Leukemia (2002) 16, 2004–2015  2002 Nature Publishing Group All rights reserved 0887-6924/02 $25.00 www.nature.com/leu REVIEW

Anti-CD20-based of : state of the art C Kosmas1, K Stamatopoulos2, N Stavroyianni2, N Tsavaris3 and T Papadaki4

1Department of Medicine, 2nd Division of Medical , ‘Metaxa’ Cancer Hospital, Piraeus, Greece; 2Department of , G Papanicolaou General Hospital, Thessaloniki, Greece; 3Oncology Unit, Department of Pathophysiology, Athens University School of Medicine, Laikon General Hospital, Athens, Greece; and 4Hemopathology Department, Evangelismos Hospital, Athens, Greece

Over the last 5 years, studies applying the chimeric anti-CD20 ficulties in identifying a completely tumor-specific target; (2) MAb have renewed enthusiasm and triggered world-wide appli- the impracticality of constructing a unique for each cation of anti-CD20 MAb-based in B cell non-Hodg- kin’s lymphoma (NHL). Native chimeric anti-CD20 and isotope- patient; (3) the development of an immune response to murine 6 labeled murine anti-CD20 MAbs are currently employed with immunoglobulins (human anti-mouse , HAMA). By encouraging results as monotherapy or in combination with the end of the 1980s enthusiasm for therapeutic MAbs was conventional and in consolidation of remission waning; murine native (unconjugated), radioactively labeled after treatments with curative intent (ie after/ in combination or toxin-conjugated MAbs failed to yield significant clinical with high-dose chemotherapy and responses; moreover, they were not uncommonly associated rescue). On the available experience, anti-CD20 MAb-based therapeutic strategies will be increasingly integrated in the with toxicities, predominantly in the form of serum sickness treatment of B cell NHL and related malignancies. from repeated administrations as a result of HAMA develop- (2002) 16, 2004–2015. doi:10.1038/sj.leu.2402639 ment, hematological or other toxicity (pulmonary toxicity and Keywords: monoclonal antibodies; B cell lymphoma; ; encephalopathy). Therefore, refinement of the antibody mol- ; ibritumomab ecule itself in order to avoid immunogenicity – HAMA by chi- merization or ‘humanization’, optimization of the method- ology to obtain more stable radioactively labeled MAbs and Introduction better understanding of the biology of antigenic epitopes expressed on developing – the counterparts of Over the last 25 years, since Kohler and Milstein1 first lymphoma cells – appeared the major prerequisites to enter described making monoclonal antibodies (MAbs), much time into the novel rapidly progressing era of Mab therapy of NHL. has been spent trying to develop these reagents in order to The most widely selected target for MAb-based therapeutic treat human disease. Until recently, progress has been notori- modalities in B cell NHL was the CD20 antigen for reasons ously slow and by 1994 only one MAb, anti-CD3 (OKT3), had that will be analyzed in the present report. been licensed for clinical use in treating renal and cardiac allograft rejection. In the past 5 years, however, the situation has changed dramatically, with numerous MAbs now having The CD20 target clinical potential, of which seven have been approved for tre- ating human disease. Furthermore, all indications are that this The CD20 antigen is restricted to B cells:7 its expression starts upward trend will continue, with a quarter of all new biologi- at the pre-B stage of B cell ontogeny and continues until the cal products currently undergoing clinical development being immunoblast stage; importantly, CD20 is not expressed on antibody based. either precursor lymphoid cells or in the vast majority of The first indication that MAbs might have significant thera- plasma cells. CD20 antigen expression on malignant B cells peutic potential came in the early 1980s, when Nadler and corresponds to the ontogenetic stage at which the malignancy colleagues,2 soon to be followed by Levy et al3 reported the is assigned: thus, non-Hodgkin’s (NHL) are CD20- first two cases of lymphoma patients experiencing a complete positive in over 90% of cases, contrasting with B cell acute response (CR) to a brief course of treatment with a ‘tailor- lymphoblastic leukemia which is positive in about half the made’ mouse anti-idiotype (anti-Id) MAb. This notable suc- cases and neoplastic plasma cells of which cess, together with (limited) animal data, sparked widespread are usually CD20-negative.8 academic and commercial interest, followed by a period of Although the function of CD20 has not yet been fully unrav- extreme enthusiasm in applying Mab-based therapeutic eled and CD20-knockout mice do not show a prominent approaches to treat human cancer.4 It was anticipated that the phenotype,9 CD20 does appear to play a role in Ca2+ transport progress MAbs had brought to biomedical research and clini- as cells transfected with CD20 increase their resting levels of cal diagnostics would be repeated for therapeutics. Unfortu- intracellular Ca2+.10–12 Some of the most interesting data on nately, this did not materialize: subsequent trials with different CD20 signalling comes from work showing that when types of murine and human-mouse chimeric MAbs in various crosslinked with MAb, CD20 is rapidly reorganized in the cancers failed to meet the success of the first anti-Id Mab case. lipid bilayer membrane.13 CD20 might be one of many signal- A number of limitations emerged from these studies:4,5 (1) dif- ling molecules (including the kinases Lyn, Fyn and Lck) able to divide into the sphingolipid and cholesterol-rich micro- domains so important in antigen receptor signalling in lymphocytes.14 Correspondence: C Kosmas, Consultant Medical Oncologist, 2nd Division of Medical Oncology, ‘Metaxa’ Cancer Hospital, 21 Apol- Certain characteristics make the CD20 antigen an appealing loniou Street, 16341 Athens, Greece; Fax: +3010-9962917 target for therapy; it is present on the Received 20 March 2002; accepted 7 May 2002 surface of mature B cells8 and has been noted in approxi- Anti-CD20 MAbs in B cell NHL C Kosmas et al 2005 mately 93% of patients with B cell lymphoma,15 but is not to moderate infusion-related toxic effects (, chills, present on B cell precursors, mature plasma cells, or other asthenia, nausea, rash, and urticaria). In the initial phase I nonlymphoid normal tissues.8,15 Additionally, it does not cir- trial, Rituximab produced rapid depletion of circulating B cells culate in the plasma as free that could competitively that slowly recovered during 3–6 months. Tumor biopsies per- inhibit MAb binding to lymphoma cells, does not shed from formed 2 weeks after a single infusion showed antibody the surface of CD20+ cells after antibody binding and does bound to tumor cells and a decrease in the percentage of B not seem to be internalized or, subsequently, downregulated cells in the tumor. In a multiple-dose study, 375 mg/m2 was on antibody binding.16,17 well tolerated and thus selected for further phase II trials.27,28 Crosslinking of CD20 with various Mabs induces a number In a seminal paper, McLaughlin et al31 reported the results of signalling events, including increased protein tyrosine phos- of a large multi-institutional trial. In that study, 166 patients phorylation, activation of protein kinase C and upregulation with relapsed or refractory low-grade or lym- of C-MYC.18 In vitro, these changes can regulate B cell growth phoma were studied. The overall response rate (RR) in the and appear to depend upon the association of CD20 with an intent-to-treat analysis was 48% (CRs: 6%): with a median ill-defined factor that couples it to the Src-kinases Lyn, Fyn time of follow-up of 11.8 months, the projected median time and Lck.19 There is a growing body of evidence confirming to progession (TTP) was 12.5 months. A detailed pharmacoki- that anti-CD20 Mabs are able to recruit immune effector netic analysis performed on a subset of patients revealed that mechanisms, such as complement-mediated lysis and anti- there was a stepwise increase of peak levels and serum half- body-dependent cellular cytotoxicity (ADCC);17 furthermore, life after each course. A significant correlation was noted they might also employ other intracellular signalling mech- between the number of circulating B cells at baseline and the anisms to achieve direct cytotoxic and/or apoptotic effects. rapidity of antibody clearance from the systemic circulation after the first infusion. Importantly, only one patient (Ͻ1%) developed human anti-chimeric antibodies (HACA). Rituximab: general features The results of the above two trials provided the basis for the fast-track approval of Rituximab by the FDA for the treatment Rituximab (IDEC-C2B8) is a highly specific mouse/human of relapsed or refractory . Since then, chimeric antibody engineered by grafting the variable regions many studies have contributed in better defining the thera- targeting the CD20 antigen from a murine anti-CD20 antibody peutic role of Rituximab as monotherapy or in combination (2B8) on to human constant regions.15 Rituximab has a longer with standard chemotherapy for management of indolent half-life than the parent murine antibody and is less immuno- lymphoma. genic, essentially eliciting no HAMA response.17,20 In an important recent paper, Colombat et al reported the The reactivity of Rituximab is restricted to B cells: Rituximab results of a multi-institutional trial of a 4-dose course of Rituxi- binds complement (C1q) and induces antibody-dependent mab in previously untreated patients with cellular cytotoxicity:17,20 in vitro, follicular lymphoma cell a low tumor burden (32). Of the fifty patients enrolled in the lines are lysed with Rituximab and human complement, albeit study, 36 responded within a month of treatment, with 10 with marked heterogeneity in the extent of the response. patients in CR, 3 in CR/unconfirmed (CRu) and 23 in PR. Dur- Rituximab also inhibits cell proliferation and directly induces ing the first year, 1/13 CR/CRu patients and 9/23 PR patients apoptosis.21 Furthermore, many data now suggest that Rituxi- showed disease progression. A noteworthy finding of that mab sensitizes malignant B cells to chemotherapy, mainly study was that a significant proportion of patients initially through disruption of anti-apoptotic pathways.22 Thus, syn- informative for bcl-2/Ig rearrangement were PCR negative in ergy with chemotherapeutics is a further mechanism of action peripheral at month 12; furthermore, a significant of Rituximab. association was noted between molecular and clinical The crucial part played by complement activation and responses. increased apoptosis in the activity of Rituximab gives some Single agent trials of Rituximab in previously untreated hints as to potential mechanisms responsible for resistance to patients with various other subtypes of indolent NHL are cur- this agent. Indeed, there is now abundant evidence in favor rently underway: interim results from these studies again sug- of a role of complement inhibitors CD55 and CD59 in resist- gest appreciable activity with minimal toxicity. In this context, ance of lymphoma cells to complement-mediated cytotoxicity at the 2001 American Society of Hematology 43rd Annual (CDC); in both lymphoma cell lines and primary patient (CLL, Meeting, two groups independently reported encouraging MCL, prolymphocytic leukemia) tumor cells, blocking anti- results with Rituximab monotherapy in extranodal marginal bodies to CD55 and CD59 increased CDC five- to six- zone lymphomas of MALT-type.33,34 Finally, the activity of fold.23,24 Nevertheless, the picture is far from clear: it was single-agent Rituximab was demonstrated in patients with pro- recently shown that both the expression of complement gressed (with 5/10 responders)35 and inhibitors CD55, CD59 and CD46 on pretreatment lymphoma patients with Waldenstom’s macroglobulinemia (WM); in a cells and their in vitro susceptibility to CDC does not predict recent retrospective analysis, Treon et al examined the out- clinical outcome after Rituximab treatment.25 come of 30 WMpatients (14/30 having failed nucleoside ana- logue therapy) receiving a median of four infusions of Rituxi- mab:36 overall, 8/30 patients (27%) achieved a PR, 10/30 Rituximab single-agent therapy of lymphoma (33%) a minor response and an additional 9/30 (30%) demon- strated stable disease, with a median time to treatment failure The efficacy and safety of Rituximab single-agent therapy has for responding patients of 8.0 months (range: 3–20+ months). been reported in patients with low-grade or follicular NHL in 26–30 a number of phase I/II studies. Phase I studies of single doses up to 500 mg/m2 and multiple-dose schedules of up to 375 mg/m2 weekly for four doses demonstrated that the anti- In 1998, Coiffier et al37 reported the results of a multicenter CD20 antibody Rituximab was well tolerated with only mild international phase II trial addressing the efficacy and safety of

Leukemia Anti-CD20 MAbs in B cell NHL C Kosmas et al 2006 Rituximab as single-agent therapy in patients with aggressive Combination therapy with Rituximab: indolent lymphoma lymphoma, including diffuse large cell lymphoma (DLCL), MCL and other intermediate or high-grade lymphomas Combination with chemotherapy (according to the ). The study included 54 patients (mostly in first or subsequent relapse or with The above studies seem to have succeeded by overcoming refractory disease or progression after an initial response); nine two major stumbling blocks: lower CD20 antigen density on elderly patients were previously untreated. The overall RR was CLL cells and shorter half-life of Rituximab in CLL patients 31% (CR 9%, PR 22%); DLCL and MCL patients had RR of (due to the ‘antigen sink’ effect42 or mediated by soluble 37% and 33%, respectively. These results demonstrated that CD2047). Their results prompted trials with combinations of Rituximab is an active agent in aggressive lymphomas, hinting Rituximab with various chemotherapeutic agents, especially at the therapeutic potential of combinations of Rituximab with fludarabine and . The rationale of such chemotherapy in this subgroup of lymphomas. trials is that Rituximab has different mechanisms of action and Two further phase II studies reported results of Rituximab toxicities from chemotherapy and, furthermore, that it can single agent treatment of MCL. In an international multicenter sensitize lymphoma cells to the cytotoxic effects of certain study, Foran et al38 administered 4 weekly doses of Rituximab chemotherapeutics. In the 2001 American Society of Hema- at 375 mg/m2 to 34 newly diagnosed and 40 previously tology 43rd Annual Meeting, Garcia Manero et al48 reported treated MCL patients; RR rates were 38% and 37%, respect- results with a chemo- regimen consisting of ively, with 10/74 patients achieving a CR; toxicity was accept- Rituximab, fludarabine and cyclophosphamide on 102 both able, while the median duration of response was 1.2 years. A previously untreated and treated (27/102 fludarabine resistant) similarly designed study by the Swiss Group for Clinical Can- CLL patients. With a median follow-up of 13+ months, using cer Research reported a RR of 22% at 12 weeks for 39 MCL NCI criteria the total RR was 72%, with a CR rate of 23%; patients.39 importantly, there were even ‘molecular’ remissions, in the sense that 5/13 patients in CR had undetectable clonal Ig rearrangements by PCR. Chronic lymphocytic leukemia The combination of Rituximab with CHOP chemotherapy was proven extremely efficacious in a phase II trial in indolent CD20 is expressed in almost all patients with chronic lympho- lymphoma conducted by Czuczman et al.49 In that study, 40 cytic leukemia (CLL), albeit with marked heterogeneity as patients (31 previously untreated) with low-grade/follicular regards antigen density (with most patients exhibiting a low lymphoma received a combination of Rituximab with stan- density);40 thus, Rituximab would be considered to have a dard CHOP chemotherapy for six courses. On an intent-to- place in the treatment of CLL. However, initial studies sug- treat analysis, the overall RR was 95% (38/40 patients), with gested that Rituximab was less active in small lymphocytic 22/40 patients (55%) attaining a CR and 16/40 (40%) a partial lymphoma (SLL)/CLL and, furthermore, that administration in response (PR). Interestingly, in some evaluable patients a con- CLL patients was associated with significant infusion-related version from PCR positivity to negativity for bcl-2/Ig toxicity.31,38,41 sequences was identified. Finally, the toxicity profile of the Two studies have evaluated the activity of higher dose and combination was comparable to that of either Rituximab or more intensive treatment with Rituximab in CLL.42 In the study CHOP alone, while the addition of Rituximab did not compro- by O’Brien et al,43 40 patients with CLL were treated with four mise CHOP dose intensity. weekly doses of Rituximab 375 mg/m2 for the first infusion, A multicenter Italian study prospectively evaluated minimal with dose escalation beginning with the second infusion and residual disease by PCR for bcl-2/Ig rearrangement after the held constant for each patient; escalated doses were from 500 sequential administration of CHOP and Rituximab in pre- to 2250 mg/m2. The overall RR was 40% with all responses viously untreated follicular lymphoma patients;50 patients being partial remission; the median time to progression was 8 either in CR or in PR after CHOP were eligible for 4 weekly months There was clear evidence of a dose–response: patients doses of Rituximab if they were persistently PCR positive. At treated at 500 to 825 mg/m2 had a 22% RR, those treated at 12 weeks, 35/77 Rituximab-treated patients were PCR nega- 1000–1500 mg/m2 had a 43% RR and, finally, those treated tive in the bone marrow and peripheral blood; at the last fol- at the highest dose of 2250 mg/m2 had a 75% RR. Importantly, low-up (+44 weeks), 25/77 patients were still PCR negative. severe first-dose toxicity was uncommon. A durable PCR negative status was associated with superior In the study by Byrd et al,44 33 patients with CLL were outcome, as freedom from recurrence at 3 years was 57% treated on a thrice weekly dosing schedule: an initial dose of compared to 20% in patients never achieving a PCR negative 100 mg/m2 followed by doses of 250 mg/m2 or 375 mg/m2 on status or reverting again to PCR positive (P Ͻ 0.001). day 3 and thereafter thrice weekly for 4 weeks. The overall A number of further studies reported on the application of RR was 45% (3% CR, 42% PR) with a median duration of Rituximab in combination with various multidrug chemo- response for the 15 responders of 10 months (range 3–17+). therapy regimens in indolent lymphoma. The German Low Only one patient discontinued therapy due to severe infusion- Grade Lymphoma Study group (GLSG) conducted a prospec- related toxicity; significant infusion-related reactions were tive, randomized trial comparing chemotherapy seen in 13 patients: they were probably attributed to cytokine (fludarabine/cyclophosphamide/mitoxantrone, FCM) plus release and resolved by the third infusion. Encouraging results Rituximab to chemotherapy (FCM) alone in patients with were also obtained by Hainsworth et al,45 even at standard relapsed follicular lymphoma.51 In 43 patients evaluable for doses albeit with prolonged administration. Thus, with the response, an overall RR of 95% was observed, which was sig- exception of the German Chronic Lymphocytic Leukemia nificantly superior to the overall RR of 68% with FCMalone Group who recently reported low efficacy of single-agent ther- (P = 0.0007); furthermore, the combined treatment was not apy,46 the results of most studies to date point to the potential associated with additional toxicity compared with standard utility of Rituximab in the treatment for CLL patients, perhaps FCM. Gregory et al52 used Rituximab as consolidation therapy as part of combination protocols. for patients with untreated advanced low-grade lymphoma

Leukemia Anti-CD20 MAbs in B cell NHL C Kosmas et al 2007 who initially received four to six courses of combined pivotal role in such an approach since it can achieve rapid fludarabine/mitoxantrone chemotherapy. In 19 patients evalu- and effective tumor cytoreduction with or without chemo- able for response, an overall RR of 95% was observed with a therapy usually leading to a state of minimal residual disease. CR rate of 53%; six patients have been maintained in CR for Moreover, as Rituximab depletes the B cell arm of the immune over 8 months during follow-up, while four have sustained PR system, subsequent boost of idiotype-specific T cells might for 9 or 10 months. Serious adverse effects and infections were prolong remission duration and probably survival. rare. Finally, Czuczman et al53 recently presented the final results of a phase II single institution trial of Rituximab plus fludarabine in 40 patients with both previously untreated and Combination therapy with Rituximab: aggressive lymphoma treated low-grade lymphoma: they reported an overall RR of 90% with a CR/CR-unconfirmed rate of 82.5%, with median Over the past 20 years, the CHOP regimen has resulted in duration of response not reached at 15+ (4+ to 36+) months. clinical responses in over 80% of aggressive lymphoma Although toxicity was deemed acceptable, the use of the com- patients; however, CHOP is curative in less than 40%. bination was associated with significant cytopenia (mostly Attempts to improve treatment outcome by utilizing more neutropenia); however, apart from a trend to increased herpes aggressive regimens or increasing CHOP dose intensity have simplex/zoster infections, no other opportunistic infections or met with no success;60 thus CHOP has remained the gold- increased incidence of bacterial infections were seen. standard therapy for aggressive lymphoma. The first study to demonstrate the safety and efficacy of Rituximab in combination with CHOP in aggressive lym- Combination with other MAbs and biological agents phoma was reported by Vose et al.61 In that phase II trial, 33 patients with previously untreated aggressive lymphoma Combinations of Rituximab with other MAbs targeting alterna- received Rituximab on day 1 of each cycle in combination tive antigens are currently under evaluation. with six cycles of CHOP chemotherapy on day 3 of each (CAMPATH-1H) is a MAb binding to the CD52 cycle. The overall RR was 94% with 20 patients (61%) antigen, which is found on the majority of T and B lympho- attaining a CR. At the time of publication of the results of the cytes, as well as other cells of the hematopoietic system, with trial, with a median follow-up of 26 months, the median dur- the exception of CD34+ progenitor cells and granulocytes. ation of response and time to progression had not been Alemtuzumab is currently licensed in the USA for treatment reached. Furthermore, the addition of Rituximab to CHOP did of patients with fludarabine-refractory B-CLL. Two phase I not increase toxicity nor did it compromise CHOP delivery. studies have examined the application of combinations of Between 1998 and March 2000, the Groupe d’Etude des Rituximab + Alemtuzumab in patients with relapsed/refractory Lymphomes de l’Adulte (GELA) conducted a randomized trial B-CLL,54,55 and demonstrated the feasibility and safety of the comparing CHOP chemotherapy plus Rituximab to CHOP combination associated with encouraging activity in this alone in elderly patients with untreated diffuse large B cell selected group mainly consisting of poor-risk patients. These lymphoma. Patients were assigned to receive either eight prompted a novel phase II study, which aims at further evalu- cycles of CHOP every 21 days (197 patients) or eight cycles ating the clinical efficacy of this regimen. Other combinations of CHOP plus Rituximab administered on day 1 of each cycle being currently explored are anti-CD22 Mab (Epratuzumab) + (202 patients). The results of this trial were recently pub- Rituximab56 and anti-CD80 MAb + Rituximab57 for lished:62 CR rate was significantly higher in the chemoimmun- relapsed/refractory NHL. otherapy grroup (76% vs 63%, P = 0.005); with a median fol- Rituximab has also been combined with interferon-alpha low-up of 2 years, event-free and overall survival were (IFNa) in low-grade lymphoma. A study by Kimby et al,58 on significantly higher in the combined modality group behalf of The Nordic Lymphoma Group reported results (P Ͻ 0.001 and P = 0.007, respectively). Importantly, a sig- obtained in 124 evaluable patients with follicular grade 1–2 nificant benefit of the combined treatment over CHOP alone CD20+ B cell NHL who had received no prior chemotherapy was observed both among patients with low risk disease (n = 90) or who had received Ͻ6 months of chlorambucil (International Prognostic Index, IPI, 0 or 1, P Ͻ 0.001) and (n = 34). All patients received weekly Rituximab × 4. Patients those with high risk disease (IPI 2 or 3, P Ͻ 0.03). The two who attained CR (11%) received no further therapy, while regimens had comparable toxicity; however, a trend for more patients who attained PR/minor response were randomized to herpes zoster infections was observed in the Rituximab plus receive either another 4 weeks of Rituximab alone or weekly CHOP group. This seminal study demonstrated the first Rituximab together with IFNa. improvement in overall survival for any regimen compared The RR for IFNa + Rituximab was 94% with 48% CRs, with CHOP and will very likely establish (at least for elderly whereas that for continued Rituximab alone was 77% with patients with aggressive lymphoma) Rituximab as an agent to 22% CRs. This study indicates that the addition of interferon be combined with standard chemotherapy for front-line treat- to Rituximab is associated with an increased chance of ment. Furthermore, these exciting results triggered the MInT attaining an objective response, when compared with con- (Mabthera International Trial) study comparing Rituximab plus tinued use of Rituximab alone. CHOP or CHOP-like regimens to CHOP or CHOP-like regi- Currently, another area of active investigation with rapidly mens alone in the management of patients aged 18–60 years increasing interest is the recognition that tumor-specific with untreated DLCL. responses can be generated against B cell NHL, since the A number of additional papers presented in the 2000/2001 tumor-associated antigen related to the B cell lymphoma Annual Meeting of the American Society of Hematology and immunoglobulin (Ig) sequence, is the Ig idiotype, which can the American Society of Clinical Oncology (ASCO) reported be more efficiently presented on patient’s dendritic cells.59 on the combination of Rituximab with various chemotherapy These vaccination strategies are best suited for consolidative regimens, including EPOCH (continuous infusion etoposide, therapy after achieving a major response/debulking with , and , and bolus cyclophosphamide) in intensive chemotherapy. At this point Rituximab could play a poor prognosis aggressive lymphoma,63 ICE (ifosfamide, eto-

Leukemia Anti-CD20 MAbs in B cell NHL C Kosmas et al 2008 poside and carboplatin) in relapsed or primary refractory tory aggressive B cell NHL underwent HCT followed by Ritux- DLCL,64 hyper-CVAD in adult Burkitt’s lymphoma65 and CDE imab 375 mg/m2 weekly for 4 doses starting on day 40 and (infusional cyclophosphamide, doxorubicin and etoposide) in repeated for four more doses starting on day 180. Rituximab HIV-associated lymphoma.66 These initial reports suggest that infusions were well tolerated with only one grade 3/4 Rituximab given with various combination chemotherapy infusion-related toxicity. The unexpected adverse event noted regimens is tolerable and associated with satisfactory RRs. in this trial was delayed neutropenia in more than half the Further evaluations of these trials are awaited. patients (19/35 patients with 46 episodes of grade 3 or 4 (MCL) is an uncommon entity usu- neutropenia); all patients recovered from neutropenia without ally affecting older adults and presenting with advanced-stage an apparent increased incidence of infections over what is disease; the prognosis of MCL with CHOP-like regimens is typically seen in AHCT. No patients had evidence of B cell poor, even prompting clinical trials of autologous hematopo- recovery at 12 months. With a median follow-up of 18 ietic cell transplantation (AHCT) as upfront treatment of newly months, estimated OS at 24 months was 85% and estimated diagnosed MCL patients. In this line, the MD Anderson group FFP was 86%, higher than expected with conventional AHCT described a CR rate of 100% as well as prolonged failure-free regimens. Buckstein et al81 used Rituximab as consolidation and overall survival by using the hyperCVAD-- therapy post high-dose therapy (CBV) and HCT in 21 patients cytarabine (HCVAD) regimen followed by AHCT in MCL with relapsed follicular lymphoma; with a median follow-up patients less than 66 years.67 The same group recently of almost 2 years, high rates of durable and molecular reported equivalent results with HCVAD combined with remissions were demonstrated. The same group applied this Rituximab instead of AHCT, with a trend for even superior protocol in 13 newly diagnosed MCL patients and recently outcome in patients above 65 years old.68 reported encouraging preliminary results.82 For both the afore- mentioned and all other similarly conducted studies, longer follow-up times are necessary to determine efficacy, durability Rituximab in the setting of hematopoietic cell of responses and the risk of severe infections. transplantation: in vivo purging and adjuvant treatment

In vivo purging Rituximab in the management of post-transplant B- lymphoproliferative disorders A major cause of relapse post-autologous hematopoietic cell transplantation (AHCT) is reinfusion of malignant cells with Post-transplant lymphoproliferative disorder (PTLD) is a severe the graft. A reduction in the rate of relapse might be expected complication of solid . The incidence of by pre-transplant elimination of tumor cells from the graft PTLD is rising as organ transplantation becomes more com- (’purging’) followed by post-transplant consolidation treat- monplace. Approximately one-third of PTLD patients will ach- ment to eradicate minimal residual disease. The ex vivo purg- ieve a CR with reduction in their immunosuppression. For ing protocols have generally been cumbersome and expens- those who do not respond, other treatments such as chemo- ive, thus finding limited application. However, the whole idea therapy are exceedingly toxic with mortality rates as high as of purging seems to have taken new directions with the 50%. Most PTLDs are composed of CD20+ B cells; this introduction of Rituximab. prompted several trials of Rituximab (usually at a dose of 375 Rituximab has now been evaluated for in vivo purging pur- mg/m2 for 4 weeks) for the treatment of patients with PTLD not poses by several groups with generally successful results.69–78 responding to reduction in immunosuppression. In the largest Some common themes emerged from these studies: (1) in vivo series reported to date,83 a French group presented results of purging with Rituximab is superior to currently available ex a retrospective analysis of Rituximab administration in 32 vivo protocols (evidenced, among other tests, by PCR patients with PTLD developing after solid organ transplants analyses); (2) the administration of Rituximab pre-transplan- (26 cases: liver 8, kidney 8, heart 4, lung 3, heart lung 1, tation concurrently with the salvage/mobilization regimen kidney–pancreas 1, liver–kidney 1) and HCT (6 cases). The does not compromise the harvest of peripheral blood progeni- treatment was well tolerated leading to an overall RR of 69% tor cells even in heavily pretreated patients; (3) stem cells col- with 20 CRs and two PRs; in solid organ transplant, the RR lected post-Rituximab administration function normally; (4) was 65% while in HCT it was 83% (5 patients achieving a prompt engraftment occurs in almost all patients; however, CR). With a median follow-up of 8 months, 24 patients were some studies report transient neutropenia some time post alive; at publication of the study, of 22 responders 15 were transplantation that resolves within some months without an alive with no evidence of disease. Similarly encouraging increased incidence of infections; as we have recently results have been reported by others;84–86 furthermore, there shown,79 this complication might in fact be an autoimmune is now evidence to suggest an impact of Rituximab on phenomenon arising in the setting of T-large granular lympho- Epstein–Barr infection that usually underlies PTLD.87 How- cyte (CD3+CD8+CD57+CD28−) proliferation; (5) the optimun ever, caution is needed as numbers are (unavoidably) small Rituximab-based purging protocol remains to be established. and follow-up is too short to assess durability of responses.

Adjuvant therapy to high-dose chemotherapy and Conjugated anti-CD20 MAbs in lymphoma therapy autologous hematopoietic cell transplantation Another aspect of MAb therapy that has generated much inter- The efficacy and safety of Rituximab has been evaluated in est is the use of radioimmunoconjugates, MAbs conjugated to the setting of minimal residual disease burden following high- radioactivity-emitting molecules. The advantage of using dose therapy and AHCT. Horwitz et al80 at Stanford reported radioimmunoconjugates is that radiotherapy is targeted to the preliminary results of a trial using Rituximab following periph- tumor cells, thereby limiting toxic effects on normal cells; the eral blood AHCT. Thirty-five patients with relapsed or refrac- approach is known as (RIT). Tumor

Leukemia Anti-CD20 MAbs in B cell NHL C Kosmas et al 2009 eradication is accomplished by the antibody-mediated effects ment infusion of a tracer dose followed by planar imaging. as well as by the cytotoxic activity of the radiation. Beta par- Responses were seen in 12/18 (67%) patients, with six patients ticles are tumoricidal over a distance of many adjacent cell (33%) achieving CR. The median duration of response was diameters and achieve killing of antigen-negative tumor cells 10.6 months, which is similar to the median of 13 months that would not be eliminated by the antibody alone (’cross- response duration following the initial 131I-tositumomab treat- firing’ or ‘bystander’ effect). ment. Patients who achieved CR to initial 131I-tositumomab Radionuclides, toxins and prodrug-converting treatment benefited most from retreatment. None of the have all been conjugated to MAbs and are at various stages patients in this study developed HAMA after retreatment. of development in clinical trials. The most promising results Hematologic toxicities encountered with 131I-tositumomab have been seen with RIT for B cell NHL, where there appears retreatment were of similar severity to those seen after initial to be a synergy between the signalling induced by anti-CD20 first-line therapy. Three patients (17%) developed myelodys- and the delivery of beta-radiation, an effect also seen in plasia (MDS) 4.5–6.1 years after retreatment with 131I-tositum- mouse lymphoma models.88 High RRs have been seen in both omab. Since the natural history of low-grade NHL is charac- newly diagnosed patients89 as well as those previously exten- terized by remissions and recurrences after each subsequent sively treated with chemotherapy.90,91 treatment, therapy that can be delivered repeatedly during Trials exploring the use of two radioimmunoconjugates, ie subsequent relapses, without significant loss of efficacy, rep- iodine-131 (131I)-tositumomab (Bexxar) and yttrium-90 (90Y)- resents a rather valuable tool in the armamentarium of the (Zevalin) will be reviewed here. available treatments for low-grade NHL. The incidence of secondary MDS observed in the above study raises significant concerns regarding RIT, and should be Iodine-131 tositumomab evaluated prospectively with care. An overview of seven trials involving 131I-tositumomab therapy of NHL in 773 patients 131I-tositumomab in low-grade and transformed NHL concerning the incidence of therapy-related MDS/AML (tMDS/tAML) was presented in the 43rd ASH meeting.96 Over- A radioimmunoconjugate with promising early data is 131I-tos- all, 20 patients had developed tMDS/tAML which was con- itumomab (Bexxar). A recent phase II study in patients with firmed on hematopathology review, representing an annual refractory low-grade or transformed low-grade B cell NHL incidence of 1.45%. Five of these 20 patients had tMDS in demonstrated a RR of 57% with a median duration of 9.9 their pre-RIT marrow. In 11/12 of these patients bone marrow months.92 Infusion of 131I-tositumomab was well tolerated cytogenetics were available and indicated abnormalities of with most of the adverse events occurring during the dosi- 5 or 7. Eight of the 15 tMDS/tAML cases were metric infusion and being mild in severity; principal toxicities from a phase I trial that enrolled 59 heavily pre-treated were hematologic. patients, who had received a median of six cytotoxic regimens Results of a trial with 131I-tositumomab in previously prior to 131I-tositumomab, including alkylating agents, topo- untreated patients with follicular lymphoma was presented at isomerase II inhibitors, and radiotherapy. With a median fol- the ASCO 2000 Meeting.93 The results of this trial were low-up of 3.2 years for these same heavily pre-treated impressive, with an overall RR of 97% (CR rate: 76%). With patients, the annualized incidence was 3.8%. In contrast, a median follow-up of 16.2 months, the duration of response there have been no cases of tMDS/tAML in 76 previously has not yet been reached. The 131I-tositumomab was well tol- untreated patients after a 2.7-year median follow-up. Overall, erated. Sixty-two percent of patients developed HAMA, and the incidence rates of tMDS/tAML following targeted systemic the majority of them experienced mild serum sickness in radiation with 131I-tositumomab appear comparable to those about 2 weeks following treatment. Long-term follow-up of reported in the pre-RIT chemotherapy ± radiotherapy era for this study is needed to fully assess the response with this low-grade NHL. Nevertheless, long-term follow-up data will agent. be required in order to assess delayed hematopoietic stem cell The results of a multi-center phase II study with 131I-tositum- damage and decrease in bone marrow reserve from RIT omab for NHL patients who progressed after treatment with strategies. Rituximab indicated a 57% overall RR with 14% CR rate.94

CHOP followed by 131I-tositumomab Retreatment with 131I-tositumomab The results of a Southwest Oncology Group (SWOG) phase II Due to the reversibility of myelosuppression, the favorable trial evaluating CHOP followed by 131I-tositumomab for the tumor-to-normal tissue ratios with resultant low radiation dose treatment of patients with newly diagnosed follicular lym- to normal organs, and the infrequent development of HAMA, phoma were presented by Press et al97 during the 43rd ASH it is appealing to consider using 131I-tositumomab for 2001 annual meeting in Orlando, Florida. Ninety-two patients retreatment in patients who relapse after initial response to with newly diagnosed follicular lymphomas were treated with this radioimmunoconjugate. In the sole such study presented CHOP followed by 131I-tositumomab RIT as consolidation. at the 2001 ASCO meeting, 18 patients with low-grade or Seventy-one patients were evaluable for response and 60 were transformed low-grade NHL who progressed after responding evaluable for toxicity. With regard to efficacy, at the time of to 131I-tositumomab therapy were re-treated with 131I-tositum- the analysis, a 52% CR rate and a 28% PR rate, for an 80% omab.95 All patients had a CR/PR of at least 3 months duration overall RR, were observed on intention-to-treat. Grade 4 tox- after initial 131I-tositumomab treatment, with a median time icities were recorded in 13% of patients, and consisted of neu- to re-treatment of 20 months. Patients were required to have tropenia, thrombocytopenia, and infusion-related anaphylac- adequate bone marrow function, Ͻ25% bone marrow toid reaction and chest or back pain. These data suggest that involvement with lymphoma and HAMA negativity. Dosing sequential therapy with CHOP×6P131I-tositumomab is well was based on individual patient dosimetry after a pre-treat- tolerated and efficacious. A prospective randomized trial com-

Leukemia Anti-CD20 MAbs in B cell NHL C Kosmas et al 2010 paring this regimen with CHOP alone and with CHOPP131I- regimens, and deliver more irradiation to disease-involved tositumomab is currently in progress by SWOG investigators. areas than to normal organs, thus constituting a more effective and less toxic modality to be combined with cytotoxic agents in this setting. RITwith 131I-tositumomab as part of the preparative regimen in hematopoietic stem cell transplantation 90Yttrium ibritumomab tiuxetan (Zevalin) Patients with aggressive NHL who are a primary induction

failure or relapse with chemo-refractory disease have a poor 90 outlook with standard high-dose chemotherapy and AHCT. Yttrium ibritumomab tiuxetan (Zevalin) is composed of a Investigators from Nebraska conducted a phase I/II trial evalu- murine monoclonal antibody, ibritumomab, which targets the 90 ating the addition of standard dose of 131I-tositumomab given CD20 antigen, and the radioisotope Y, which are linked by sequentially with the high-dose BEAM(BCNU, etoposide, Ara- the bifunctional chelator, tiuxetan. C, and melphalan) transplant regimen followed by AHCT in patients with aggressive NHL and primary induction failure or relapsed chemo-refractory disease.98 Twenty-three patients Phase I–II study of 90Y-ibritumomab in relapsed NHL with follicular (n = 4), diffuse large cell (n = 14), or MCL (n = 5) 131 received I-tositumomab on an outpatient basis. The patients In a phase I/II study of patients with relapsed or refractory low- 131 − received a tracer dose of I-tositumomab on day 19 fol- grade and intermediate grade (WF groups A–G), Witzig et 131 lowed by the calculated total body therapy dose (TBD) of I- al100 demonstrated a maximum tolerated dose of 0.4 mCi/kg − tositumomab on day 12 in four dose cohorts (30 cGy, (0.3 mCi/kg in patients with mild thrombocytopenia). Patients 45 cGy, 60 cGy and 75 cGy). The BEAMchemotherapy was received the 90yttrium ibritumomab tiuxetan infusions in an − administered starting on day 6 followed by ASCT. The outpatient setting. They were well tolerated with no infusion- ␮ median time to reach an absolute neutrophil count 500/ lwas related toxic effects. Adverse effects were primarily hematol- 10 days, median time to platelet transfusion independence ogic and transient. At the 0.4-mCi/kg dose level, the median was 12 days, and median time to red blood cell transfusion nadir values of platelets, absolute granulocytes, and hemoglo- independence was 9 days. There were no treatment-associa- bin were 50 000/␮l, 1100/␮l, and 9.9 g/dl, respectively. Five ted deaths. The CR rate was 57% and PR rate of 9% for an patients (10%) had platelet nadirs less than 10 000/␮l, and overall RR of 66%. With a median follow-up of 12 months 27% of patients had absolute granulocyte counts of less than (range, 4–28) the estimated 1 year event-free survival was 500/␮l. The overall RR in the intent-to-treat analysis was 67% 60% and the estimated OS 78%. The authors concluded that (complete RR, 26%). The RR was 82% for low-grade 131 the addition of I-tositumomab at standard doses, which can lymphoma and 43% for intermediate-grade lymphoma. be delivered on an outpatient basis with the BEAMtransplant regimen, is easily administered with no delay in engraftment and looks promising as a synergisitic treatment for refractory 90 aggressive NHL. A phase II trial with 131I-tositumomab at 75- Y-ibritumomab vs Rituximab in relapsed/refractory cGy TBD sequentially with BEAMhigh-dose chemotherapy low-grade NHL followed by ASCT has been initiated. High-dose 131I-tositumomab has been applied as a part of At the ASH 2000 Annual Meeting, the same group presented the preparative/conditioning regimen in combination with the final results of a randomized phase II trial comparing 90Y- etoposide, cyclophosphamide and ASCT for patients with ibritumomab with Rituximab in patients with relapsed or relapsed or refractory MCL.99 Fifteen relapsed or refractory refractory low-grade lymphoma.101 The 90Y-ibritumomab regi- MCL patients were treated with high-dose chemo-RIT using men consisted of day 0 Rituximab 250 mg/m2 followed by a 131I-tositumomab, etoposide, cyclophosphamide and ASCT. A tracer dose of 5 mCi 111indium (111In)-labeled-ibritumomab CR rate of 73% was achieved in 13 evaluable patients, a PR tiuxetan (for imaging/dosimetry) and day 7 Rituximab rate of 9%, while two patients in remission pre-transplant 250 mg/m2 followed by 0.4 mCi/kg 90Y-ibritumomab. Patients remained progression free. Almost 50% of patients with PCR+ in the control arm received 4 weekly doses of 375 mg/m2 bone marrow converted to PCR negativity at 1 month post Rituximab. With a total of 143 patients randomized between transplant. All 15 patients remained alive without progression the two treatment arms, overall RRs were 80% in the 90Y-ibrit- with a median follow-up of 12 months from AHCT and 44 umomab arm vs 56% in the Rituximab arm (P = 0.002) with months since diagnosis. Toxicities were comparable to stan- 30% CR in the 90Y-ibritumomab vs 16% CR in the Rituximab dard transplant regimens with a median time of neutrophil arm (P = 0.04) and 4% unconfirmed CR in each arm. Duration count Ͻ500 of 12 days (range, 9–19 days). Therefore, high- of responses were not statistically different at 10.9+ and 11.5+ dose 131I-tositumomab, etoposide, cyclophosphamide and months. Median times to next anti-lymphoma therapy had not AHCT may provide a beneficial therapeutic option for been reached for 90Y-ibritumomab and for Rituximab was relapsed MCL patients that otherwise carry a poor prognosis, 15.2 months, while in those who had progressed by the time although longer follow-up and additional patients will be of the report, time to next therapy was 11.5 vs 7.8 months, needed to assess the reproducibility and durability of these respectively. 90Y-ibritumomab adverse events were primarily findings. hematologic, transient and reversible with 32% of patients The above two studies, attempting to incorporate high-dose developing grade 4 neutropenia and 5% grade 4 thrombocy- RIT as a part of high-dose chemotherapy preparative regimens topenia. Only 7% of patients required hospitalization for with AHCT in relapsed/refractory B cell NHL, indicate that infection. This phase III trial demonstrated that 90Y-ibritumo- radiolabeled anti-CD20 MAbs may substitute total body mab RIT is safe and effective and that objective RRs achieved irradiation (TBI), an effective cytoreductive modality in hema- with 90Y-ibritumomab RIT were statistically superior to those tologic malignancies usually incorporated in conditioning achieved with Rituximab alone.

Leukemia Anti-CD20 MAbs in B cell NHL C Kosmas et al 2011 90Y-ibritumomab (Zevalin) RITin heavily pretreated followed by 90Y-ibritumomab at an initial dose calculated to and bulky NHL deliver no more than 100 cGy to critical organs was adminis- tered. The 90Y-ibritumomab dose was escalated in cohorts of Fifty-seven patients, median age of 54 years, with relapsed three patients. High-dose BEAMwas administered days −6to NHL and a predominantly follicular histology (95%), refrac- −1 followed on day 0, by infusion of у2.0 × 106 CD34+ tory to Rituximab (no response or TTP Ͻ6 months) were cells/kg, with G-CSF 5 ␮g/kg beginning on day 0. Three treated with 90Y-ibritumomab.102 Patients could not have had patients had MCL, seven had diffuse aggressive NHL, and two prior myeloablative therapy or RIT, external beam radiation had follicular NHL. Grade III/IV toxicities included fever, to Ͼ25% of active bone marrow, or у25% bone marrow infection, hemorrhage, nausea, vomiting, diarrhea, and stoma- involvement by lymphoma. The majority of the patients (82%) titis consistent with those seen in patients receiving BEAM were resistant to their last and had alone. Engraftment for granulocytes was seen at a median of bulky disease (у5 cm in 74% patients). 90Y-ibritumomab was 10 days (range, 8–17) and for platelets on day 20 (range, 16– administered in the outpatient setting at a dose of 0.4 mCi/kg. 39). It was concluded that the addition of a therapeutic dose The overall RR was 74% with 15% CRs. Median duration of of 90Y-ibritumomab to high-dose BEAMchemotherapy response was significantly longer for 90Y-ibritumomab than for is likely to be without serious toxicity, and further phase II prior Rituximab (8.4+ vs 4 months, P = 0.008). Response to evaluation is ongoing. 90Y-ibritumomab was better in patients who had responded to prior Rituximab, with a TTP Ͻ6 months, than Rituximab nonresponders; 77% vs 51%, respectively. Among patients Comparison between 131I-tositumomab (Bexxar) and 90Y- who had a response to their last chemotherapy regimen, 65% ibritumomab tiuxetan (Zevalin) responded to 90Y-ibritumomab as compared with a RR of 47% among patients who had disease that was resistant to their last There are several differences between these two radioimmun- chemotherapy regimen. Half of the patients with bulky disease oconjugates. Although both 131I and 90Y are ␤-emitters, 90Y (Ͼ10 cm) responded to 90Y-ibritumomab. Toxicity of 90Y-ibrit- emits ␤-particles of higher energy, a longer path length, and umomab was predominantly hematologic with grade 4 neu- a shorter half-life. Radiolabeling of the two MAbs differs sub- tropenia in 35% and grade 4 thrombocytopenia in 9% of stantially; 131I is attached to the antibody on tyrosine residues patients. One patient developed HAMA, and one patient and the procedure is easy and widely applicable in contrast developed acute myelogenous leukemia (AML) 8 months to 90Y which requires a bifunctional chelating agent (tiuxetan; post treatment. Mx-DTPA) to be first attached to the antibody by specialized A small study in patients with advanced NHL failing prior radiochemistry methodology, available in specialized labora- 90Y-ibritumomab tiuxetan evaluated the safety of high-dose tories. With respect to in vivo stability, 131I-labeled antibodies chemotherapy with AHCT rescue and demonstrated that these are relatively unstable, as 131I is easily dettached from the anti- patients could be treated efficiently with this approach despite body by blood and tissue dehalogenases, while 90Y is main- prior RIT. All but one patient, who died during absolute neu- tained rather stably on the antibody through the chelator, and tropenia, engrafted and all had mobilized stem cells success- is only minimally detached by binding to circulating trans- fully despite concerns about potential hematopoietic stem cell ferrin. Moreover, with respect to bifunctional chelating agents, damage from prior RIT.103 we have demonstrated in the past that these are potently A total of 349 patients with relapsed/refractory low-grade, immunogenic107,108 and therefore, care should be taken with follicular, transformed, or intermediate-grade B cell NHL has monitoring potential immunogenicity of tiuxetan in NHL RIT been treated with 90Y-ibritumomab tiuxetan (Zevalin) in five trials. Because 90Y is not a ␥-emitter, planar imaging or dosi- clinical trials of RIT. Overall, treatment has been found to be metric calculations with 90Y-ibritumomab requires the use of well tolerated, despite the increased risk for toxicity in this an 111In conjugate. There are differences in dosing, adminis- population.104 Moreover, a single case of WM, that had been tration, safety requirements (particular to radioactive iodine), heavily pretreated with multiple chemotherapy regimens and and cost. 131I-tositumomab and 90Y-ibritumomab have not Rituximab achieving no or minor response, received 90Y-ibrit- been compared directly, and it remains to be determined umomab, which led to a long-lasting CR.105 which radioimmunoconjugate is best for each of the many possible indications. Clinical studies described in the previous sections add to the growing evidence of significant efficacy of RITwith 90Y-ibritumomab tiuxetan (Zevalin) as part of RIT in various clinical scenarios. the preparative regimen in hematopoietic stem cell Pharmacokinetics of the anti-CD20-radiolabeled antibodies transplantation depends on a number of patient-specific and disease-specific factors. Because these lead to high variability in the half-life The first phase I–II study aiming to determine the MTD of of the drug, dosimetry may be important to ensure the delivery absorbed irradiation to critical organs delivered by 90Y-ibritu- of a prescribed dose of RIT. However, dosimetry has signifi- momab tiuxetan in combination with standard high-dose cant practical shortcomings in that it is cumbersome and adds BEAMchemotherapy and autologous AHCT was reported in additional costs to therapy. A fixed dosing regimen is clearly the 43rd ASH meeting. Twelve patients with relapsed or not as accurate but might still result in an acceptable safety refractory CD20+ NHL were treated in cohorts of three to six and efficacy profile. The experience with 90Y-ibritumomab patients at doses calculated to result in increasing irradiation radioimmunoconjugate, indicates that dosimetry can be omit- exposure (100, 300 or 500 cGy) to the critical organ (liver, ted safely in the majority of patients.109 Because the 90Y iso- lung or kidney).106 On day −22, patients received Rituximab tope used in 90Y-ibritumomab is a pure ␤-emitter, dosimetry 250 mg/m2 followed by the imaging dose of 111In-ibritumo- with that agent requires the preparation of an alternative mab (5 mCi), with immunolocalization studies performed at radioimmunoconjugate between anti-CD20 MAb and 111In to 0, 4, 24, 72 and 144 h post-Mab injection; dosimetry was per- permit ␥-camera imaging. formed on day −15. On day −14, Rituximab at 250 mg/m2 The present clinical development of 131I-tositumomab and

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