Critical Reviews in Oncology/Hematology 58 (2006) 257–265
`
`Treatment of mantle cell lymphoma:
`Current approach and future directions
`∗
`
`Joshua Brody, Ranjana Advani
`
`Department of Medicine, Division of Oncology, Stanford University Medical Center, Clinical Cancer Center,
`875 Blake Wilbur Drive, Stanford, CA 94305, USA
`
`Accepted 5 October 2005
`
`Contents
`
`1. Diagnosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.
`Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3. Treatment approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1. Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.2. Rituximab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.3. Autologous stem cell transplant. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.4. Role of purging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.5. Allogeneic transplantion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.6. Radioimmunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.7. Other immunotherapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.8. Newer agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Summary and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
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`Abstract
`
`Although mantle cell lymphoma has been described as “moderately aggressive” it has become clear that it carries a worse long-term prognosis
`than other subtypes of non-Hodgkin’s lymphoma. In recent years, this has prompted numerous clinical trials of novel and more aggressive
`therapies in hopes of impacting these poor outcomes. These include more intensive combination chemotherapy regimens, monoclonal antibody
`therapy in conjunction with other treatments or conjugated to radioactive isotopes, high-dose chemotherapy followed by autologous or
`allogeneic stem cell transplantation, and newer targeted therapies based on increasing understanding of the molecular pathways of this
`malignancy.
`© 2005 Elsevier Ireland Ltd. All rights reserved.
`
`Keywords: Mantle cell lymphoma; Clinical trials; Non-Hodgkin’s lymphoma
`
`Mantle cell lymphoma (MCL) is a distinct non-Hodgkin’s
`lymphoma (NHL) subtype first put forward by an interna-
`tional consensus panel [1] in 1992 and then incorporated into
`
`∗
`
`Corresponding author. Tel.: +1 650 723 1479; fax: +1 650 725 9113.
`E-mail addresses: josho@stanford.edu (J. Brody),
`radvani@stanford.edu (R. Advani).
`
`the REAL-WHO classification system in 1994 [2]. It com-
`prises a group of subtypes including those previously classi-
`fied as centrocytic, lymphocytic or diffuse small-cleaved cell
`lymphoma. This subtype represents approximately 4–6% of
`all non-Hodgkin lymphomas [3,4] with an incidence of 2–3
`per 100,000 years and with a median age at diagnosis of 63
`years. Diagnosis is based on histologic, immunophenotypic,
`
`1040-8428/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved.
`doi:10.1016/j.critrevonc.2005.10.001
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`
`cytogenetic and molecular criteria, most importantly the char-
`acteristic t(11;14) (q13;q32) translocation which places the
`immunoglobulin heavy chain locus upstream of the BCL1
`gene causing overexpression of its gene product—cyclin D1.
`In a series of 81 patients diagnosed from 1988 to 1990 MCL
`carried the worst 5-year failure free survival rate of any of the
`major subtypes (∼11%) and median overall survival of less
`than 3 years [5].
`Because of this poor prognosis there has been an ongo-
`ing search for improved treatments. In contrast to the more
`common aggressive lymphomas (e.g. diffuse large B-cell
`lymphoma (DLBCL)) there is not one regimen that has
`demonstrated superiority or equivalence compared to mul-
`tiple alternatives, hence there is little agreement amongst
`clinicians regarding appropriate first-line therapy. The pur-
`pose of this review is to consider the rationale and available
`data for commonly used treatment regimens and to survey
`promising future therapies currently being developed and
`tested.
`
`1. Diagnosis
`
`Selection of appropriate treatment regimens for patients
`with MCL and the pursuit of continually better regimens
`relies upon uniformity of diagnostic criteria for this entity.
`Clinically, MCL has a male predominance and a tendency for
`extra-nodal involvement including the bone marrow, spleen
`and GI tract (particularly the colon). The histologic pattern
`may be diffuse, nodular, mantle-zone, or a combination of
`the three with some reports suggesting a better prognosis
`for those with a mantle-zone pattern [6]. The malignant cell
`type of classic MCL is composed of small to medium sized
`lymphocytes with irregular nuclei and condensed chromatin,
`though there also exists a broad spectrum of morphologic fea-
`tures ranging from small cell to blastoid types and these may
`reflect distinct biologic characteristics. Patients can present
`de novo or during the course of their disease with a blastoid
`variant composed of medium size rounded nuclei with dis-
`persed chromatin, scant cytoplasm and a high mitotic index,
`resembling lymphoblasts. Interestingly, one series found that
`although this “transformation” was found in 32% of patients
`during the course of disease, 70% of autopsy specimens
`revealed some site of blastoid disease [7].
`The immunophenotype of MCL corresponds to mature,
`na¨ıve pre-germinal center B cells with expression of CD19,
`CD20, CD22, CD79A, IgM and/or IgD. They are usually
`−
`−
`CD5+ and CD43+, but CD10
`and CD23
`. Though there
`are exceptions, this basic schema can be helpful in distin-
`guishing between the common small B-cell NHL subtypes
`(see Table 1).
`The most distinctive aspects of MCL are its numerous
`genetic aberrations that are important both in its diagnosis and
`in its pathophysiology. The most pathognomonic of these is
`t(11;14) (q13;q32) translocation. Other well-described muta-
`tions include loss of the ataxia telangiectasia mutated (ATM)
`
`Table 1
`Immunophenotype of small B-cell NHL subtypes [73]
`
`SLL/CLL
`
`MCL
`
`Follicular
`
`MZL
`
`CD20
`CD5
`CD23
`CD43
`CD10
`
`+
`+
`+
`−
`+
`+
`−
`−
`+
`+
`+
`+
`−
`−
`−
`Abbreviations: SLL/CLL, small lymphocytic lymphoma/chronic lympho-
`cytic leukemia; MZL, marginal zone lymphoma.
`
`+
`−
`−
`−
`+
`
`gene (frequently through 11q deletion), deletions of 9p21
`and 17p13 (thought to be important for the loss P16 and
`P53, respectively) and 8q22–24 amplification (thought to be
`important for its consequent over-expression of c-myc) [8].
`The t(11;14) translocation juxtaposes the BCL1 gene to the
`B-cell immunoglobulin transcription enhancer and results in
`the over-expression of cyclin D1 and cell-cycle dysregula-
`tion. In approximately 50% of cases the translocation occurs
`in one identified region called the major translocation cluster.
`In most of these cases PCR can be used to diagnose and (more
`importantly) to follow response to treatment at the molecu-
`lar level. Generally fluorescence in situ hybridization (FISH)
`assessment for the translocation is the gold standard when
`definitive genetic testing is required. This technique is 95%
`sensitive for the specific translocation and can be performed
`on paraffin fixed specimens.
`
`2. Prognosis
`
`There are numerous clinical and pathologic parameters
`of negative prognostic significance including: age, poor per-
`formance status [9], splenomegaly, nodal (as opposed to
`non-nodal leukemic) disease [10], anemia, non-mantle zone
`histology [6], blastoid morphology, high mitotic index [11],
`topoisomerase II␣ [12], cyclin D1 [13] and c-myc [14] over-
`expression. More recently, it has been shown that specifically
`VH3-21 gene rearrangement (compared to other gene rear-
`rangements) correlates with an improved prognosis [15].
`Also, RNA expression profiling, has identified gene sets,
`which can prognosticate MCL patients more accurately than
`clinical parameters (such as morphology) [16]. In the lat-
`ter study, genes associated with a high proliferation index
`were associated with aggressive disease and a shorter sur-
`vival. In this study, patients could be stratified into subsets
`with median survival differences of greater than 5 years. Cer-
`tainly some of these parameters will be helpful in the future to
`guide appropriate therapy for each patient; however, there has
`been no evidence so far that higher risk groups have greater
`benefit from more aggressive treatment regimens.
`
`3. Treatment approaches
`
`Considering the poor prognosis of all current therapies
`there is currently no standard treatment for the disease. Treat-
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`
`Table 2
`Summary of mantle cell lymphoma treatment options
`
`Treatment
`
`CHOP [28]
`R-CHOP [28,29]
`
`HCVAD (>65 years) [20]
`R-HCVAD [31]
`HCVAD-ASCT [21]
`◦
`
`ASCT [38] 1
`therapy
`◦
`therapy
`and 2
`ASCT (GELA)[37] 1
`◦
`therapy
`ASCT–R-HDS [46] 1
`◦
`◦
`and 2
`ASCT (EORTC) [40] 1
`◦
`Bexxar®-ASCT [58] 2
`therapy
`◦
`therapy
`Allo BMT [49] 2
`◦
`NMA-allo [52,52] 2
`therapy
`
`◦
`
`therapy
`
`N
`
`60
`62
`40
`25
`97
`45
`
`62
`24
`28
`195
`16
`16
`18
`33
`
`ORR (%)
`
`CR (%)
`
`PFS/EFSa
`
`75
`94
`96
`92
`100
`94
`
`98
`100
`100
`88
`100
`100
`100
`85
`
`7
`34
`48
`68
`87
`38
`
`81
`79
`100
`67
`91
`86
`94
`75
`
`19 m
`20 m
`16.6 m
`15 m
`64%a
`◦
`: 72%a
`1
`◦
`: 17%a
`2
`39 m
`55%a
`79%a
`33%
`61%
`55%
`82%a
`60%a
`
`OS
`
`82%
`84%
`
`92%
`82%
`◦
`1
`: 92 %
`◦
`2
`: 25 %
`83%
`68%
`89%
`50 %
`93 %
`55%
`86%
`65%
`
`Median follow-up
`
`18 m
`18 m
`25 m
`17 m
`3 y
`3 y
`
`3 y
`3 y
`35 m
`5 y
`3 y
`3 y
`26 m
`24.6 m
`
`CHOP: cyclophosphamide, adriamycin, vincristine, prednisone; R: rituximab; HCVAD: high-dose cytarabine, cyclophosphamide, vincristine, adriamycin,
`◦
`◦
`dexamethasone; 1
`therapy: initial treatment; 2
`therapy: treatment of relapsed or refractory disease; HDS high-dose cyclophosphamide, high-dose cytarabine,
`high-dose melphalan and high-dose mitoxantrone plus melphalan; NMA: non-myeloablative.
`a For those timepoints measuring EFS where events are usually defined as progression or death from any cause.
`
`ment options are varied and in general the more aggressive
`approaches improve progression free survival (PFS) how-
`ever, no therapy to date is curative. Various approaches are
`summarized in Table 2.
`
`3.1. Chemotherapy
`
`Though available data have not suggested an optimal first
`line treatment for MCL, the standard of care has developed
`from the understanding that the clinical course of MCL is
`aggressive; treatments have been similar to those for other
`aggressive lymphomas. An anthracycline-based approach
`has been standard although most randomized clinical stud-
`ies have not proven a survival advantage attributable to the
`inclusion of anthracycline [17–19].
`Before the introduction of the monoclonal antibody rit-
`uximab, the most commonly used first line regimen was
`cyclophosphamide, adriamycin, vincristine and prednisone
`(CHOP), which has shown complete response (CR) rates
`ranging 20–80%, median failure free survival (FFS) of 10–16
`months, and median overall survival (OS) of 3 years. Other
`approaches have used dose intensified, CHOP-like regimens.
`Several trials at the MD Anderson Cancer Center have uti-
`lized the intensive leukemic regimen hyper-CVAD (a dose
`intense, hyper-fractionated CHOP-like combination in com-
`bination with high-dose methotrexate (MTX) and cytosine
`arabinoside (ara-C)) both as primary and as salvage therapy.
`The number of cycles of therapy has varied from four to
`eight depending on whether or not stem cell transplant was
`included as primary treatment. In a study of primary ther-
`apy for 25 patients over age 65 years, overall response rates
`(ORR) of 92%, CR rates of 68% and median duration FFS of
`15 months were reported [20]. Another study of 45 patients
`with advanced stage MCL (50% previously treated) received
`four cycles of hyper-CVAD and patients that achieved a CR
`
`went on to autologous stem cell transplant (ASCT) or allo-
`geneic transplant. The ORR was 93.5% with 38% of patients
`achieving a CR [21]. Previously untreated patients had a 3-
`year OS and event free survival (EFS) of 92% and 72%,
`respectively, significantly higher than CHOP-treated histori-
`cal controls with 3-year OS and EFS rates of 25% and 17%.
`Although it is difficult to dissect the impact of hyper-CVAD
`from that of the preparative regimen for ASCT (cyclophos-
`phamide and total body irradiation) it does seem that this
`intensified regimen is at least as effective for primary or sal-
`vage therapy as its predecessor. It must be emphasized these
`results represent single-institution data and have not been
`validated by other centers or in a randomized study.
`Another approach has been to incorporate regimens used
`in salvage therapy of other lymphoma subtypes as part of a
`primary treatment regimen for mantle cell. In a phase II, trial
`of 28 patients with aggressive MCL, four cycles of CHOP
`induced CR in only 7%. Remarkably, for those patients with
`a partial response, the addition of DHAP to CHOP in a
`sequential fashion induced a complete response in 84% of
`the remaining patients compared to CHOP alone [22].
`Despite the lack of randomized studies evaluating the dif-
`ferent treatment regimens for MCL, it appears that newer,
`more intensive approaches may result in superior ORR com-
`pared to CHOP or CHOP-like therapy. The superiority of
`these regimens may be due to the use of high-dose AraC,
`which is therefore being tested in ongoing clinical trials.
`Whether the improved remission rates translate into
`improved survival is unclear as the median follow-up of all
`these studies in short (<3 years). Patients should be enrolled
`on clinical trials in order to evaluate these new approaches.
`
`3.2. Rituximab
`
`Because MCL is a B-cell malignancy that expresses CD20,
`the anti-CD20 antibody (Ab), rituximab, has been studied
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`as a single agent in mantle cell lymphoma with response
`rates of 20–40% [23–26]. As in other lymphoma subtypes,
`it has also been studied as longer term maintenance ther-
`apy. A randomized trial followed 61 MCL patients who did
`not progress during rituximab induction therapy assigned to
`either maintenance (every 2 months for four treatments) rit-
`uximab or observation [27]. In this trial, maintenance therapy
`showed a statistically non-significant trend towards increased
`EFS of 12 months versus 6 months. More commonly, rit-
`uximab has been studied in combination with chemother-
`apy such as CHOP (i.e. R-CHOP). A prospective study by
`the German Lymphoma Study Group (GLSG) randomized
`untreated patients with advanced disease to conventional
`CHOP or R-CHOP. Responding patients received six cycles
`of CHOP or R-CHOP followed by a second randomization
`to ␣-interferon maintenance or a myeloablative consolida-
`tion followed by ASCT (depending on the patient’s age). Of
`the 122 patients evaluated prior to transplant, R-CHOP was
`resulted in a significantly superior ORR and CR rates com-
`pared to CHOP alone: 94% versus 75% (p = 0.005) and 34%
`versus 7% (p = 0.00024) [28]. Although the addition of ritux-
`imab increased time to treatment failure (TTF) from 14 to 21
`months, median PFS and OS were not statistically improved.
`The lack of an effect on OS is possibly due to the confounding
`effect of the second randomization.
`Similar results were achieved in an earlier phase II study
`in which R-CHOP yielded ORR and CR rates of 96% and
`48% with a median PFS of 16.6 months [29]. However, in
`the latter study patients obtaining a molecular CR did not
`have significantly improved PFS.
`The GLSG have also recently updated preliminary results
`of a prospective randomized trial of rituximab in combination
`with fludarabine, cyclophosphamide, mitoxantrone (FCM)
`compared to FCM alone in patients with relapsed or refrac-
`tory MCL. Of 50 patients randomized, R-FCM achieved
`higher CR and overall median survival times: 29% versus
`0% (p = 0.004) and 2.5 years versus 0.9 years (p = 0.031)
`[30]. After the superiority of the rituximab arm was demon-
`strated, an additional 45 patients were assigned to combined
`immunotherapy and confirmed these promising results.
`Rituximab has also been studied in phase II trials with
`more aggressive regimens such as hyper-CVAD. In 56
`untreated patients, R-hyper-CVAD for at
`least 6 cycles
`yielded a CR rate of 90% and 2-year FFS and OS were 72%
`and 90% (median follow-up of 14 months). Subset analy-
`sis revealed that patients younger than 65 years treated with
`R-hyper-CVAD without ASCT did as well historical con-
`trols receiving the same hyper-CVAD regimen with ASCT.
`In a recent update of this trial on 97 patients the 3-year FFS
`and OS were 64% and 82%, respectively [31]. The toxicity
`of this regimen, is of concern as five deaths were reported
`during treatment and four occurrences of myelodysplasia or
`leukemia developing in patients during CR. More recently, a
`modified hyper-CVAD regimen that added rituximab induc-
`tion and maintenance therapy but removed MTX and ara-C
`was shown to have comparable efficacy as primary therapy
`
`with ORR of 85%, CR of 70% and median progression free
`survival (PFS) and OS not reached after 22.5 months [32].
`While the results of this modified approach compare favor-
`ably with the original regimen from MD Anderson, longer
`follow-up along with validation by other centers will be
`required. Taken together, these data suggest that the addi-
`tion of rituximab to standard induction regimens appears to
`result in improved response rates.
`Two studies have suggested that post-transplant rituximab
`increases the clinical and molecular response rate of MCL
`patients receiving ASCT [33,34]. In one study of advanced
`stage MCL all patients who received post-transplant ritux-
`imab were alive without clinical or molecular relapse at 239
`days post-transplant. The treatment was well tolerated and
`encouraging albeit longer follow-up is needed.
`
`3.3. Autologous stem cell transplant
`
`Myeloablative dose chemotherapy followed by stem cell
`transplantation can improve survival in other subtypes of
`lymphoma. This treatment has also been applied to MCL
`with mixed results [35–37]. Most studies have utilized this
`approach in patients with relapsed or refractory disease.
`Recently, the European MCL Network reported the results
`of the first prospective randomized trial comparing myeloab-
`lative radio-chemotherapy versus ␣-interferon maintenance
`therapy in 122 patients that achieved at least a PR after a
`CHOP-like induction regimen [38]. ASCT consisted of a
`mobilization regimen of dexamethasone, BCNU, etoposide,
`ara-C and melphalan (dexa-BEAM) followed by consol-
`idative therapy with total body irradiation (TBI) and high-
`dose cyclophosphamide (CTX). Compared to the IFN-␣
`arm, patients in the ASCT arm experienced a significantly
`longer PFS with a median of 39 months versus 17 months
`(p = 0.0108), but no difference in 3-year OS: 83% versus 77%
`(p = 0.18).
`Similar outcomes have been described in other mature
`phase II studies; with a median follow-up of four years,
`a trial of 25 patients were treated with rituximab plus
`induction chemotherapy followed by high-dose chemother-
`apy ± radiotherapy and ASCT [39]. Induction allowed all
`patients to achieve either CR (36%) or PR (64%) and 3 year
`OS is 80%.
`Data from other trials have also suggested that ASCT is
`of greater benefit earlier in the course of disease. A retro-
`spective analysis of the European Blood and Bone Marrow
`Transplant registries of 195 MCL patients treated with ASCT
`reported OS at 2- and 5-year as 76% and 50% with PFS as
`55% and 33%, respectively [40]. Patients who were trans-
`planted in first CR were 33% less likely to die from MCL
`than patients with chemosensitive disease transplanted later
`in their course. Results were similar in a retrospective analysis
`of 69 patients at Stanford and City of Hope who underwent
`ASCT [41]. Patients who were in first CR at the time of
`transplant had 3- and 5-year OS/DFS rates of 93%/74% and
`77%/50%, respectively. In comparison, the OS/DFS rates at
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`3 and 5 years for patients who were not in first remission
`at the time of transplant were 64%/51% and 39%/21%. The
`median time to relapse in the group transplanted in first CR
`was 32 months compared to 10.5 months.
`As described above, hyper-CVAD remission induction for
`MCL has yielded 3 year OS and EFS rates were 92% and
`72% [21]; these compare favorably with the randomized trial
`described using CHOP or CHOP-like regimens [38]. A ret-
`rospective analysis by Conde et al. evaluated the induction
`regimens used for MCL [42,43]. An international database
`of 119 patients with MCL who had received ASCT between
`1988 and 2002 was evaluated. The induction regimens were
`primarily hyper-CVAD and CHOP-like therapy and the esti-
`mated 10-year OS and DFS were impressive at 50% and 32%,
`respectively. Patients receiving hyper-CVAD had a 4-year
`DFS of 68% compared to 33% in patients treated with other
`regimens. It should be noted that none of these regimens
`employed rituximab along with the induction chemother-
`apy. Though there were differences in baseline characteristics
`between these two groups, these data suggest the need to
`evaluate the role of these newer therapies in prospective ran-
`domized trials.
`
`3.4. Role of purging
`
`As in other B-cell malignancies, the role of “purging” of
`the mobilized autologous stem cell product prior to trans-
`plant has been examined in MCL. One such approach is
`the use of ex vivo treatment of stem cell products with anti-
`CD20 Ab and complement-mediated lysis. A study assessing
`for minimal residual disease (MRD) at the time of trans-
`plant using PCR amplification of the Bcl-1/IgH translocation
`product showed ex vivo purging to be effective in only 2
`of 19 patients [44]. Alternatively, the use of in vivo purging
`using rituximab has been more promising with evidence of
`clinical and molecular remissions. The first of these studies
`demonstrated that stem cell products collected after high-
`dose cyclophosphamide and cytarabine still had a high rate
`of MRD versus a parallel cohort that received rituximab after
`high-dose therapy (60% versus 7%; p = 0.007) [45]. The sig-
`nificance of this study for MCL treatment is limited by its
`inclusion of non-MCL sub-types of NHL. A follow-up study
`treated 28 MCL patients with cisplatin or doxorubicin-based
`debulking chemotherapy followed by high-dose sequential
`therapy with rituximab and ASCT [46]. The 54-month OS
`and EFS rates were 89% and 79%, respectively as com-
`pared to historical controls with 42% and 18%. Again, after
`cyclophosphamide, cytarabine and rituximab mobilization,
`19 out of 19 evaluable patients had stem cell products that
`were without MRD. Adding cytarabine with rituximab in vivo
`purging to a CHOP-like regimen compared to the latter regi-
`men alone, showed benefit both in pre-transplant CR rate and
`post-transplant PCR negativity [47].
`Cumulatively these data suggest that in addition to its
`above noted uses in remission induction and salvage therapy,
`rituximab also may have an important pre-transplant role both
`
`as part of conditioning regimens and for in vivo. Again, none
`of these studies have a long enough follow-up to assess the
`impact on overall survival.
`
`3.5. Allogeneic transplantion
`
`Although ASCT has demonstrated prolonged survival for
`patients with MCL, there has been no evidence of cure with
`these modalities so more aggressive approaches are still being
`evaluated. As allogeneic transplantation has demonstrated
`increased effectiveness in other lymphoma sub-types because
`of a graft-versus-lymphoma (GVL) effect [48], this approach
`has been considered for MCL patients refractory to other ther-
`apies (or occasionally those in first CR). Along with degree
`and duration of clinical response, evaluation for evidence of
`this GVL effect has been an important outcome in such trials.
`In an early study, 16 patients underwent allogeneic trans-
`plant after myeloablative regimens of cyclophosphamide plus
`TBI (11 patients) or BEAM (3 patients) or a non-ablative
`preparative regimen consisting of cisplatin, cytarabine and
`fludarabine [49]. OS and failure-from-progression (FFP) at
`3 years were both 55% (28–83%) including a high treatment
`related mortality of 38%. The suggestion of a GVL effect
`was evident in several patients who converted to a molec-
`ular CR months after the completion of chemotherapy and
`coincident with the development of graft-versus-host dis-
`ease (GVHD). Another trial using a myeloablative regimen
`in 20 MCL patients has reported nine patients alive and dis-
`ease free 1–9 years post-transplant [50]. This and other [51]
`reports of long-term DFS raise the question as to whether this
`approach has curative potential for some patients.
`Because MCL occurs more in older patients who are not
`candidates for myeloablative allogeneic transplants, there has
`been consideration of non-myeloablative regimens followed
`by allogeneic transplant (NMA-allo). Early results have been
`mixed. A recent trial investigated non-myeloablative trans-
`plant in 18 patients with MCL who had failed multiple prior
`chemotherapies including 28% who had failed prior ASCT.
`CR was achieved in 17 of 18 patients and with a median
`follow-up of 26 months the estimated 3-year survival rate and
`current PFS was 85.5% and 82%, respectively [52]. Another
`study of 33 MCL patients using a non-myeloablative con-
`ditioning regimen of fludarabine and 2 Gy TBI followed by
`related or unrelated allogeneic transplantation demonstrated
`2-year OS and DFS of 65% and 60% with a non-relapse mor-
`tality of 24% [53]. Still, the outcomes for this approach have
`been mixed as a larger trial of non-myeloablative chemother-
`apy followed by allogeneic transplant included 22 patients
`with MCL and yielded 2-year OS and PFS of 12% and 0%
`[54].
`These data plus other recent retrospective analyses [55,56]
`suggest that myeloablative conditioning or, in older patients,
`non-myeloablative conditioning, followed by allogeneic stem
`cell transplantation is feasible for MCL patients in first CR
`and after salvage therapy. The high treatment related mor-
`tality rates are consistent with results from other lymphoma
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`sub-types and suggest use of this modality in those patients
`at highest risk for rapid disease recurrence and progression.
`The reports of clinical responses correlating with GVHD
`and remote from chemotherapy suggest a GVL effect, which
`should prompt investigation into other immunotherapeutic
`approaches.
`
`3.6. Radioimmunotherapy
`
`Though radiation therapy (RT) has been described to be
`effective in MCL [57], external beam RT has little role in
`MCL because of the rarity of limited stage disease. Because
`immunotherapy with rituximab has shown additive effect
`with chemotherapy, radio-immunotherapy is an attractive
`therapeutic option for patients with MCL. The two clini-
`cally available radio-immunoconjugates are iodine 131I tosi-
`tumomab (Bexxar®) and yttrium 90Y ibritumomab tiuxetan
`(Zevalin®).
`A recent study of Bexxar in 16 patients with relapsed
`MCL utilized an 131I dose calculated to deliver 20–25 Gy to
`vital organs [58]. The treatment was followed 10 days later
`by high-dose etoposide, cyclophosphamide and ASCT. The
`3-year OS and PFS were estimated at 93% and 61%. Subse-
`quently, in a study of 15 patients with a median of three prior
`therapies, patients were treated with Zevalin at 0.3–0.4 mCi
`90Y kg [59]. Treatment was well tolerated and the ORR was
`33% with CR rate of 20%. The median PFS in this group was
`only 4.9 months (and only 5.7 months in responding patients).
`The role of radio-immunotherapy in the upfront manage-
`ment of MCL is also being assessed. A strategy employed
`by the Eastern Cooperative Oncology Group was to use R-
`CHOP for four cycles to induce remission (in an attempt to get
`systemic control and marrow clearing). Responding patients
`who met standard criteria for RIT administration were treated
`with a single dose of Zevalin. This study has just completed
`accrual. Another recent trial treated 24 newly diagnosed MCL
`patients who were ineligible for ASCT with Bexxar followed
`by CHOP 12 weeks later. After Bexxar, the ORR and CR rate
`were 83% and 42%. Nine of the 15 patients who have com-
`pleted their therapy remain in remission after 2–36 months of
`follow-up and 2 patients who progressed were successfully
`able to receive ASCT [60]. Longer follow-up will be required
`to see if these novel strategies improve outcomes.
`
`3.7. Other immunotherapies
`
`More recently, idiotype vaccines that deliver a recom-
`binant protein derived from the surface immunglobulin of
`an individual patient’s MCL have been investigated with
`promising early results [61]. These trials have advanced to
`take advantage of lessons learned from recent advances in
`melanoma immunotherapy [62] such as treating patients with
`minimal disease burden and after lymphodepletion (to reduce
`regulatory T cell interference). A recent example used idio-
`type vaccinations 3 months after ASCT in eight MCL patients
`[63]. Six of these patients were in CR after ASCT and four
`
`remain in CR 14–38 months later. CD4+ T cell and humoral
`responses against the individual’s idiotype were seen in most
`patients.
`
`3.8. Newer agents
`
`Bortezomib is a potent and specific proteasome inhibitor
`that was FDA approved in 2003 for the treatment of relapsed
`multiple myeloma. There have been several smaller studies
`of this agent, but the largest so far (PINNACLE study) has
`yielded initial data on 48 of the 102 enrolled patients. All
`patients had failed one or two prior regimens and response
`rate was 40% [64]. Though it is too early to draw conclusions
`regarding the significance of these data, they are encouraging
`considering that these patients have been treated with aggres-
`sive prior regimens.
`Thalidomide in combination with rituximab was evaluated
`in relapsed/refractory MCL patients with impressive anti-
`tumor activity recently reported. In one study, 16 patients
`with relapsed/refractory MCL were treated with rituximab
`at 375 mg/m2 for four weekly doses concomitantly with
`thalidomide. Eighty percent (13/16) experienced an objective
`response with five achieving a CR (31%) [65]. The median
`PFS was 20.4 months (95% CI, 17.3–23.6), and estimated 3-
`year survival