Mantle Cell Lymphoma:
`Therapeutic Strategies
`Are Different from CLL
`Wolfgang Hiddemann, MD
`Martin Dreyling, MD*
`
`Address
`*Department of Medicine III, University Hospital Grosshadern/LMU,
`Marchioninistrasse 15, 81377 Munich, Germany.
`E-mail: martin.dreyling@med3.med.uni-muenchen.de
`Current Treatment Options in Oncology 2003, 4:219–226
`Current Science Inc. ISSN 1527-2729
`Copyright © 2003 by Current Science Inc.
`
`Opinion statement
`In contrast to the typical course of chronic lymphocytic lymphoma and despite an
`indolent lymphoma-like presentation, the clinical outcome of mantle cell lymphoma
`(MCL) is dismal, with a median survival time of 3 years and virtually no long-term
`survivors. Most patients are diagnosed with advanced stage III/IV disease. Although
`clinical studies did not prove a clear superiority of anthracyclin-containing combina-
`tions, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like regimens
`represent the standard therapeutic approach in MCL. Recent randomized studies have
`shown a benefit of a combined immunochemotherapy strategy (chemotherapy plus
`rituximab) increasing the complete and overall response rates, whereas further follow-
`up is pending for evaluation of the progression-free and overall survival. In patients
`younger than 65 years, a dose-intensive consolidation comprising high-dose radio-
`chemotherapy and subsequent autologous stem cell transplantation after a CHOP-like
`induction results in an improved progression-free survival. However, despite the bene-
`fits of this multimodal approach, most patients relapse even after high-dose therapy.
`The only curative approach is allogeneic stem cell transplantation, which may be
`adapted to the elderly MCL patient cohort by modified dose-reduced conditioning
`regimens. Prospective randomized trials remain critical to further improve the clinical
`course of MCL with the addition of newer treatment modalities, such as radioactively
`labeled antibodies and targeted therapies (eg, flavopiridol and PS-341).
`
`Introduction
`Mantle cell lymphoma (MCL) is characterized by the
`chromosomal translocation t(11;14)(q13;q32) and the
`resulting overexpression of the cell cycle regulator cyclin-
`D1 in virtually all cases [1,2]. The clinical presentation is
`similar to indolent lymphoma subtypes. The median age
`is 60 to 65 years with a 3:1 to 4:1 male preponderance.
`Eighty percent to 85% of patients are diagnosed with
`advanced stage III/IV disease [3•,4(cid:127)]. Splenomegaly
`(35%–55%) and bone marrow involvement is frequent
`(60%–80%) in patients. Accordingly, leukemic generali-
`zation is detectable in approximately 30% to 60% of
`patients, depending on the method applied. This clinical
`presentation may hamper the differential diagnosis to
`
`chronic lymphocytic lymphoma (CLL) based on
`cytomorphology alone [5]. Other extranodal presenta-
`tions include involvement of the gastrointestinal tract
`(up to 25%; polyposis coli) and the central nervous
`system (4%–22% of relapsed MCL) [6,7]. Because the
`cytomorphology of MCL is variable (classic centrocytic
`cells vs blastoid variants), morphologic diagnosis of MCL
`may be complex and often difficult. In addition to
`the coexpression of the T-cell marker CD5 and different
`B-cell markers (CD19, CD20, CD22, CD79a; higher
`expression level than CLL), MCL cells lack the CD23
`expression frequently detected in CLL [4(cid:127)]. In contrast to
`the “cytic” morphology and a low proliferation rate, the
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`clinical course of MCL is aggressive with a low propor-
`tion of long-time survivors [3(cid:127)]. Thus, a wait-and-see
`strategy similar to classic CLL is not recommended in
`MCL. Because of the extensive consequences for the
`therapeutic strategies, the definite diagnosis of MCL
`should be confirmed by immunophenotyping and
`
`optional detection of cyclin-D1 overexpression. The
`International Prognostic Index may be applied to
`identify different risk groups [8,9]. However, in various
`studies, proliferation-derived parameters such as mitoses
`per high-power field or Ki67 immunostaining were
`superior to the International Prognostic Index [10,11].
`
`Treatment
`Radiotherapy
`
`Systemic treatments
`Conventional chemotherapy
`
`• Limited stage I/II disease is diagnosed in only 10% to 15% of patients with
`MCL. In various case reports, regional radiation therapy has been shown to
`be a potentially curative approach in these rare cases. Extrapolating from
`other aggressive and indolent lymphomas, a dose of 30 to 40 Gy seems to
`be reasonable. Based on the limited data published thus far, extended field
`radiation therapy seems to reduce the rate of local recurrences but not
`the relapse-free and overall survival in comparison to an involved field
`therapy [12]. Current study concepts test the additional application of
`total nodal radiation (German Low-Grade Lymphoma Study Group) or
`low-dose total body irradiation (European Organization for Research and
`Treatment of Cancer).
`(cid:127) In advanced stage III/IV disease, the benefit of radiation therapy in addition to
`systemic chemotherapy is unproven. Thus, local radiation should be reserved
`for patients with bulky disease not responding to conventional chemotherapy.
`
`(cid:127) Eighty percent to 85% of patients with MCL are diagnosed with advanced
`stage III/IV disease with bone marrow or other extranodal involvement
`[3(cid:127),4(cid:127)]. In addition, MCL has the lowest long-term survivor rate of all
`lymphoma subtypes. Therefore, a wait-and-see strategy is not recommended,
`but treatment should be initiated as soon as diagnostic procedures, including
`confirmation of histologic diagnosis, are completed. Various systemic
`chemotherapeutic regimens induce overall response rates of approximately
`70% to 80%. However, the rate of complete remissions (CR) is lower than in
`other lymphoma subtypes (approximately 20%–30%) and there are virtually
`no long-term survivors. In the largest series presented thus far, different
`conventional chemotherapy regimens showed only modest differences
`concerning progression-free and overall survival [3(cid:127)].
`
`Anthracyclin-containing regimens
`(cid:127) In various studies, the role of anthracyclin-containing regimens, mostly
`CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like
`regimens, was investigated in MCL. In a retrospective analysis of 65 patients,
`Zucca et al. [13] reported the superiority of an anthracyclin-containing
`regimen concerning complete response rate, failure-free survival, and overall
`survival. In contrast, in the only prospective randomized study of 63 patients
`with MCL, Meusers et al. [14] observed a similar efficacy of anthracyclin-
`containing CHOP and another standard regimen (cyclophosphamide,
`vincristine, and prednisone [COP]). CR and overall remission (OR) rates
`were 58% and 89%, respectively, for patients treated with CHOP and 41%
`and 84%, respectively, for patients treated with COP. Accordingly, no
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`Purine analogs
`
`differences were detected for relapse-free and overall survival (CHOP: 10 and
`32 months, respectively; COP: 7 and 37 months, respectively) time. Another
`randomized study also detected no difference in the remission rate between
`fludarabine monotherapy and an anthracyclin-containing combination with
`idarubicin [15]. However, the combination regimen achieved a significantly
`longer progression-free survival.
`(cid:127) Therefore, although the study results are partially inconsistent, most
`authors accept an anthracyclin-containing (mostly CHOP-like) regimen
`as a standard approach in MCL, especially as part of a sequential approach
`with subsequent interferon maintenance or myeloablative consolidation
`and subsequent autologous stem cell transplantation.
`– CHOP: Cyclophosphamide 750 mg/m2 on day 1, doxorubicin
`50 mg/m2 on day 1, vincristine 1.4 mg/m2 (maximum 2 mg) on
`day 1, and prednisone 100 mg on days 1 to 5.
`– COP: Cyclophosphamide 400 mg/m2 on days 1 to 5, vincristine
`1.4 mg/m2 (maximum 2 mg) on day 1, and prednisone 100 mg
`on day 1.
`
`(cid:127) In contrast to CLL, single-agent fludarabine has only moderate activity in
`MCL with an overall response rate of 30% to 40% and rare CR [16–18].
`However, several clinical studies demonstrated a superior outcome after
`an anthrachinone or alkylating drug-containing combination implicating
`a superadditive effect of these cytostatic drugs.
`(cid:127) In a phase II study of 18 newly diagnosed patients with MCL, another
`purine analog (cladribine) in combination with mitoxantrone achieved a
`CR and OR rate of 48% and 100%, respectively [19]. In a recent phase III
`study including 38 patients with MCL, a fludarabine/cyclophosphamide/
`mitoxantrone regimen (FCM) achieved a 33% remission rate in relapsed
`MCL [20(cid:127)(cid:127)]. Cohen et al. [21(cid:127)] reported the efficacy of a fludarabine plus
`cyclophosphamide (FC) combination in 30 patients with MCL. CR and
`OR rates were 30% and 63%, respectively. In newly diagnosed MCL, this
`scheme achieved a CR rate of 70%, implying a remarkably high efficacy
`in chemotherapy-genuine MCL.
`(cid:127) Fludarabine-containing combinations seem to be the most effective
`conventional chemotherapy in relapsed MCL. A randomized study has
`been initiated by the European MCL Network to evaluate the role of an
`upfront therapy with a fludarabine combination (FC) in comparison to
`a standard CHOP-like regimen.
`– Fludarabine 25 mg/m2 on days 1 to 5.
`– FCM: Fludarabine 30 mg/m2 on days 1 to 3, cyclophosphamide
`200 mg/m2 on days 1 to 3, and mitoxantrone 8 mg/m2 on day 1.
`– FC: Fludarabine 30 mg/m2 on days 1 to 3 and cyclophosphamide
`600 to 750 mg/m2 on day 1.
`– F-Ida: Fludarabine 25 mg/m2 on days 1 to 5 and idarubicine
`12 mg/m2 on day 1.
`– 2-CDA-Mitox: Cladribine 5 mg/m2 on days 1 to 3 and mitoxantrone
`8 mg/m2 on days 1 to 2.
`
`Other chemotherapeutic regimens
`(cid:127) A new cytostatic approach in the treatment of MCL is the incorporation
`of high-dose cytarabine. Overall response rates of up to 67% in relapsed
`MCL have been reported for the DHAP (dexamethasone, Ara-C, and
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`Biologic modifiers
`
`Interferon-␣
`
`cisplatin) regimen [22]. The French group has investigated a sequential
`CHOP-DHAP hybrid in 28 newly diagnosed patients with MCL [23(cid:127)(cid:127)].
`After four cycles of CHOP, only 7% of patients achieved a CR. In the
`remaining patients, an additional four cycles of DHAP resulted in a CR
`rate of 84%. Based on these results, a randomized phase III study of the
`European MCL network has been initiated.
`(cid:127) Another attempt is the more aggressive treatment strategy presented by
`Romaguera et al. [24(cid:127)(cid:127)]. In a phase II study of 25 elderly patients with
`MCL, an alternating regimen (cyclophosphamide, doxorubicin, vincristine,
`and dexamethasone [Hyper-CVAD] and high-dose methotrexate/cytarabine
`[MA]) achieved an impressing CR rate of 68% in newly diagnosed patients
`with MCL. This regimen seems to be also feasible in elderly patients.
`Promising results have also been reported for the combination of cisplatin,
`fludarabine, and cytarabine (PFA) [25].
`– DHAP: Dexamethasone 40 mg on days 1 to 4, Ara-C 2 × 2000 mg/m2
`on day 2, and cisplatin 100 mg/m2 on day 1.
`– Hyper-CVAD: Cyclophosphamide 2 × 300 mg/m2 every 12 hours on
`days 1 to 3, doxorubicin 50 mg/m2 on day 4, vincristine 2 mg on days
`4 and 11, and dexamethasone 40 mg on days 1 to 4 and 11 to 14.
`– MA: Methotrexate 1000 mg/m2 on day 1, cytarabine 2 3000 mg/m2
`every 12 hours on days 2 and 3, methylprednisolone 2 × 50 mg on
`days 1 to 3.
`– PFA: Cisplatin 25 mg/m2 on days 1 to 4, fludarabine 30 mg/m2 on
`days 3 and 4, and cytarabine 500 mg/m2 on days 3 and 4.
`
`(cid:127) In various studies, interferon-␣ administered as maintenance therapy seems
`to prolong the progression-free survival in MCL [3(cid:127),26]. However, because
`of the small number of cases, none of the studies achieved a statistically
`significant result. Based on the moderate efficacy of chemotherapy only,
`interferon maintenance may be reasonable, especially in patients with
`relapsed MCL, to extend the achieved remission.
`
`Standard dosage Three to 5 million IU subcutaneously three times weekly. Recent data suggest
`that interferon-␣ may be substituted by the pegylated substance ␮g/kg body
`weight administered once a week based on pharmacokinetic data in patients
`with hepatitis C [27,28].
`Contraindications Recent history of myocardial infarction, pre-existing liver or central nervous
`system disorders, and serious psychiatric condition.
`Main side effects Initial fatigue and flu-like symptoms (eg, malaise, fevers, chills, and arthralgias)
`are the most frequent side effects and may lead to a temporary dose reduction.
`Accordingly, prophylactic antiphlogistic drugs may improve or limit the clinical
`symptoms. Liver function abnormalities up to fatal hepatotoxicity have been
`observed. Psychiatric symptoms, especially depression and even suicide, have been
`associated with interferon therapy. Other potential but rare side effects are nausea,
`vomiting, and thyroid function abnormalities.
`Special points Besides the observed side effects, approximately 60% of patients tolerate this
`maintenance therapy for more than 3 to 4 years. In the future, the pegylated
`substance may improve these side effects (side effects have a similar profile but
`only once a week).
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`Lymphocyte-specific antibodies
`(cid:127) In many studies, monotherapy with the lymphocyte-specific anti-CD20 anti-
`body rituximab showed only moderate activity in MCL with a remission rate
`of 20% to 40% [29,30]. However, previous in vitro studies have suggested a
`synergistic effect of the simultaneous application of chemotherapy and ritux-
`imab [31]. In a recent phase II study, a combined immunochemotherapy
`(R-CHOP) achieved a high CR rate of 48% and an OR rate of 96% [32(cid:127)(cid:127)].
`However, the progression-free survival time in this study was only 16
`months, emphasizing the aggressive clinical course of MCL.
`(cid:127) In a prospective randomized study, the German Low-Grade Lymphoma
`Study Group investigated the effect of rituximab in combination with a
`fludarabine-containing regimen (R-FCM) in 35 patients with relapsed MCL
`[20(cid:127)(cid:127)]. CR and OR rates were significantly higher in the immunochemo-
`therapy group (35% and 65%, respectively, vs 0 % and 33%, respectively),
`confirming the superadditive effect of a combined chemotherapy plus anti-
`body concept (Table 1). In a randomized study of 62 patients with newly
`diagnosed MCL, a combined immunochemotherapy approach (R-CHOP)
`achieved a significantly higher remission rate in comparison to standard
`chemotherapy alone (97% vs 69%) [33(cid:127)]. Thus, the combined chemo-
`therapy plus rituximab regimens represent the current golden standard in
`MCL. The role of a rituximab maintenance therapy is being investigated by
`different study groups.
`(cid:127) Another innovative antibody-based approach is the application of radio-
`active-labeled lymphocyte-specific antibodies with 90Yttrium or 131Iod
`in conventional or myeloablative dosage. Recent studies, although based
`on a limited number of patients, reported impressive survival rates of up
`to 83% after 2 years in patients with relapsed MCL [34(cid:127)(cid:127),35]. Future
`studies will focus on the combination with conventional or high-dose
`chemotherapy.
`
`Rituximab
`
`Standard dosage 375 mg/m2 on days 1, 8, 15, and 22 (monotherapy), and 375 mg/m2 on day 1 of
`each cycle (combined immunochemotherapy). Infusion starts at 50 mg/h. The rate
`will be step-wise increased by 50 mL/h if no side effects occur.
`Contraindications Known hypersensitivity to mouse/humanized antibodies or proteins.
`Main side effects Especially during the first application, anaphylactic reactions with fever, flushes, and
`rigors occur in up to 15% of patients (12% grade 3/grade 4). If symptoms diminish
`after infusion has been stopped, infusion may be restarted at a reduced rate.
`Special points Side effects are usually only mild during subsequent courses of rituximab.
`
`Autologous stem cell transplantation
`(cid:127) Since the first report by Stewart et al. [36] in 1995, myeloablative therapy
`with subsequent autologous stem cell transplantation has become an
`established therapeutic option in patients with MCL. Initial phase II studies
`showed a wide range of remission and 2-year survival rates (16%–100%),
`most likely because of the different time of transplantation (first remission
`vs relapsed disease) and other patient selection criteria. In a retrospective
`multivariate analysis, total body irradiation was an additional independent
`prognostic factor [37].
`(cid:127) In 1996, a prospective European Intergroup study was initiated to evaluate
`the impact of myeloablative radiochemotherapy with subsequent autolo-
`gous stem cell transplantation in first remission after a CHOP-like regimen
`[38(cid:127)]. The analysis of 109 evaluable patients showed a significant improve-
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`Table 1. Randomized comparison of a fludarabine-containing
`regimen ± rituximab
`
`FCM (n = 17)
`
`R-FCM (n = 18)
`
`CR
`PR
`OR
`PD
`ED
`
`0%
`33%
`33%
`50%
`17%
`
`35%
`29%
`65%
`35%
`0%
`
`CR—complete remission; ED—early death; FCM—fludarabine, cyclophosphamide,
`mitoxantrone; OR—overall remission; PD—progressive disease; PR—partial response;
`R-FCM—fludarabine, cyclophosphamide, mitoxantrone plus rituximab.
`(Adapted from Hiddemann et al. [20(cid:127)(cid:127)].)
`
`ment of progression-free survival in comparison to an interferon mainte-
`nance regimen. After a median follow-up of approximately 3 years, only
`11 of 42 patients relapsed in the high-dose cohort, whereas 28 of 47
`patients showed a progression of the disease in the interferon maintenance
`arm. These differences correspond to a reduction of risk of relapse of more
`than 65%. Therefore, intensive consolidation in first remission represents
`the standard treatment in patients younger than 65 years suitable for high-
`dose therapy.
`(cid:127) However, despite such a multimodal approach, most patients will relapse
`even after myeloablative radiochemotherapy, most likely because of the
`contamination of the harvested stem cells with leukemic mantle cells.
`Previous studies were not successful to completely eliminate the contami-
`nating lymphoma cells [39]. Preliminary results of an in vivo purging with
`rituximab suggest that this approach is more effective and may further
`improve the clinical outcome after high-dose therapy [40].
`
`Allogeneic stem cell transplantation
`(cid:127) The only potentially curative approach is allogeneic stem cell transplanta-
`tion. Different small series suggested that the induced graft-versus-lymphoma
`effect is able to achieve long-lasting complete remissions, even in patients
`with relapsed MCL [41–43]. Because transplant-related toxicity is high, a
`dose-reduced regimen adapted to the elderly patient with MCL cohort may
`be applied. However, even after less toxic conditioning, delayed infectious
`complications caused by chronic graft-versus-host disease are frequently
`observed [44]. Therefore, this approach may be applied mostly to relapsed
`MCL after intensive first-line therapy.
`
`Emerging therapies
`
`(cid:127) A new molecular-targeted approach is the specific inhibition of the character-
`istic overexpression of cyclin-D1 detected in virtually all MCL by flavopiridol.
`Different schedules were investigated (three times weekly, 72 hours continu-
`ous infusion); however, no convincing remissions could be achieved in dif-
`ferent studies [45]. Future investigations may focus on the role of flavopiridol
`as a chemosensitizer in combination with cytostatic drugs.
`(cid:127) Another innovative approach is the proteasome inhibitor PS-341, which
`led to the suppression of different transcription factors and cell growth in
`the mouse model [46]. Clinical studies have been recently activated.
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`References and Recommended Reading
`Papers of particular interest, published recently, have been highlighted as:
`(cid:127)
`Of importance
`(cid:127)(cid:127) Of major importance
`
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`
`6.
`
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`
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