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`Expert Review of
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`Expert Review ofAnticancer Therapyis the definitive journal for researchers and
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`x‘flAblin PU. Innopharma, USA - Atkins MB, Beth Israel Deaconos Medical Center. USA 0 Bernier J, Ospedale san Giovanni, Swrtzerland - Blackledge GRP.
`/ Astra Zeneca, UK I Brandes AA, Azienda OspedaIe-Universita, Italy ° Cassidy I, University of Aberdeen, UK 0 Dalgleish AG, St George's Hospital. UK ' Ualton
`/ WS, Lee Mottiti Cancer Center and Research Institute, USA - Dhingra K. Hoffmann-La Roche. USA . Edelman MJ. Greenebaurn CancerCenterrUSA - Ettinger
`05. John Hopkins Oncology Center, USA 0 Giaccone 6, Free University of Amsterdam, The Netherlands - Gibbs J, Merck, USA 0 Hall AG, UniverSIty of Newcastle,
`UK 0 Hivama E. Hiroshima University, Japan - Kaspers GJL, University HospitalVrlJe UniverSiteit, The Netherlands 0 Kramer RA, Bristol-Myers Squibb, USA '
`Lobell R, Pfizer. USA - Mendelsohn J, MD Anderson Cancer Centre, USA ' Posner MR. Dana~Farber Cancer Institute, USA - Przepiorka D, Baylor College of
`Medicine. USA - Reed E, West Virginia Health Sciences Center, USA 0 Saijo M, National CancerCenter Hospital, Japan . Shin DM. UniverSIty of'Pittsburgh
`Cancer Institute, USA 0 Van Oosterom A. University Hospital Gasthuistrg, Belgium 0 Vermorken JB, Antwerp University Hospital, Belgium D V0igtl'l .
`Melanoma Research Project, Germany - Waxman S, Mount Sinai School of Medicine. USA - White CA, IDEC Pharmaceuticals, San Diego, USA 0 Wemer 1M,
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` Expert Review of
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`465
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`LEUKEMIA & LYMPHOMA
`Role of allogenelc stem cell
`transplantatlon ln multlple myeloma
`KJ Thomson & Ks Peggs
`
`Proteasome lnhlbltlon as a therapeutlc
`strategy for hematologlc mollgnancles
`CS MIts/ades, N Mltslodes, THldeshlma,
`PG Richardson & KC Anderson
`
`Treatment of mantle cell lymphoma:
`targeting the mlcroenvlronment
`J Drach, S Se/dl & H Kaufmann
`
`Treatment of hemotologlc
`mallgnancles and solid tumors by
`lnhlbltlng lGF receptor slgnallng
`CS Mltslades & N Mltslades
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`is material wascap'ied
`© 2005 Future Drugs Lfijl
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`Anticancer Therapy
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`Edltorlal
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`The ODAC Chronicles: Part 5. Prostate
`cancer endpoints
`AJ Gr/Ilo—Lépez
`News In Brlel‘
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`Meetlng Report
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`Drug Profiles
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`Atrasentan: a novel and ratlonally
`deslgned therapeutlc alternative In
`the management of cancer
`A Jlmeno & M Carduccl
`
`Gemcltablne ln metastatlc
`breast cancer
`V Helnemann
`
`Fulvestrant In the treatment of
`postmenopausal women wlth
`advanced breast cancer
`W Grad/shar
`
`Revlews
`
`June 2005
`
`Expert Rev Ant/cancer Ther. 5(3)
`
`501
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`515
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`523
`
`537
`
`549
`
`567
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`569
`
`572
`
`HM!) & NH .‘K CANCL I"
`Head and neck squamous cell
`carclnoma: optlmlzlng the
`therapeutlc Index
`0/ Rosenthal & AI Blanco
`
`lntenslty-modulated radlatlon therapy
`for head and neck cancer
`WW Chou, DR Purl & NV Lee
`6/ MM, ONO >l our
`T-cell receptor—Ilke antibodles: novel
`reagents for cllnlcal cancer
`Immunology and lmmunotherapy
`I? Noy, M Epel, M Haus~Cohen,
`E Klechevsky O Makler, YMIchae/I,
`e Denkberg & VRe/l‘er
`Dendrltlc cell-derlved exosomes ln
`cancer lmmunotherapy: exploltlng
`nature’s antlgen dellvery pathway
`A Delcayre, H Shu & J-B Le Pecq
`Chemopreventlon of lung cancer:
`concepts and strategles
`V Cohen & FR Khurt
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`Glossary
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`lndlces
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`Acknowledgements
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`Calendar
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`ISSN 14737140
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`ApoteX EX. 1003, p. 3
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`Apotex Ex. 1003, p. 3
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`

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`Commissioning Editor
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`

`

`Review
`
`Treatment of mantle cell
`lymphoma: targeting the
`microenvironment
`Johannes Oracht, Sonja Seidl and Hannes Kaufmann
`
`ManHe celilymphama Is a disHnct entity among the non-Hodgkin's lymphomas
`characterlzed by a speclftc chromosomal translocaHon, the t(11 ;14)(q13;q32),
`overexpresslon of cyclin-O 1 and frequent disease manifestoHons at extranodal sites.
`ManHe celilymphomo remains difficult to treot and belongs to the lymphomas with the
`poorest long-term outcome. Recent advances In our understanding of lymphoma biology
`suggest that both alterations of the lymphoma cells themselves and interacHons with the
`microenvironment are Important for the growth and survival of the malignant 8-cell clone.
`This novel approach to therapy Is being exploited by evaluaHng drugs such as bortezomlb
`and thalidomide that target interactions between tumor cells and cells of the
`microenvironment. Thus, with the use of noveltherapeuHc IntervenHons, It Is hoped that
`clinicians will be able to Improve the outcome of poHents with manHe celilymphomo.
`
`Expm IlL •. Anticanc" Th" 5(3). 477-485 (2005)
`
`ManHe cell lymphoma os a dlsHnct
`Iymphomo entily
`Mande cell
`lymphoma (MCl) represents a
`clistinct entity among
`the non-Hodgkin's
`lymphomas, wlUch has been recognized by the
`recent consensus conferences on the classification
`of lymphomas III. Several features are unique to
`Mel, including the typical morphologic appear(cid:173)
`ance, a characteristic immunophenorypic pattern
`(positivity for the B-ceU antigens C019, C020,
`C022 and pan-T cell antigen C05, bur lack of
`C023 expression), and the specific chromosomal
`translocation r(il ;14)(qI3;q32) with consecutive
`overexpression of cyclin-Ol. MCl represents
`approximately 6% of all non-Hodgkin's lympho(cid:173)
`mas and mainly affects elderly
`inclividuals
`(median age at cliagnosis, 65 years), with an
`approximately 2: I male to female predominance.
`
`Unique clinical features of MCL
`Patients with MeL usually present at an
`advanced stage of the clisease with generalized
`(71-90% of cases) and
`lymphadenopathy
`frequent
`involvemem of the bone marrow
`(53-90%) and other extranodal
`sites,
`in
`particular the gastrointestinal tract (an almost
`
`universal fincling at cliagnosis). Although Mel
`was initially regarded as belonging to the lym(cid:173)
`phomas with an indolent cowse, recent clinical
`observations suggest quite the contrary. Retro(cid:173)
`spective analyses of patients enroUed in indolent
`lymphoma trials of the Southwest Oncology
`Group (SWOG) have inclicated that the median
`progression-ftee survival (PFS) following induc(cid:173)
`in
`tion
`tream1cnt was only
`the order of
`20 months and meclian overall survival (OS) was
`only 3-4 years, without evidence of cure even in
`a fraction of patients (i O-year survival rate of
`only 8%) 12]. Results of various other clinical tri(cid:173)
`als were remarkably consistent with these obser(cid:173)
`vations, suggesting that MCL has a rather aggres(cid:173)
`sive clinical course, and that MCL belongs to the
`lymphomas with the worst prognosis. MCl has
`therefore been
`identified as an area where
`innovative
`forms
`of
`treaanent
`are
`urgently required .
`
`Curren' treatment ot mantle celf lymphoma
`Conventional chematherapy
`In the absence of an established standard treat(cid:173)
`ment for MCl, combination chemotherapy
`accorcling
`the
`cyclophosphamide,
`to
`
`10.1586114737140.5.3.477
`
`© 2005 Future Drugs Ltd
`
`ISSN 1473·7140
`
`477
`
`~for-J. rMM.t
`D.,. -:'c·lkwl.
`MMiaII~ofVi<-.
`ofo-lriD
`C/JJdNI
`\IIIWrVp: Gwrt# /8-24
`A-l~ v ........ AmIM
`TtL +43 UOIOO 5457
`IF
`Ji0400#61
`~..e.",
`
`KImrOItDs:
`bot,,,,","b, miaocnvironmmt.
`rinalmab. .""ma1
`edit, rIIalidomide
`
`Apotex Ex. 1003, p. 6
`
`

`

`Drach, Seidl & Kaufmann
`
`doxorubicin, vincristine and prednisone (CHOP) regimen was
`widely used as the initial treatment. However, the rates of
`complete responses (CR) were consistently lower in MCL com(cid:173)
`pared with other lymphoma entities, ranging only between 13
`and 51 % in the reported series [3]. Some controversy remains con(cid:173)
`cerning the role of anthracyclines in MCL. In one randomized
`clinical trial comparing chemotherapy with cyclophosphamide,
`oncovin and prednisone (COP) versus CHOP, there was lack of
`statistically significant differences with regard to response rates,
`median relapse-free survival (10 vs. 7 months) and median OS
`(32 vs. 37 months) [4] . In another small randomized study of pre(cid:173)
`viously untreated MCL patients, intensive treatment (a CHOP(cid:173)
`like regimen and a modified prednisone, methotrexate, doxoru(cid:173)
`bicin, cyclophosphamide. etoposide. mllstine, vincristine and pro(cid:173)
`carbazine [ProMACE-MOPPj regimen) was superior to COP
`with regard to response rates, but the median OS was 45 months
`in all treatment arms. In this study, there was also no benefit from
`maintenance therapy with interferon-a [5]. The study by Zucca
`and colleagues showed a superiority of anthracycline-containing
`regimens with regard to CR rate, failure-free survival and OS in
`MCL patients considered
`to be
`in a more
`favorable
`prognostic group [6].
`in
`Fludarabine monotherapy has only moderate efficacy
`patients with MCL [7]. In relatively small Phase II studies,
`reported overall response rates were generally low (40-50%; CR
`rate of 20-30%), and remission periods tended to be short
`(4-8 months). In patients with relapsed or refractoty MCL, the
`response rates to single-agent fludarabine are even less favorable. It
`is therefore recommended to use fludarabine monotherapy only
`in the setting of pretreated MCL patients when other therapeutic
`options are not available. Fludarabine-containing chemotherapy
`regimens that include antracyclines or alkylating agents are effi(cid:173)
`cient as a first-line ueaunent in MeL, bur it remains unclear
`whether or not this will lead to improved survival rates of MCL
`patients (reviewed in [7]). A promising approach is the combina(cid:173)
`tion of fludarabine, cyclophosphamide and mitoxantrone with
`anti-CD20 immunotherapy (riruximab) as described below.
`
`High-dose chemolherapy
`Due
`to
`the beneficial effect of high-dose chemotherapy
`supported by autologous stem cell transplantation in aggressive
`non-Hodgkin's lymphomas, similar strategies have also been eval(cid:173)
`uated in MCL. However, early studies exarning the role of high(cid:173)
`dose therapy and autologous stem cell transplantation for MCL
`have yielded discouraging results (reviewed in [8]) . More recently,
`new evidence has emerged that autologous transplantation may
`be of benefit in MCL if used earlier during the course of the dis(cid:173)
`ease, particularly in first CR. For example, a retrospective analysis
`of the European Blood and Marrow Transplantation regiStries
`yielded survival data on 195 MCL patients [9] ; 2- and 5-year OS
`was 76 and 50%, respectively, with 2- and 5-year PFS of 55 and
`33%, respectively. However, the subgroup of patients trans(cid:173)
`planted in first CR were significantly less likely to die of disease
`than patients transplanted with chemotherapy-sensitive disease
`later in the course of MCL. Results from several other trials have
`
`confirmed these observations [10,1 1]. Of note, a prospective rand(cid:173)
`omized trial performed by the German Lymphoma Study Group
`comparing interferon-a maintenance therapy with high-dose
`chemotherapy plus autologous stem cell transplantation as con(cid:173)
`solidation after CHOP-induction chemotherapy provides evi(cid:173)
`dence for prolonged PFS in the high-dose therapy arm (17 vs.
`39 months; p = 0.0108) [12]. Thus, patients consolidated in first
`CR by autologous transplantation may have a better outcome
`than patients treated by high-dose therapy la[Or in the course of
`tI,eir disease, but the development of more effective induction
`regimens is of particular importance. This is supported by studies
`demonsttating persistence of lymphoma cells in autografts, even
`after extensive antibody ex vivo purging [13].
`The Hyper-CVAD regimen (fractionated cyclophosphamide,
`doxorubicin, vincristine and dexamethasone), with and without
`stem cell transplantation, was developed and evaluated at the
`MD Anderson Cancer Center (TX, USA) [14J . In one of the first
`reports, Hyper-CVAD alternating with high-dose Ara-C and
`methotrexate (A-M) induced an overall response rate of 94%
`(CR, 38%; partial response [PRJ, 56%). Untreated patients with
`MCL treated by Hyper-CVAD/A-M had a better 3-year event(cid:173)
`free survival (EFS) rate compared with a historic control group
`that received a CHOP-like regimen (72 vs. 28%), as well as a
`superior overall response rate (92 vs. 56%). More recently, rituxi(cid:173)
`mab has been added to the Hyper-CV ADI A-M regimen, which
`eliminated the need for stem cell transplantation [IS]. However, it
`needs to be considered that patients with the greatest benefit
`from
`this treatment program were those with a low P2-
`microglobulin and/or few features of adverse prognosis (e.g.,
`bulky disease, B symptoms, Stage IIIIN disease or elevated lac(cid:173)
`tate dehydrogenase) . Also, toxicity remains an issue, particularly
`in patients beyond the age of 65 years. Further srudy is clearly
`required prior to conclud ing that Hyper-CVAD may be a
`superior induction regimen for MCL.
`
`Antibody therapy
`Riluximab alone & in combination with chemotherapy in Mel
`The development of the anti-CD20 antibody rituximab has
`greatly enhanced the therapeutic armamentarium against B-cell
`non-Hodgkin's lymphomas. Also, in MCL, CD20 represents
`an attractive target since it is almost universally expressed by
`MCL cells. Several clinical trials have documented the activity
`of rituximab as a single agent in M CL, with an approximate
`30% response rate in both chemotherapy-naive and -pretreated
`patients; the median response duration was in the range of
`between 6 and 12 months.
`Consequently, riruximab has been added to different chemo(cid:173)
`therapy regimens, which was shown to improve response catc and
`-
`in the setting of relapsed disease - even OS in patients with
`MCL. This has recently been demonstrated by the German Low
`Grade Lymphoma Study Group reporting their results of a
`Phase III study comparing fludarabine, cyclophosphamide and
`mitoxantrone (FCM) alone versus FCM plus rituximab (R(cid:173)
`FCM) in patients with relapsed follicular lymphoma and MCL
`[16] . Analysis of the MCL patient population revealed an overall
`
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`Treatment of mantle cell lymphoma
`
`response rate of 62% with R-FCM versus 43% with FCM
`(p = O.IS) and a CR rate of 33% with R-FCM versus 0% with
`(p = 0.003), which
`translates
`into a
`significant
`FCM
`prolongation of OS in the R-FCM arm (p = 0.005S).
`With respect to front-line therapy, rituximab was added to the
`standard CHOP regimen (R-CHOP). Howard and colleagues
`reported on 40 MCL patients treated with R-CHOP, which
`resulted in a CR rate of 4S%, while another 4S% achieved a
`PR 117]. However, median PFS was only approximately
`16 months, which appeared to be similar to that reported with
`CHOP alone 13.5.6]. Of note, even in the subgroup of patients
`achieving a molecular remission, there was no evidence for pro(cid:173)
`longed PFS (median IS.S YS. 16.5 months in patients without
`molecular CR). Hiddemann and colleagues have performed a
`randomized study comparing R-CHOP with CHOP alone in
`previously untreated patients with MCL. Recenrly published
`results indicate that R-CHOP induces a higher remission rate
`(94%) than CHOP (75%; p = 0.0054), in particular a higher
`CR rate (34 vs. 7%; p = 0.00024) l i B). Patients in the R-CHOP
`arm also experienced an improved time to treatment failure
`(21 months after R-CHOP vs. 14 months after CHOP;
`p = 0.0131), but at the time of this analysis there were no statisti(cid:173)
`cally significant differences regarding PFS and OS. Collectively,
`available data suggest that R-CHOP is of benefit for remission
`induction in MeL, bue it fails [Q have an impact on survival, as
`seen in the diffuse large B-cell lymphomas. This underlines the
`need for new serategies in MCL directed towards some of the
`unique features of this lymphoma entity.
`
`Radiaimmunotherapy
`The efficacy of anti-C020-directed antibody therapy may be
`further enhanced by application of radiolabeled (l3I iodine or
`90yrtrium) anti-C020 molecules. Small studies have reported
`remarkably high remission rates of sometimes long-lasting
`duration. Of particular note is the study by Gopal and col(cid:173)
`leagues using high doses of the 131 iodine-labeled anti-C020
`antibody
`tositumomab
`in 16 heavily pretreated MCL
`patients (19) . An overall response rate of 100% was reported,
`and the estimated 3-year OS was 93%.
`
`Rituximob & autologous transplantation
`An imeresting concept is the use of riruximab as an in VlVO
`purging agent for MCL. Gianni and colleagues used high-dose
`sequential therapy with peripheral stem cells obtained after
`cyclophosphamide and rituximab treatment (20) . Impressive
`results were reponed, not only with respect to the ability [0
`achieve a high percentage of PCR-negative grafts, but also
`regarding clinical outcome, with a 54-month estimated EFS
`rate of 79% and OS rate of S9%.
`Rituximab may also have a role as a consolidative agent after
`autologous transplantation. Combined observarions from two
`studies suggest that post-transplant rimximab increases the
`clinical and molecular response rates of MCL patients receiving
`autologous transplants (21.22). Further study is needed to
`appreciate the long-tetm benefit of this advantage in response.
`
`Also, this approach needs to be evaluated in the context of
`infectious complications as a high frequency of pneumonia
`requiring hospitalization was reported (22) .
`
`Role of Ihe microenvironment In lymphoma biology
`The currene paradigm for cancer initiation and progression is
`based upon genetic alterations leading to the dysregulated
`function of known oncogenes and rumor suppressor genes as
`well as genes involved in critical signal transduction pathways.
`However, it has become clear that single genetic events, or even
`the sequential acquisition of mutations/genetic gains and losses,
`undetestimate the nature of the genetic and epigenetic changes
`in tumor cells and do not aCCQum for (he observation that
`many cancer susceptibility genes show a high degree of [issue
`specificity in their association with neoplastic transformation .
`Therefore, the cellular and tissue context itself must confer
`additional information necessary for perturbated genes to exert
`their influence. Several recent observations suggest that this is
`also true for non-Hodgkin's lymphomas in a way that the
`rumor microenvironment
`is crucial
`for survival and/or
`proliferation of the malignant B-cell clone 123.24) .
`In follicular lymphoma, the histologic features resemble the
`structures of normal germinal centers and show a characteristic
`association of the lymphoma cells with helper T-cells, follicular
`dendritic cells and macrophages. Dave and colleagues recenrly
`presented data of their microarray analysis of follicular lymph(cid:173)
`omas [25} . This study was aimed at the definition of molecular
`predictors for prognosis and survival, and indeed four patient
`groups with signicantly different survival (medians between 3.9
`and 13.6 years) could be identified. Of note, the genes that best
`defined the prognostic signatures were not expressed by the
`lymphoma cells themselves but by T-cells, macrophages and
`dendritic cells. Thus, the lymphoma cells seem to need a close
`association and interaction wiili their microenvironment. This
`is further supported by observations that follicular lymphoma
`cells can proliferate in vitro only if they are cocultured with
`C04' T-cells, or with Stromal cells and an antibody against
`C040 126.27] . Activation of C040, which is expressed by
`lymphoma cells, represents a Strong survival factor for germinal
`center B-cells.
`A second example is derived from the study of B-cell duonic
`lymphocytic leukemia (B-CLL), where the leukemic cells in the
`peripheral blood show very low proliferative activity, indicating
`that expansion of the tumor clone may take place at orner sites
`involved by the lymphoma. Proliferation of B-CLL cells is
`indeed observed in lymph nodes and bone marrow, where the
`cells are in contact with T- and stromal cells (2B) . In vitro, B(cid:173)
`CLL cells grow very poorly, but their survival can be extended
`by coculturing the leukemic cells with stromal cells. Thus,
`interactions between Stromal and B-CLL cells, pardy involving
`the C040-C040-ligand system 129), provide signals for
`proliferation and survival of the lymphoma clone.
`Interactions with tumor-infiltrating lymphocytes are also
`relevant for low-grade gastric mucosa-associated lymphoid
`tissue
`lymphomas, which are closely associated with
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`....
`
`Drach. Seid l & Kaufmann
`
`Helieobacter pylori infection. In vitro. H. pylori stimulates the
`proliferation of tumor-infiltrating T-cells. but not oflymphom(cid:173)
`atous B-cells directly. T-cells. however. provide contact-depend(cid:173)
`ent signals to promote the survival and proliferation of these
`lymphoma B-cells [30,3 ' ]. The clinical observation that eradica(cid:173)
`tion of H. pylori by appropdate antibiotic therapy often .results
`lymphoma further augments the
`in a regression of the
`supportive role of such interactions for lymphoma progression.
`Studies exploring interactions between MCL cells and their
`microenvironment have not yet been performed. Nevertheless,
`observations from B-cell entities. as described above. as well as
`from multiple myeloma (MM). where targeting the tumor cell
`and
`its microenvironment represents a new
`treatment
`paradigm. provide the framework f