Leukemia (2014) 28, 2117–2130
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`
`HOW TO MANAGE...
`How to manage mantle cell lymphoma
`M Dreyling1,5, S Ferrero2,5 and O Hermine3,4
`
`Mantle cell lymphoma (MCL) is no longer a hopeless disease. Considered to carry a uniformly dismal prognosis so far, during the
`last years it has been rediscovered as a heterogeneous clinical and biological entity. Such a complexity has been highlighted by
`molecular genetics, unraveling different pathways of cell survival and progression. Concurrently, the application of new therapeutic
`paradigms including rituximab, high-dose cytarabine and stem cell transplantation dramatically improved treatment activity and
`the introduction of innovative targeted molecules has already led to new patient perspectives. In this completely new and
`continually evolving landscape, the clinical hemato-oncologist might feel disoriented on what are the best current strategies to
`handle such a critical disease and the gold standard therapeutic options for MCL. Here we address some burning questions on how
`to manage MCL patients, spacing from prognostic issues to the dilemma of personalized treatment in different scenarios of the
`disease: how to diagnose an MCL? Which are the fundamental staging procedures? What are the most reliable prognosticators?
`Is there a place for watch and wait? Which are the best treatment options for younger, elderly and frail patients? Which patients are
`addressable to high-dose therapy? What is the role of allogeneic transplantation? What is the most appropriate approach for
`relapsing disease in different categories of patients? What novelties are going to be introduced in the near future? The practical
`algorithms here discussed represent an evidence-based approach derived from results of multicenter and randomized trials.
`
`Leukemia (2014) 28, 2117–2130; doi:10.1038/leu.2014.171
`
`INTRODUCTION
`Mantle cell
`lymphoma (MCL) is a distinct histological subtype
`occurring in both elderly (465 years) and young (o65 years)
`patients, with a pathognomonic chromosomal
`translocation
`t(11;14).1 During the last three decades MCL was considered as
`a disease with a uniformly dismal prognosis; however, with the
`introduction of high-dose cytarabine chemotherapy (± auto-
`logous stem cell transplantation, SCT) and anti-CD20 antibody
`therapy with rituximab especially the outcome of younger
`patients has
`improved significantly, with some patients
`experiencing long-term disease-free survival.2–7 At
`the same
`time, thanks to the promising results of combined induction
`conventional chemotherapy and rituximab, followed by rituximab
`maintenance, the therapeutic possibilities of elderly patients have
`also dramatically improved, with unprecedented levels of
`cytoreduction disclosed in minimal
`residual disease (MRD)
`studies.8–11
`In addition, small molecules targeting specific signal pathways,
`including molecular alterations of
`the disease, are being
`incorporated into the therapeutic armamentarium and will further
`improve prognosis.12 In the near future, more individualized
`approaches will take into account risk factors present at diagnosis,
`predictive biomarkers representing molecular alterations, as well
`as quality of the response assessed by molecular MRD analysis.
`In this article we will discuss our clinical approach to the
`management of MCL patients. First, we will present the criteria
`that allow a reliable diagnosis of MCL, and then we will discuss our
`personal algorithm and the rising questions that should help us to
`decide the best strategy of
`treatment
`in different clinical
`scenarios: first-line therapy for younger patients, for elderly (or
`
`unfit to receive high-dose chemotherapy) patients or for frail
`patients and the difficult challenge of salvage treatment of
`relapsed MCL in each of these different patient categories.
`
`HOW TO DIAGNOSE A MCL?
`The diagnosis of MCL is established according to the criteria of the
`WHO classification of hematological neoplasms.
`In general,
`histologic confirmation of diagnosis is mandatory and a lymph
`node biopsy is strongly recommended; in contrast, lymph node
`fine-needle biopsy is not appropriate. A bone marrow aspiration
`complemented using flow cytometry to identify the typical
`lymphoma immunophenotype and a bone marrow biopsy to
`quantify the percentage of infiltration are mandatory. Most tumors
`have a classic morphology of small–medium sized cells with
`irregular nuclei, dense chromatin and unapparent nucleoli.
`In addition to classic MCL, a blastoid variant of the disease has
`been described, characterized by high mitotic rate and particularly
`aggressive behavior with risk of central nervous system relapse,
`and is associated with INK4a/ARF deletions, TP53 mutations and
`complex karyotypes.1,13–17 However, tumor cells may present with
`a spectrum of morphological variants, raising some difficulties in
`the differential diagnosis apart
`from chronic
`lymphocytic
`leukemia, marginal zone lymphomas, large B-cell lymphomas or
`blastic hematological proliferations. As an accurate histologic
`diagnosis
`is essential,
`second opinion by an experienced
`hematopathologist is advisable.18
`Beside the classical immunophenotype (immunoglobulin M/D,
`CD19, CD20, CD22, CD43, CD79a, CD5 positive and CD23, CD10,
`CD200, BCL6 usually negative),
`the detection of cyclin D1
`
`1Department of Medicine III, University Hospital Grohadern/LMU Mu¨ nchen, Medizinische Klinik und Poliklinik III, Klinikum der Universita¨t, Mu¨ nchen, Germany; 2Division of
`Hematology, Department of Molecular Biotechnologies and Health Sciences, University of Torino, Torino, Italy; 3Department of Adult Hematology, Necker Hospital, Assistance
`Publique, Paris, France and 4Imagine Institute, Sorbonne Paris Cite´ University, Paris, France. Correspondence: Professor Dr M Dreyling, Department of Medicine III, University
`Hospital Grosshadern/LMU Mu¨ nchen, Medizinische Klinik und Poliklinik III, Klinikum der Universita¨t, Marchioninistrasse 15, Mu¨ nchen, Bavaria 81377, Germany.
`E-mail: Martin.Dreyling@med.uni-muenchen.de
`5These authors contributed equally to this work.
`Received 11 February 2014; revised 28 April 2014; accepted 19 May 2014; accepted article preview online 23 May 2014; advance online publication, 15 July 2014
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`2118
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`The management of MCL patients
`M Dreyling et al
`
`is
`translocation t(11;14)
`the chromosomal
`overexpression or
`essential, as histomorphological phenotypes may differ signifi-
`cantly.1 Nevertheless, rare cases of cyclin D1-negative variant of
`MCL have been recognized,19 characterized by the same gene
`expression profile and secondary genomic alterations as classical
`MCL. In around 50% of these cases a cyclin D2 translocation may
`be detected.20 SOX11, a transcription factor expressed in 90% of
`MCL, might also be applied to identify at least some of these cyclin
`D1-negative variants.21 Moreover, Ki67 proliferative index staining
`is strongly recommended as a powerful prognostic indicator of
`long-term outcome.5,18,22,23
`Finally, the classical laboratory evaluation comprises differential
`blood count, particularly
`leukocyte
`count,
`and standard
`serum chemistry analysis, including the determination of lactate
`dehydrogenase as one of the major risk parameters.24
`
`HOW TO DEFINE THE STAGE AND PROGNOSIS OF MCL?
`In order to define the stage of MCL, a computed tomography scan
`with iodine contrast of the neck, chest, abdomen and pelvis is
`mandatory. Positron emission tomography scan is not included in
`the consensus recommendations based on scarce data and
`especially limited therapeutic consequences, as the large majority
`of patients presents with an advanced-stage MCL (stages III–IV
`due to frequent bone marrow and/or gastrointestinal
`involve-
`ment).25–27 Thus, only among the rare stage I–II patients positron
`emission tomography scan may be applied to confirm early-stage
`disease and guide localized treatment.28
`Owing to the risk of central nervous system involvement in
`blastoid cases, cerebrospinal fluid evaluation might be considered
`at diagnosis for these patients. Cranial
`imaging with magnetic
`resonance is not usually required at first presentation, unless
`neurologic symptoms are present.16,17 Additional diagnostics
`depends on the clinical presentation and includes an ear–nose–
`throat consultation and gastroscopy/colonoscopy, based on up to
`60% asymptomatic infiltration of the bowel.29 As the results from
`upper and lower endoscopy generally have only a modest impact
`on therapeutic decisions, they are mandatory only in limited stage
`or symptomatic patients and as confirmation of complete
`response within clinical trials.
`International
`the classical
`After
`the diagnosis of an MCL,
`Prognostic Index is not suited to characterize its prognosis.30
`Instead, a new dedicated prognostic score, the MCL International
`Prognostic
`Index, allows
`to discriminate three prognostic
`subgroups: the low-risk group with a 5-year median overall
`survival (OS) of 60%, and the intermediate- and the high-risk
`group with a median OS of 51 and 29 months, respectively.24 This
`score takes into account four parameters (age, performance status,
`lactate dehydrogenase and leukocyte count), could be easily
`calculated (see www.european-mcl.net/en/clinical_mipi.php) but
`proved to be effective also in a simplified categorized version
`(Table 1).24,31 Although very effective in stratifying elderly patients,
`its usefulness is limited among youngest, as only a few patients
`under 65 years are classified in the high-risk group. Nevertheless,
`as MCL International Prognostic Index is highly applicable and has
`been validated in most independent series,31–33 its use should be
`routinely applied in the clinical practice.18
`
`IS THERE A PLACE FOR INITIAL WATCH AND WAIT?
`Whereas most patients with MCL follow an aggressive clinical
`course associated with rapid progression, only temporary
`to chemotherapy and a high recurrence rate,34
`responses
`a minority of MCL cases (10–15%) will have an indolent behavior
`and may not need therapy for several years; in fact, a delayed
`treatment did not have an impact on the OS in this lower-risk
`group.35 Most of these patients present with normal Eastern
`Cooperative Oncology Group performance status, normal serum
`
`Table 1.
`
`Simplified MIPI calculation
`
`Points
`
`Age (years)
`
`ECOG
`Performance
`Status
`
`LDH/ULN
`
`Leukocytes
`(  109/l)
`
`0
`1
`2
`3
`
`o50
`50–59
`60–69
`469
`
`0–1
`—
`2–4
`—
`
`o0.670
`0.670–0.999
`1.000–1.499
`41.499
`
`6700
`6700–9999
`10 000–14 999
`414 999
`
`Risk stratification
`
`0–3 Points
`4–5 Points
`6–11 Points
`
`Low risk
`Intermediate risk
`High risk
`
`Abbreviations: ECOG, Eastern Cooperative Oncology Group; LDH, lactate
`dehydrogenase; MIPI, Mantle Cell Lymphoma International Prognostic
`Index; ULN, upper limit of normal. For each prognostic factor, 0–3 points
`are given to each patient and points are summed up to define a category
`of risk.
`
`lactate dehydrogenase level, splenomegaly, bone marrow and
`blood involvement, but without adenopathy. Nevertheless, a
`reliable diagnosis of such an indolent subtype is difficult to
`confirm, and most series are mainly based on a retrospective
`diagnosis.
`Biomarker expression on tumor samples at diagnosis could give
`a more precise definition of these ‘Watch and Wait’ patients and
`are currently under evaluation: in fact, it would be worthwhile to
`recognize this patient subset upfront, especially in those frail
`elderly patients for whom a Watch and Wait approach is
`considered a serious option. Indolent MCLs predominantly show
`hypermutated immunoglobulin genes, noncomplex karyotypes
`and a peculiar gene expression profile (with a signature of
`13 genes underexpressed in comparison with typical MCL).36,37
`In contrast, the role of transcription factor SOX11 expression is still
`controversial and not standardized as diagnostic tool, thus should
`not be applied alone to predict prognosis.18,38,39
`is a valuable
`In such selected patients, Watch and Wait
`management approach and observation duration may vary from
`few months to more than a decade. These patients may undergo
`clinical evaluation every 3 months at least of the first 2 years,
`along with radiological evaluations in case of suspected progres-
`sion or symptoms.35 However, the clinical and biological studies
`on indolent MCL are still limited and further investigations are
`needed to clarify these issues.18
`
`HOW TO DEFINE THE GROUP OF PATIENTS THAT MAY RECEIVE
`INTENSIFIED THERAPY?
`Although no curative treatment is available for MCL so far, an
`intensive approach consisting of high-dose cytarabine and
`rituximab, followed by an autologous SCT, has been demonstrated
`to induce the highest response and survival rates in young and fit
`patients.2,3,5–7,18 However,
`as MCL mostly
`affects
`elderly
`individuals,
`the toxic effects of
`treatment
`regimens are of
`particular concern, as underlying comorbidities or decreased
`organ function may compromise the eligibility for cytotoxic
`chemotherapy. Given that a good performance status and the
`absence of comorbidities are required for any intensified
`treatment aiming at complete remission (CR), a common
`approach consists of an upfront stratification of patients into
`younger (fit or unfit), elderly (fit or unfit) and frail categories. The
`Comprehensive Geriatric Assessment was demonstrated as a
`reliable tool
`for estimating life expectancy and tolerance of
`treatment to objectively identify patients eligible for a high-dose
`chemotherapy targeting at long-term control of the disease or
`patients for less intensive approaches only.40,41 Thus, considering
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`the non-negligible toxicity of an autologous SCT program (even
`more severe if applied after
`intensive induction such as
`HyperCVAD4,42,43), we believe that high-dose therapy can be
`safely delivered only in younger and fit patients, usually o65
`years but even up to 70 years for selected cases.44 Therefore, a
`careful
`identification of patients eligible to autologous SCT is
`essential.
`Moreover, as already stated, an early identification of the less
`common indolent variants of MCL would be valuable, as for this
`category of patients an intensive treatment may be spared.35
`
`WHICH IS THE BEST TREATMENT OPTION IN THE GROUP OF
`YOUNGER FIT PATIENTS?
`The major clinical trials of the last decade focused on improve-
`ment of the front-line treatment of MCL, leading to the definition
`of a ‘gold standard’ therapy for young and fit patients consisting
`of high-dose cytarabine and rituximab, followed by an autologous
`SCT.2,3,5–7,18,45–47 First of all
`in CHOP-responding patients a
`consolidation with total body
`irradiation (TBI), high-dose
`cyclophosphamide and autologous SCT resulted in longer
`median progression-free survival
`(PFS 39 versus 17 months,
`P¼ 0.011)
`compared with a maintenance
`therapy with
`interferon-alpha.
`In a subsequent meta-analysis, OS was also
`superior in the autologous SCT arm after a longer follow-up.48
`Moreover, several phase II studies suggested that incorporation of
`high-dose cytarabine and rituximab to the induction regimen
`before autologous SCT leads to an increase in CR and PFS
`rates.2,5,6,49 Finally, the recent European MCL Network younger
`phase III trial confirmed that an alternating induction of three
`courses of R-CHOP and R-DHAP followed by a high-dose
`cytarabine-containing myeloablative consolidation supported by
`autologous SCT achieved a significantly improved median time to
`treatment failure (TTF 88 versus 46 months, P ¼ 0.038) and median
`OS (not reached versus 83 months, P¼ 0.045) in comparison with
`an R-CHOP induction followed by autologous SCT, with a
`comparable number of treatment-related deaths in both arms.7
`Impact of cytarabine on the TTF rate was closely linked to the
`quality of molecular remission, which was increased from 32 to
`73% after induction.50 Finally, for patients with compromised renal
`function or elderly, oxaliplatin could be a valuable alternative to
`cisplatin, considering its minor renal and also neural toxicity
`(‘DHAOx’ schedule instead of ‘DHAP’).51
`Alternative effective immunochemotherapy induction regimens
`have been also explored outside of the context of an autologous
`SCT schedule. Rituximab-bendamustine (BR), either alone or in
`combination with
`cytarabine
`(R-BAC),
`showed
`excellent
`responses and survival
`rates, both in patients at diagnosis
`and relapsed MCL.11,52,53 A randomized phase II trial is currently
`being performed by the Southwest Oncology Group, comparing
`BR versus R-HyperCVAD as upfront induction therapy before
`autologous SCT consolidation in younger patients (NCT01412879).
`However,
`the latter
`regimen seems to be more toxic and
`peripheral blood stem cell collection might be impaired.
`The applied conditioning regimens before autologous SCT are
`similar to those used in other lymphoma subtypes, mainly BEAM
`or TBI-based.3,5,6,47 Owing to the radiosensitivity of MCL cell
`lines, the role of TBI remains an important question. A small
`retrospective study suggested that TBI resulted in prolonged
`disease-free survival and OS compared with BEAM;54 however, this
`observation has not been confirmed by a recent large survey.55
`A retrospective EBMT register study on more than 400 patients
`showed that TBI might benefit only for patients in partial response
`but not in CR after induction, with no significant improvement of
`OS.56 Similarly in a comparative retrospective study including
`Nordic group, HOVON and European MCL Network protocols, TBI
`seems also to be beneficial only in the group of patients in partial
`response but not in CR.57 Taken together, these studies suggest
`
`2119
`
`The management of MCL patients
`M Dreyling et al
`
`in first CR but
`is not mandatory in patients
`that TBI
`should be strongly considered in patients in partial response.18
`In contrast, the addition of rituximab during conditioning, as well
`as
`the benefit of
`the radioimmunotherapy (RIT), has not
`been demonstrated in interstudy comparisons.2,5,58,59 Finally,
`integration of bendamustine into the BEAM regimen instead of
`carmustine (BeEAM) is currently explored in MCL.60
`Besides autologous SCT-based regimens, another dose-intensi-
`fied approach (R-HyperCVAD) with alternating R-CHOP-like and
`high-dose methotrexate/cytarabine cycles also achieved very high
`response and survival rates in a mono-center phase II study
`(overall response rate, ORR 97%, CR 87%, median TTF 4.6 years
`and 8-years OS 68%, among patients o65 years).4 Unfortunately,
`these excellent results could not be replicated in multicenter
`approaches42,43 and were never tested in a randomized, phase III
`trial. Moreover, this regimen is hampered by a significant therapy-
`associated toxicity, which led to a high dropout rate in the
`multicenter trial (63%). As yet no direct comparison has been
`performed between R-HyperCVAD and an autologous SCT-based
`approach: the only published report is a small retrospective
`analysis not powered to lead to reliable conclusions.61 Finally, the
`recent combination of bortezomib to modified R-HyperCVAD has
`not yet demonstrated a clear superiority over
`the classical
`regimen.62
`As no plateau in PFS curves has been observed even after such
`optimized treatments, and the achievement of molecular remis-
`sion seems to be critical
`in MCL, the question of maintenance
`therapy has to be discussed in the setting of autologous SCT.8,63
`Although rituximab maintenance should be considered the new
`standard for elderly patients after R-CHOP induction,10 these data
`still need to be confirmed for young patients in the context of
`intensive chemotherapy and autologous SCT. This question is
`currently addressed in the randomized Lyma trial (NCT00921414)
`and results are eagerly awaited. Thus, so far a maintenance
`therapy cannot be uniformly recommended after autologous
`SCT.18 In this regards a recent phase II
`trial evaluating RIT
`consolidation with yttrium-90-ibritumomab tiuxetan (90Y-IT)
`afterR-Hyper-CVAD resulted in unacceptable toxicity, advising
`against its use after high-dose chemotherapy.64
`A rational algorithm for first-line treatment of young MCL
`patients is presented in Figure 1. Table 2A displays a list of the
`actively recruiting upfront clinical trials, whereas Table 3 describes
`the most important published clinical studies investigating first-
`line high-dose therapy in MCL.
`
`IS ALLOGENEIC SCT A THERAPEUTIC OPTION IN FIRST LINE?
`The approach of allogeneic SCT in MCL has emerged in the late
`1990s, as highly toxic. Myeloablative allogeneic SCT could
`nevertheless achieve cure in some relapsed/refractory MCL
`patients.65 Reduced-intensity conditioning regimens (RIC-allo),
`entailing lower toxicity and reduced transplant-related mortality,
`provided better results, making allogeneic SCT an option for a
`larger MCL population.58 Although most authors agree that RIC-
`allo may be curative for some MCL patients, the paucity of
`literature does not allow any strong recommendations in favor of
`allogeneic SCT in first-line treatment of MCL. Most studies are
`mono-center reports or registry-based retrospective analysis and
`is available.58,65–69 In none of these
`only one prospective trial
`studies, allogeneic SCT has been proved to be superior
`to
`autologous SCT. Moreover, the long-term disease control after
`rituximab and cytarabine-supplemented autologous SCT schemes
`along with the recent impressive efficacy and safety data coming
`targeting the B-cell-receptor pathway70
`from drugs
`are
`challenging the role of the more toxic allogeneic approaches.
`In conclusion, allogeneic SCT cannot be recommended upfront in
`MCL but may be considered for fit relapsed/refractory patients
`after an appropriate first-line treatment.18 Whether an allogeneic
`
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`YOUNGER
`
`Unfit
`
`ELDERLY
`
`Fit
`
`High dose
`therapy
`
`R-CHOP/R-DHAP
`+
`
`myeloablative regimen
`
`+
`ASCT
`
`Fit
`
`Unfit
`
`Frail
`
`Conventional
`immuno-CT
`+ R maintenance
`
`Less toxic
`immuno-CT
`+ R maintenance
`
`R-CHOP
`R-BAC
`BR
`
`BR
`R-CVP
`R-Chl
`
`Mild CT,
`mainly per
`os +/- R
`
`R-Chl
`PEP-C
`BR
`
`INDOLENT
`MCL
`
`W&W until
`progression
`
`then therapy like conventional MCL
`
`Figure 1. Therapeutic algorithm for first-line MCL patients. R, rituximab; CHOP, cyclophosphamide-doxorubicin-vincristine-prednisone; DHAP,
`dexamethasone-cytarabine-cisplatin; ASCT, autologous stem cell
`transplantation; CT, chemotherapy; BAC, bendamustine-cytarabine;
`B, bendamustine; CVP, cyclophosphamide-vincristine-prednisone; Chl, chlorambucil; PEP-C, metronomic prednisone-etoposide-
`procarbazine-cyclophosphamide; W&W, watch and wait.
`
`SCT consolidation in first CR could confer a survival advantage for
`very high-risk MCL patients (for example, blastoid variant, elevated
`Ki67, TP53 mutations) is an intriguing hypothesis that still needs to
`be addressed in prospective trials and in the context of new
`targeted therapies.
`
`WHICH ARE THE PREFERABLE TREATMENT OPTIONS IN
`ELDERLY PATIENTS OR UNFIT TO RECEIVE HIGH-DOSE
`CHEMOTHERAPY?
`The standard first-line therapy for elderly MCL patients recently
`established consists of R-CHOP immunochemotherapy, followed
`by rituximab maintenance: such an approach resulted in a
`considerable improvement in response rates, MRD clearance and
`OS for patients not eligible to high-dose regimens.10
`Both anthracycline (R-CHOP-like) and fludarabine-based (R-FC
`like)
`immunochemotherapy schedules already demonstrated
`efficacy for elderly fit patients with MCL.49,71,72 On this basis, the
`European MCL Network
`conducted a
`large international
`phase III
`trial comparing R-CHOP with R-FC (followed by a
`second randomization between maintenance phase with
`patients.10
`interferon-alpha
`versus
`rituximab)
`for
`elderly
`Unexpectedly,
`the outcome of
`the fludarabine-containing
`regimen was disappointing: in fact, although CR rates after R-FC
`and R-CHOP were similar (40% versus 34%, P¼ 0.10), progressive
`disease was more frequent during R-FC (14% versus 5%). The
`median OS was also significantly inferior afterR-FC (4-year survival
`rate, 47% versus 62%, P ¼ 0.005) and more patients in the
`fludarabine arm died due to relapsed lymphoma or infections. This
`inferior outcome is mostly due to a more frequent, long-lasting
`hematologic grade III–IV toxicity after R-FC. Thus, the use of
`upfront R-FC in elderly MCL patients is discouraged.18 In contrast,
`rituximab maintenance reduced the risk of progression or death
`by 45% (58% patients in remission after 4 years versus 29% with
`interferon-alpha, P ¼ 0.01), almost doubled duration of remission
`and significantly improved OS among patients responsive to
`
`R-CHOP.10 In addition, promising data came also from two
`small series of elderly patients receiving maintenance rituximab
`after a reduced R-HyperCVAD±bortezomib.62,73 Thus, rituximab
`maintenance (one dose every 2 months until progression) should
`be offered to all patients
`responding to R-chemotherapy,
`especially R-CHOP induction.18
`On the basis of
`the excellent performance of high-dose
`cytarabine containing induction arm of
`the European MCL
`Network Younger trial,7 the current MCL R2 Elderly trial (EudraCT
`Number 2012-002542-20)
`randomizes patients to a standard
`induction with R-CHOP versus an alternating R-CHOP/R-HAD
`(rituximab,
`intermediate age-adjusted dose cytarabine and
`dexamethasone) arm.
`Bendamustine combinations represent alternative attractive
`upfront
`regimens
`for elderly MCL patients. Notably,
`in a
`randomized first-line trial with 94 MCL patients, the BR schedule
`was at least as effective as R-CHOP (median PFS 35 versus 22
`months, P ¼ 0.004) and with fewer toxic effects (lower neutrope-
`nia,
`infections, polyneuropathy and alopecia), but OS was
`comparable in both study arms.53 Furthermore, the promising
`activity of a new regimen combining rituximab, bendamustine
`and cytarabine (R-BAC) has been recently confirmed in primary
`and relapsed MCL (90% ORR with 83% CR on the total series of 40
`patients), resulting in an excellent 2-year PFS of 70% for relapsed
`and 95% for first-line patients, respectively.11 Currently, a phase II
`study of R-BAC accruing untreated elderly ‘fit’
`(according to
`Comprehensive Geriatric Assessment) MCL patients is ongoing
`(EudraCT Number: 2011-005739-23).
`Another candidate for combination with immunochemotherapy
`is bortezomib. Trials integrating the proteasome inhibitor with
`R-CHOP or into a doxorubicin, dexamethasone, chlorambucil and
`rituximab regimen (RiPADþ C) showed promising results, although
`safety issues should be still more extensively assessed.74,75 Two
`clinical trials are currently ongoing, evaluating the combination of
`BR plus bortezomib or lenalidomide in first-line treatment of MCL
`patients (NCT01415752 and NCT00963534, respectively).
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`Table 2A. Actively recruiting clinical trials for MCL patients (first-line)
`
`NCT code
`
`Study features
`
`Estimated
`enrollment
`(patients)
`
`Estimated
`primary
`completion
`date
`(month/years)
`
`The management of MCL patients
`M Dreyling et al
`
`2121
`
`Therapeutic regimen
`
`Sponsor
`
`Location countries
`
`Phase III
`00209222
`
`Phase III, randomized younger
`
`01865110
`
`Phase III, randomized elderly
`
`EudraCT:
`2009 01280725
`
`Phase III, randomized younger
`
`01776840
`
`Phase III, randomized elderly
`
`Phase II
`01412879
`
`01415752
`
`01662050
`00963534
`
`01457144
`00477412
`
`00114738
`01472562
`
`Phase II, randomized younger
`
`Phase II, randomized elderly
`
`Phase II, single arm elderly
`Phase II, single arm elderly
`
`Phase II, single arm elderly
`Phase II, single arm both
`
`Phase II, single arm both
`Phase II, single arm both
`
`360
`
`633
`
`250
`
`520
`
`180
`
`332
`
`57
`60
`
`76
`110
`
`80
`31
`
`12/2014
`
`06/2021
`
`01/2015
`
`03/2018
`
`12/2016
`
`04/2015
`
`01/2014
`09/2014
`
`04/2015
`04/2015
`
`06/2016
`12/2014
`
`R-CHOP þ TBI þ ASCT
`versus R-CHOP/R-DHAP þ
`HD-araC þ ASCT
`R-CHOP versus R-CHOP/
`R-HAD þ maintenance
`rituximab versus rituximab/
`lenalidomide
`R-CHOP þ HD-
`araC þ ASCT±lenalidomide
`maintenance
`BR versus BR þ ibrutinib
`
`R-HyperCVAD þ ASCT versus
`BRþ ASCT
`BR±bortezomib þ rituximab
`maintenance±lenalidomide
`R-BAC
`BRþ lenalidomide
`
`RiBVD
`R-HyperCVADþ bortezomib
`
`R-EPOCH þ bortezomib
`Rituximab þ lenalidomide
`
`GLSG and
`EuMCLNeT
`
`LYSARC and
`EuMCLNeT
`
`France, Germany, Poland
`
`France, Belgium,
`Germany, Italy,
`Netherlands, Portugal
`
`FIL
`
`Italy, Portugal
`
`Worldwide
`
`Janssen
`Research and
`Development
`LLC
`
`USA
`
`USA
`
`Italy
`Denmark, Finland
`Norway, Sweden
`France
`USA
`
`USA
`USA
`
`SWOG
`
`ECOG
`
`FIL
`NLG
`
`GOELAMS
`M.D.
`Anderson
`Cancer Center
`NCI
`Weill Medical
`College of
`Cornell
`University
`
`Table 2B. Actively recruiting clinical trials for MCL patients (relapsed)
`
`NCT code
`
`Study features
`
`Estimated
`enrollment
`(patients)
`
`Estimated primary
`completion date
`(month/years)
`
`Therapeutic regimen
`
`Sponsor
`
`Location
`countries
`
`France,
`Germany
`Wordwide
`
`Phase III
`01449344
`
`Phase III, randomized relapse
`
`01646021
`
`Phase III, randomized relapse
`
`Phase II
`01078142
`01389427
`
`01838434
`
`Phase I/II, single arm relapse
`Phase I/II, single group
`assignment relapse
`Phase I/II, randomized both
`
`00513955
`
`Phase II, randomized both
`
`01439750
`
`Phase I/II, single arm elderly
`
`01880567
`
`Phase II, single arm both
`
`01497275
`
`Phase II, single arm both
`
`01652144
`
`Phase II, single arm both
`
`01695941
`01504776
`
`Phase II, single arm both
`Phase II, single arm both
`
`175
`
`280
`
`72
`63
`
`99
`
`90
`
`50
`
`50
`
`35
`
`30
`
`24
`24
`
`09/2016
`
`R-HAD versus R-HADB
`
`EuMCLNet
`
`08/2014
`
`Ibrutinib versus Temsirolimus
`
`Janssen Research
`and Development
`LLC
`
`03/2014
`06/2013
`
`08/2017
`
`08/2014
`
`10/2014
`
`12/2019
`
`03/2015
`
`08/2014
`
`08/2015
`04/2014
`
`BERT
`R.CHOP or R-FC or
`R-HAD þ Temsilorimus
`Rituximab and
`Lenalidomide±idelalisib
`CHOP±bortezomib
`Rituximab þ bortezomibþ cladribine
`Rituximab þ ibrutinib
`Rituximab þ 90Y-ibritumumab
`tiutexan þ bortezomib
`AT7519M
`Alisertib þ bortezomib þ rituximab
`Panobinostat þ bortezomib
`
`GLSG and EuMCLNet
`GOELAMS
`
`Germany
`France
`
`Alliance for Clinical
`Trials in Oncology
`Plymouth Hospitals
`NHS Trust
`Milton S. Hershey
`Medical Center
`M.D. Anderson
`Cancer Center
`Duke University
`
`NCIC Clinical Trials
`Group
`NCI
`Anand Jillella
`
`USA
`
`UK
`
`USA
`
`USA
`
`USA
`
`Canada
`
`USA
`USA
`
`rituximab-bendamustine; CHOP,
`transplantation; B, bendamustine; BAC, bendamustine-cytarabine; BR,
`Abbreviations: ASCT, autologous stem cell
`cyclophosphamide-doxorubicin-vincristine-prednisone; DHAP, dexamethasone-cytarabine-cisplatin; ECOG, Eastern Cooperative Oncology Group; EPOCH,
`ethoposide-prednisone-vincristine-cyclophosphamide-doxorubicin; EuMCLNet, European MCL Network; FIL, Fondazione Italiana Linfomi; GLSG,German Low-
`Grade Lymphoma Study Group; GOELAMS, Groupe Ouest Est d’Etude des Leuce´ mies et Autres Maladies du Sang; HAD, cytarabine-dexamethasone; HD-araC,
`high-dose cytarabine; HyperCVAD, hyperfractionated cyclophosphamide-vincristine-doxorubicin-dexamethasone þ methotrexate-cytarabine; LYSARC, The
`Lymphoma Academic Research Organization; MCL, mantle cell lymphoma; NCI, National Cancer Institute; NCIC, National Cancer Institute of Canada; NCT,
`national clinical trial; NLG, Nordic Lymphoma Group; R, rituximab; RiBVD, rituximab-bendamustine-bortezomib-dexamethasone; SWOG, South West Ongology
`Group; TBI, total body irradiation. Details of the studies can be found at the internet site: http://www.clinicaltrials.gov.
`
`& 2014 Macmillan Publishers Limited
`
`Leukemia (2014) 2117 – 2130
`
`SANDOZ INC.
`
`IPR2023-00478
`
`Ex. 1015, p. 5 of 14
`
`

`

`The management of MCL patients
`M Dreyling et al
`
`2122
`
`Table 3. Published clinical studies investigating first-line dose-intensified therapy in MCL
`
`Author
`
`Study features
`
`Evaluable
`patients
`
`Therapeutic regimen
`
`ORR% (CR%)
`
`Median
`PFS (years)
`
`Median OS (years)
`
`Dropout rate
`
`TRM
`
`Secondary
`tumor rate
`
`ASCT based regimens
`Dreyling et al.3
`
`Hermine et al.7
`
`Phase III,
`randomized
`
`Phase III,
`randomized
`
`Damon et al.45
`
`Phase II
`
`Van’t Veer et al.46
`
`Phase II
`
`Geisler et al.5
`
`Phase II
`
`122
`
`455
`
`77
`
`87
`
`160
`
`98 (81) versus
`99 (37)
`
`3.3 versus
`1.4
`
`98 (63) versus
`99 (61)
`
`3.8 versus
`7.3
`
`88 (69)
`
`70 (64)
`
`96 (54)
`
`NR (83%
`3-y OS) versus NR
`(77% 3-y OS)
`6.8 versus NR
`
`NR (64% 5-y OS)
`
`NR (66% 4-y OS)
`
`NR (64% 10-y OS)
`
`13% versus na
`
`5% versus
`0%
`
`na
`
`13%
`
`30%
`
`9%
`
`4%
`
`3%
`
`5%
`
`5%
`
`5%
`
`na
`
`na
`
`na
`
`4%
`
`R-CHOPþ TBIþ ASCT versus
`R-CHOPþ TBIþ interferon-a
`R-CHOPþ TBIþ ASCT versus
`R-CHOP/R-DHAPþ HD-
`araCþ ASCT
`R-CHOPþ methotrexateþ
`HD-araC/etoposide þ ASCT
`R-CHOPþ HD-araCþ ASCT
`R-Maxi-CHOPþ HD-
`araCþ ASCT
`R-CHOP/R-DHAPþ HD-
`araCþ ASCT
`Different ASCT-based
`schedules
`
`R-HyperCVAD
`
`R-HyperCVAD
`
`R-HyperCVAD
`
`60
`
`396
`
`97
`
`60
`
`49
`
`NR (56%
`5-y PFS)
`NR (36%
`4-y PFS)
`7.4
`
`100 (96)
`
`83 (77)
`
`97 (87)
`
`83 (72)
`
`86 (55)
`
`6.9
`
`NR (75% 5-y OS)
`
`NR (67%
`3-y PFS)
`
`NR (83% 3-y OS)
`
`4.6
`
`NR (64% 10-y OS)
`
`NR (73%
`5-y PFS)
`4.8
`
`NR (61% 5-y OS)
`
`6.8
`
`18%
`
`na