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 malignant 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, throat swelling, cough, appear to impact response, implying that patients fatigue, hypotension and transient bronchospasm in a regarded as having a poor prognosis may respond majority of patients. These symptoms are part of the to rituximab. Median rituximab serum levels were cytokine-release syndrome. Their intensity correlates significantly higher in responders, compared with the with the number of circulating malignant cells at time of non-responders (Berinstein et al., 1998). Mean serum infusion. More severe infusional toxicity includes antibody concentration was inversely correlated with

Oncogene Rituximab therapy B Coiffier 3605 the bulk of the disease and the number of circulating B have a relapse-free survival longer than 5 years and an cells, suggesting that patients with a higher tumor load excellent OS for all patients: only three deaths (Solal- might need higher doses or prolonged treatment, to Celigny et al., 2004). A randomized study is currently achieve the necessary serum levels (Gordan et al., 2005). underway in UK challenging this finding in these Patients relapsing after initial response to rituximab otherwise ‘watch and wait’ patients. treatment may be retreated with comparable response Rituximabalone was also studied in patients with a rates (RR) and adverse side effects, but, interestingly, more aggressive presentation, needing treatment at median time for progression might be longer than after diagnosis or after some follow-up without treatment first treatment (Davis et al., 2000a; Lemieux et al., (Hainsworth et al., 2002). The RR, just after four 2004a). Patients who progressed after rituximabretreat- infusions, was comparable with the one observed in ment respond again to further courses (Lemieux et al., relapsing patients (50% and less than 10% of CR). 2004a). About 10% of patients had progressive disease during Whether rituximabprolonged treatment or mainte- the immediate post-treatment period and progression nance is able to further improve RR and to prolong occurred in less than 12 months among 50% of the remission duration is of considerable interest. Several responding patients. If this schedule has the favor of arguments are in favor of this approach: the success of some physicians because it avoids chemotherapy, results re-treatment or the strong correlation between rituxi- are quite inferior to combination of chemotherapy and mabplasma levels and RR (Berinstein et al., 1998). A rituximab (see below) and no indication has yet been recent randomized trial showed that adding mainte- given regarding OS. In our opinion, it should not be the nance doses of rituximabprolonged response duration recommended choice of treatment until randomized (Ghielmini et al., 2004): 202 patients with newly trials have compared it to the combined treatment. diagnosed or refractory/relapsed FL were treated with In another study, Hainsworth et al. (2005) compared standard rituximab(375 mg/m 2 weekly Â 4). Patients prolonged treatment to retreatment at demand and did responding, or with stable disease, were randomized to not show any benefit in terms of duration of rituximab no further treatment or prolonged rituximabadminis- response or time to chemotherapy. This study has tration (375 mg/m2 every 2 months for four times). With several drawbacks, among them an early termination a median follow-up of 35 months, the median event-free and a lack of power to conclude. Thus the Eastern survival (EFS) was prolonged in the treated group, Cooperative Group has launched the RESORT study 23 months vs 12 months in the control group. In a (rituximabextended schedule or retreatment trial) to nonrandomized prospective study, prolonged treatment clarify this question (Kahl, 2006). in first-line patients seems also associated with a higher and longer efficacy (Hainsworth, 2004). However, in both studies, patients relapsed within the 6 months after Rituximab in combination with chemotherapy stopping rituximabtreatment. In another randomized In a phase II study, the combination of six cycles of study, Hainsworth et al. (2005) showed that retreatment CHOP (cyclophosphamide, doxorubicin, vincristine and at relapse or prolonged treatment have the same benefit prednisone) with rituximabgiven before,during, and in terms of duration of rituximabefficacy or time to after chemotherapy in 40 patients with predominantly chemotherapy. untreated FL increased the RR (55% CR and 40% PR), Several questions remain without clear response: what with no added related toxicity (Czuczman et al., 2005). is the optimal prolonged treatment? What is the optimal Median time to progression was 82 months. duration maintenance? Which patients benefit from Several randomized studies have now demonstrated prolonged treatment? And, finally, is prolonged treat- that the addition of rituximabto a standard chemo- ment or retreatment at progression better in terms of therapy regimen results in higher RR and longer time survival or impact on transformation rate? to progression and EFS for patients treated with a combination of rituximab plus chemotherapy in first- line or in first-relapse (Table 1). In first line patients, Rituximab alone in untreated FL four studies have reported a benefit in terms of CR rates Usually, patients with no adverse prognostic factors are and PFS, although an OS benefit was only showed in the not treated until they develop such adverse parameters two studies using a doxorubicin-containing regimen (Ardeshna et al.,. 2003). However, because of its low (Herold, 2004; Salles et al., 2004; Hiddemann et al., profile toxicity, its presumed low rate of secondary 2005; Marcus et al., 2005). The first study randomized malignancy and its lack of stem cell toxicity, rituximab patients between eight cycles of cyclophosphamide, single agent was investigated in this setting (Colombat vincristine and prednisone CVP and R-CVP (Marcus et al., 2001): in a series of 50 patients, a RR of 73% was et al., 2005). Overall and CR rates were 81 and 41% in obtained, with 26% of CR; 57% of the informative the R-CVP arm vs 57 and 10% in the CVP arm, patients in CR reached a molecular remission. However, respectively (Po0.0001). At a median follow-up of 53 even patients in CR and in molecular response did not months, patients treated with R-CVP had a highly seem to benefit from this treatment because the median significantly prolonged time to progression (median 32 time to progression was only 2 years, not longer than months vs 15 months for CVP; Po0.0001). Median time without treatment. A 5-year follow-up of this study to treatment failure was 27 months in patients receiving showed that some patients (34% of responders) may R-CVP and 7 months in the CVP arm (Po0.0001). OS

Oncogene Rituximab therapy B Coifﬁer 3606 Table 1 Randomized studies comparing chemotherapy with the combination of rituximab and chemotherapy in patients with follicular lymphoma Setting Response rates (%) CR rates (%) EFS Time to progression OS

First-line patients Marcus et al. (2005) R-CVP 81 41 27 m 32 m Not CVP 57** 10** 7 m** 15 m** different Hiddemann et al. (2003) R-CHOP 97 20 68 m 50 m Not analysed CHOP 90 17 21 m** 15 m** Salles et al. (2004) R-CHVP-Ifn Not analysed 79 Not reached Not reached Not analysed CHVP-Ifn 63** Herold (2004) R-MCP 85.50 42 Not reached Not reported Not reported MCP 65.5** 20** 19 m**

Relapsing patients Forstpointner et al., (2004, 2006) R-FCM 79 33 Not analyzed 16 m Not reached FCM 58** 13** 10 m* 24 m**

Adjuvant rituximab Hochster et al. (2004) CVP-R Not reported 30 Not reported 4.2 years Trend in favor of R CVP 22* 1.5 years**

Abbreviations: CHOP, chemotherapy; CR, complete response; CVP, cyclophosphamide, vincristine and prednisone; EFS, Event-free survival; FCM, fudarabine cyclophosphamide and mitoxantrone; MCP, mitoxantrone, cyclophosphamide and prednisone; OS, overall survival. *Po0.05; **Po0.01.

was longer for R-CVP than CVP (19 vs 29% patients patients treated with rituximab(91 compared to 84% died, P ¼ 0.03) (Marcus et al., 2006). surviving at 3.5 years, P ¼ 0.029). In the second study, patients were randomized In relapsing patients, the fudarabine cyclophospha- between six cycles of cyclophosphamide þ doxo- mide and mitoxantrone (FCM) study showed that rubicin þ vincristine þ prednisolone (CHOP) and rituxi- R-FCM is superior to FCM alone for relapsing patients mab(R)-CHOP (Hiddemann et al., 2005). In 428 with FL or mantle cell lymphoma (MCL) (Forstpointner patients, R-CHOP revealed a significantly higher RR et al., 2004). An update of this study showed that (96 vs 90%, P ¼ 0.011) and a longer treatment failure responding patients, treated either with FCM or R-FCM (TTF) (median not reached vs 2.6 years, Po0.0001). In had a prolonged PFS if they received a maintenance with the second German study, patients with indolent rituximab(Forstpointner et al., 2006). The EORTC lymphoma (56% follicular) were randomized between study compared R-CHOP and CHOP alone in first-or six cycles of MCP (mitoxantrone, cyclophosphamide second-line patients not previously treated with doxo- and prednisone) and R-MCP (Herold, 2004). The rubicin (van Oers et al., 2006). This last study is overall RR and the CR for all patients was 85.5 and particularly interesting because preliminary results 42% in the R-MCP arm versus 65.5% and 20% in the showed a benefit of R-CHOP over CHOP but also a MCP arm (Po0.0001). EFS was significantly prolonged benefit of rituximab maintenance after CHOP only for patients receiving R-MCP vs MCP alone (Po0.001). induction. Rituximabmaintenance yielded a median Median EFS for MCP was 19 months and 73% for PFS from second randomization of 51.5 months versus R-MCP. Follow-up was too short in these two studies 15 months with observation (HR, 0.40; Po0.001). for studying OS. Improved PFS was found both after induction with In the French study, patients were random- CHOP (HR, 0.30; Po0.001) and R-CHOP (HR, 0.54; ized between CHVP þ interferon for 18 months and P ¼ 0.004). R maintenance also improved OS from R-CHVP þ interferon (Salles et al., 2004; Foussard et al., second randomization: 85% at 3 years versus 77% with 2006). This first analysis of all patients demonstrated observation (HR, 0.52; P ¼ 0.011). a significant improvement of response to therapy with The German study in relapsing patients with FLs and R-CHVP þ interferon compared to CHVP þ interferon, MCLs looked at the effect of rituximabmaintenance both at 6 months (CR þ CRru 49 vs 76%; PR 36 after salvage with FCM or R-FCM (Forstpointner vs 18%; respectively (Po0.0001)) and at 18 months et al., 2006). The first randomization was stopped after (CR þ CRu 79% vs 63%; PR 5 vs 10%; respectively 147 patients when an interim analysis showed a (P ¼ 0.004)). In the control arm, estimated 3.5 years EFS statistically significant advantage for R-FCM over was 46 vs 67% with R-CHVP þ interferon (Po0.0001). FCM. Patients continued to enter the R-FCM arm for Even if the median follow-up is only 3.5 years, this study the second randomization, with or without mainte- showed a statistically significant OS advantage for nance. Response duration was significantly prolonged

Oncogene Rituximab therapy B Coiffier 3607 by rituximab maintenance after R-FCM with the chemotherapy combinations. Currently, only phase II median not being reached vs 16 months (P ¼ 0.001). studies or preliminary data are available preventing any This beneficial effect was also observed when analysing definitive conclusions (Davis et al., 2000b; Kimby, FL (P ¼ 0.035) and MCL (P ¼ 0.049) separately. Hence, 2002). Phase I trials combining rituximab with other rituximabmaintenance is effective after salvage with R- cytokines such as IL-2, IL-12, granulocyte-colony FCM chemotherapy and significantly prolongs response stimulating factor and granulocyte macrophage colony- duration in patients with relapsed or refractory FL or stimulating factor have shown promising preliminary MCL. results that need to be confirmed in phases II trials Finally, one study reported that maintenance with (van der Kolk et al., 2002; Eisenbeis et al., 2004). rituximabin patients treated with chemotherapy increases CR rates and prolongs PFS (Hochster et al., 2004). However, the role of rituximabmaintenance after a combination of rituximab plus chemotherapy in first- Rituximab in diffuse large B-cell lymphoma line patients remains unclear and it is not currently recommended in CR patients. The combination regimen R-CHOP, consisting of These different studies have implemented the use of rituximabplus CHOP (cyclophosphamide, doxorubicin, combining rituximab with chemotherapy as standard vincristine and prednisone), is now considered as the treatment in patients with FL who need to be treated. standard treatment for treating young and elderly Which of the chemotherapy regimens is better is not yet patients with diffuse large B-cell lymphoma (DLBCL) demonstrated but the comparison of CR rates, EFS, because of the superior activity demonstrated in three PFS and OS from the different studies seems to show a randomized studies (Table 2). Results from the GELA larger benefit with the R-CHOP regimen. The compari- study have been recently updated with a 5-year median son of results obtained with R-CHOP to those reached follow-up and showed a persisting advantage for with rituximabonly in the same type of patients equally patients treated with R-CHOP (Table 3) (Coiffier favors the use of R-CHOP. However, these conclusions et al., 2002; Feugier et al., 2005). In this study, patients need to be taken with caution because no randomized with DLBCL and aged 60–80 years were treated either study has compared these different regimens. with eight cycles of CHOP or eight cycles of R-CHOP. The difference observed between the two arms was already statistically significant for EFS, PFS and OS Rituximab in combination with cytokines with a median follow-up of 1 year and improve with Interferona2 has a direct antilymphoma activity but it follow-up (Figure 1). may also upregulate CD20 antigen expression on The MInT study compared in 824 patients six cycles lymphoma cells and, then, potentially augments the of R-CHOP-like chemotherapy to CHOP-like in young immune response induced by rituximab (Portlock et al., patients with a low-risk DLBCL (Pfreundschuh et al., 2006). Hence, its combination with rituximab could 2006). After a median time of follow-up of 34 months, potentially represent an alternative to the rituximab- R-CHEMO patients had a significantly longer (TTF)

Table 2 Randomized studies comparing CHOP with R-CHOP in patients with diffuse large B-cell lymphoma Coifﬁer et al. (2002); Feugier et al. (2005) Habermann et al. (2003) Pfreundschuh et al. (2004)

Setting 60–80 years old 60–80 years old o60 years old No stage I No stage I IPI 0-1 CHOP Maintenance CHOP or CHOP-like Median follow-up 5 years 2.7 years 2 years CR rates R-CHOP 75% 78% 85% CHOP 63%** 77% 65%** Early progression rates R-CHOP 9% 15% 16% CHOP 22%** 17% 5%** Relapses R-CHOP 34% Not reported Not reported CHOP 20%** Event-free survival 2-year TTF R-CHOP 3.8 years 3.4 y 81% CHOP 1.1 years** 2.4 years 58%** Progression-free survival R-CHOP Not reached Not reported Not reported CHOP 1.0 year** Overall survival 2-year OS R-CHOP Not reached Not different 95% CHOP 3.1 years** 85%**

Abbreviations: CR, complete response; CHOP, chemotherapy; TTF, treatment failure. *Po0.05, **Po0.01.

Oncogene Rituximab therapy B Coiffier 3608 Table 3 Five-year survivals observed in the GELA study comparing In a population-based analysis, the impressive efficacy eight cycles of R-CHOP and CHOP in elderly patients with diffuse results of the GELA trial can be as well repeated as the large B-cell lymphoma (Feugier et al., 2005) safety results be confirmed (Sehn et al., 2005): outcomes R-CHOP CHOP P-value for patients with DLBCL were compared between two periods, CHOP then R-CHOP treatment recommenda- Median EFS 3.8 years 1.1 years 0.00002 5-year EFS 47% 29% tions. Both PFS (risk ratio, 0.56; 95% CI 0.39-0.81; Median PFS Not reached 1 year o0.00001 P ¼ 0.002) and OS (risk ratio, 0.40; 95% CI 0.27–0.61, 5-year PFS 54% 30% Po0.0001) were significantly improved in the post- Median OS Not reached 3.1 years 0.0073 rituximabgroup. 5-year OS 58% 45% If this R-CHOP regimen had a great activity in good risk patients, progresses still have to be made in the Abbreviations: CHOP, chemotherapy; EFS, event-free survival; OS, overall survival; PFS progression-free survival. group of poor-risk patients. Several ways are currently been tested such dose–dense and dose–intense regimens or the association of other biologics (Coiffier and Reyes, 2005; Coiffier, 2005c, 2006). One interesting observation was the fact that prognostic parameters such as those described in the International Prognostic index seem to loose some importance in patients treated with R-CHOP (Sehn et al., 2007). Even the new prognostic parameters described with microarray gene analyses are less important than bcl-2 or bcl-6 protein expression (Farinha et al., 2006; Mounier et al., 2006; Winter et al., 2006). However, which parameters are associated with the risk of recurrence and dying in patients treated with R-CHOP is not yet described.

Rituximab in other lymphomas

Figure 1 LNH-98.5 results are stable over the years. Small lymphocytic lymphoma The efficacy of rituximabalone in this lymphoma is not very well known, with few and discordant results. In a European study in relapsing patients, the efficacy was (Po0.00001), with estimated 2-year TTF rates of low, with only a 10% RR (Foran et al., 2000). In 60% (CHEMO) vs 76% (R-CHEMO). Complete remis- untreated patients, in contrast, found a 51% RR after sion rates of evaluable patients (CR) were signifi- four injections, with only 4% CR, and a median PFS of cantly different (67% CHEMO vs 81% R-CHEMO, 18 and 6 months Hainsworth et al. (2003). Further Po0.0001) as were the rates of progressive disease studies are warranted to define the modality of use during treatment (15% vs 4%, Po0.00001). Similarly, of rituximabmonotherapy in this lymphoma, and overall survival was significantly different (Po0.001), its possible benefit. As small lymphocytic leukemia with 2-year survival rates of 87% (CHEMO) and is closely related to CLL, the use of rituximabin 94% (R-CHEMO), respectively. The American study combination with fludarabine and/or cyclophosphamide (ECOG/SWOG/CALGB study) was associated with a should be tested because of its efficacy in CLL patients statistically benefit in the primary end point time to TTF (Keating et al., 2005). for the addition of rituximabto CHOP vs CHOP alone (Habermann et al., 2006). However, the complicated design of this study makes conclusions difficult com- Marginal zone lymphoma pared to the two other studies. Furthermore, the Mostly case reports have shown an efficacy of rituximab administration of significantly less rituximabcompared in these lymphomas, which seems comparable to what is to the other studies may very well have contributed to observed in FL (Paydas et al., 2003). Efficacy was the somewhat inferior results. The interesting point of demonstrated in relapsing mucosa-associated lymphoid this study is the second randomization looking at the tissue (MALT) lymphoma (Conconi et al., 2003). A effect of rituximabin patients who reached a CR or current International Extranodal Lymphoma Study a PR. If rituximabmaintenance may decrease the Group trial randomizes chlorambucil vs chlorambu- progression rate in patients treated with CHOP only, cil þ rituximabin new or relapsing patients with MALT it has no effect on patients treated with R-CHOP. This lymphoma. was the only study looking at rituximabmaintenance in DLBCL in first line but the analysis of this negative Mantle cell lymphoma study is difficult because of its poor design and it must MCL has indolent lymphoma characteristics, but tends be tested in patients at risk, particularly relapsing to pursue an aggressive clinical course and is incurable patients after autologous transplant. with standard chemotherapy. An interim analysis of a

Oncogene Rituximab therapy B Coiffier 3609 randomized trial comparing FCM to FCM plus arms (Kaplan and Scadden (2004)). However, this study rituximabhas shown a striking improvement in RR did not have the power to show a significant difference with rituximab(65 vs 33%; CR 35 vs 0%), with a trend and the follow-up is extremely short. In another phase II towards longer OS (Forstpointner et al., 2004). Inter- study, R-CHOP produced a CR rate of 77% and a estingly, about one-third of the patients achieved a 2-year survival rate of 75% without severe infectious molecular remission. A maintenance with rituximabwas complications (Boue et al., 2006). scheduled for responding patients and allow to prolong the duration of response (Forstpointner et al., 2006). Long-term remissions have been reported with intensive chemotherapy and autologous stem-cell transplantation MAb and high-dose therapy with ASCT (ASCT) plus rituximab(see below). Rituximabhas beenused as an in vivo purging agent Chronic lymphocytic leukemia (CLL) before and as maintenance therapy after ASCT, in FL Rituximab, given weekly as a single agent has low and MCL (Gianni et al., 2003; Belhadj et al., 2004) and activity in relapsing patients with CLL. A better activity in aggressive lymphoma (Horwitz and Horning, 2004), has been observed in untreated patients (Hainsworth in first line or in relapse, with promising results. An et al., 2003). Dose escalation, achieved by a thrice- ongoing international trial in relapsed and refractory weekly dosing schedule (Byrd et al., 2001), or higher aggressive lymphoma randomizes rituximab(dexa- weekly doses, 500–2250 mg/m2 (O’Brien et al., 2001), is methasone, aracytine, cisplatin) vs rituximab(ifosfa- necessary to reach significant clinical activity, with a RR mide, carboplatin, etoposide) before ASCT and with a of respectively 45 and 36%, as a single agent. The second randomization between rituximab maintenance concurrent administration of rituximabwith fludarabine and observation (CORAL study) (Hagberg and Gissel- resulted in better results with a RR rate of 90%, with brecht, 2006). Rituximab given after ASCT might have 47% CR (Byrd et al., 2003). Ongoing clinical studies are the interest to complete the remission and to further examining the use of rituximabassociated with fludara- decrease the relapse rate. In a German study, CR rates bine and cyclophosphamide, which has shown great developed overtime (57% at 6 months and 88% at 12 promise in a single-center phase II study (Keating et al., months), and after 2 years 29 out of 30 patients were in 2005; Wierda et al., 2005). An historical comparison persistent CR, whereas molecular response increased among two studies from the CALGB showed that in from 22% pretransplant to 72% 4 weeks after rituximab multivariate analyses controlling for pretreatment charac- and 100% 6 months after transplantation (Brugger, teristics, the patients receiving fludarabine and rituximab 2004). However, this treatment may be associated with had a significantly better PFS (Po0.0001) and OS more infections (Neumann et al., 2006). It had been (P ¼ 0.0006) than patients receiving fludarabine therapy associated with severe decrease in immunoglobulin (Byrd et al., 2005). Two year PFS probabilities were 0.67 levels (Lim et al., 2005) and more frequent neutropenia vs 0.45, and 2-year OS probabilities were 0.93 vs 0.81. (Lemieux et al., 2004b).

Other lymphomas Rituximabhas beenused successfully in lymphocyte predominant Hodgkin’s lymphoma or classical Conclusion Hodgkin’s lymphoma (Ekstrand et al., 2003; Rehwald et al., 2003; Younes et al., 2003). Few phase II studies Rituximabwas the first Mabregistered in the treatment exist for Burkitt’s lymphoma: results regarding response of lymphomas and it has allowed one of the major and relapse seems good but it is difficult to know the progresses for the treatment of lymphoma patients. improvement secondary to rituximabuse (Thomas et al., Alone, it is a very well-tolerated drug and it has a great 2006). In post-transplant lymphoproliferative disease activity in relapsing patients. However, it will hardly several phase II have shown a good activity with result in cure in this setting. In combination with rituximabalone or in combination with chemotherapy chemotherapy, rituximaballowed for the highest RRs (Milpied et al., 2000; Blaes et al., 2005; Jain et al., 2005). and longest EFs and OS ever described in follicular and The only yet reported randomized study without DLBCL. It has activity but less well demonstrated in benefit in the rituximab arm was in patients with human other B-cell lymphomas. Other Mabs targeting CD20 or immunodeficiency virus -associated lymphoma: the RR other antigens are on their way but their activity is not was not statistically different in R-CHOP or CHOP yet well defined compared to rituximab.

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