepted 07 Mar 2009, Published online: 21 Jul 2009

References

  • Cheson B D, Leonard J P. Drug therapy: monoclonal antibody therapy for B-cell non-Hodgkin's lymphoma. N Engl J Med 2008; 359: 613–626
  • Maloney D G, GrilloLopez A J, White C A, Bodkin D, Schilder R J, Neidhart J A, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 1997; 90: 2188–2195
  • McLaughlin P, Grillo-Lopez A J, Link B K, Levy R, Czuczman M S, Williams M E, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: 2825–2833
  • Treon S P, Agus T B, Link B, Rodrigues G, Molina A, Lacy M Q, et al. CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom's macroglobulinemia. J Immunother 2001; 24: 272–279
  • Ghielmini M, Schmitz S FH, Cogliatti S B, Pichert G, Hummerjohann J, Waltzer U, et al. Prolonged treatment with Rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly × 4 schedule. Blood 2004; 103: 4416–4423
  • Tsimberidou A M, Catovsky D, Schlette E, O'Brien S, Wierda W G, Kantarjian H, et al. Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with Rituximab with or without chemotherapy or chemotherapy alone. Cancer 2006; 107: 125–135
  • Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP chemotherapy plus Rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 2002; 346: 235–242
  • Hiddemann W, Kneba M, Dreyling M, Schmitz N, Lengfelder E, Schmits R, et al. Frontline therapy with Rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005; 106: 3725–3732
  • Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, et al. CHOP-like chemotherapy plus Rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379–391
  • Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 1998; 92: 1927–1932
  • Nadler L M, Ritz J, Hardy R, Pesando J M, Schlossman S F, Stashenko P. A unique cell-surface antigen identifying lymphoid malignancies of B-cell origin. J Clin Investig 1981; 67: 134–140
  • Stashenko P, Nadler L M, Hardy R, Schlossman S F. Characterization of a human lymphocyte-B-specific antigen. J Immunol 1980; 125: 1678–1685
  • Ernst J A, Li H, Kim H S, Nakamura G R, Yansura D G, Vandlen R L. Isolation and characterization of the B-cell marker CD20. Biochemistry 2005; 44: 15150–15158
  • Binder M, Otto F, Mertelsmann R, Veelken H, Trepel M. The epitope recognized by Rituximab. Blood 2006; 108: 1975–1978
  • Polyak M J, Deans J P. Alanine-170 and proline-172 are critical determinants for extracellular CD20 epitopes; heterogeneity in the fine specificity of CD20 monoclonal antibodies is defined by additional requirements imposed by both amino acid sequence and quaternary structure. Blood 2002; 99: 3256–3262
  • Ishibashi K, Suzuki M, Sasaki S, Imai M. Identification of a new multigene four-transmembrane family (MS4A) related to CD20, HTm4 and β subunit of the high-affinity IgE receptor. Gene 2001; 264: 87–93
  • Hemler M E. Tetraspanin functions and associated microdomains. Nat Rev Mol Cell Biol 2005; 6: 801–811
  • O'Keefe T L, Williams G T, Davies S L, Neuberger M S. Mice carrying a CD20 gene disruption. Immunogenetics 1998; 48: 125–132
  • Uchida J, Lee Y, Hasegawa M, Liang Y H, Bradney A, Oliver J A, et al. Mouse CD20 expression and function. Int Immunol 2004; 16: 119–129
  • Tedder T F, Engel P. Cd20 – a regulator of cell-cycle progression of B-lymphocytes. Immunol Today 1994; 15: 450–454
  • Polyak M J, Li H D, Shariat N, Deans J P. CD20 homo-oligomers physically associate with the B cell antigen receptor – dissociation upon receptor engagement and recruitment of phosphoproteins and calmodulin-binding proteins. J Biol Chem 2008; 283: 18545–18552
  • Walshe C A, Beers S A, French R R, Chan C HT, Johnson P W, Packham G K, et al. Induction of cytosolic calcium flux by CD20 is dependent upon B cell antigen receptor signaling. J Biol Chem 2008; 283: 16971–16984
  • Hsueh R C, Scheuermann R H. Tyrosine kinase activation in the decision between growth, differentiation, and death responses initiated from the B cell antigen receptor. Adv Immunol 2000; 75: 283–316
  • Kurosaki T. Regulation of B-cell signal transduction by adaptor proteins. Nat Rev Immunol 2002; 2: 354–363
  • Pierce S K. Lipid rafts and B-cell activation. Nat Rev Immunol 2002; 2: 96–105
  • Petrie R J, Deans J P. Colocalization of the B cell receptor and CD20 followed by activation-dependent dissociation in distinct lipid rafts. J Immunol 2002; 169: 2886–2891
  • Scharenberg A M, Humphries L A, Rawlings D J. Calcium signalling and cell-fate choice in B cells. Nat Rev Immunol 2007; 7: 778–789
  • Harwood N E, Batista F D. New insights into the early molecular events underlying B cell activation. Immunity 2008; 28: 609–619
  • Haidar J H, Shamseddine A, Salem Z, Mrad Y A, Nasr M R, Zaatari G, et al. Loss of CD20 expression in relapsed lymphomas after Rituximab therapy. Eur J Haematol 2003; 70: 330–332
  • Kennedy G A, Tey S K, Cobcroft R, Marlton P, Cull G, Grimmett K, et al. Incidence and nature of CD20-negative relapses following Rituximab therapy in aggressive B-cell non-Hodgkin's lymphoma: a retrospective review. Br J Haematol 2002; 119: 412–416
  • varo-Naranjo T, Jaen-Martinez J, Guma-Padro J, Bosch-Princep R, Salvado-Usach M T. CD20-negative DLBCL transformation after Rituximab treatment in follicular lymphoma: a new case report and review of the literature. Ann Hematol 2003; 82: 585–588
  • 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: 792–797
  • Johnson N A, Leach S, Woolcock B, Deleeuw R J, Bashashati A, Sehn L H, et al. 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: 423–427
  • Hiraga J, Tomita A, Sugimoto T, Shimada K, Ito M, Nakamura S, et al. Down-regulation of CD20 expression in B-cell lymphoma cells after treatment with Rituximab-containing combination chemotherapies: its prevalence and clinical significance. Blood 2009, DOI 10.1182/blood-2008-08-175208
  • Wojciechowski W, Li H F, Marshall S, Dell'Agnola C, Espinoza-Delgado I. Enhanced expression of CD20 in human tumor B cells is controlled through ERK-dependent mechanisms. J Immunol 2005; 174: 7859–7868
  • Czuczman M S, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, et al. Acquirement of Rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and post-transcriptional levels. Clin Cancer Res 2008; 14: 1561–1570
  • Winiarska M, Bil J, Wilczek E, Wilczynski G M, Lekka M, Engelberts P J, et al. Statins impair antitumor effects of Rituximab by inducing conformational changes of CD20. PLoS Med 2008; 5: 502–517
  • Bannerji R, Kitada S, Flinn I W, Pearson M, Young D, Reed J C, et al. Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo Rituximab resistance. J Clin Oncol 2003; 21: 1466–1471
  • Czuczman M S, Olejniczak S, Gowda A, Kotowski A, Binder A, Kaur H, et al. Acquirement of Rituximab resistance in lymphoma cell lines is associated with both global CD20 gene and protein down-regulation regulated at the pretranscriptional and post-transcriptional levels. Clin Cancer Res 2008; 14: 1561–1570
  • Olejniczak S H, Hernandez-Ilizaliturri F J, Clements J L, Czuczman M S. Acquired resistance to rituximeb is associated with chemotherapy resistance resulting from decreased Bax and Bak expression. Clin Cancer Res 2008; 14: 1550–1560
  • Mankai A, Bordon A, Renaudineau Y, Martins-Carvalho C, Takahashi S, Ghedira I, et al. Purine-rich box-1-mediated reduced expression of CD20 alters Rituximab-induced lysis of chronic lymphocytic leukemia B cells. Cancer Res 2008; 68: 7512–7519
  • Chan H TC, Hughes D, French R R, Tutt A L, Walshe C A, Teeling J L, et al. CD20-induced lymphoma cell death is independent of both caspases and its redistribution into Triton X-100 insoluble membrane rafts. Cancer Res 2003; 63: 5480–5489
  • Janas E, Priest R, Wilde J I, White J H, Malhotra R. Rituxan (anti-CD20 antibody)-induced translocation of CD20 into lipid rafts is crucial for calcium influx and apoptosis. Clin Exp Immunol 2005; 139: 439–446
  • Deans J P, Kalt L, Ledbetter J A, Schieven G L, Bolen J B, Johnson P. Association of 75/80-Kda phosphoproteins and the tyrosine kinases Lyn, Fyn, and Lck with the B-cell molecule-Cd20 – evidence against involvement of the cytoplasmic regions of Cd20. J Biol Chem 1995; 270: 22632–22638
  • Bezombes C, Grazide S, Garret C, Fabre C, Quillet-Mary A, Muller S, et al. Rituximab antiproliferative effect in B-lymphoma cells is associated with acid-sphingomyelinase activation in raft microdomains. Blood 2004; 104: 1166–1173
  • Bonavida B. ‘Rituximab-induced inhibition of antiapoptotic cell survival pathways: implications in chemo/immunoresistance, Rituximab unresponsiveness, prognostic and novel therapeutic interventions’. Oncogene 2007; 26: 3629–3636
  • Suzuki E, Umezawa K, Bonavida B. Rituximab inhibits the constitutively activated PI3K-Akt pathway in B-NHL cell lines: involvement in chemosensitization to drug-induced apoptosis. Oncogene 2007; 26: 6184–6193
  • Jazirehi A R, Vega M I, Chatterjee D, Goodglick L, Bonavida B. Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-(xL) down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. Cancer Res 2004; 64: 7117–7126
  • Jazirehi A R, Huerta-Yepez S, Cheng G H, Bonavida B. Rituximab-mediated inhibition of the constitutive NIK/IKK/I κ B/NF-κ B signaling pathway in non-Hodgkin's lymphoma (NHL) B-cell lines: role in chemo-sensitization. Blood 2004; 104: 86A
  • Vega M I, Huerta-Yepaz S, Garban H, Jazirehi A, Emmanouilides C, Bonavida B. Rituximab inhibits p38 MAPK activity in 2F7 BNHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance. Oncogene 2004; 23: 3530–3540
  • Stolz C, Hess G, Hahnel P S, Grabellus F, Hoffarth S, Schmid K W, et al. Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to Rituximab-induced apoptosis. Blood 2008; 112: 3312–3321
  • Vega M I, Huerta-Yepaz S, Garban H, Jazirehi A, Emmanouilides C, Bonavida B. Rituximab inhibits p38 MAPK activity in 2F7 BNHL and decreases IL-10 transcription: pivotal role of p38 MAPK in drug resistance. Oncogene 2004; 23: 3530–3540
  • Pedersen I M, Buhl A M, Klausen P, Geisler C H, Jurlander J. The chimeric anti-CD20 antibody Rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism. Blood 2002; 99: 1314–1319
  • Leseux L, Laurent G, Laurent C, Rigo M, Blanc A, Olive D, et al. PKC zeta-mTOR pathway: a new target for Rituximab therapy in follicular lymphoma. Blood 2008; 111: 285–291
  • Tomita A, Hiraga J, Kiyoi H, Ninomiya M, Sugimoto T, Ito M, et al. Epigenetic regulation of CD20 protein expression in a novel B-cell lymphoma cell line, RRBL1, established from a patient treated repeatedly with Rituximab-containing chemotherapy. Int J Hematol 2007; 86: 49–57
  • 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: 1270–1281
  • Dalle S, Dupire S, Brunet-Manquat S, Reslan L, Plesa A, Dumontet C. In vivo model of follicular lymphoma resistant to Rituximab. Clin Cancer Res 2009; 15: 851–857
  • Bader A G, Kang S Y, Zhao L, Vogt P K. Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 2005; 5: 921–929
  • Uddin S, Hussain A R, Siraj A K, Manogaran P S, Al-Jomah N A, Moorji A, et al. Role of phosphatidylinositol 3′-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood 2006; 108: 4178–4186
  • Yuan T L, Cantley L C. PI3K pathway alterations in cancer: variations on a theme. Oncogene 2008; 27: 5497–5510
  • Garcia-Echeverria C, Sellers W R. Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 2008; 27: 5511–5526
  • Wanner K, Hipp S, Oelsner M, Ringshausen I, Bogner C, Peschel C, et al. Mammalian target of rapamycin inhibition induces cell cycle arrest in diffuse large B cell lymphoma (DLBCL) cells and sensitises DLBCL cells to Rituximab. Br J Haematol 2006; 134: 475–484
  • Igney F H, Krammer P H. Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002; 2: 277–288
  • Wobser M, Voigt H, Eggert A O, Houben R, Kauczok C S, Brocker E B, et al. Bcl-2 expression in Rituximab refractory cutaneous B-cell lymphoma. Br J Cancer 2007; 96: 1540–1543
  • Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell 2007; 12: 171–185
  • Cragg M S, Glennie M J. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood 2004; 103: 2738–2743
  • Glennie M J, French R R, Cragg M S, Taylor R P. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007; 44: 3823–3837
  • Fischer L, Penack O, Gentilini C, Nogai A, Muessig A, Thiel E, et al. The anti-lymphoma effect of antibody-mediated immunotherapy is based on an increased degranulation of peripheral blood natural killer (NK) cells. Exp Hematol 2006; 34: 753–759
  • Wang S Y, Racila E, Taylor R P, Weiner G J. NK-cell activation and antibody-dependent cellular cytotoxicity induced by Rituximab-coated target cells is inhibited by the C3b component of complement. Blood 2008; 111: 1456–1463
  • Joshi T, Ganesan L P, Cheney C, Ostrowski M C, Muthusamy N, Byrd J C, et al. The PtdIns 3-kinase/Akt pathway regulates macrophage-mediated ADCC against B cell lymphoma. PLoS ONE 2009; 4: e4208
  • Hernandez-Ilizaliturri F J, Jupudy V, Ostberg J, Oflazoglu E, Huberman A, Repasky E, et al. Neutrophils contribute to the biological antitumor activity of Rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model. Clin Cancer Res 2003; 9: 5866–5873
  • Di Gaetano N, Cittera E, Nota R, Vecchi A, Grieco V, Scanziani E, et al. Complement activation determines the therapeutic activity of Rituximab in vivo. J Immunol 2003; 171: 1581–1587
  • Golay J, Cittera E, Di Gaetano N, Manganini M, Mosca M, Nebuloni M, et al. The role of complement in the therapeutic activity of Rituximab in a murine B lymphoma model homing in lymph nodes. Haematologica 2006; 91: 176–183
  • Introna M, Cittera E, Nota R, Grieco V, Vecchi A, Scanziani E, et al. Complement activation determines the therapeutic activity of Rituximab in vivo. Blood 2002; 100: 161A–162A
  • Zhou X, Hu W, Qin X. The role of complement in the mechanism of action of Rituximab for B-cell lymphoma: implications for therapy. Oncologist 2008; 13: 954–966
  • Manches O, Lui G, Chaperot L, Gressin R, Molens J P, Jacob M C, et al. In vitro mechanisms of action of Rituximab on primary non-Hodgkin lymphomas. Blood 2003; 101: 949–954
  • van Meerten T, van Rijn R S, Hol S, Hagenbeek A, Ebeling S B. Complement-induced cell death by Rituximab depends on CD20 expression level and acts complementary to antibody-dependent cellular cytotoxicity. Clin Cancer Res 2006; 12: 4027–4035
  • Cittera E, Leidi M, Buracchi C, Pasqualini F, Sozzani S, Vecchi A, et al. The CCL3 family of chemokines and innate immunity cooperate in vivo in the eradication of an established lymphoma xenograft by Rituximab. J Immunol 2007; 178: 6616–6623
  • zum Buschenfelde C M, Fetterstacke Y, Gotze K S, Scholze K, Peschel C. GM1 expression of non-Hodgkins lymphoma determines susceptibility to Rituximab treatment. Cancer Res 2008; 68: 5414–5422
  • Dall'Ozzo S, Tartas S, Paintaud G, Cartron G, Colombat P, Bardos P, et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration–effect relationship. Cancer Res 2004; 64: 4664–4669
  • Hatjiharissi E, Xu L A, Santos D D, Hunter Z R, Ciccarelli B T, Verselis S, et al. Increased natural killer cell expression of CD16, augmented binding and ADCC activity to Rituximab among individuals expressing the Fcγ RIIIa-158 V/V and V/F polymorphism. Blood 2007; 110: 2561–2564
  • Kim D H, Du Jung H, Kim J G, Lee J J, Yang D H, Park Y H, et al. FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma. Blood 2006; 108: 2720–2725
  • Nimmerjahn F, Ravetch J V. Fcγ receptors as regulators of immune responses. Nat Rev Immunol 2008; 8: 34–47
  • Racila E, Link B K, Weng W K, Witzig T E, Ansell S, Maurer M J, et al. A polymorphism in the complement component C1qA correlates with prolonged response following Rituximab therapy of follicular lymphoma. Clin Cancer Res 2008; 14: 6697–6703
  • Wang M, Han X H, Zhang L, Yang J, Qian J F, Shi Y K, et al. Bortezomib is synergistic with Rituximab and cyclophosphamide in inducing apoptosis of mantle cell lymphoma cells in vitro and in vivo. Leukemia 2008; 22: 179–185
  • Zhao W L, Wang L, Liu Y H, Yan J S, Leboeuf C, Liu Y Y, et al. Combined effects of histone deacetylase inhibitor and Rituximab on non-Hodgkin's B-lymphoma cells apoptosis. Exp Hematol 2007; 35: 1801–1811
  • Pro B, Leber B, Smith M, Fayad L, Romaguera J, Hagemeister F, et al. Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with Rituximab in patients with recurrent B-cell non-Hodgkin lymphoma. Br J Haematol 2008; 143: 355–360
  • Ramanarayanan J, Hernandez-Ilizaliturri F J, Chanan-Khan A, Czuczman M S. Pro-apoptotic therapy with the oligonucleotide Genasense (TM) (oblimersen sodium) targeting Bcl-2 protein expression enhances the biological anti-tumour activity of Rituximab. Br J Haematol 2004; 127: 519–530
  • Oltersdorf T, Elmore S W, Shoemaker A R, Armstrong R C, Augeri D J, Belli B A, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005; 435: 677–681
  • Konopleva M, Contractor R, Tsao T, Samudio I, Ruvalo P P, Kitada S, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006; 10: 375–388
  • van Delft M F, Wei A H, Mason K D, Vandenberg C J, Chen L, Czabotar P E, et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10: 389–399
  • Tse C, Shoemaker A R, Adickes J, Anderson M G, Chen J, Jin S, et al. ABT-263: a potent and orally bioavailable Bcl-2 family inhibitor. Cancer Res 2008; 68: 3421–3428
  • Ackler S, Xiao Y, Mitten M J, Foster K, Oleksijew A, Refici M, et al. ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. Mol Cancer Therapeut 2008; 7: 3265–3274
  • Daniel D, Yang B, Lawrence D A, Totpal K, Balter I, Lee W P, et al. Cooperation of the proapoptotic receptor agonist rhApo2L/TRAIL with the CD20 antibody Rituximab against non-Hodgkin lymphoma xenografts. Blood 2007; 110: 4037–4046
  • Maddipatla S, Hernandez-Ilizaliturri F J, Knight J, Czuczman M S. Augmented antitumor activity against B-cell lymphoma by a combination of monoclonal antibodies targeting TRAIL-R1 and CD20. Clin Cancer Res 2007; 13: 4556–4564
  • Stel A J, ten Cate B, Jacobs S, Kok J W, Spierings D CJ, Dondorff M, et al. Fas receptor clustering and involvement of the death receptor pathway in Rituximab-mediated apoptosis with concomitant sensitization of lymphoma B cells to Fas-induced apoptosis. J Immunol 2007; 178: 2287–2295
  • Leonard J P, Friedberg J W, Younes A, Fisher D, Gordon L I, Moore J, et al. A phase I/II study of galiximab (an anti-CD80 monoclonal antibody) in combination with Rituximab for relapsed or refractory, follicular lymphoma. Ann Oncol 2007; 18: 1216–1223
  • Zent C S, Call T G, Shanafelt T D, Tschumper R C, Jelinek D F, Bowen D A, et al. Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and Rituximab. Cancer 2008; 113: 2110–2118
  • Smolewski P, Duechler M, Linke A, Cebula B, Grzybowska-Izydorczyk O, Shehata M, et al. Additive cytotoxic effect of bortezomib in combination with anti-CD20 or anti-CD52 monoclonal antibodies on chronic lymphocytic leukemia cells. Leuk Res 2006; 30: 1521–1529
  • Cruz R I, Hernandez-Ilizaliturri F J, Olejniczak S, Deeb G, Knight J, Wallace P, et al. CD52 over-expression affects Rituximab-associated complement-mediated cytotoxicity but not antibody-dependent cellular cytotoxicity: preclinical evidence that targeting CD52 with alemtuzumab may reverse acquired resistance to Rituximab in non-Hodgkin lymphoma. Leuk Lymphoma 2007; 48: 2424–2436
  • Tobin E, Denardo G, Zhang N, Epstein A L, Liu C, DeNardo S. Combination immunotherapy with anti-CD20 and anti-HLA-DR monoclonal antibodies induces synergistic anti-lymphoma effects in human lymphoma cell lines. Leuk Lymphoma 2007; 48: 944–956
  • Leonard J P, Schuster S J, Emmanouilides C, Couture F, Teoh N, Wegener W A, et al. Durable complete responses from therapy with combined epratuzumab and Rituximab final results from an international multicenter, phase 2 study in recurrent, indolent, non-Hodgkin lymphoma. Cancer 2008; 113: 2714–2723
  • Brusamolino E, Rusconi C, Montalbetti L, Gargantini L, Uziel L, Pinotti G, et al. Dose-dense R-CHOP-14 supported by pegfilgrastim in patients with diffuse large B-cell lymphoma: a phase II study of feasibility and toxicity. Haematologica 2006; 91: 496–502
  • Waller E K. The role of sargramostim (rhGM-CSF) as immunotherapy. Oncologist 2007; 12: 22–26
  • Schuster S J, Venugopal P, Kern J C, McLaughlin P. GM-CSF plus Rituximab immunotherapy: translation of biologic mechanisms into therapy for indolent B-cell lymphomas. Leuk Lymphoma 2008; 49: 1681–1692
  • Hashino S, Morioka M, Irie T, Shiroshita N, Kawamura T, Suzuki S, et al. Cost benefit and clinical efficacy of low-dose granulocyte colony-stimulating factor after standard chemotherapy in patients with non-Hodgkin's lymphoma. Int J Lab Hematol 2008; 30: 292–299
  • Berdeja J G, Hess A, Lucas D M, O'Donnell P, Ambinder R F, Diehl L F, et al. Systemic interleukin-2 and adoptive transfer of lymphokine-activated killer cells improves antibody-dependent cellular cytotoxicity in patients with relapsed B-cell lymphoma treated with Rituximab. Clin Cancer Res 2007; 13: 2392–2399
  • de Menezes D EL, is-Mize K, Tang Y, Ye H, Kunich J C, Garrett E N, et al. Recombinant interleukin-2 significantly augments activity of Rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma. J Immunother 2007; 30: 64–74
  • Khan K D, Emmanouilides C, Benson D M, Hurst D, Garcia P, Michelson G, et al. A phase 2 study of Rituximab in combination with recombinant interleukin-2 for Rituximab-refractory indolent non-Hodgkin's lymphoma. Clin Cancer Res 2006; 12: 7046–7053
  • Ansell S M, Geyer S M, Maurer M J, Kurtin P J, Micallef I NM, Stella P, et al. Randomized phase II study of interleukin-12 in combination with Rituximab in previously treated non-Hodgkin's lymphoma patients. Clin Cancer Res 2006; 12: 6056–6063
  • Ansell S M, Witzig T E, Kurtin P J, Sloan J A, Jelinek D F, Howell K G, et al. Phase 1 study of interleukin-12 in combination with Rituximab in patients with B-cell non-Hodgkin lymphoma. Blood 2002; 99: 67–74
  • Gowda A, Roda J, Hussain S RA, Ramanunni A, Joshi T, Schmidt S, et al. IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro. Blood 2008; 111: 4723–4730
  • Kimby E, Jurlander J, Geisler C, Hagberg H, Holte H, Lehtinen T, et al. Long-term molecular remissions in patients with indolent lymphoma treated with Rituximab as a single agent or in combination with interferon α- 2a: a randomized phase II study from the Nordic Lymphoma Group. Leuk Lymphoma 2008; 49: 102–112
  • Herold M, Haas A, Srock S, Neser S, Al-Ali K H, Neubauer A, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group hematology and oncology study. J Clin Oncol 2007; 25: 1986–1992
  • Moga E, Alvareza E, Canto E, Vidal S, Rodriguez-Sanchez J L, Sierra J, et al. NK cells stimulated with IL-15 or CpG ODN enhance Rituximab-dependent cellular cytotoxicity against B-cell lymphoma. Exp Hematol 2008; 36: 69–77
  • Friedberg J W, Kim H, McCauley M, Hessel E M, Sims P, Fisher D C, et al. Combination immunotherapy with a CpG oligonucleotide (1018 ISS) and Rituximab in patients with non-Hodgkin lymphoma: increased interferon-α/β-inducible gene expression, without significant toxicity. Blood 2005; 105: 489–495
  • Lapalombella R, Gowda A, Joshi T, Mehter N, Cheney C, Lehman A, et al. The humanized CD40 antibody SGN-40 demonstrates pre-clinical activity that is enhanced by lenalidomide in chronic lymphocytic leukaemia. Br J Haematol 2009; 144: 848–855
  • Lapalombella R, Yu B, Triantafillou G, Liu Q, Butchar J P, Lozanski G, et al. Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of Rituximab on primary chronic lymphocytic leukemia cells. Blood 2008; 112: 5180–5189
  • Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, et al. Lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of Rituximab-treated CD20(+) tumor cells. Clin Cancer Res 2008; 14: 4650–4657
  • Reddy N, Hernandez-Ilizaliturri F J, Deeb G, Roth M, Vaughn M, Knight J, et al. Immunomodulatory drugs stimulate natural killer-cell function, alter cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity of Rituximab in vivo. Br J Haematol 2008; 140: 36–45
  • Gerber H P, Stone I, Kung-Sutherland M, Miyamoto J, Okeley N, Alley S C, et al. Potent antitumor activity of the anti-CD19 auristatin antibody-drug conjugate hBU12-vcMMAE in Rituximab sensitive and resistant lymphomas. Eur J Cancer (Suppl) 2008; 6: 161
  • Horning S J, Younes A, Jain V, Kroll S, Lucas J, Podoloff D, et al. Efficacy and safety of tositumomab and iodine-131 tositumomab (Bexxar) in B-Cell lymphoma, progressive after Rituximab. J Clin Oncol 2005; 23: 712–719
  • Press O W, Unger J M, Braziel R M, Maloney D G, Miller T P, LeBlanc M, et al. A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911. Blood 2003; 102: 1606–1612
  • Jacobs S A, Swerdlow S H, Kant J, Foon K A, Jankowitz R, Land S R, et al. Phase II trial of short-course CHOP-R followed by Y-90-ibritumomab tiuxetan and extended Rituximab in previously untreated follicular lymphoma. Clin Cancer Res 2008; 14: 7088–7094
  • Hagenbeek A, Gadeberg O, Johnson P, Pedersen L M, Walewski J, Hellmann A, et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood 2008; 111: 5486–5495
  • Stanglmaier M, Faltin M, Ruf P, Bodenhausen A, Schroder P, Lindhofer H. Bi20 (FBTA05), a novel trifunctional bispecific antibody (anti-CD20 × anti-CD3), mediates efficient killing of B-cell lymphoma cells even with very low CD20 expression levels. Int J Cancer 2008; 123: 1181–1189
  • Micallef I NM, Kahl B S, Maurer M J, Dogan A, Ansell S M, Colgan J P, et al. A pilot study of epratuzumab and Rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated, diffuse large B-cell lymphoma. Cancer 2006; 107: 2826–2832
  • DiJoseph J F, Dougher M M, Kalyandrug L B, Armellino D C, Boghaert E R, Hamann P R, et al. Antitumor efficacy of a combination of CMC-544 (inotuzumab ozogamicin), a CD22-targeted cytotoxic immunoconjugate of calicheamicin, and Rituximab against non-Hodgkin's B-cell lymphoma. Clin Cancer Res 2006; 12: 242–249
  • Pathan N I, Chu P, Hariharan K, Cheney C, Molina A, Byrd J. Mediation of apoptosis by and antitumor activity of lumiliximab in chronic lymphocytic leukemia cells and CD23(+) lymphoma cell lines. Blood 2008; 111: 1594–1602
  • Law C L, Gordon K A, Collier J, Klussman K, McEarchern J A, Cerveny C G, et al. Preclinical antilymphoma activity of a humanized anti-CD40 monoclonal antibody, SGN-40. Cancer Res 2005; 65: 8331–8338
  • Zent C S, Secreto C R, LaPlant B R, Bone N D, Call T G, Shanafelt T D, et al. Direct and complement dependent cytotoxicity in CLL cells from patients with high-risk early-intermediate stage chronic lymphocytic leukemia (CLL) treated with alemtuzumab and Rituximab. Leuk Res 2008; 32: 1849–1856
  • Tobin E, Denardo G, Zhang N, Epstein A L, Liu C, DeNardo S. Combination immunotherapy with anti-CD20 and anti-HLA-DR monoclonal antibodies induces synergistic anti-lymphoma effects in human lymphoma cell lines. Leuk Lymphoma 2007; 48: 944–956
  • Ganjoo K N, An C S, Robertson M J, Gordon L I, Sen J A, Weisenbach J, et al. Rituximab, Bevacizumab and CHOP (RA-CHOP) in untreated diffuse large B-cell lymphoma: safety, biomarker and pharmacokinetic analysis. Leuk Lymphoma 2006; 47: 998–1005
  • Paoluzzi L, Gonen M, Gardner J R, Mastrella J, Yang D J, Holmlund J, et al. Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. Blood 2008; 111: 5350–5358
  • Stolz C, Hess G, Hahnel P S, Grabellus F, Hoffarth S, Schmid K W, et al. Targeting Bcl-2 family proteins modulates the sensitivity of B-cell lymphoma to Rituximab-induced apoptosis. Blood 2008; 112: 3312–3321
  • Vega M I, Martinez-Paniagua M, Jazirehi A R, Huerta-Yepez S, Umezawa K, Martinez-Maza O, et al. The NF-κB inhibitors (bortezomib and DHMEQ) sensitise Rituximab-resistant AIDS-B-non-Hodgkin lymphoma to apoptosis by various chemotherapeutic drugs. Leuk Lymphoma 2008; 49: 1982–1994
  • Johnson A J, Wagner A J, Cheney C M, Smith L L, Lucas D M, Guster S K, et al. Rituximab and 17-allylamino-17-demethoxygeldanamycin induce synergistic apoptosis in B-cell chronic lymphocytic leukaemia. Br J Haematol 2007; 139: 837–844

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.