Comprehensive
`Review
`
`Mantle Cell Lymphoma: New Treatments Targeted
`to the Biology
`
`Francesco Bertoni,1,2 Michele Ghielmini,2 Franco Cavalli,2
`Finbarr E. Cotter,1 Emanuele Zucca2
`Abstract
`
`Mantle cell lymphoma (MCL) represents a distinct lymphoma subtype. The prognosis of patients with MCL is the poorest among lym-
`phoma patients and the response to conventional treatments is inadequate. New approaches targeted to the biology of MCL and the ge-
`netics underlying the disease are being studied. Monoclonal antibodies directed at molecules expressed on MCL cells are already used in
`the clinical setting. This article reviews the literature on these and other new possible treatment modalities.
`
`Clinical Lymphoma, Vol. 3, No. 2, 90-96, 2002
`Key words: Monoclonal antibodies, Rituximab, Tositumomab, Ibritumomab, Apoptosis, CD20, Proteasome inhibitors
`
`Introduction
`Mantle cell lymphoma (MCL) represents approximately 6%
`of all non-Hodgkin’s lymphomas.1 Despite being previously con-
`sidered a low-grade and indolent lymphoma, it appears to have
`the worst characteristics of both low- and high-grade lym-
`phomas: incurability and rapid growth.2 Mantle cell lymphoma
`patients have a median age of > 60 years, are predominantly
`male, and often have disseminated disease at diagnosis. Mantle
`cell lymphoma median time to progression and survival are the
`shortest among all lymphoma subtypes.1
`Mantle cell lymphoma comprises a group of lymphoma sub-
`types previously classified as centrocytic lymphoma, lymphocyt-
`ic lymphoma of intermediate differentiation, intermediate cell
`lymphoma, or diffuse small cleaved–cell lymphoma.2-7 Two
`main cytologic subtypes, typical and blastoid (blastic) variant,
`are recognized in the new World Health Organization classifica-
`tion.8 Mantle cell lymphoma seems to derive from a subset of
`antigen-naive pregerminal center B cells localized in primary fol-
`licles or in the mantle region of secondary follicles. Mantle cell
`lymphoma cells express moderate to strong IgM and/or IgD sur-
`face immunoglobulins and pan B-cell antigens (CD19, CD20,
`CD22, CD24).2,4,5,7,9 They are positive for CD79a, CD5,
`CD43, and cyclin D1, but are negative for CD23 and CD10.
`The genetics of MCL are characterized by the presence of the
`t(11;14)(q13;q32) translocation that determines cyclin D1/Bcl-1
`
`1Department of Experimental Hematology, Barts and The London-Queen
`Mary’s School of Medicine and Dentistry, London, United Kingdom
`2Division of Medical Oncology, Oncology Institute of Southern Switzerland,
`Ospedale San Giovanni, Bellinzona, Switzerland
`Submitted: Feb. 5, 2001; Revised: Jun. 12, 2001; Nov. 29, 2001; Jul. 29, 2002;
`Accepted: Aug. 15, 2002
`Address for correspondence: Emanuele Zucca, MD, Division of Medical
`Oncology, Oncology Institute of Southern Switzerland, Ospedale San
`Giovanni, 6500 Bellinzona, Switzerland
`Fax: 41-91-8119182; e-mail: ielsg@ticino.com
`
`deregulation, in association with other molecular abnormalities
`mainly involving the cell cycle.4 A series of prognostic factors have
`been associated with worse outcome: blastoid variant, high mi-
`totic index, high International Prognostic Index, blood involve-
`ment, male sex, high serum β
`2-microglobulin levels, P53 inacti-
`vation, loss of P27 expression, and karyotype complexity.
`Many of the published papers on MCL treatment are retro-
`spective studies, and data regarding MCL have often been extrap-
`olated from series including other lymphoma subtypes together
`with untreated and treated patients in the prospective studies.
`Currently, there is no convincing evidence that any conventional
`chemotherapy regimen is curative.2,7,10,11 Doxorubicin-contain-
`ing regimens appear more effective than those without doxoru-
`bicin. Studies to date fail to demonstrate a plateau in the survival
`curve, which normally indicates a potential for cure.12-19 In re-
`sponse to the failure of MCL to conventional chemotherapies,
`high-dose regimens with autologous or allogenic bone marrow
`transplantation (BMT) have been performed in younger MCL
`patients.20-27 The published studies of intensive chemotherapy as-
`sociated with total-body irradiation, followed by autologous stem
`cell transplant or purged BMT yielded mixed, and generally
`rather disappointing, results.28,29 A retrospective analysis of the
`European Group for Blood and Marrow Transplantation data-
`base, comprising 150 evaluable patients with MCL treated with
`autologous BMT, underlined that there is no plateau of the over-
`all survival (OS) curve.30 The inclusion of high-dose methotrex-
`ate or cytarabine in preconsolidation regimens improved outcome
`and may be an advance in therapy.29,31,32 In this article, the cur-
`rent literature regarding therapeutic strategies related to the biol-
`ogy and genetics underlying MCL is reviewed (Table 1).
`
`Monoclonal Antibodies
`Mantle cell lymphoma cells express the pan B-cell antigen
`CD20. This antigen is normally expressed on the surface of B
`cells from the early pre-B stage to the mature B stage, but is ab-
`
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`Table 1 New Possible Therapies in Mantle Cell
`Lymphoma
`
`Therapeutic Approach
`
`Stage of Development
`
`Monoclonal antibodies
`
`Clinical use/Clinical trials
`
`Cyclin-dependent kinase inhibitors
`
`Proteasome inhibitors
`
`DNA vaccines
`
`Modulation of polyamine synthesis
`
`Clinical trials
`
`Clinical trials
`
`Clinical trials
`
`Clinical trials
`
`alternative caspase-dependent killing mechanism37,39,44 suggests
`the combination with agents modulating the apoptotic machin-
`ery.49,50
`An alternative mechanism of action has been reported in ac-
`quired immune deficiency syndrome–related lymphoma cell
`lines.50 Rituximab downregulates interleukin-10 (IL-10) expres-
`sion, with subsequent downregulation of bcl-2, an IL-10 target
`gene, sensitizing the cells to chemotherapy-induced apoptosis. As
`IL-10 seems to play an important role in MCL proliferation,51 it
`will be interesting to see if a similar effect can be seen in MCL.
`
`Multicenter Phase II Trials. Few clinical studies have been
`published on rituximab (Table 4). In a multicenter phase II trial
`from Europe and Australia, the overall response (OR) to ritux-
`imab was 33% (4 out of 12 evaluable MCL patients).52 The re-
`sponse rate was similar to that observed in the diffuse large B-
`cell lymphoma subgroup (11 out of 30, 37%). Sixty-seven as-
`sessable MCL patients were treated with rituximab (a standard
`dose of 375 mg/m2/week × 4) within a European multicenter
`phase II study.53 The OR was the same in treated and untreat-
`ed patients: 38% (12 out of 32) and 37% (13 out of 35), re-
`spectively. However, the complete remission (CR) rates were
`only 16% (5 out of 32) and 14% (5 out of 35) in the 2 groups,
`with a median duration of response of 1.2 years. Elevated lactate
`dehydrogenase at the time of therapy, and prior therapy with
`alkylating agents were associated with a significantly lower
`
`Table 2
`
`Anti-CD20 Monoclonal Antibodies Used in
`the Clinical Setting
`
`Monoclonal Antibody
`
`Origin
`
`Commercial Name
`
`Rituximab; IDEC-C2B8
`
`chimeric
`
`Rituxan®, MabThera®
`
`90Y-Ibritumomab tiuxetan;
`IDEC-Y2B8
`
`Tositumomab/131I-Tositumomab;
`anti-B1
`
`murine
`
`Zevalin™
`
`murine
`
`Bexxar®
`
`– *
`
`131I-IDEC-C2B8
`
`111In-Ibritumomab tiuxetan;
`IDEC-In2B8
`
`chimeric
`
`murine
`
`*Used for imaging and dosimetry before IDEC-Y2B8
`
`sent on immunoglobulin-secreting plasma cells. The CD20 has
`4 predicted membrane-spanning domains with both C and N
`termini located in the cytoplasm; only a small portion of the
`molecule is on the external cell surface. The molecule is neither
`shed nor secreted and is not internalized after binding with dif-
`ferent monoclonal antibodies (B1, 1F5, C2B8) recognizing dif-
`ferent epitopes of this surface fragment (Table 2).
`
`Rituximab
`Rituximab (Rituxan®, IDEC-C2B8, Genentech Inc, South
`San Francisco, CA, and IDEC Pharmaceutical Corporation, San
`Diego, CA; MabThera®, Hoffman-La Roche, Basel, Switzerland)
`is the anti-CD20 compound most commonly used in the clinical
`setting. It is commercially available for relapsed or refractory in-
`dolent lymphomas in Europe and in the United States.33-35
`
`Clinical Development of Rituximab. The function of the
`CD20 molecule and the actual mechanism of action of anti-
`CD20 monoclonal antibodies are still unclear. The effect of
`anti-CD20 ligands seems to depend heavily on the nature of the
`CD20 epitopes recognized by the antibodies, the differentiation
`stage of the lymphoma cell, and the presence of potential cosig-
`nals. The effects are broad, spanning from increased prolifera-
`tion to growth arrest, and from inhibition to induction of apop-
`tosis. The cascade of events following CD20 binding by anti-
`bodies comprise the activation of the Src family kinases
`p56/53lyn, p56lck, and p59fyn, with tyrosine phosphorylation of
`phospholipase C-γ1 and C-γ2, a calcium influx, and caspase-3
`activation.36 The precise order of these events is not fully eluci-
`dated. CD20 itself, with its 4 transmembrane domains, may be
`a calcium-ion channel36 or, alternatively, could induce calcium
`influx via the protein tyrosine kinase activity.37 CD20–mediat-
`ed apoptosis requires kinase activation, calcium influx, and cas-
`pase activation.37-39 Different mechanisms seem to cooperate in
`the anti-CD20–mediated cell killing, and probably depend on
`the clonal neoplastic cell biology (Table 3). Anti-CD20 anti-
`bodies alone induce only weak growth arrest and apoptosis on
`lymphoma cell lines.38,40-42 The in vitro direct growth arrest
`and proapoptotic effect is increased when rituximab is used as a
`homodimer or cross-linked with goat antimouse IgG,37,40,43,44
`causing a clustering of CD20 molecules. The same effect can
`also be obtained using rituximab in the presence of Fc recep-
`tor–expressing cells.43
`
`Potential Mechanism of Action. The main mechanisms of ac-
`tion of rituximab are antibody-dependent cytotoxicity and com-
`plement-mediated cytotoxicity (CDC), by a caspase-independ-
`ent mechanism.41,42,45,46 The effect of the latter is regulated by
`the possible presence on the cell surface of complement in-
`hibitors such as CD35, CD55, and CD59.42,45,47 Anti-CD59
`strongly increases in vitro CDC, suggesting that the combina-
`tion of anti-CD20 and anti-CD59 monoclonal antibodies
`could result in better antitumor activity.42,45,47 However, a later
`study failed to confirm this and did not show any correlation
`between the levels of CD55 and CD59 expressed on MCL cells
`and their in vivo and in vitro response rate to rituximab.48 The
`
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`New Treatments for Mantle Cell Lymphoma
`
`Table 3
`
`Anti-Lymphoma Mechanisms of Anti-CD20
`Monoclonal Antibodies
`
`Antibody-dependent cytotoxicity
`
`Complement-mediated cytotoxicity
`
`Growth arrest
`
`Induction of apoptosis
`
`Chemosensitization
`
`OR.54 In another small study, 2 of 10 MCL patients (20%) had
`a partial response with rituximab.55 In the Swiss Group for
`Clinical Cancer Research (SAKK) protocol 35/98, MCL pa-
`tients were randomized between the standard rituximab scheme
`with or without 4 additional rituximab courses, at 2-month in-
`tervals.56 Preliminary results on the first 36 MCL cases showed
`an OR of 22% with no CR at 12 weeks, in comparison to an
`OR of 52% in follicular lymphomas.
`
`Rituximab and Combination Chemotherapy. In vitro data sug-
`gest that anti-CD20 antibodies sensitize cells to antineoplastic
`drugs and to toxins.40,44,57-60 Clinical trials combining rituximab
`with chemotherapy regimens are open for MCL patients. The
`CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone)
`regimen combined with rituximab has already shown encouraging
`results in follicular and diffuse large B-cell lymphomas.61-63 A
`phase II trial of CHOP plus concomitant rituximab showed a
`48% CR rate in untreated MCL patients, but none of the re-
`sponses lasted longer than 36 months.64 The German Low-Grade
`Lymphoma Study Group randomized 27 MCL patients to FCM
`(fludarabine/cyclophosphamide/mitoxantrone) with or without
`rituximab; the OR rate was 77% versus 27%, respectively with no
`apparent increase in toxicity.65 Concurrent rituximab has been
`added to the highly effective HCVAD (hyper-cyclophosphamide,
`vincristine, doxorubicin, dexamethasone, high dose of cytarabine
`and methotrexate with leucovorin rescue therapy) regimen,19,32 re-
`placing BMT in untreated patients achieving CR after chemother-
`apy.19,66 The CR rate was 92% (54 out of 59) with a similar re-
`sponse rate among patients > 65 years of age (21 out of 23, 91%)
`and ≤ 65 years of age (33 out of 36, 92%; Table 5).66 With a me-
`dian follow-up of 14 months, the addition of rituximab to the
`HCVAD (R-HCVAD) suggested that BMT is unnecessary for pa-
`tients ≤ 65 years of age and appeared to improve the prognosis in
`the older subset of patients (Table 5).
`
`Table 4 Results Obtained with Rituximab as a Single
`Agent in Patients with Mantle Cell Lymphoma
` Overall
`Complete
`No. of
`Response Rate
`Remission Rate
`Patients
`
`Study
`
`Coiffier et al52
`
`Foran et al54
`
`Nguyen et al55
`
`Ghielmini et al56
`
`12
`
`87
`
`10
`
`36
`
`33%
`
`34%
`
`20%
`
`22%
`
`0%
`
`14%
`
`0%
`
`0%
`
`Rituximab in In Vivo Purging of Neoplastic Cells. The lack of ben-
`efit in terms of survival after autologous BMT and the low rate of
`patients achieving a molecular remission might be partially ex-
`plained by the presence of neoplastic cell contamination of the
`harvested peripheral-blood stem cells.7 Rituximab could be used as
`in vivo purging to overcome this contamination.67 Rituximab
`alone induces a clearance of circulating lymphomatous cells;56,64
`within the SAKK 35/98 trial, 42% of the patients with initial cir-
`culating neoplastic cells, as evaluated with t(11;14) polymerase
`chain reaction (PCR) assay, achieved a conversion to a negative sta-
`tus, despite a lack of response on lymph node and bone marrow
`sites.56 At the National Cancer Institute in Milan, 10 untreated
`MCL patients underwent sequential high-dose chemotherapy fol-
`lowed by autologous BMT.31 In vivo purging with rituximab (2
`doses after high-dose cyclophosphamide, 2 doses after high-dose
`cytarabine, and 2 doses after myeloablative mitoxantrone and mel-
`phalan) induced eradication of contaminating neoplastic cells in 7
`of 7 patients in comparison to 2 of 3 patients who had ex vivo
`purging. Six of the 7 patients maintained a CR at a median follow-
`up of 14 months. Twenty-six of the 28 patients treated with the
`same schedule remained disease free after a median follow-up of 22
`months; all the leukaphareses were PCR negative.68 Another trial
`exploring the role of rituximab in the BMT setting has been re-
`cently published.69 Twelve untreated MCL patients underwent de-
`bulking chemotherapy with CHOP, followed by myeloablative
`chemotherapy with cyclophosphamde/carmustine/etoposide, after
`stem cell mobilization with granulocyte colony-stimulating factor
`(G-CSF) plus rituximab. Eight of the 12 patients received 8 post-
`transplant ritixumab consolidative treatments, while 4 patients
`had only the first post-transplant rituximab. After a median post-
`transplant follow-up of approximately 8 months, all 12 patients
`were alive and in CR.
`
`Ibritumomab Tiuxetan
`Anti-CD20 antibodies have been conjugated to radionuclides
`in order to exploit the radiosensitivity of lymphoma cells.29,70-72
`In comparison with their cold counterparts, an advantage of radi-
`olabeled monoclonal antibodies is their ability to kill lymphoma
`cells even devoid of the CD20 molecule, but within close prox-
`imity of those actually targeted. Ibritumomab (IDEC-Y2B8, Ze-
`valin™; IDEC Pharmaceuticals, San Diego, CA) is a mouse mon-
`oclonal antibody that recognizes the same rituximab epitope and
`is linked through tiuxetan to yttrium 90, a pure β emitter. Given
`on an outpatient basis, it induced an OR of 67% in MCL and
`80% in low-grade lymphomas, with half of cases already resistant
`to rituximab.73-76 A randomized comparison of rituximab and
`90Y-ibritumomab in patients with follicular or transformed lym-
`phomas revealed a response rate of 80% in the ibritumomab arm
`compared to 55% with rituximab (P = 0.002), with a CR/un-
`confirmed CR rate of 34% versus 20%, respectively.77
`
`Tositumomab/131I-Tositumomab
`Tositumomab/iodine 131-tositumomab (Bexxar®; Coulter
`Pharmaceuticals, Inc, South San Francisco, CA) is an 131I-radiola-
`beled anti-CD20 B1 antibody. Up to 34% and 79% of CRs fol-
`lowing nonmyeloablative and myeloablative doses of tositu-
`
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`Table 5 Results Obtained with R-HCVAD Regimen in
`Previously Untreated Patients with Mantle
`Cell Lymphoma66
`No. of
`Patients
`Patients ≤ 65 Years of Age
`
`Regimen
`
` Complete
`Remission Rate
`
`2-Year Overall
`Survival
`
` R-HCVAD
`
` HCVAD
`
`36
`
`26
`
`Patients > 65 Years of Age
`
` R-HCVAD
`
` HCVAD
`
`23
`
`22
`
`92%
`
`100%
`
`90%
`
`70%
`
`87%*
`
`96%*
`
`96%*
`
`77%*
`
`*P > 0.05
`Abbreviations: HCVAD = hyper-cyclophosphamide, vincristine, doxorubicin,
`dexamethasone, high dose of cytarabine and methotrexate with leucovorin rescue
`therapy; R = rituximab
`
`momab/131I-tositumomab, respectively, have been reported in re-
`lapsed, refractory, or transformed low-grade lymphomas.78-82
`Sixteen MCL patients were treated in two sequential phase I/II
`trials with 131I-tositumomab/etoposide/cyclophosphamide fol-
`lowed by BMT.83,84 The estimated 3-year overall and progres-
`sion-free survival rates were 93% and 61%, respectively, after a
`median follow-up of 19 months.
`
`131I-Labeled Rituximab
`Seven patients, all previously relapsed after high-dose
`chemotherapy and BMT, underwent myeloablative treatment
`with 131I-labeled rituximab.85 Six patients obtained CR and 5
`were in continuous CR after a median follow-up of 25 months.
`
`Interferon-α
`Interferon-α has small advantages as maintenance or consoli-
`dation therapy in patients with MCL responding to first-line
`therapy.7,18,86 The European MCL Intergroup enrolled 180 pa-
`tients in a randomized trial comparing BMT (DexaBEAM, total
`body irradiation and cyclophosphamide) versus interferon-α as
`consolidation treatment after CHOP.87 An interim analysis of
`the first 76 patients showed relapses in 6 of 36 patients (17%)
`treated with BMT and in 21 of 40 patients (53%) treated with
`interferon-α, which correlates with a statistically significant re-
`duction of relapses with the BMT arm (P < 0.05) but with no
`difference in terms of OS.
`In vitro data and some early clinical trials suggest that cotreat-
`ment with cytokines, such as interferon-α, can increase the CD20
`expression on neoplastic cells or the binding affinity of rituximab
`to the molecule.88-91 The combination of rituximab and interfer-
`on-α has been reported in 2 studies of small lymphocytic and fol-
`licular lymphomas with promising results.88,92
`
`Cyclin-Dependent Kinase Inhibitors
`A number of new agents have been developed to target mol-
`ecules involved in cell cycle regulation. Since deregulation of the
`cell cycle is relevant in MCL, such drugs might play a role in the
`
`Francesco Bertoni et al
`
`treatment of this lymphoma subtype. Cyclin-dependent kinase
`inhibitors, such as flavopiridol and 7-hydroxy-staurosporine
`(UCN-01), are undergoing preclinical and clinical evaluation as
`single agents and in combination with chemotherapy.93-96 Their
`mechanism of action might have a broad spectrum involving
`other cellular pathways besides cyclin-dependent kinases. The
`results of the first phase I/II studies are disappointing, particu-
`larly for flavopiridol in solid tumors.97-99 However, it is still too
`early to draw any conclusion, as the scheduling has not yet been
`fully defined.
`Proteasome Inhibitors
`The proteasome pathway is crucial for intracellular protein
`degradation. The increased degradation of the P27 protein, an in-
`hibitor of both cyclins D and E, in MCL,100 might suggest a role
`for proteasome inhibitors in this lymphoma subtype. The protea-
`some inhibitor PS-341 gave promising results in a mouse model
`of MCL.101 Clinical trials with the proteasome inhibitor PS-341
`are underway,19,96,102-104 but there are not yet any available data.
`DNA Vaccines
`Immunoglobulins are expressed on the cell surface of MCL
`cells and they do not undergo the process of intraclonal somat-
`ic mutations. They might be good targets for vaccines, with au-
`tologous tumor-derived immunoglobulin idiotypes105 or with
`DNA vaccines encoding the tumor immunoglobulin idio-
`types.106-108 However, vaccines require a low burden of disease
`to be active, eradicating subclinical tumor cells and prolonging
`the disease-free status. Since the CR rate in MCL is very low
`with current available therapies, vaccination trials are combined
`with other experimental treatments, including consolidation
`after high-dose chemotherapy supported by BMT. A pilot study
`of 5 cycles of the EPOCH-R (doxorubicin/etoposide/cy-
`clophosphamide/vincristine/prednisone/rituximab) regimen
`followed by 5 cycles of idiotype-KLH vaccine is presently ongo-
`ing at the Bethesda National Cancer Institute for untreated
`MCL patients; the CR rate was 93% after chemotherapy in the
`first 14 of 21 evaluable patients.109
`Methylthioadenosine Phosphorylase
`The housekeeping enzyme methylthioadenosine phosphory-
`lase (MTAP) is important for the salvage of adenine nucleotides
`and methionine consumed in polyamine synthesis. The MTAP
`gene is located at 9p21, close to the p16c/p14 locus, a region that
`is deleted in 15%-30% of MCL cases. Treatment approaches in-
`volving inhibition of adenine nucleotide synthesis with L-alano-
`sine, followed by rescue with methylthioadenosine or depletion
`of plasma methionine by bacterial methiolase, with methylth-
`ioadenosine rescue of normal cells, could be feasible,110 as shown
`in vitro on T-cell acute lymphoblastic leukemia cells.111
`
`Conclusion
`No standard treatment is available for patients with MCL,
`and, whenever feasible, patients should be treated within clini-
`cal trials. Up to now, monoclonal antibodies are the only wide-
`ly used targeted treatments for MCL. Trials aimed at better
`
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`New Treatments for Mantle Cell Lymphoma
`
`defining their role, both as single agents and in combination
`with conventional or myeloablative chemotherapy regimens, are
`ongoing. Other specific therapeutic tools are part of preclinical
`and clinical studies. Time will tell whether these novel thera-
`peutic approaches can change the particularly poor outcome of
`this disease, and certainly, they deserve thorough evaluation.
`Acknowledgements
`This work was partially supported by the Swiss Cancer
`League, Bern, Switzerland, the Fondazione San Salvatore,
`Lugano, Switzerland, and the Leukaemia Research Fund, Lon-
`don, United Kingdom.
`
`04.
`
`05.
`
`03.
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