rituximab: perspective on single agent experience, and future directions in combination trials

Critical Reviews in Oncology/Hematology 40 (2001) 3–16

Rituximab: perspective on single agent experience, and futuredirections in combination trials

Peter McLaughlin *Uni�ersity of Texas M.D. Anderson Cancer Center, 1515 Holcombe Bl�d., Box 429, Houston, TX 77030, USA

Accepted 19 February 2001

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

2. Monoclonal antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.1. Murine antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.2. Immunoglobulin isotype . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42.3. Chimeric/humanized antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.4. Other constructs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52.5. Payload delivery, including radioimmunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . 5

3. CD20 target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.1. Lineage specificity/normal cell counterpart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53.2. Physiologic function of CD20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.3. Properties of the CD20 target . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63.4. Other B-cell target antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4. Rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64.1. Preclinical. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64.2. Phase I–II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74.3. Indolent lymphoma: the pivotal trial and others . . . . . . . . . . . . . . . . . . . . . . . . . . 74.4. Trials in aggressive lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84.5. ‘In-vivo purging’ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94.6. Other B-cell disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

5. Toxicity and other stumbling blocks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95.1. Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95.2. Antigen expression. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105.3. Antibody distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

5.3.1. Antigen sink . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105.3.2. Compartments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105.3.3. Possible sanctuary sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

5.4. Mechanisms of resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

6. Combination therapy with rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116.1. Rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116.2. Cytokines in combination with rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116.3. Rituximab combined with chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

6.3.1. Indolent lymphoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116.3.2. Aggressive lymphoma and other B-cell malignancies . . . . . . . . . . . . . . . . . . . 12

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P. McLaughlin / Critical Re�iews in Oncology/Hematology 40 (2001) 3–164

6.3.3. Adjuvant rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

7. Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

Abstract

The chimeric anti-CD20 antibody rituximab is the first monoclonal antibody to gain regulatory approval for the treatment ofany malignancy. As such, its development represents a major milestone in cancer therapy. It is an effective single agent for patientswith CD20-positive B-cell malignancies, using a well-tolerated and brief (weekly×4) schedule that has become the acceptedstandard. Since this weekly×4 schedule is not a maximum tolerated dose, additional research is being done on different doses andschedules of rituximab. Researchers are also exploring the use of rituximab in conjunction with cytokines or chemotherapy.Further developments in the use of rituximab and other targeted therapy approaches can be expected as we learn more about themechanisms of action of, and resistance to, rituximab. © 2001 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Rituximab; Monoclonal antibody therapy; CD20; B-cell lymphoma; Malignant lymphoma

1. Introduction

For years, monoclonal antibodies have been regardedas highly promising therapeutic agents. By virtue oftheir specificity and their action in concert with thehost’s own immune system, selective activity with littleor no toxicity was expected.

However, stumbling blocks were encountered in thedevelopment of this therapeutic approach. A com-pletely tumor-specific target proved difficult to identify.Developing a unique antibody for each patient provedimpractical. Murine antibodies were found to havelimitations.

Recombinant technology has permitted a transitionfrom the use of murine antibodies to chimeric or hu-manized antibodies. Presumably, the design of antibodyconstructs will continue to be optimized in the future.In this evolving story, with its rocky start and its verybright future, the development of the chimeric anti-CD20 antibody rituximab represents an importantchapter.

2. Monoclonal antibodies

2.1. Murine antibodies

In 1975, the late Georges Kohler (then aged 28) andCesar Milstein reported on a technique to use fusedcells to secrete antibodies of predefined specificity [1].This work eventually led to their receiving, togetherwith Niels Jerne, a Nobel Prize in 1984. Monoclonal

antibodies are now taken for granted and used widelyfor diagnostic and research purposes.

The first treatment of a patient with a murine mono-clonal antibody was reported in 1980 by Nadler et al.[2]. Substantial work was also done by Levy and col-leagues at Stanford, providing important insights intomurine monoclonal antibody therapy in general, andanti-idiotype therapy in particular [3].

Most monoclonal antibodies are produced in rodenthybridomas, so they are rodent proteins. The limita-tions of murine antibodies are substantial. Once apatient develops a human anti-mouse antibody(HAMA) response [4], further therapy with the murinemonoclonal is not realistic. Another disadvantage ofmurine antibodies is their short half-life. One circum-stance in which this short half-life is felt to be anadvantage is in the setting of radioimmunotherapy,because of dose– time issues related to the isotope.

2.2. Immunoglobulin isotype

The immunoglobulin class and isotype are importantdeterminants of antibody function. From a practicalstandpoint, IgG antibodies have been developed fortherapy, although IgM is a more potent activator of thecomplement pathway. IgG subclasses, or isotypes, arelargely distingished by differences in the length andnumber of disulfide bonds in the hinge region of theantibody, which has an impact on the flexibility of theFab arms. Both IgG1 and the longer-hinged IgG3 haverelatively free movement of the Fab arms. Amonghuman IgG isotypes, IgG1 and IgG3 are better media-

P. McLaughlin / Critical Re�iews in Oncology/Hematology 40 (2001) 3–16 5

tors of effector functions than IgG2 and IgG4, includ-ing complement fixation and recruitment of effectorcells through Fc receptor binding [5].

2.3. Chimeric/humanized antibodies

In the late 1980s, the development of humanized orchimeric antibodies was a major breakthrough [6,7].The first one to enter clinical trial was Campath-1H,reported by Hale et al. [8].

Chimeric or humanized antibodies are less antigenicthan murine antibodies. Based on the large experiencewith rituximab, it is rare to find anti-antibody re-sponses, and patients who do show such a responseappear to have no adverse effects. Thus, retreatment isa reality with humanized or chimeric antibodies.

In addition, the human immunoglobulin constantregion of the chimeric antibody permits better fixationof complement and better mediation of antibody-de-pendent cell-mediated cytotoxicity (ADCC), which aremechanisms by which unconjugated antibodies maywork, at least in part.

2.4. Other constructs

Antibody fragments are also being developed. Usinga fragment has some advantages in terms of penetrationof the moiety into more bulky tumors [7], because anintact monoclonal antibody is a large protein. Con-versely, IgA-like dimers may have some advantages,since dimers may be more effective mediators of effec-tor functions [9,10].

2.5. Payload deli�ery, including radioimmunotherapy

The potential of targeted therapy is substantiallybroadened by conjugating the antibody (or other lig-and) to a toxin or isotope, thereby creating a targeteddelivery system.

The subject of immunotoxins in lymphoma has beenrecently reviewed [11], and will not be covered in detailin the current review. Notably, there are already someimmunotoxins that are approved for use in hematologicmalignancies [12,13].

Since a toxin needs to be delivered into the cytoplasmof the target cell, it is important to select a receptor thatinternalizes upon binding its ligand. CD20 is thus notan ideal target for this approach. CD20 does not mod-ulate or internalize, which is an advantage for targetingby an unconjugated antibody, but a disadvantage ifinternalization for delivery of a payload is desired.CD19, CD22, or CD25 are targets that are better suitedthan CD20 for immunotoxin therapy (see Section 3.3).Other important issues (and stumbling blocks) in theimmunotoxin approach relate to the toxin. Theseproteins can themselves be immunogenic, creating a

problem analogous to the HAMA problem that ham-pers murine monoclonal antibody therapy. Moreover,the toxin has the potential of causing collateral damageif cells other than the desired target are exposed to thetoxin. The extensive literature that has addressed mod-ifications of the plant toxin ricin (deletion of the �chain; deglycosylation; ‘blocking’ of the sugar moietieson the � chain) provides a good example of the com-plexity of the biochemistry that underlies the develop-ment of immunotoxins [14,15].

Radioimmunotherapy (RIT) is another hot topicwhich has been reviewed elsewhere [16]. After pioneer-ing early work by the DeNardos [17] and high-profilebreakthrough work by Press et al. and Kaminiski et al.[18,19], arrival of RIT to the mainstream of lymphomatherapy finally seems imminent [20,21]. Approaches toRIT are likely to remain in evolution for some time, asinvestigators define better the ideal isotope (131I, 90Y,67Cu [22], etc.), the best targets (CD20, Lym-1, CD22,etc.), and other issues such as the timing of therapy anddose intensity. Toxicity issues with RIT are more com-plex than with unconjugated antibodies, particularlymyelosuppression. At higher, myeloablative doses, ef-fects on other organs such as the lungs are dose-limit-ing. RIT represents a powerful new treatmentapproach, about which we still have much to learn.

3. CD20 target

3.1. Lineage specificity/normal cell counterpart

Lineage specificity is one of the great advantages ofmonoclonal antibody therapy. The CD20 antigen [23–25] is restricted to B-cells. It is expressed starting in thepre-B stage of development, before immunoglobulin isdetectable. The expression of CD20 continuesthrough B-cell maturation until the plasmacytoid im-munoblast phase. CD20 is not expressed on plasmacells, and, importantly, it is not expressed on lymphoidstem cells.

CD20 expression on malignant B-cells correspondswith the phase of B-cell development to which themalignancy is related [26]. B-cell lymphomas are CD20-positive in over 90% of cases. B-cell acute lymphocyticleukemia (ALL) is CD20-positive in about 50% ofcases. Multiple myeloma is characteristically negativefor CD20, but expression can be induced by certaincytokines (see Section 5.2 below). The expression ofCD20 in Waldenstrom’s macroglobulinemia has onlyrecently been well studied; in most cases, it appears tobe CD20-positive [27]. B-cell chronic lymphocyticleukemia (CLL) is usually CD20-positive, but it is clearthat CD20 [28], like other surface proteins [29], is lessdensely expressed in small lymphocytic lymphoma andCLL than in many other B-cell malignancies.


3.2. Physiologic function of CD20

Binding of CD20 by anti-CD20 antibody impacts oncell-cycle regulation, and substantial evidence suggeststhat CD20 functions as a calcium channel [30–32].Cross-linking may be a key step in the process by whichCD20 participates in signaling. CD40 and/or the MHCclass II molecule may play a role in this cross-linkingprocess [33,34]. Redistribution of CD20 on the cellsurface occurs after antibody binding, and this redistri-bution is likely to be a key early step in the initiation ofsignaling via CD20 [35].

The ability of anti-CD20 antibodies to induce apop-tosis in B-cell lines has been demonstrated by manyinvestigators [36–40]. Even Fab� fragments can accom-plish this, so the human constant region of the chimericrituximab is not essential for this process.

3.3. Properties of the CD20 target

CD20 is a B-cell-specific surface protein. It has fourcell membrane-spanning domains, compatible with itsbeing an ion channel. The human CD20 gene is on thelong arm of chromosome 11, at band q12–q13.1[24,25]. There is substantial amino acid sequence simi-larity between CD20 and the � subunit of the high-affinity IgE receptor (Fc�RI); these proteins may bemembers of a family of proteins that play a role insignal transduction [41].

Binding of CD20 by antibody does not appear toinduce antigen modulation or internalization, meaningthat CD20 is a relatively fixed, appealing target formonoclonal antibody therapy. Some early pioneeringwork with promising therapeutic monoclonal antibod-ies encountered insurmountable problems when thetarget antigen was found to either modulate [42], orshed to the point that plasmapheresis was needed tominimize binding of the therapeutic monoclonal anti-body to circulating free antigen [43]. Some B-cell anti-gens (e.g. CD19 and CD22) internalize after antibodybinding [44], making them more suitable for delivery ofa payload such as a toxin, for which internalization is akey. Conversely, the absence of shedding of CD20 is animportant key to the appeal of anti-CD20 therapeuticantibodies.

3.4. Other B-cell target antigens

Although anti-CD20 antibodies are the most com-monly used monoclonals for lymphomas at present,other interesting antibodies are available or in develop-ment. The pan-B antigen, CD22, has been targeted bytechnetium-labelled Fab� fragments for imaging, andboth murine and humanized anti-CD22 antibodies havebeen developed for radioimmunotherapy [45]. Anti-CD22 immunotoxins have also been extensively ex-

plored, particularly by Vitetta and colleagues [46].Recently, a humanized unconjugated anti-CD22 anti-body has shown promise in patients with relapsedB-cell lymphoma [47].

HLA-DR is expressed throughout B-cell differentia-tion. Lym-1 is an interesting antibody that recognisesthe HLA-DR10 locus, which, rather than being a pan-Bantibody, appears to be quite tumor-specific [48]. It isexpressed on 80% of B-cell non-Hodgkin’s lymphomasand also on about 40% of CLL. So far, it has beendeveloped mainly as a radioimmunotherapy tool, aspioneered by the DeNardos. It has predominantly beenused conjugated with 131I, but there are also someexciting recent data on its use with 67Cu [22,49].

CD52 is an antigen that is expressed on B-cells, butalso on T-cells, monocytes, and some other (mainlyhematopoietic) cells. The humanized anti-CD52 anti-body, Campath-1H, has shown promising activity inCLL and B-cell lymphoma, particularly with respect toclearing the peripheral blood and bone marrow ofmalignant cells [50]. Table 1.

4. Rituximab

4.1. Preclinical

Reff et al., in a landmark paper in 1994, reported onthe construction of the chimeric anti-CD20 monoclonalantibody rituximab (then known as IDEC C2B8). Theyprofiled its reactivity with B-cells, demonstrated itsability to fix complement and mediate ADCC, anddescribed in-vivo work in cynomolgus monkeys [51].

The parent murine antibody, IDEC 2B8, is thesource of the variable regions of rituximab. IDEC 2B8was developed against the human lymphoblastoid cellline SB. The constant regions of rituximab are made of

Table 1Appeal of rituximab

A. CD20 target1. B-cell restrictiona. Not on stem cells; B-cell depletion is transient2. Stability on cell surfacea. Does not shed, modulate, or internalizeb. Rare antigen-negative relapsec. Cytokines can upregulate expression

B. Chimeric antibody1. Longer half-life than murine antibody2. Less antigenica. Essentially no HAMA response3. Mediates effector functionsa. Fixes and activates complementb. Recruits effector cells4. Binding to CD20 target mediates signalinga. Induces apoptosis in some cell lines


human IgG1 heavy chain and kappa light chain con-stant regions. Rituximab is produced in a Chinesehamster ovary (CHO) transfectoma, containing an ex-pression vector in which the mouse (2B8) light chainand heavy chain variable regions were spliced to therespective human 1gG1 constant domains.

The reactivity of anti-CD20 antibodies in general,and rituximab in particular, is restricted to Blymphocytes. Rituximab binds human C1q and acti-vates complement-dependent cytotoxicity on humanEBV-transformed B lymphocytes. It mediates ADCCagainst CD20-positive target cells, but not againstCD20-negative cells. It binds to human Fc�RI andFc�RII transfected cells. Besides its mediation of effec-tor mechanisms, it also directly inhibits cell growth inthe B-cell lines Raji, FL-18, Ramos, and others [36–40].

The safety of rituximab was first established in ani-mals. Cynomolgus monkeys tolerated the antibodywell. Some reductions in white blood cells, neutrophils,and platelets were observed, but they were transient.B-cell depletion occurred, as expected, and persisted for2–3 months after a single dose.

4.2. Phase I–II

In the initial phase I rituximab trial reported byMaloney et al., patients with relapsed CD20-positiveB-cell lymphoma received a single dose of the antibody.Doses from 10 to 500 mg/m2 were studied. A truemaximum tolerated dose (MTD) was not reached.Based on the rate of the infusion, the 500 mg/m2 dosewas judged to be the practical limit for out-patientadministration of rituximab in 1 day. As expected,B-cell depletion was observed; it persisted for up to 1–2months. Antibody was detectable in tumor biopsiesfrom the majority of patients biopsied 2 weeks aftertreatment. Even in this phase I study, two patientsachieved partial remissions [52].

A multiple-dose trial was subsequently conducted,exploring four weekly doses of the antibody at doses of125, 250, and 375 mg/m2. Again, a true MTD was notreached. Again, tumor responses were seen: In thephase II portion of this trial, at the 375 mg/m2 doselevel, 17 of 34 patients (50%) responded. Based on theseobservations, and taking into consideration practicalissues such as the duration of the infusion, and thethen-limited production capacity of the antibody, thedose selected for the pivotal trial was 375 mg/m2 qweek×4 [53,54].

Pharmacokinetic studies in these initial phase I–IItrials reveled that the chimeric antibody had a longerhalf-life than would a murine monoclonal antibody.With multiple-dose schedules, it was observed thatthere was a stepwise increase of peak levels and of theserum half-life of the antibody, which was corroboratedin the later pivotal trial [55,56]. It was also evident that

patients in the multiple-dose trial typically had fewerside-effects with their second and subsequent infusionsthan with the first infusion.

Different doses and schedules of rituximab have beenexplored. Piro et al. reported on a weekly×8 schedulein 37 patients with indolent lymphoma [57]. The overallresponse rate was 60%, slightly higher than that re-ported in trials of the weekly×4 schedule. Since thepivotal trial [55] (see Section 4.3) had already notedthat small lymphocytic lymphoma (SLL) was poorlyresponsive to the weekly×4 schedule, it was disap-pointing that the weekly×8 trial also was fairly ineffec-tive in SLL, with only one of 7 patients responding.Coiffier et al. conducted a weekly×8 trial in 54 pa-tients with aggressive lymphoma, in which half of thepatients received a dose escalation from 375 mg/m2 to500 mg/m2 for weeks 2–8 [58]. The eight doses in thesetrials, and the modest increase of the dose in somepatients, did not substantially change the toxicityprofile of rituximab; the majority of adverse eventswere grade 1–2 and were most commonly seen with thefirst dose. In the aggressive lymphoma trial, 18 of the54 patients did not complete all eight doses, but themajority of these (14) were due to progressivelymphoma. Discontinuation of rituximab infusions dueto infusion-related toxicity occurred more often in pa-tients receiving the 500 mg/m2 rituximab dose.

Disappointing response rates in small lymphocyticlymphoma, coupled with pharmacokinetic and otherobservations (see Section 5.3.1), has prompted moreintensive dosing in CLL trials. Byrd et al. have reporteda three times weekly schedule [59], and O’Brien et al.have reported dose escalations up to 2250 mg/m2 [60].With these schedules, response rates of up to 40–50%are seen in patients with CLL. The lesson from thesestudies appears to be that, in small lymphocyticlymphoma and CLL, the weekly×4 schedule of ritux-imab at standard dose is not optimal.

4.3. Indolent lymphoma: the pi�otal trial and others

The large multicenter pivotal trial of rituximab wasconducted between 1995 and 1996. The data from thattrial led to the approval of rituximab in November of1997 by the United States Food and Drug Administra-tion. The definitive report on the pivotal trial waspublished in 1998 [55]. Further details on the statisticaldesign and response criteria were provided in an updatein 1999 [61], as well as a synthesis of pharmacokineticdata [56,61]. A ‘user’s guide’, focusing on practicalissues relating to administration of rituximab, also ap-peared in 1998 [62].

In the pivotal trial, 166 patients with relapsed indo-lent lymphoma were entered from 31 centers in theUnited States and Canada. At the standard dose of 375mg/m2 weekly times 4, 48% of patients responded,


using stringent response criteria that were quality-con-trolled by an independent review panel [55]. When theresponse data were later re-analyzed using criteria re-cently proposed by an international group of experts[63], the response rate was even higher [64]. Impor-tantly, toxicity with rituximab was minimal, even inpatient subsets who often tolerate cytotoxic chemother-apy poorly. Elderly patients responded as well asyounger patients. Patients whose prior treatment hadincluded high-dose therapy with stem-cell transplanttolerated rituximab well and had a high rate of re-sponse. Patients with small lymphocytic lymphoma,however, had a significantly lower response rate thanthose with follicular lymphoma.

In the subset of patients who had a detectable rear-rangement of bcl-2 by PCR in the peripheral blood ormarrow, 26 of 45 (62%) reverted to negative in theblood, and nine of 16 (56%) reverted to negative in thebone marrow. These molecular remission data provideanother measure of the efficacy of rituximab in clearingmalignant cells from the blood and bone marrow, eventhough many of these patients were judged only partialresponders because of residual adenopathy.

In addition to the pivotal trial and the phase I–IItrials that preceded it, there have been other rituximabtrials in indolent lymphoma, which have shown gener-ally similar results. Gupta et al. reported on a multicen-ter British trial in which 48% of patients responded [65].This trial also corroborated the finding that rituximabcan result in the attainment of molecular remission: asubset of patients with detectable rearrangement ofbcl-2 by PCR were monitored, and 17 of 28 (61%)reverted from positive to negative.

Nguyen et al. reported a trial in 48 patients, many ofwhom had small lymphocytic lymphoma [66]. Of 22patients with relapsed follicular lymphoma, 27% at-tained response, all of which were partial (PR). Of 15patients with SLL/CLL or variants (one with lympho-plasmacytic lymphoma), only one achieved PR, andthis one responder had a bright CD20 expression, sup-porting the notion that the intensity of CD20 expres-sion (see Section 5.2) may play a role in the response torituximab.

Other focused trials have studied rituximab in indo-lent lymphoma patients with bulky nodes [67] and inthe re-treatment patients who had relapse after previousresponse to rituximab [68]. In patients with bulky dis-ease (nodal masses �10 cm), 12 of 31 patients (39%)responded. In the re-treatment of previous responders,40% of patients responded. Since these were selectedpatients who had previously responded, the non-re-sponders in this trial presumably had acquired resis-tance to rituximab. The study of such patients mightprovide important insights into the mechanism of ac-tion of rituximab.

Single agent trials of rituximab in patients with previ-ously untreated indolent lymphoma are also underway[69–71]. As expected, tolerance of therapy has beengood. Response rates of around 60% have been re-ported, including 20–30% CR. Molecular remissionscan occur and appear to correlate with the clinicalresponse and durability of remission. In the report byHainsworth et al., patients with SLL responded just aswell as patients with follicular lymphoma [69]. So far,the follow-up is short on these trials, so the data onduration of response are limited.

4.4. Trials in aggressi�e lymphoma

Some of the early trials of rituximab included smallnumbers of patients with aggressive lymphoma, but thefirst sizable and focused trial of rituximab in aggressivelymphoma was reported by Coiffier et al. [58]. Asmentioned previously, this trial used a weekly×8schedule, with doses up to 500 mg/m2. In this trial,there were 12 evaluable patients with mantle celllymphoma (MCL), 30 patients with diffuse large celllymphoma (DLCL), and 10 with other aggressive B-celllymphomas. The group included nine previously un-treated patients, who were all elderly. The overall re-sponse rate was 31%, including a 33% response rate inMCL and a 37% response rate in DLCL, establishingthat rituximab is an active agent in aggressive B-celllymphomas.

Additional trials have studied rituximab in MCL.Foran et al. treated 87 patients, mostly with theweekly×4 schedule. Almost half were newly diag-nosed, previously untreated patients. The overall re-sponse rate was 35%, and responders had a medianduration of response of 1.2 years [72]. Ghielmini et al.treated 43 patients with relapsed MCL, as part of alarger trial, using the weekly×4 schedule, and 22% ofthe MCL patients responded [73].

B-cell malignancies in which rituximab has not yetbeen extensively studied include B-cell ALL, AIDS-re-lated lymphoma, primary brain lymphoma, lymphocytepredominant (LP) Hodgkin’s disease, multiplemyeloma, and others. In a report of three cases withrelapsed childhood B-ALL or Burkitt’s lymphoma, twocomplete responses were seen following rituximab [74].One of two patients with relapsed HIV-associated B-cell lymphoma attained a partial response with ritux-imab [75], and an even more dramatic response hasbeen reported, which was complicated by tumor lysis[76]. In three patients with refractory primary brainlymphoma, two had radiographic improvement of par-enchymal brain lesions following rituximab [77]. Fivepatients with LP Hodgkin’s disease were treated withrituximab, and all five responded, including three com-plete responses [78]. In myeloma, CD20 is usually ab-sent from the plasma cells, but clonally linked precursor


Fig. 1. Incidence of rituximab-related adverse events among 166 patients treated on the pivotal trial. Most events were minor (grade 1–2). About70% of patients have some toxicity with the first infusion, but less than half of patients have any toxicity after the first infusion.

B-cells can be CD20-positive, so single agent trials withrituximab are being pursued [79]. Perhaps more inter-esting are attempts to use cytokines to induce expres-sion of CD20 on the target plasma cells (see Section5.2).

4.5. ‘In-�i�o purging’

In light of the predictable and prompt depletion ofcirculating B-cells that occurs with rituximab, it is anappealing agent to consider for ‘in-vivo purge’ purposesprior to stem-cell collection. The safety and efficacy ofthis approach have been reported in detail by Bucksteinet al. [80]. Many groups are employing this strategyprior to stem-cell harvest for patients with B-celllymphoma [81]. PCR analysis will provide a stringentmeasure of the efficacy of rituximab in depleting malig-nant B-cell from the stem-cell harvest.

4.6. Other B-cell disorders

Some patients with non-malignant B-cell disordershave also been treated with rituximab, including post-transplant lymphoproliferative disorders (PTLD) andautoimmune disorders such as immune thrombocytope-nia (ITP).

The rationale for the use of rituximab for the treat-ment of PTLD is straightforward, since these are B-celldisorders [82]. The clinical experience with rituximab inPTLD is limited but encouraging, including evidencefor some impact on the Epstein–Barr virus infectionthat usually underlies PTLD [83].

Autoimmune disorders in which there are dysfunc-tional B-cell proliferative responses represent anotherpotential application for rituximab. One clinical trial inpatients with refractory ITP reported that about 20% ofpatients benefited from rituximab [84]. Lessons learned

from the treatment of B-cell malignancies may be perti-nent for these investigations in non-malignant disease.It will be important to study the density of CD20 onthe target B-cell population (see Section 5.2), and toassess for the possibility of an ‘anitgen sink’ phe-nomenon (see Section 5.3), e.g. the spleen in ITP.

5. Toxicity and other stumbling blocks

5.1. Toxicity

Rituximab is generally well tolerated. Most patientsexperience minor infusion-related effects with the firstdose, typically including fevers, chills, or myalgias.With slowing or temporary interruption of the infusion,the adverse effects usually subside promptly. With thesecond infusion and later, the majority of patients haveno toxicity (Fig. 1).

B-cell depletion is an expected and consistent obser-vation with rituximab. After the weekly×4 schedule,B-cell recovery is noted 6–9 months later. Depressionof immunoglobulin levels is observed in only a minorityof patients. Other hematologic effects are infrequentand transient; about 10% of patients do have reductionsof platelets or neutrophils, although the cytopenias aresevere in only about 1%. When rituximab is given inconjunction with chemotherapy (see Section 6.3), somehave noted a moderately higher rate of neutropeniathan with chemotherapy alone [85,86]. Despite the B-cell depletion and minimal impact on neutrophils, noincrease in the rate and type of infections, above whatwould be expected in this population, has been ob-served following the integration of rituximab into com-bination chemotherapy [85,87,88]

Serious or life-threatening toxicity has been observedinfrequently following rituximab. If hypotension oc-


curs, it is rarely necessary to do anything more thaninterrupt the rituximab, give saline, and wait for theblood pressure to normalize before resuming the ritux-imab infusion. Similarly, brochospasm is usually mod-est and transient; bronchodilators are infrequentlyneeded. More serious, occasionally fatal, events haveoccurred, usually in the setting of the first rituximabinfusion in patients with aggressive lymphomas andhigh circulating lymphocyte counts. Tumor lysis andcytokine release can be manifestations of these severereactions [76,89–92].

Some serious late effects have been reported, weeksto months after rituximab therapy, that are probablyimmune phenomena. These have included: arthralgias,vasculitis, and rashes reminiscent of serum sickness;cytopenias; uveitis; and bullous cutaneous reactions[92].

5.2. Antigen expression

As previously noted, rituximab has been found to beless effective against small lymphocytic lymphoma(SLL) than against follicular lymphoma, and part ofthe reason for this may be the lower CD20 density onSLL cells than on follicular lymphoma cells [28,93].These observations, coupled with pharmacokinetic ob-servations (see Section 5.3.1), prompted some of thephase I trials in CLL that were described earlier.

The potential ramifications of the lower CD20 den-sity on the target cell surface are perhaps most perti-nent if effector mechanisms are a key to the activity ofrituximab. Effector cells bearing the high-affinity Fcreceptor (Fc�RI) can bind to monomeric immunoglob-ulin, but the low-affinity receptor (Fc�RII) only bindsto polymeric or complexed IgG, so proximity of thebound rituximab molecules may be important. Simi-larly, activation of complement is most efficient whenC1q binds to at least two Fc sites, so it may bedesirable to have sufficient CD20 density to permit twoanti-CD20 molecules to be close enough to bind theC1q molecule. This view may be oversimplified, how-ever, since conformational changes and complexing oc-cur in the process of B-cell signalling in which CD20participates [35].

CD20 antigen-negative relapse has been describedafter rituximab therapy [94]. Loss of CD20 antigenexpression appears to be a rare development, in con-trast to the relatively high frequency of emergence ofidiotype variants that had been seen in trials usinganti-idiotype antibodies [95].

5.3. Antibody distribution

5.3.1. Antigen sinkPharmacokinetic data suggest that there may be an

‘antigen sink’ for rituximab [55,56]. Significantly higher

sustained rituximab levels are found in responders com-pared to non-responders, and in follicular lymphomapatients compared to those with SLL. This differencewas not apparent immediately after the dose (the peaklevel), but became apparent during the treatment courseand after the course of treatment had finished. Therewas a convincing pattern of significantly higher, moresustained levels of rituximab at the 1 week, 1 month,and 3 month time points after therapy in responderscompared to non-responders, and in follicularlymphoma patients compared to those with SLL. Sothese data indicate that, in SLL in particular and innon-responders in general, the antibody is depletedpromptly, presumably by reaching its target quite well,perhaps too well.

An alternate explanation for the rapid depletion ofrituximab in SLL patients is suggested by a recentobservation that circulating free CD20 can be detectedin some patients with CLL [96]. The phenomenon ofantigen shedding was a major stumbling block foranti-idiotype antibody approaches (see Section 3.3).The established efficacy of rituximab, coupled with ourcurrent understanding that the CD20 antigen is a stabletarget, suggests that circulating free CD20 antigen isnot a major issue, but further work can be expected onthis topic.

5.3.2. CompartmentsImmunoglobulins are large molecules, so valid issues

exist concerning their ability to penetrate into bulky orpoorly vascularized masses. In some of the early experi-ence with the radioimmunoconjugate 131I-anti-B1, unfa-vorable dosimetry was noted in patients withsplenomegaly [97]. With the unconjugated humanizedanti-CD52 antibody, Campath-1H, a striking patternhas been noted of impressive clearing of the blood andmarrow, but poor efficacy in nodal masses and mostother solid tissue sites of disease [50]. Thus, with Cam-path-1H, there is a clear pattern of better efficacy insome body compartments than others.

Taken in this context, the experience with rituximabcompares favorably. In the pivotal trial, bidimension-ally measurable disease was required, and the responserate was 48% [55]. In the trial that focused on patientswith bulky disease, the response rate was 39% [67].Nodal and other masses can clearly regress after ritux-imab therapy. However, the molecular monitoring dataare suggestive of a compartment effect with rituximab,since the blood was cleared of bcl-2 rearranged cellsmore often than the marrow, and nodal disease oftenpersisted despite the clearing of blood and marrow[55,98].

5.3.3. Possible sanctuary sitesThe brain is a sanctuary site for many chemothera-

peutic agents by virtue of the blood–brain barrier. So


far, there is little information available on the CSFpharmacokinetics of rituximab. Based on limited expe-rience, it appears that rituximab can penetrate into theCSF, although at substantially lower levels than in theblood [77,99,100].

5.4. Mechanisms of resistance

Since loss of CD20 expression is rare, researchers areexploring other possible mechanisms of resistance torituximab. So far, there are no clear answers, but thereare some intriguing clues.

Several groups of investigators have observed thatcomplement inhibitors such as protectin (CD59) orCD55 can impair responsiveness to rituximab [101–105]. Conversely, blocking of these inhibitors can en-hance the efficacy of rituximab, at least in cell lines.The fact that complement depletion is one measurableeffect observed after rituximab therapy suggests thatfurther study of complement inhibitors is warranted.

Analogous to the situation with complement, thereare inhibitors of ADCC, e.g. Fas ligand [106]. A betterunderstanding of these mechanisms of resistance maylead to more effective utilization of monoclonal anti-body therapy. The impairment of the immune systemfrom the underlying lymphoma and/or chemotherapy isanother important area for investigation and possibleintervention. We and others are studying the potentialfor the concurrent use of rituximab and cytokines toaddress these problems (see Section 6.2).

A highly promising area for investigation is themechanisim of induction of apoptosis by rituximab. Itis not yet known why only some cell lines undergoapoptosis after exposure to rituximab [36–40]. Resis-tance to apoptosis can be successfully counteracted, forexample by bcl-2 antisense oligonucleotides in somecases of lymphoma [107]. Such an agent can also re-verse the resistance to chemotherapy that is conferredby overexpression of Bcl-2 [108]. Such insights may berelevant to monoclonal antibody therapy.

6. Combination therapy with rituximab

6.1. Rationale

There is a good rationale for combining rituximabwith chemotherapy, since the mechanisms of action andtoxicities differ between chemotherapy and rituximab.Moreover, rituximab can sensitize some lymphoma celllines to the cytotoxic effects of some chemotherapeuticagents, including cisplatin and doxorubicin, but appar-ently not etoposide [109]. In experiments using a differ-ent anti-CD20 antibody, anti-B1, the murine antibodydid not enhance the cytotoxicity of ara-C, althoughcytotoxicity was enhanced by the radioimmunoconju-

gate 131I-anti-B1 [110]. To date, such information onsynergism is available for only a limited number of celllines and chemotherapeutic agents. More research anda better understanding of these drug-antibody interac-tions are needed.

6.2. Cytokines in combination with rituximab

There are theoretical reasons to believe that cytoki-nes may improve the efficacy of rituximab, e.g. byincreasing the number of effector cells. Rituximab hasbeen used in combination with G-CSF in a smallnumber of patients; the response rate may be higherthan with rituximab alone [111]. An early report of thecombination of rituximab with interferon-� appeareddisappointing, since no major difference in responsefrom rituximab alone was noted [112]; however, up-dated information on that trial suggests that the re-sponses may be more durable with the combinationthan would have been expected with rituximab alone[113]. Moreover, a preliminary report of an Italian trialof �-interferon plus rituximab showed a more encour-aging response rate in 73% in 58 patients with relapsedindolent lymphoma, including 29% complete respon-ders [114].

Cytokines can upregulate CD20 expression. In CLLcells, Venugopal et al. have demonstrated that IL-4,TNF-�, G-CSF, and GM-CSF can increase CD20 ex-pression [115]. Since there is only faint expression ofCD20 on small lymphocytic lymphoma cells and CLLcells, the intelligent use of cytokines may be a goodapproach to that particular problem. In plasma cells,which characteristically do not express CD20, �-inter-feron can induce expression of CD20 [65], so rituximabplus �-interferon may be an interesting combination toexplore for patients with myeloma.

6.3. Rituximab combined with chemotherapy

6.3.1. Indolent lymphomaRituximab is increasingly being used in combination

with chemotherapy. The first reported experience wasin 40 patients with indolent lymphoma who were givenrituximab and CHOP, reported by Czuczman et al.,with an overall response rate of 95%, including 55%CRs [87].

The current stage IV indolent lymphoma trial beingconducted at the M.D. Anderson Cancer Center [85]combines rituximab with the FND regimen (fludara-bine, mitoxantrone, and dexamethasone) [116], togetherwith interferon maintenance. Both arms of this studyconsist of eight cycles of FND followed by 1 year ofmaintenance interferon plus dexamethasone. The ques-tion being addressed in this trial is how to integraterituximab, either concurrently with FND, or sequen-tially. Concurrent rituximab is given with the first five


cycles of FND in one arm, and adjuvant rituximab isgiven in the other arm, starting at month 12. Allpatients receive the same number of courses ofFND, the same amount of interferon, and the samenumber of doses of rituximab. It is just the sequencethat varies.

Molecular endpoints (i.e. PCR for bcl-2 gene rear-rangement [117,118]) are being studied in this trial, aswell as standard clinical endpoints. This is an importantissue because half of the patients on this trial arereceiving rituximab at a time when they are in completeremission, without any measurable disease, so monitor-ing by this molecular endpoint may be an importantway to assess the impact of the rituximab.

One of the aspects of this trial that is being moni-tored carefully is whether there may be increased toxic-ity using rituximab in conjunction with FND. Clearly,both T and B cells are being depleted. The preliminarydata suggest that there is no significant additivetoxicity, although there may be slightly more neutrope-nia in patients who receive concurrent FND plus ritux-imab [85]. Czuczman et al. have reported that usingfludarabine in the standard 5 day schedule in conjunc-tion with rituximab did cause increased myelosuppres-sive toxicity [86]. This is an issue that needs carefulmonitoring.

6.3.2. Aggressi�e lymphoma and other B-cellmalignancies

Using rituximab plus CHOP in aggressivelymphomas, Link, Vose and colleagues have demon-strated a response rate of 96% [119,120]. Recent datafrom Coiffier et al., in a large randomized multicentertrial in elderly patients with aggressive lymphoma, sug-gest that the inclusion of rituximab with CHOP signifi-cantly improves the response rate and the early patternsof both relapse-free and overall survival [121].

In mantle cell lymphoma, Howard et al. have re-ported good response rates using CHOP plus ritux-imab, with almost 50% CRs and an overall responserate of 97% [122]; however, their early data indicatethat those responses may not be durable. Romaguera etal. have reported encouraging data using rituximabwith the hyper-CVAD regimen [123].

In patients with HIV-associated B-cell lymphoma,rituximab has been given together with the CDE regi-men (cyclophosphamide, doxorubicin, etoposide), withtolerance comparable to CDE alone [124].

In CLL, rituximab has been given in conjunctionwith fludarabine and cyclophosphamide. The regimenhas been well tolerated. It also appears to be highlyeffective, with more prompt reduction of thelymphocyte count and higher rates of complete remis-sion than had been seen with either fludarabine aloneor the fludarabine–cyclophosphamide combination[125].

6.3.3. Adju�ant rituximabThe adjuvant use of rituximab following FND is

being explored, as mentioned above, in the current U.T.M.D. Anderson trial in patients with stage IV indolentlymphoma. Another adjuvant trial, following inductiontherapy with cyclophosphamide and mitoxantrone, hasbeen reported by Emmanuouilides et al. Twenty-fourpatients who responded to chemotherapy received adju-vant rituximab for four doses, with good tolerance[126]. In one trial using single-agent rituximab as front-line therapy for patients with indolent lymphoma, addi-tional rituximab is being given every 6 months for amaximum of four cycles over 2 years [69]. To date, noadverse consequences have been reported from the re-sultant more prolonged B-cell depletion; monitoring ofthese patients’ B-cell recovery patterns will beinformative.

Adjuvant therapy is also being explored followingbone marrow transplant [127], and could be consideredin numerous other settings. In the absence of measur-able disease, efficacy endpoints are problematic. Themonitoring of molecular endpoints such as PCR forbcl-2, the use of randomized trials, or comparisons withlarge numbers of well characterised controls will beneeded to assess the role of rituximab (or any other)adjuvant therapy.

7. Conclusions and future directions

The success of rituximab has provided a model and astandard by which to judge new biological therapies. Itsefficacy and lack of toxicity make rituximab an appeal-ing treatment option, even by itself; single agent ther-apy with rituximab is likely to be utilized widely,especially in older or debilitated patients who mighttolerate more intensive therapy poorly. But as ourunderstanding grows about the safety of rituximab incombination regimens, and about possibly synergisticcombinations, it seems likely that rituximab will beused increasingly in conjunction with approaches thatalready have established efficacy. In the not-too-distantfuture, it is foreseeable that rituximab will be utilized incocktails of multiple monoclonal antibodies, and insequential treatment strategies, e.g. brief chemotherapyprograms for debulking and marrow clearing, followedby RIT for patients in partial remission, and thencontinuation of therapy with unconjugated monoclonalantibody therapy.

A looming question is whether the availability ofspecifically targeted therapies might ultimately supplantchemotherapy and become the mainstay of treatmentprograms. At the present time, such discussion isprovocative and challenging, but premature. It is clearthat we still have much to learn about monoclonalantibody therapy before such speculation can become a


reality. But the arrival of specifically targeted therapieshas created new standards and expectations that hope-fully will move us from the era of the chemotherapeuticbludgeon to a more enlightened and precise era ofcancer therapy.

Reviewers

Dr Bertrand Coiffier, Centre Hospitalier Lyon Sud,Haematology/Oncology Service, F-69495 Pierre Benite,Cedex France.

Russell Schilder, Department of Medical Oncology,Fox Chase Cancer Center, 7701 Burholme Avenue,Philadelphia, PA 19111, USA.

Dr Dimitri O. Papadopoulos, Medical Manager,Roche Pharma (schweiz) S.A., CH-1453 Reinach,Switzerland.

Acknowledgements

Supported in part by NCI Core Grant CA16672awarded to U.T. M.D. Anderson Cancer Center

References

[1] Kohler G, Milstein C. Continuous cultures of fused cells secret-ing antibody of predefined specificity. Nature 1975;256:495–7.

[2] Nadler LM, Stashenko P, Hardy R, et al. Serotherapy of apatient with a monoclonal antibody directed against a humanlymphoma-associated antigen. Cancer Res 1980;40:3147–54.

[3] Miller RA, Maloney DG, Warnke R, Levy R. Treatment ofB-cell lymphoma with monoclonal anti-idiotype antibody. NewEngl J Med 1982;306:517–22.

[4] Dillman RO. Human antimouse and antiglobulin responses tomonoclonal antibodies. Antibody Immunocon Radiopharm1990;3:1–15.

[5] Klein J, Horejsi V. Immunology, second ed. Oxford: BlackwellScience, 1997.

[6] Jones PT, Dear PH, Foote J, Neuberger MS, Winter G. Re-placing the complementarity-determining regions in a humanantibody with those from a mouse. Nature 1986;321:522–5.

[7] Owens RJ, Young RJ. The genetic engineering of monoclonalantibodies. J Immunol Meth 1994;168:149–65.

[8] Hale G, Clark MR, Marcus R, et al. Remission induction innon-Hodgkin’s lymphoma with reshaped human monoclonalantibody CAMPATH-1H. Lancet 1988;2:1394–9.

[9] Ghetie M-A, Podar EM, Ilgen A, Gordon BE, Uhr JW, VitettaES. Homodimerization of tumor-reactive monoclonal antibod-ies markedly increases their ability to induce growth arrest orapoptosis of tumor cells. Proc Natl Acad Sci USA1997;94:7509–14.

[10] Jiang L, Pan L-Z, Hariharan K, et al. Enhanced effectorfunction of dimeric forms of IDEC-C2B8 (rituximab). Blood1999;94(Suppl. 1):86a abstr.

[11] Thrush GR, Lark LR, Clinchy BC, Vitetta ES. Immunotoxins:an update. Ann Rev Immunol 1996;14:49–71.

[12] Nichols J, Foss F, Kuzel TM, et al. Interleukin-2 fusionprotein: an investigational therapy for interleukin-2 receptorexpressing malignancies. Eur J Cancer 1997;33(Suppl. 1):34–6.

[13] Sievers EL, Appelbaum FR, Spielberger RT, et al. Selectiveablation of acute myeloid leukemia using antibody-targetedchemotherapy: a phase I study of an anti-CD33 calicheamicinimmunoconjugate. Blood 1999;93:3678–84.

[14] Vitetta ES, Thorpe PE, Uhr JW. Immunotoxins: magic bulletsor misguided missiles? Immunol Today 1993;14:252–9.

[15] Lambert JM, Goldmacher VS, Collinson AR, et al. An im-munotoxin prepared with blocked ricin: a natural plant toxinadapted for therapeutic use. Cancer Res 1991;51:6236–42.

[16] DeNardo SJ, Kroger LA, DeNardo GL. A new era for radiola-beled antibodies in cancer? Curr Opin Immunol 1999;11:563–9.

[17] DeNardo GL, Lamborn KR, Goldstein DS, et al. Increasedsurvival associated with radiolabeled Lym-1 therapy for non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Can-cer 1997;80:2706–11.

[18] Press OW, Eary JF, Appelbaum FR, et al. Radiolabeled-anti-body therapy of B-cell lymphoma with autologous bone mar-row support. New Engl J Med 1993;329:1219–24.

[19] Kaminski MS, Zasadny KR, Francis IR, et al. Radioim-munotherapy of B-cell lymphoma with [131I] anti-B1 (anti-CD20) antibody. New Engl J Med 1993;329:459–65.

[20] Kaminski MS, Estes J, Zasadny KR, et al. Radioimmunother-apy with iodine 131I tositumomab for relapsed or refractoryB-cell non-Hodgkin lymphoma: updated results and long-termfollow-up of the University of Michigan experience. Blood2000;96:1259–66.

[21] Wiseman GA, White CA, Witzig TE, et al. Radioimmunother-apy of relapsed non-Hodgkin’s lymphoma with Zevalin, a90Y-labeled anti-CD20 monoclonal antibody. Clin Cancer Res1999;5:3281s–6s.

[22] O’Donnell RT, DeNardo GL, Kukis DL, et al. 67Copper-2-iminothiolane-6-[p-(bromoacetamido)benzyl]-TETA-Lym-1 forradioimmunotherapy of non-Hodgkin’s lymphoma. Clin Can-cer Res 1999;5:3330s–6s.

[23] Stashenko P, Nadler LM, Hardy R, Schlossman SF. Character-ization of a human B lymphocyte-specific antigen. J Immunol1980;125:1678–85.

[24] Einfeld DA, Brown JP, Valentine MA, Clark EA, LedbetterJA. Molecular cloning of the human B cell CD20 receptorpredicts a hydrophobic protein with multiple transmembranedomains. EMBO J 1988;7:711–7.

[25] Zhou L-J, Tedder TF. CD20 workshop panel report. In:Schlossman SF, Boumsell L, Gilks W, Harlan JM, KishimotoT, Morimoto C, Ritz J, Shaw S, Silverstein R, Springer T,Tedder TF, Todd RF, editors. Leucocyte Typing V: White CellDifferentiation Antigens. Oxford: Oxford University Press,1995:511–4.

[26] Anderson K, Bates M, Slaughenhoup B, Pinkus GS, Schloss-man SF, Nadler LM. Expression of human B cell-associatedantigens on leukemias and lymphomas: a model of human Bcell differentiation. Blood 1984;63:1424–33.

[27] Weber DM, Gavino M, Huh Y, Cabanillas F, Alexanian R.Phenotypic and clinical evidence supports rituximab forWaldenstrom’s macroglobulinemia. Blood 1999;94(Suppl.1):125a abstr.

[28] Almasri NM, Duque RE, Iturraspe J, Everett E, Braylan RC.Reduced expression of CD20 antigen as a characteristic markerfor chronic lymphocytic leukemia. Am J Hematol 1992;40:259–63.

[29] Cossman J, Neckers LM, Hsu S-M, Longo D, Jaffe ES. Low-grade lymphomas: Expression of developmentally regulatedB-cell antigens. Am J Pathol 1984;115:117–24.


[30] Tedder T, Boyd A, Freedman AS, Nadler LM, Schlossman SF.The B-cell surface molecule B1 is functionally linked with B cellactivation and differentiation. J Immunol 1985;135:973–9.

[31] Bubien JK, Zhou L-J, Bell PD, Frizzell RA, Tedder TF.Transfection of the CD20 cell surface molecule into ectopic celltypes generates a Ca2+ conductance found constitutively inB-lymphocytes. J Cell Biol 1993;121:1121–32.

[32] Golay JT, Clark EA, Beverley PCL. The CD20 (Bp35) antigenis involved in activation of B-cells from the G0 to the G1 phaseof the cell cycle. J Immunol 1985;135:3795–801.

[33] Leveille C, Al-Daccak R, Mourad W. CD20 is physically andfunctionally coupled to MHC class II and CD40 on human Bcell lines. Eur J Immunol 1999;29:65–74.

[34] Szollosi J, Horejsı V, Bene L, Angelisova P, Damjanovich S.Supramolecular complexes of MHC class I, MHC class II,CD20, and tetraspan molecules (CD53, CD81, and CD82) atthe surface of a B cell line JY. J Immunol 1996;157:2939–46.

[35] Polyak MJ, Tailor SH, Deans JP. Identification of a cytoplas-mic region of CD20 required for its redistribution to a deter-gent-insoluble membrane compartment. J Immunol1998;161:3242–8.

[36] Shan D, Ledbetter JA, Press OW. Signaling events involved inanti-CD20-induced apoptosis of malignant human B cells. Can-cer Immunol Immunother 2000;48:673–83.

[37] Maloney DG, Smith B, Appelbaum FR. The anti-tumor effectof monoclonal anti-CD20 antibody therapy includes directanti-proliferative activity and induction of apoptosis in CD20positive non-Hodgkin’s lymphoma cell lines. Blood1996;88(Suppl. 1):637a abstr.

[38] Taji H, Kagamii Y, Okada Y, et al. Growth inhibition ofCD20-positive B lymphoma cell lines by IDEC-C2B8 anti-CD20 monoclonal antibody. Jpn J Cancer Res 1998;89:748–56.

[39] Flieger D, Beier I, Sauerbruch T, Schmidt-Wolf I. Mode ofaction of monoclonal antibody IDEC-C2B8 against CD20 ex-pressing lymphoma cell lines. Eur J Cancer 1999;35(Suppl.5):S57 abstr.

[40] Withoff S, Kroesen BJ, de Leij LFMH. B-cell killing bymonospecific and bispecific �-CD20 antibodies. Proc AACR2000;41:287–8 abstr.

[41] Adra CN, Lelias J-M, Kobayashi H, Kaghad M, Morrison P,Rowley JD, Lim B. Cloning of the cDNA for a hematopoieticcell-specific protein related to CD20 and the � subunit of thehigh-affinity IgE receptor: Evidence for a family of proteinswith four membrane-spanning regions. Proc Natl Acad SciUSA 1994;91:10178–82.

[42] Foon KA, Schroff RW, Bunn PA, et al. Effects of monoclonalantibody therapy in patients with chronic lymphocyticleukemia. Blood 1984;64:1085–93.

[43] Meeker TC, Lowder J, Maloney DG, Miller RA, ThielemansK, Warnke R, Levy R. A clinical trial of anti-idiotype therapyfor B cell malignancy. Blood 1985;65:1349–63.

[44] Press OW, Farr AG, Borroz KI, Anderson SK, Martin PJ.Endocytosis and degradation of monoclonal antibodies target-ing human B-cell malignancies. Cancer Res 1989;49:4906–12.

[45] Behr TM, Wormann B, Gramatzki M, et al. Low- versushigh-dose radioimmunotherapy with humanized anti-CD22 orchimeric anti-CD20 antibodies in a broad spectrum of B cell-as-sociated malignancies. Clin Cancer Res 1999;5(Suppl.):3304s–14s.

[46] Amlot PL, Stone MJ, Cunningham D, et al. A phase I study ofan anti-CD22-deglycosylated ricin A chain immunotoxin in thetreatment of B-cell lymphomas resistant to conventional ther-apy. Blood 1993;82:2624–33.

[47] Leonard JP, Coleman M, Schuster MW, et al. Immunotherapyof NHL with Epratuzumab (Anti-CD22 monoclonal antibody):Excellent tolerability with objective responses. Proc ASCO2000;19:17a abstr.

[48] Rose LM, Gunasekera AH, DeNardo SJ, DeNardo GL,Meares CF. Lymphoma-selective antibody Lym-1 recognizes adiscontinuous epitope on the light chain of HLA-DR10. CancerImmunol Immunother 1996;43:26–30.

[49] DeNardo GL, Denardo SJ, Goldstein DS, et al. Maximum-tol-erated dose, toxicity, and efficacy of 131I-Lym-1 antibody forfractionated radioimmunotherapy of non-Hodgkin’slymphoma. J Clin Oncol 1998;16:3246–56.

[50] Lundin J, O� sterborg A, Brittinger G, et al. CAMPATH-1Hmonoclonal antibody in therapy for previously treated low-grade non-Hodgkin’s lymphomas: A Phase II multicenterstudy. J Clin Oncol 1998;16:3257–63.

[51] Reff ME, Carner K, Chambers KS, et al. Depletion of B cellsin vivo by a chimeric mouse human monoclonal antibody toCD20. Blood 1994;83:435–45.

[52] Maloney DG, Liles TM, Czerwinski DK, Waldichuck C,Rosenberg J, Grillo-Lopez A, Levy R. Phase I clinical trialusing escalating single-dose infusion of chimeric anti-CD20monoclonal antibody (IDEC-C2B8) in patients with recurrentB-cell lymphoma. Blood 1994;84:2457–66.

[53] Maloney DG, Grillo-Lopez AJ, Bodkin DJ, et al. IDEC-C2B8:Results of a phase I multiple-dose trial in patients with relapsednon-Hodgkin’s lymphoma. J Clin Oncol 1997;15:3266–74.

[54] Maloney DG, Grillo-Lopez AJ, White CA, et al. IDEC-C2B8(Rituximab) anti-CD20 monoclonal antibody therapy in pa-tients with relapsed low-grade non-Hodgkin’s lymphoma.Blood 1997;90:2188–95.

[55] McLaughlin P, Grillo-Lopez AJ, Link BK, et al. Rituximabchimeric anti-CD20 monoclonal antibody therapy for relapsedindolent lymphoma: half of patients respond to a four-dosetreatment program. J Clin Oncol 1998;16:2825–33.

[56] Berinstein NL, Grillo-Lopez AJ, White CA, et al. Associationof serum rituximab (IDEC-C2B8) concentration and anti-tumorresponse in the treatment of recurrent low-grade or follicularnon-Hodgkin’s lymphoma. Ann Oncol 1998;9:995–1001.

[57] Piro LD, White CA, Grillo- Lopez AJ, et al. Extended ritux-imab (anti-CD20 monoclonal antibody) therapy for relapsed orrefractory low-grade or follicular non-Hodgkin’s lymphoma.Ann Oncol 1999;10:655–61.

[58] Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20monoclonal antibody) for the treatment of patients with relaps-ing or refractory aggressive lymphoma: a multicenter phase IIstudy. Blood 1998;92:1927–32.

[59] Byrd JC, Grever MR, Davis B, et al. Phase I/II study of thriceweekly rituximab in chronic lymphocytic leukemia /smalllymphocytic lymphoma: a feasible and active regimen. Blood1999;94(Suppl. 1):704a abstr.

[60] O’Brien SM, Thomas DA, Freireich EJ, Andreeff M, Giles FJ,Keating MJ. Rituxan has significant activity in patients withCLL. Blood 1999;94(Suppl. 1):603a abstr.

[61] McLaughlin P, Hagemeister FB, Grillo-Lopez AJ. Rituximabin indolent lymphoma: the single-agent pivotal trial. SeminOncol 1999;26(Suppl. 14):79–87.

[62] McLaughlin P, White CA, Grillo-Lopez AJ, Maloney DG.Clinical status and optimal use of rituximab for B-celllymphomas. Oncology 1998;12:1763–9.

[63] Cheson BD, Horning SJ, Coiffier B, et al. Report of aninternational workshop to standardize response criteria fornon-Hodgkin’s lymphomas. J Clin Oncol 1999;17:1244–53.

[64] Grillo-Lopez AJ, McLaughlin P, Cheson BD, et al. First reporton the application of the new response criteria proposed forNHL: The rituximab pivotal trial. Proc ASCO 1999;18:13aabstr.

[65] Gupta RK, Summers KE, Lister TA. PCR analysis for thet(14;18) translocation in patients with recurrent follicularlymphoma following immunotherapy with rituximab (IDEC-C2B8). Blood 1998;92(Suppl. 1):239a abstr.


[66] Nguyen DT, Amess JA, Doughty H, Hendry L, Diamond LW.IDEC-C2B8 anti-CD20 (rituximab) immunotherapy in patientswith low-grade non-Hodgkin’s lymphoma and lymphoprolifera-tive disorders: evaluation of response on 48 patients. Eur JHaematol 1999;62:76–82.

[67] Davis TA, White CA, Grillo-Lopez AJ, et al. Single-agentmonoclonal antibody efficacy in bulky non-Hodgkin’slymphoma: Results of a phase II trial of rituximab. J ClinOncol 1999;17:1851–7.

[68] Davis TA, Grillo-Lopez AJ, White CA, et al. Final report onthe safety and efficacy of retreatment with rituximab for pa-tients with non-Hodgkin’s lymphoma. Blood 1999;94(Suppl.1):88a abstr.

[69] Hainsworth JD, Burris HA, Morrissey LH, et al. Rituximabmonoclonal antibody as initial systemic therapy for patientswith low-grade non-Hodgkin lymphoma. Blood 2000;95:3052–6 abstr.

[70] Solal-Celigny Ph, Salles G, Brousse N, et al. Rituximab asfirst-line treatment of patients with follicular lymphoma and alow-burden tumor: clinical and molecular evaluation. Blood1999;94(Suppl. 1):631 abstr.

[71] Gutheil JC, Finucane D, Rodriguez R, Saleh F, Stahler S,Royston I. Phase II study of rituximab (Rituxan) in patientswith previously untreated low-grade or follicular non-Hodgkin’s lymphoma. Proc ASCO 2000;19:22a abstr.

[72] Foran JM, Rohatiner AZS, Cunningham D, et al. Europeanphase II study of rituximab (chimeric anti-CD20 monoclonalantibody) for patients with newly diagnosed mantle-celllymphoma and previously treated mantle-cell lymphoma, im-munocytoma, and small B-cell lymphocytic lymphoma. J ClinOncol 2000;18:317–24.

[73] Ghielmini M, Hsu-Schmitz SF, Pichert BG, et al. The effect ofrituximab on patients with follicular and mantle cell lymphoma.Ann Oncol 1999;10(Suppl. 3):33 abstr.

[74] Veerman AJP, Nuijens JH, Van der Schoot CE, Kardos G,Zwaan CM. Rituximab in the treatment of childhood B-ALLand Burkitt’s lymphoma, report on three cases. Blood1999;94(Suppl. 1):269b abstr.

[75] Barrett JC, Linn CA, Arani RB, Rosenberg J, Saleh MN. Apilot study of anti-CD20 MoAb rituximab in AIDS-associatednon-Hodgkin’s lymphoma. Blood 1999;94(Suppl. 1):258b abstr.

[76] Yang H, Rosove MH, Figlin RA. Tumor lysis syndrome occur-ring after the administration of rituximab in lymphoprolifera-tive disorders: high-grade non-Hodgkin’s lymphoma andchronic lymphocytic leukemia. Am J Hematol 1999;62:247–50.

[77] Raizer JJ, Lisa DM, Zelenetz AD, Lauren AE. Activity ofrituximab in primary central nervous system lymphoma. ProcASCO 2000;19:166a abstr.

[78] Lucas JB, Hoppe R, Clark B, Horning SJ. Rituximab therapyof lymphocyte predominance Hodgkin’s disease. Proc AACR2000;41:760 abstr.

[79] Treon SP, Shima Y, Preffer FI, et al. Treatment of plasma celldyscrasias by antibody-mediated immunotherapy. Semin Oncol1999;26(Suppl. 14):97–106.

[80] Buckstein R, Imrie K, Spaner D, et al. Stem cell function andengraftment is not affected by ‘In vivo purging’ with rituximabfor autologous stem cell treatment for patients with low-gradenon-Hodgkin’s lymphoma. Semin Oncol 1999;26(Suppl.14):115–22.

[81] Flinn IW, O’Donnell P, Noga SJ, et al. In vivo purging andadjuvant immunotherapy with rituximab during PBSC trans-plant for NHL. Blood 1998;92(Suppl. 1):648a abstr.

[82] Swinnen LJ. Overview of posttransplant B-cell lymphoprolifer-ative disorders. Semin Oncol 1999;26(Suppl. 14):21–5.

[83] Kuehnie I, Huls MH, Liu Z, et al. CD20 monoclonal antibody(rituximab) for therapy of Epstein–Barr virus lymphoma afterhemopoietic stem-cell transplantation. Blood 2000;95:1502–5.

[84] Saleh MN, Gutheil J, Moore M, et al. A pilot study ofanti-CD20 MoAb rituximab in patients with refractory immunethrombocytopenic purpura. Blood 2000;96(Suppl. 1):252a abstr.

[85] McLaughlin P, Hagemeister FB, Rodriguez MA, et al. Safetyof fludarabine, mitoxantrone, and dexamethasone combinedwith rituximab in the treatment of stage IV indolent lymphoma,Semin Oncol 2000;27(Suppl. 12):37–41.

[86] Czuczman MS, Jonas C, Stephan M, et al. Pilot study ofrituxan in combination with fludarabine chemotherapy in pa-tients with low-grade or follicular non-Hodgkin’s lymphoma.Proc ASCO 1999;18:17a abstr.

[87] Czuczman MS, Grillo-Lopez AJ, White CA, et al. Treatment ofpatients with low-grade B-cell lymphoma with the combinationof chimeric anti-CD20 monoclonal antibody and CHOPchemotherapy. J Clin Oncol 1999;17:268–76.

[88] Coiffier B, Bienvenu J, Chvetzoff R, et al. Laboratory changesassociated with rituximab treatment: A prospective study indiffuse large B-cell lymphoma patients randomized betweenCHOP and CHOP plus rituximab. A GELA study. Blood2000;96(Suppl. 1):138a abstr.

[89] Winkler U, Jensen M, Manzke O, Schultz H, Diehl V, EngertA. Cytokine-release syndrome in patients with B-cell chroniclymphocytic leukemia and high lymphocyte counts after treat-ment with an anti-CD20 monoclonal antibody (Rituximab,IDEC-C2B8). Blood 1999;94:2217–24.

[90] Byrd JC, Waselenki JK, Maneatis TJ, et al. Rituximab therapyin hematologic malignancy patients with circulating blood tu-mor cells: association with increased infusion-related side effectsand rapid blood tumor clearance. J Clin Oncol 1999;17:791–5.

[91] Jensen M, Winkler U, Manzke O, Diehl V, Engert A. Rapidtumor lysis in a patient with B-cell chronic lymphocyticleukemia and lymphocytosis treated with an anti-CD20 mono-clonal antibody (IDEC-C2B8, rituximab). Ann Hematol1998;77:89–91.

[92] 1999 Rituximab package insert.[93] Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R,

Catovsky D. Levels of expression of CD19 and CD20 inchronic B cell leukaemias. J Clin Pathol 1998;51:364–9.

[94] Davis TA, Czerwinski DK, Levy R. Therapy of B-celllymphoma with anti-CD20 antibodies can result in the loss ofCD20 antigen expression. Clin Cancer Res 1999;5:611–5.

[95] Meeker T, Lowder J, Cleary M, Stewart S, Warnke R, Sklar J,Levy R. Emergence of idiotype variants during treatment ofB-cell lymphoma with anti-idiotype antibodies. New Engl JMed 1985;312:1658–65.

[96] Manshouri T, Saffer H, Keating M, Albitar M. Clinical rele-vance of circulating CD20 in patients with chronic lymphocyticleukemia. Blood 2000;96(Suppl. 1):369a abstr.

[97] Press OW, Eary JF, Appelbaum FR, et al. Radiolabeled-anti-body therapy of B-cell lymphoma with autologous bone mar-row support. New Engl J Med 1993;329:1219–24.

[98] Czuczman MS, Grillo-Lopez AJ, Maloney D, White CA,McLaughlin P, Weaver R, Rosenberg J. Rituximab clearance ofbcl-2 from peripheral blood and bone marrow from patientswith relapsed low-grade or follicular lymphoma. Proc AACR1999;40:719 abstr.

[99] Harjunpaa A, Wiklund T, Janes R, et al. Complement activa-tion in blood and central nervous system after rituximab treat-ment of B-cell lymphoma. Proc ASCO 2000;19:40a abstr.

[100] Ruhstaller TW, Amsler U, Cerny T. Rituximab: active treat-ment of central nervous system involvement by non-Hodgkin’slymphoma? Ann Oncol 2000;11:374–5.

[101] Golay J, Zaffaroni L, Vaccari T, et al. Biologic response of Blymphoma cells to anti-CD20 monoclonal antibody rituximabin vitro: CD55 and CD59 regulate complement-mediated celllysis. Blood 2000;95:3900–8.


[102] Harjunpaa A, Junnikkala S, Meri S. Rituximab (anti-CD20)therapy of B-cell lymphomas: Direct complement killing issuperior to cellular effector mechanisms. Scand J Immunol2000;51:634–41.

[103] Treon SP, Mitsiades CS, Mitsiades NS, et al. Tumor cellexpression of CD59 is associated with resistance to CD20serotherapy in B-cell malignancies. Blood 2000;96(Suppl. 1):99aabstr.

[104] Bannerji R, Pearson M, Flinn IW, et al. Cell surface comple-ment inhibitors CD55 and CD59 may mediate chroniclymphocytic leukemia resistance to rituximab therapy. Blood2000;96(Suppl. 1):164a abstr.

[105] Golay J, Lazzari M, Facchinetti V, et al. The susceptibility offreshly isolated B-non-Hodgkin lymphoma cells to rituximaband complement is determined by CD20 levels and the CD55/CD59 inhibitors. Blood 2000;96(Suppl. 1):338a abstr.

[106] Villunger A, Egle A, Marschitz I, et al. Constitutive expressionof Fas (Apo-1/CD95) ligand on multiple myeloma cells: Apotential mechanism of tumor-induced suppression of immunesurveillance. Blood 1997;90:12–20.

[107] Cotter FE. Antisense therapy of hematologic malignancies.Semin Oncol 1999;36(Suppl. 6):9–14.

[108] Jansen B, Schlagbarer-Wadl H, Brown BD, et al. bcl-2 anti-sense therapy chemosensitizes human melanoma in SCID mice.Nat Med 1998;4:232–4.

[109] Demidem A, Lam T, Alas S, Hariharan K, Hanna N, BonavidaB. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibodysensitizes a B cell lymphoma cell line to cell killing by cytotoxicdrugs. Cancer Biother Radiopharm 1997;12:177–86.

[110] Johnson TA, Press OW. Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treat-ment of B-cell lymphomas. Int J Cancer 2000;85:104–12.

[111] van der Kolk L, Grillo-Lopez AJ, Gerritsen W, Jonkhoff AR,Baars J, van Oers MHJ. Chimeric anti-CD20 monoclonal anti-body (rituximab) plus G-CSF in relapsed B-cell lymphoma: aphase I/II clinical trial. Blood 1998;92(Suppl. 1):241b abstr.

[112] Davis T, Maloney D, White CA, et al. Combination im-munotherapy of low grade or follicular non-Hodgkin’slymphoma with rituximab and alpha-interferon: interim analy-sis. Proc ASCO 1998;17:11a abstr.

[113] Davis TA, Maloney DG, Grillo-Lopez AJ, et al. Combinationimmunotherapy of relapsed or refractory low-grade or follicularnon-Hodgkin’s lymphoma with rituximab and interferon-�-2a.Clin Cancer Res 2000;6:2644–52.

[114] Sacchi S, Federico M, Vitolo U, et al. Phase II study ofrituximab after priming with IFN in patients with relapsedLG/F B-cell lymphoma. Blood 1999;94(Suppl. 1):91a abstr.

[115] Venugopal P, Sivaraman S, Huang X, Chopra HK, O’Brein T,Jajeh A, Preisler HD. Upregulation of CD20 expression inchronic lymphocytic leukemia cells by in vitro exposure tocytokines. Blood 1998;92(Suppl. 1):247a abstr.

[116] McLaughlin P, Hagemeister FB, Romaguera JE, et al. Fludara-bine, mitoxantrone, and dexamethasone: an effective new regi-men for indolent lymphoma. J Clin Oncol 1996;14:1262–8.

[117] Gribben JG. Attainment of molecular remission: a worthwhilegoal? J Clin Oncol 1994;12:1532–4.

[118] Lopez-Guillermo A, Cabanillas F, McLaughlin P, et al. Theclinical significance of molecular response in indolent follicularlymphomas. Blood 1998;91:2955–60.

[119] Link BK, Grossbard ML, Fisher RI, Czuczman M, Gilman P,Lowe AM, Vose JM. Phase II pilot study of the safety andefficacy of rituximab in combination with CHOP chemotherapyin patients with previously untreated intermediate- or high-grade NHL. Proc ASCO 1998;17:3a abstr.

[120] Vose JM, Link BK, Grossbard ML, et al. Phase II study ofrituximab in combination with CHOP chemotherapy in patientswith previously untreated intermediate- or high-grade non-Hodgkin’s lymphoma. Blood 1999;94(Suppl. 1):89a abstr.

[121] Coiffier B, Lepage E, Herbrecht R, et al. MabThera (rituximab)plus CHOP is superior to CHOP alone in elderly patients withdiffuse large cell lymphoma (DLCL): Interim results of arandomized GELA trial. Blood 2000;96(Suppl. 1):223a abstr.

[122] Howard O, Gribben J, Neuberg D, Grossbard M, Poor C,Janicek M, Shipp M. Rituxan/CHOP induction therapy innewly diagnosed patients with mantle cell lymphoma. Blood1999;94(Suppl. 1):631a abstr.

[123] Romaguera JE, Dang NH, Hagemeister FB, et al. Preliminaryreport of rituximab with intensive chemotherapy for untreatedaggressive mantle cell lymphoma. Blood 2000;96(Suppl. 1):733aabstr.

[124] Sparano JA, Tirelli U, Hopkins U, Vaccher E, Spina M. Pilottrial of infusional cyclophosphamide, doxorubicin, & etoposide(CDE) plus rituximab in HIV-associated non-Hodgkin’slymphoma. Blood 1999;94(Suppl. 1):268b abstr.

[125] Keating MJ, O’Brien S, Lerner S, et al. Combination chemo-antibody therapy with fludarabine, cyclophosphamide and rit-uximab achieves a high CR rate in previously untreated chroniclymphocytic leukemia. Blood 2000;96(Suppl. 1):514a abstr.

[126] Emmanouilides C, Teletar M, Rosen P, et al. Excellent toler-ance of rituxan when given after mitoxantrone-cyclophos-phamide: an effective and safe combination for indolent NHL.Blood 1999;94(Suppl. 1):92a abstr.

[127] Kuyu H, Keung YK, Radford JE, Perry JJ, Cruz JM, ZamkoffKW, Hurd DD. Efficacy of rituximab in relapsed low gradeB-cell non-Hodgkin’s lymphoma after autologous peripheralblood stem cell transplantation. Blood 1999;94(Suppl. 1):172aabstr.

Biography

Dr McLaughlin is Professor of Medicine in the De-partment of Lymphoma and Myeloma at the Univer-sity of Texas MD Anderson Cancer Center in Houston.Dr McLaughlin received his undergraduate degree fromHarvard College and his MD from Tufts UniversitySchool of Medicine Boston, Ma. Dr McLaughlin wasthe lead investigator on the 1995 multicenter pivotaltrial of rituximab that led to its approval by the FDAin 1997.

rituximab: perspective on single agent experience, and future directions in combination trials

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