Ann Hematol (2004) 83:71–77
`DOI 10.1007/s00277-003-0774-2
`
`R E V I E W A R T I C L E
`
`G. Lenz · M. Dreyling · W. Hiddemann
`Mantle cell lymphoma: established therapeutic options
`and future directions
`
`Received: 13 August 2003 / Accepted: 20 August 2003 / Published online: 11 December 2003
` Springer-Verlag 2003
`
`Abstract During the last few years, new insights into the
`biology of mantle cell lymphoma have been obtained.
`However, with a median survival of only 3 years, mantle
`cell lymphoma remains the lymphoma subtype with the
`poorest prognosis. At
`initial diagnosis most patients
`present with advanced Ann Arbor stage III or IV and
`conventional chemotherapy hardly alters the continuously
`declining survival curve. Recently,
`two prospective
`randomized studies of the German Low Grade Lympho-
`ma Study Group (GLSG) clearly confirmed the superior-
`ity of a combined immunochemotherapy. In a randomized
`study of the European mantle cell lymphoma Network,
`consolidation with myeloablative radiochemotherapy fol-
`lowed by autologous stem cell transplantation improved
`the progression-free survival in patients younger than
`65 years. However, relapses are still observed at a high
`frequency. Thus, new therapeutic strategies such as
`radioactively labeled antibodies or molecular targeting
`agents (e.g. Bortezomib or flavopiridol) are urgently
`warranted to further improve the clinical outcome of
`mantle cell lymphoma.
`
`Keywords Mantle cell lymphoma · Review · Biology ·
`Therapy · Prognosis
`
`Introduction
`
`Mantle cell lymphoma has been recognized as a distinct
`subentity of lymphoma in the recent WHO lymphoma
`classification [29]. With a median age of 65 years at
`diagnosis, it primarily represents a disorder of the male
`elderly. The incidence of mantle cell
`lymphoma is
`approximately 2–3/100,000/year
`[9, 25]
`representing
`
`G. Lenz ()) · M. Dreyling · W. Hiddemann
`Department of Internal Medicine III, Großhadern Hospital,
`Ludwig-Maximilians University,
`81377 Munich, Germany
`e-mail: georg.lenz@med3.med.uni-muenchen.de
`Tel.: +49-89-70951
`Fax: +49-89-70955550
`
`approximately 5–10% of all lymphoma cases in North
`America and Europe [40, 60].
`In contrast
`to other
`lymphoma subtypes, the etiology and molecular patho-
`genesis of mantle cell lymphoma remains unknown.
`In recent years, important insights into the molecular
`biology of mantle cell lymphoma have been obtained.
`However, due to the aggressive clinical course of the
`disease, mantle cell lymphoma is still characterized by a
`poor prognosis with a median survival of only 3 years and
`only 10–15% long-term survivors. The purpose of this
`review is to summarize biological as well as clinical
`aspects of mantle cell lymphoma with a special focus on
`recent improvements in the therapy.
`
`Biology
`
`Histology and immunophenotype
`
`Mantle cell lymphoma is derived from a subset of naive
`pregerminal center cells, localized in primary follicles or
`in the mantle region of secondary follicles. Accordingly,
`the majority of cases display an unmutated immunoglob-
`ulin heavy chain locus [59]. Mantle zone, nodular or
`diffuse growth pattern may be observed [4, 60]. Cyto-
`logically, two subsets can be distinguished, the classic
`mantle cell lymphoma and the blastoid variant (approx-
`imately 10% of cases [9]).
`The characteristic immunophenotype of mantle cells
`includes the co-expression of the pan-T-cell antigen CD5
`and a variety of pan-B-cell antigens (CD19, CD20, CD22
`and CD79a) and the HLA-DR antigen. In contrast to
`chronic lymphocytic leukemia (CLL),
`the cells are
`usually negative for CD23, although a weak expression
`may be detected by flow cytometry in some cases. They
`almost always bear surface IgM and often IgD, but are
`negative for the CD10 antigen.
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`72
`
`Cytogenetics
`
`Genetically, mantle cell lymphoma is characterized by the
`chromosomal translocation t(11; 14) (q13; q32), which
`results in a juxtaposition of the bcl-1 gene locus to the Ig
`heavy chain promoter and the subsequent overexpression
`of the cell cycle regulator protein cyclin D1 in the vast
`majority of cases [47]. Cyclin D1 plays an important role
`in the cell cycle regulation by propelling cells from the G1
`into the S phase as the activated cyclin D1/cyclin-
`dependent kinase (CDK) inactivates the tumor suppressor
`retinoblastoma protein (pRb) [9]. However, cyclin D1
`overexpression alone is not sufficient to induce lympho-
`ma development [7]. Accordingly, in more than 80% of
`mantle cell lymphoma cases, secondary alterations can be
`detected, 40–50% with complex cytogenetic alterations
`[11, 50, 62].
`
`Clinical features of presentation
`
`lymphoma cases are
`The majority of mantle cell
`diagnosed at advanced Ann Arbor stages III or IV
`(Table 1). Extranodal involvement is found in approxi-
`mately 90% of cases, including bone marrow, liver and
`gastrointestinal tract [8, 23, 45, 49, 58]. A characteristic
`extranodal presentation of mantle cell
`lymphoma is
`multiple lymphomatous polyposis of the intestine. How-
`ever,
`this feature is frequently not diagnosed due to
`incomplete staging procedures [30]. Less common extra-
`nodal sites are skin, lung, breast or soft tissues. Central
`nervous system involvement is found in up to 4–22% of
`relapsed mantle cell lymphoma cases [43]. B-symptoms
`are described in less than 50% of cases (Table 1).
`
`Prognostic factors
`
`Important clinical prognostic factors that have been
`identified in previous studies are poor performance status,
`splenomegaly, anemia and age [3, 8, 13]. The published
`data on the prognostic value of morphologic parameters
`such as cytology or the growth pattern are contradictory
`[6, 8, 42, 55, 61]. Various studies confirmed the poor
`
`prognosis of p53 mutations [21, 22, 63]. However, the
`most important biological prognostic factor in multiple
`series was the proliferation rate determined by the number
`of mitoses or the Ki67 staining index. In a study by Bosch
`et al., patients with >2.5 mitoses/high power field (HPF)
`had a median survival of only 24 months, whereas those
`with 2.5 mitoses/HPF had a survival of 50 months,
`clearly indicating the prognostic value of cell prolifera-
`tion [8]. Similarly, in a large retrospective study of 350
`patients with confirmed diagnosis of mantle cell lympho-
`ma, different proliferation indices represented the most
`powerful prognostic marker, clearly superior to cytomor-
`phology and clinical parameters [13]. These results have
`been confirmed by a recent RNA array study, which again
`identified cell proliferation markers as the most powerful
`prognostic tool in mantle cell lymphoma [47].
`
`Clinical management
`
`Radiation in early stages
`
`The small number of patients with limited Ann Arbor
`stage I-II may potentially be cured by modified extended
`or involved field radiation. In addition, a recent study
`suggested an advantage of sequential radiochemotherapy
`[35]. In contrast, in advanced stage III-IV, the benefit of
`radiation therapy in addition to chemotherapy is not
`proven. Thus,
`local radiation therapy should only be
`performed in cases with bulky disease not responsive to
`conventional therapy.
`
`Conventional chemotherapy
`
`Mantle cell lymphoma has the poorest long-term survival
`of all lymphoma subtypes. Consequently, a wait-and-see
`strategy is not
`justified, although in advanced stages
`conventional chemotherapy represents only a non-cura-
`tive treatment option. Different chemotherapeutic regi-
`mens achieve overall response rates of approximately
`70%, with complete remissions in up to 20–40% of cases
`[40, 57, 64].
`
`Table 1 Features of presentation
`
`Berger et al. 1994 [5]
`Zucca et al.1995 [64]
`Norton et al.1995 [42]
`Fisher et al. 1995 [14]
`Pittaluga et al. 1995 [45]
`Hiddemann et al. 1996 [23]
`Velders et al. 1996 [58]
`Majlis et al. 1997 [37]
`Bosch et al. 1998 [8]
`
`N
`
`52
`65
`66
`36
`55
`573
`41
`46
`59
`
`Median age
`(yr)
`
`Stage IV
`
`Sex (m/
`f)
`
`Bone
`marrow
`
`Leukemic
`expression
`
`Splenomegaly GI tract
`
`58% >60
`64
`62
`55
`68
`63
`68
`54
`63
`
`89% (III + IV) NA
`72%
`2/1
`82%
`3.7/1
`NA
`4/1
`62%
`6.8/1
`75%
`2.5/1
`78%
`1.6/1
`82% (III + IV)
`1.7/1
`95% (III + IV)
`3/1
`
`82%
`58%
`80%
`53%
`66%
`69%
`80%
`69%
`81%
`
`49%
`20%
`NA
`NA
`NA
`NA
`NA
`NA
`58%
`
`59%
`35%
`48%
`NA
`NA
`NA
`NA
`NA
`44%
`
`20%
`15%
`12%
`19%
`NA
`NA
`NA
`24%
`17%
`
`yr years, m male, f female, NA not available
`
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`73
`
`The use of purine analogs (fludarabine or cladribine; 2-
`CdA) in the therapy of mantle cell lymphoma has been
`investigated in different studies [12, 15, 48]. Single-agent
`fludarabine showed only moderate activity with response
`rates of 32–41%. In contrast, combinations with alkylat-
`ing agents or anthracyclines were able to achieve higher
`remission rates [10, 27, 48].
`Other chemotherapy regimes as gemcitabine, dexa-
`methasone and cisplatin or cisplatin, fludarabine and
`cytarabine achieved remarkable response rates in up to
`88% of relapsed or refractory mantle cell lymphoma [41,
`51]. However, response duration was short.
`
`Interferon-a
`
`In various phase II studies, a prolonged progression-free
`survival after an interferon-a maintenance has been
`observed similarly to follicular lymphomas [24, 54].
`However, the number of investigated patients was too low
`to reach statistical significance. Nevertheless, interferon-a
`may be part of future approaches, e.g., in combination
`with rituximab.
`
`Monoclonal antibodies
`
`In the past few years, various studies investigated the
`efficacy of the anti-CD20 antibody rituximab in mantle
`cell lymphoma. The monotherapy with rituximab showed
`only a moderate activity, with partial response rates of
`approximately 20–40% [16, 17, 56]. In contrast,
`the
`combined
`immunotherapy
`(rituximab
`and CHOP)
`achieved remarkably high overall and complete response
`rates (96 and 48%) [28], suggesting a chemosensitizing
`effect of rituximab. Nevertheless, the higher response
`rates did not translate into a prolonged progression-free
`survival (median progression-free survival: 16.6 months;
`Table 2).
`More encouraging results were recently published by
`Hiddemann et al. [27]. In a prospective randomized study
`of the German Low Grade Lymphoma Study Group
`(GLSG), the combination of FCM chemotherapy (flu-
`darabine, cyclophosphamide and mitoxantrone) and rit-
`uximab was compared to FCM alone in refractory and
`relapsed mantle cell lymphoma. The addition of rituximab
`resulted in significantly improved complete remission
`
`N
`
`24
`
`40
`40
`
`Regimen
`
`R-FCM
`Rituximab 375 mg/m2/dx1
`Fludarabine 25 mg/m2/dx3
`Cyclophosphamide 200 mg/m2/dx3
`Mitoxantrone 8 mg/m2/d x 1
`R-CHOP
`R-CHOP
`
`CR/OR
`33%/62%a
`
`48%/96%
`45%/90%a
`
`Fig. 1 Event-free interval after different chemotherapy regimens in
`MCL
`
`The use of anthracycline-containing regimens was
`evaluated in various studies. In the only randomized
`study, no advantage of the CHOP regimen (cyclophos-
`phamide, doxorubicin, vincristine and prednisone) in
`comparison to a non-anthracyclin combination (COP:
`cyclophosphamide, vincristine and prednisone) was de-
`tectable [39]. The overall response rate was 84% after
`COP and 89% after CHOP, with a median overall survival
`of 32 and 37 months, respectively. In contrast,
`in a
`retrospective study, Zucca and colleagues claimed a
`superiority of anthracycline-containing regimens with
`regard to the complete response rate, failure-free and
`overall survival
`in the low-risk group of mantle cell
`lymphoma patients [64]. Thus, although clinical studies
`did not clearly prove a superiority of anthracycline-
`containing combinations, CHOP-like regimens currently
`represent the standard therapeutic approach (Fig. 1).
`Encouraging results have been achieved in various
`phase II studies implementing high-dose cytarabine (Ara-
`C). After a sequential CHOP-DHAP regimen (dexameth-
`asone, high-dose cytarabine and cisplatin), over 80% of
`the treated patients obtained a complete remission [34].
`Similarly, high response rates of more than 90% could be
`achieved by a dose-intensified approach of the M.D.
`Anderson Cancer Center applying an alternating regimen
`of Hyper-CVAD (fractionated cyclophosphamide, vin-
`cristine, doxorubicin and dexamethasone) with high-dose
`cytarabine and methotrexate [46]. As these data suggest a
`high efficacy of high-dose cytarabine in mantle cell
`lymphoma, this concept is currently being tested by the
`European mantle cell lymphoma Network.
`
`Table 2 Rituximab and che-
`motherapy in mantle cell lym-
`phoma
`
`Authors
`
`Hiddemann et al. 2002 [27]
`
`Howard et al. 2002 [28]
`Hiddemann et al. 2002 [27]
`
`n number of patients, CR complete remission, OR overall response
`a Significant improvement in comparison to chemotherapy alone
`
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`74
`
`Fig. 2 Prospectively randomized comparison of progression-free
`survival after peripheral blood stem cell
`transplantation and
`interferon-a maintenance. Patients assigned to stem cell transplan-
`tation experience significantly longer progression-free survival
`
`rates (33 vs. 0%; p=0.003) and a 20% increase of overall
`response rates (62 vs. 43%), clearly indicating the
`superiority of a combined immunochemotherapy in
`mantle cell
`lymphoma (Table 2). After a median
`follow-up of 19 months (23 months for patients alive)
`these high remission rates resulted in a significantly
`improved overall survival (p=0.005). In another prospec-
`tive, randomized study of the GLSG, the addition of
`rituximab in the first line therapy (R-CHOP) resulted in a
`similar improvement of remission rates (overall response:
`90 vs. 71%; p=0.031; complete remission: 45 vs. 10%;
`p<0.001; Table 2) [27]. However, longer follow-up is
`necessary to evaluate the impact on overall survival.
`Future study concepts focus on the role of rituximab
`maintenance and in vivo purging prior to autologous stem
`cell transplantation [18].
`Another innovative approach is the application of radio
`(131iodine or 90yttrium) labeled anti-CD20 antibodies in a
`conventional or myeloablative dosage. Different studies
`achieved remarkably high and long-lasting remissions in
`relapsed or refractory mantle cell lymphoma patients [19].
`
`Autologous stem cell transplantation
`
`One of the options, established in the meantime, in the
`treatment of mantle cell
`lymphoma is myeloablative
`therapy followed by autologous stem cell transplantation.
`This approach significantly improves the progression-free
`survival and may partially overcome the therapeutically
`dilemma of mantle cell lymphoma.
`In a randomized prospective study of more than 200
`patients, the European mantle cell lymphoma Network
`evaluated a consolidating myeloablative radiochemother-
`apy followed by autologous stem cell transplantation after
`a CHOP-like induction [26]. Patients receiving such a
`myeloablative consolidation achieved a significantly
`longer disease-free survival and a borderline improve-
`ment of overall survival in comparison to interferon-a
`maintenance therapy (Fig. 2). In contrast, the efficacy in
`relapsed mantle cell lymphoma seems to be limited [52].
`Consequently, high-dose-consolidation in first remission
`
`should be considered as standard therapy in younger
`mantle cell lymphoma patients. However, even after such
`a dose-intensified approach the majority of patients will
`finally relapse, possibly due to a contamination of the
`harvested stem cells with lymphoma cells. Standard
`immunological
`in vitro purging procedures failed to
`eradicate these circulating mantle cells [2, 53].
`In
`contrast, rituximab in vivo purging prior to autologous
`stem cell transplantation may be more effective. Remark-
`ably high overall survival rates of 89% after a median
`follow-up of 35 months have been reported after such an
`antibody-based concept [18]. However, these encouraging
`results have to be confirmed in prospective phase III
`studies.
`
`Allogenic transplantation
`
`In mantle cell lymphoma the only curative therapy so far
`is allogenic stem cell transplantation. Different studies
`showed that
`long-lasting complete remission can be
`achieved even in patients with relapsed or refractory
`mantle cell lymphoma [1, 33, 38]. Khouri et al. [31]
`reported that allogenic transplantation resulted in an
`overall and failure-free survival of 55% at 3 years.
`Molecular
`remission was achieved in five of seven
`patients within 7 months post
`transplant. These data
`strongly support
`the role of a graft-versus-lymphoma
`effect
`in mantle cell
`lymphoma. However,
`infectious
`complications are common and transplant-related toxicity
`and mortality may be high even after a dose-reduced
`conditioning regimen.
`
`New therapeutic modalities
`
`in the treatment of
`A new molecular targeting agent
`mantle cell lymphoma is the specific inhibitor of the
`cyclin-dependent kinase (CDK)4-cyclin D1 complex
`flavopiridol. Kouroukis et al.
`[32]
`investigated the
`efficacy of flavopiridol given three times per week every
`3 weeks in a recent phase II study. However, neither this
`scheme (no complete remissions and only 11% partial
`responses) nor a 72-h continuous infusion [36] showed a
`significant efficacy in relapsed or refractory mantle cell
`lymphoma. As cell culture experiments
`suggest a
`chemosensitizing effect,
`flavopiridol might be more
`effective in combination with chemotherapy.
`The proteasome inhibitor Bortezomib (Velcade, for-
`merly PS-341)
`represents another molecular
`targeted
`approach in the treatment of mantle cell
`lymphoma.
`Bortezomib is highly effective in mantle cell lymphoma
`derived cell lines and SCID mouse models by sensitizing
`lymphoma cells to apoptosis [44]. In addition, Borte-
`zomib showed its efficacy in a recent phase II study of the
`M.D. Anderson Cancer Center; five of eight (62.5%)
`previously heavily pre-treated mantle cell
`lymphoma
`patients responded to a Bortezomib therapy at a dose of
`1.5 mg/m2 [20].
`
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`Conclusion
`
`Mantle cell lymphoma remains one of the most challeng-
`ing problems in the diagnosis and therapy of malignant
`lymphoma. So far, CHOP-like combinations have repre-
`sented the standard therapeutic approach. Recent prospec-
`tive randomized studies have confirmed the benefit of a
`combined immunochemotherapy with rituximab in newly
`diagnosed as well as relapsed mantle cell lymphoma. In
`addition, in younger patients myeloablative radiochemo-
`therapy followed by autologous stem cell transplantation
`represents the standard approach. Unfortunately, the only
`curative approach is allogenic bone marrow transplanta-
`tion, indicating that new therapeutic strategies are war-
`ranted to improve the clinical outcome of mantle cell
`lymphoma.
`
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