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Rituximab Therapy in Malignant Lymphoma

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Rituximab Therapy in Malignant Lymphoma Oncogene (2007) 26, 3603–3613 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Rituximab therapy in malignant lymphoma B Coiffier Hematology Department, Hospices Civils de Lyon and Claude Bernard University, Pierre-Benite, France Rituximab is the first monoclonal antibody to have been indication of indolent B-cell lymphomas to virtually any registered for the treatment of B-cell lymphomas. CD20-positive lymphoma. Randomized studies haves demonstrated its activity in follicular lymphoma (FL), mantle cell lymphoma and diffuse large B-cell lymphoma (DLBCL) in untreated or relapsing patients. Non-comparative studies have shown Mechanisms of action of rituximab an activity in all other lymphomas. Because of its high activity and low toxicity ratio, rituximab has transformed The mechanisms of action of MAbdiffer with the type the outcome of patients with B-cell lymphoma. A combi- of antibody, the antigen they target and their use: alone, in combination with chemotherapy, conjugated to a nation of rituximab plus chemotherapy, rituximab þ toxin or a radionucleide. In case of rituximab, different cyclophosphamide þ doxorubicin þ vincristine þ prednisolone et al (R-CHOP), has the highest efficacy ever described with mechanisms have been identified (Cartron ., 2004). any chemotherapy in DLBCL and FL. Some patients are CD20 binding by rituximab is followed by homotypic refractory to rituximab but the precise mechanisms of this aggregation, rapid translocation of CD20 into specia- refractoriness are not understood. lized plasma membrane microdomains known as rafts Oncogene (2007) 26, 3603–3613. doi:10.1038/sj.onc.1210376 and induction of apoptosis. Membrane rafts concentrate src family kinases and other signaling molecules y Keywords: rituximab; R-CHOP; follicular lymphoma; (phospholipases, caspases ), and the anti-CD20- diffuse large B-cell lymphoma; monoclonal antibodies induced apoptotic signals are though to occur as a consequence of CD20 accumulation in rafts (Janas et al., 2005). The role of complement-dependent cytotoxicity (CDC) is suggested by the consumption of complement observed after rituximab administration but in vitro CDC does not correlate with clinical Introduction response in lymphomas (Winkler et al., 1999; Weng and Levy, 2001). However, CDC seems to be the most Non-Hodgkin’s lymphoma is a heterogeneous group of important mechanism of cell lysis in chronic lymphocy- B- and T-cell cancers, with a large variety of patterns of tic leukemia (CLL) patients (Kennedy et al., 2004). growth, clinical presentations and responses to treat- CDC is probably involved in the cytokine-release ment. Outcome depends on histological subtype, tumor syndrome and its toxicity (Bienvenu et al., 2001). characteristics host responses and treatment. About The importance of antibody-dependent cellular cyto- 90% of lymphomas have a B-cell phenotype and for toxicity (ADCC) has been demonstrated in vivo when them recent therapeutic progress came from the rituximabis used alone (Cartron et al., 2002). The Fc introduction of monoclonal antibodies (MAb) alone or receptor (FcgR) of effector cells has two alleles and the in combination with chemotherapy (Coiffier, 2005a,b; valine/valine (V/V) allele of FcgRIIIa that confers a Traulle and Coiffier, 2005). The first antigen that has higher affinity for IgG1 and rituximabis associated with been targeted for therapeutic purpose with success was an increase responsiveness to rituximab(Cartron et al., the CD20 antigen, a transmembrane protein expressed 2002; Weng and Levy, 2003). If the clinical relevance of by more than 99% of B-cell lymphomas. Rituximab was the FcgRIIIa receptor dimorphism was established in a the first MAbengineered to target the CD20 antigen and number of studies with rituximab used alone, it does not the first approved MAbfor the treatment of lymphoma seem to play a major role when rituximabis used in patients. Through the last 10 years clinical trials with combination with chemotherapy (Boettcher et al., 2004) rituximabhave confirmed its efficacy in follicular even if one study showed an increased response for lymphoma (FL) as well as in aggressive lymphomas patients with the V/V allele without difference for and its use has expanded significantly beyond the initial progression-free survival (PFS) or overall survival (OS) (Kim et al., 2006). Finally, evidences that rituximabcould synergize with Correspondence: Professor B Coiffier, Department of Hematology, chemotherapeutic agents in B-cell killing were provided CH Lyon-Sud, 69495 Pierre-Benite, France. by Demidem et al. (1997). Subsequent investigations E-mail: bertrand.coiffi[email protected] have confirmed synergy of rituximabwith fludarabine, Rituximab therapy B Coiffier 3604 doxorubicin and other anticancer drugs (Alas et al., bronchospasm, angioedema and acute lung injury, often 2000; Alas and Bonavida, 2001; Ghetie et al., 2001). In associated with high circulating cell counts or pre- one hypothesis, this synergism is mediated, at least in existing cardiac or pulmonary disease. part, via downregulation of interleukin-10 (IL-10) by Another common toxicity is the rapid depletion of rituximab, which in turn causes downregulation of the normal CD20-positive B lymphocytes from blood, bone antiapoptotic protein bcl2 and increased sensitivity to marrow and lymph nodes of the recipient, lasting apoptosis (Vega et al., 2004). Another mechanism between 3 and 6 months following the last administra- involves the inhibition of the activity of P-glycoprotein tion of rituximab. In the case of short rituximab and, thus, the efflux of drugs like doxorubicin or treatment, this depletion does not compromise immu- vincristine (Ghetie et al., 2006). In cell lines, the P- nity: immunoglobulins do not decrease significantly, and glycoprotein pump is translocated out of the lipids rafts. patients do not have an increased risk for infections This activity seems independent of the classical anti- during and after rituximabtherapy (Grillo-Lopez et al., proliferative effect of rituximab(Ghetie et al., 2006). 2002; Kimby, 2005), except for some virus like herpes virus, cytomegalovirus or hepatitis B virus. Maintenance treatment, particularly after autologous transplant, might be associated with a decrease in immunoglobulins Mechanisms of resistance (Lim et al., 2004) and late toxicity (Kimby, 2005). Rare toxic events comprised delayed neutropenia and If multiple mechanisms of rituximabaction have been pulmonary reactions. Delayed neutropenia usually reported, it remains unclear which is/are most important occurs in patients treated with rituximabalone or in in patients, and therefore it is difficult to know the combination with chemotherapy. It appears between relative importance of potential mechanisms of resis- 1 and 6 months after the last infusion, may be transient, tance. Conceptual approaches of resistance mechanisms rarely associated with infection and resolve sponta- may be resumed as followed (Smith, 2003). neously in most of the cases (Lemieux et al., 2004b). The Concerning events up to antigen binding, resistance to mechanisms are not fully understood. Pulmonary rituximabmay besecondary to low-serum levels or reactions are rare and diverse, usually related to rapid metabolism of the MAb; development of anti- rituximab because of the temporal relation (Kimby, monoclonal antibodies (HAMA), most frequent with 2005). nonhumanized antibodies than with rituximab or anti- chimeric (HACA) antibodies (not yet demonstrated in patients); possibly different distribution within malig- nant nodes, blood cells, marrow and extranodal sites Clinical studies and responsible for poor tumor penetration; high level of soluble antigen target (not yet demonstrated for A few MAbs have been registered for the treatment of CD20 antigen); high tumor burden; and poor surface lymphoma patients: rituximab(Rituxan or MabThera), antigen expression. 90Y-ibritumomab tiuxetan (Zevalin), 131I-tositumomab Events that may induce resistance to rituximabafter (Bexxar), and denileukin diftitox (OnTak), the last two the antigen binding are alteration of induced intracel- only in the USA. However, a lot of other MAbare lular signals; reduction of direct apoptosis effect in cases currently in preclinical studies, phase I or phase II of elevated bcl-2 protein; inhibition of CDC by studies. Rituximabis certainly the MAbwhere the complement inhibitors; and alteration of cell-mediated largest experience exists and the MAbwith several immunity. Gene microarray analysis has shown that demonstrative randomized studies. patients who failed to respond to rituximabhave altered patterns of gene expression, with an overexpression of genes important in cell-mediated immunity (Bohen Rituximab in FL et al., 2003). Rituximab alone in relapse When used alone, rituximabis usually given as four Safety and tolerability weekly injections of 375 mg/m2 (Maloney, 1999). The pivotal multicentre phase II study that included 166 The safety of rituximabis mainly related to infusion patients treated with four infusions of rituximabshowed toxicity, a toxicity most MAbhave in common (Kimby, an overall remission rate of 48% (including 6% of CR), 2005). These side effects are observed during the and a median time to progression of 13 months infusion or in the first hours after drug infusion and (McLaughlin et al., 1998). Elevated b2-microglobulin, particularly for the first infusion. They include fever, elevated LDH, bulky disease and age >60 years did not chills, dizziness, nausea, pruritus,
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