Leukemia & Lymphoma
`
`ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20
`
`Treatment for patients with relapsed/refractory
`mantle cell lymphoma: European-based
`recommendations
`
`Martin Dreyling, Igor Aurer, Sergio Cortelazzo, Olivier Hermine, Georg Hess,
`Mats Jerkeman, Steven Le Gouill, Vincent Ribrag, Marek Trněný, Carlo Visco,
`Jan Walewski, Francesco Zaja & Pier Luigi Zinzani
`
`To cite this article: Martin Dreyling, Igor Aurer, Sergio Cortelazzo, Olivier Hermine, Georg Hess,
`Mats Jerkeman, Steven Le Gouill, Vincent Ribrag, Marek Trněný, Carlo Visco, Jan Walewski,
`Francesco Zaja & Pier Luigi Zinzani (2017): Treatment for patients with relapsed/refractory
`mantle cell lymphoma: European-based recommendations, Leukemia & Lymphoma, DOI:
`10.1080/10428194.2017.1403602
`To link to this article: https://doi.org/10.1080/10428194.2017.1403602
`
`© 2017 The Author(s). Published by Informa
`UK Limited, trading as Taylor & Francis
`Group
`
`View supplementary material
`
`Published online: 27 Nov 2017.
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`

`

`LEUKEMIA & LYMPHOMA, 2017
`https://doi.org/10.1080/10428194.2017.1403602
`
`ORIGINAL ARTICLE: CLINICAL
`Treatment for patients with relapsed/refractory mantle cell lymphoma:
`European-based recommendations
`
`, Mats Jerkemanf
`, Sergio Cortelazzoc, Olivier Hermined, Georg Hesse
`Martin Dreylinga, Igor Aurerb
`, Marek Trnenyi
`Steven Le Gouillg
`, Vincent Ribragh
`, Carlo Viscoj
`, Jan Walewskik,
`Francesco Zajal
`and Pier Luigi Zinzanim
`aMedizinische Klinik und Poliklinik III, Klinikum der Universit€at M€unchen, LMU M€unchen, Germany; bDepartment of Internal Medicine,
`University Hospital Centre Zagreb, Zagreb, Croatia; cOncology Unit, Humanitas/Gavazzeni Clinic, Bergamo, Italy; dDepartment of Adult
`Haematology, Paris Descartes University, Paris, France; eUniversity Medical School of the Johannes Gutenberg-University, Mainz,
`Germany; fDepartment of Oncology, Lund University, Lund, Sweden; gCHU Nantes, Nantes, France; hInstitut Gustave Roussy, Villejuif,
`France; iGeneral Hospital, Charles University, Praha, Czech Republic; jSan Bortolo Hospital, Vicenza, Italy; kMaria Sklodowska-Curie
`Institute Oncology Centre, Warszawa, Poland; lClinica Ematologica, Centro Trapianti e Terapie Cellulari “Carlo Melzi,” University of
`Udine, Udine, Italy; mInstitute of Hematology “Seragnoli,” University of Bologna, Bologna, Italy
`
`,
`
`ABSTRACT
`Patients with mantle cell lymphoma (MCL) usually respond to initial combination chemotherapy,
`but the disease inevitably relapses and often follows an aggressive course. Here, clinical study
`results published since 2008 for patients with relapsed/refractory MCL were reviewed to compare
`available evidence for treatment guidance. Most trials identified were non-randomized, phase II
`studies performed at a limited number of sites, and many evaluated MCL as one of multiple
`non-Hodgkin lymphoma subtypes. Additional
`randomized, comparative trials are needed.
`Treatment selection generally depends on patient need, age and fitness, time of relapse, and
`line of therapy. Combination regimens typically produce higher response rates than single
`agents, and adding rituximab generally improves outcomes. The inclusion of ibrutinib, lenalido-
`mide, temsirolimus, and bortezomib, represents an important advance for patients ineligible for,
`unable to tolerate, or failing high-intensity combination chemotherapy. A high need for effective
`treatments in relapsed/refractory MCL remains, particularly for elderly and frail patients.
`
`ARTICLE HISTORY
`Received 21 September 2017
`Revised 17 October 2017
`Accepted 5 November 2017
`
`KEYWORDS
`Chemotherapy; clinical
`trials; mantle cell
`lymphoma; molecular
`targeted therapy
`
`Introduction
`
`is a distinct histologic
`lymphoma (MCL)
`Mantle cell
`type of non-Hodgkin lymphoma (NHL), with a median
`age of 65 years at diagnosis and predominantly more
`aggressive course of disease [1,2]. Diagnosis is based
`(CD20þ,
`on morphology
`and immunophenotype
`CD5þ, CD23–, and FMC7þ), but detection of chromo-
`somal translocation t(11;14)(q13;q32) or the resulting
`cyclin D1 overexpression is mandatory [3,4]. Although
`technically categorized as an indolent form of NHL,
`MCL typically follows an aggressive clinical course and
`is considered incurable. The majority of patients
`receive treatment upon diagnosis, except for a small
`fraction of patients with very indolent disease identifi-
`able by gene expression profiling [5,6] or low-risk char-
`acteristics and/or evolution of disease [7,8].
`Median overall survival (OS) following initial induc-
`tion therapy is 3–5 years with the use of dose-intense
`
`incorporation
`chemotherapy or combination therapy,
`of antilymphoma antibodies, and autologous stem cell
`transplantation [1,2,9–11]. US guidelines issued by the
`National Comprehensive Cancer NetworkVR
`(NCCNVR )
`categorize induction based on aggressive versus less
`aggressive treatment [12], whereas the European (EU)
`guidelines categorize induction based on the patient’s
`age (<65 versus 65 years) and status (fit versus frail)
`[1,2,13]. Aggressive treatment in the US guidelines and
`treatment of fit patients 65 years of age in EU guide-
`lines consist of high-dose chemoimmunotherapy fol-
`lowed by consolidation with high-dose therapy and
`autologous stem cell transplantation. R-hyperCVAD (rit-
`uximab combined with hyperfractionated cyclophos-
`phamide, vincristine, doxorubicin, and dexamethasone
`alternating with high-dose methotrexate and cytara-
`bine) is also recommended as an aggressive regimen
`in US but not EU guidelines. Less aggressive treatment
`
`CONTACT Martin Dreyling
`Martin.Dreying@med.uni-muenchen.de
`Marchioninistrasse 15, Munich, Germany
`ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
`This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-
`nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed,
`or built upon in any way.
`
`Medizinische Klinik und Poliklinik III, Klinikum der Universit€at M€unchen,
`
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`2
`
`M. DREYLING ET AL.
`
`in the US and treatment of fit, elderly patients in the
`EU consist of a conventional regimen such as R-CHOP
`(rituximab, cyclophosphamide, doxorubicin, vincristine,
`and prednisone) or BR (bendamustine and rituximab).
`Although MCL generally responds to initial treat-
`ment, the disease inevitably relapses, even after an
`intensive intervention [14]. Treatment of relapsed or
`refractory disease, characterized by increasingly shorter
`periods of remission with successive lines of treatment
`and progression to more clinically aggressive pheno-
`type, is challenging [1,2,14,15]. This review covers cur-
`rent
`treatment options
`in the relapsed/refractory
`setting, examining selection based on prior therapy,
`patient characteristics, performance status, and line of
`therapy. Conventional chemotherapy approaches as
`well as newer molecular-based therapies are included.
`
`Methods
`
`the literature was carried out using
`A review of
`PubMed to identify studies reporting clinical
`trial
`results in patients with relapsed/refractory MCL pub-
`lished between January 2008 and July 2017. Search
`terms included: title mantle cell lymphoma, publication
`type clinical trial, and language English. Abstracts from
`major
`conferences
`(American Society of Clinical
`Oncology [ASCO], American Society of Hematology
`[ASH], European Hematology Association [EHA], and
`International Conference on Malignant Lymphoma
`[ICML]) were also evaluated. Trials
`in previously
`untreated MCL patients, those with <10 MCL patients,
`pharmacokinetic studies, and publications such as let-
`ters to the editor were excluded, and the resulting list
`was focused on studies of key marketed and investiga-
`tional agents. Studies were categorized as monother-
`apy,
`chemotherapy/chemoimmunotherapy,
`chemotherapy/immunotherapy
`combinations with
`molecular-based agents, and combination biologic
`therapies.
`
`Study data
`
`Chemoimmunotherapy
`
`in relapsed/refractory
`trials
`Chemoimmunotherapy
`MCL are shown in Table 1, with key results discussed
`below [16–26]. Many recommendations regarding use
`of chemoimmunotherapy to treat relapsed/refractory
`MCL are based on limited studies and few randomized
`comparative trials. The most commonly used combina-
`tions in this setting are CHOP and regimens containing
`bendamustine, cytarabine, or fludarabine in combin-
`ation with rituximab. The addition of
`rituximab to
`
`chemotherapy regimens has shown improved OS [27].
`These combination regimens tend to be more appro-
`priate in first and second relapse in younger patients
`and elderly fit patients. While they appear to produce
`higher response rates than monotherapy, few compari-
`sons have been made in randomized trials.
`The alkylating agent bendamustine in combination
`with rituximab (BR regimen) has high activity in
`relapsed/refractory MCL [28]. Phase II findings with BR
`within this time period showed 92% overall response
`rate (ORR), 55% complete response (CR)/CR uncon-
`firmed (CRu), and median duration of response (DOR)
`of
`19 months
`in relapsed/refractory MCL
`[17].
`Subsequent studies of BR showed significantly pro-
`longed progression-free survival (PFS), producing a sig-
`nificantly higher ORR compared with fludarabine plus
`rituximab (FR)
`in a phase III study conducted in
`patients with relapsed follicular, indolent, and mantle
`cell lymphomas [18]. Among MCL patients who were
`randomized to BR or FR, ORR was 71% (38% CR) and
`26% (13% CR), respectively, and median PFS was 17.6
`and 4.7 months, respectively (p¼ .01). BR was also
`associated with improved OS (median 35.3 versus 20.9
`months). Among all patients treated with BR, the most
`common grade 3/4 adverse events (AEs) were leuko-
`penia (13%), neutropenia (9%), and nausea and emesis
`(4%).
`In a phase II study with relapsed or refractory
`MCL (median 2 prior therapies), BR treatment resulted
`in an 82% ORR (40% CR), median PFS of 17.2 months,
`and a 3-year OS rate of 55% [19]. Among patients
`evaluated by positron emission tomography (PET)
`scan, complete metabolic response was observed in
`75%. Grade
`3/4 neutropenia
`and lymphopenia
`occurred in 44 and 89% of patients,
`respectively.
`Serious AEs occurred in 40% of patients, but only
`three patients withdrew from the study due to AEs.
`The use of BR in the treatment of relapsed/refractory
`MCL has increased steadily based on recent results
`from the multicenter, randomized, phase III non-infer-
`iority StiL and BRIGHT studies, which reported signifi-
`cantly prolonged PFS and CR rates, respectively,
`in
`comparison to R-CHOP or R-CVP (rituximab, cyclophos-
`phamide, vincristine, and prednisone),
`in the small
`subsets of previously untreated MCL [29–32].
`
`Novel monotherapy treatment options for
`relapsed/refractory MCL
`
`trials of monotherapy options in relapsed/
`Pivotal
`refractory MCL are shown in Table 2 and results from
`key studies are discussed below [33–54]. Multiple
`treatment options are available in this setting, but no
`clear standard of care is recognized in EU or US
`
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`

`EU TREATMENT: MANTLE CELL LYMPHOMA
`
`3
`
`(54%),neutropenicfever(11%)
`
`Neutropenia(60%),thrombocytopenia
`
`Myelosupression(percentagesnot
`
`reported),infection(14%)
`
`19
`
`11
`
`Notreported
`
`Notreported
`
`93%(45%)
`
`82%(46%)
`
`62%grade3or4hematologicaltox-
`
`icity;febrileneutropenia(29%)
`
`Notreported
`
`Notreported
`
`52%(19%)
`
`Neutropenia(5%),thrombocytopenia
`
`anemia(33%)
`penia(67%),leukopenia(53%),
`Neutropenia(100%),thrombocyto-
`
`(3%)
`
`Efficacypresentedwithexvivodata;
`
`nosafetyreported
`
`Lymphopenia(89%),leukopenia
`
`(10%)
`thrombocytopenia(10%),infection
`Neutropenia(37%),leukopenia(30%),
`
`(12%),neutropenia(7%)
`penia(9%)FR:leukocytopenia
`BR:leukocytopenia(13%),neutro-
`
`Neutropenia(72%),leukopenia(65%),
`
`(6%),grade3infection(7%)a
`thrombocytopenia(16%),anemia
`
`Grade3AEs
`
`(44%),neutropenia(44%)
`
`Thrombocytopenia(83%),leukopenia
`
`(67%),neutropenia(49%)
`
`37
`
`30
`
`28
`
`18
`
`Notreached
`
`Notreached
`
`47%(20%)
`
`Notreached
`
`Notreached
`
`80%(70%)
`
`Notreported
`20.9
`35.3
`
`17.2
`4.7
`17.6
`
`Notreported
`
`Notreported
`
`92%(55%)
`
`1-yearPFS¼90%
`
`Notreached
`
`MedianOS,months
`
`Notreported
`
`MedianPFS,
`
`months
`
`ORR(CR/CRu)
`
`b65%combinedwithrituximab;56%combinedwithanthracyclines.
`aThesetrialsalsoincludedpatientswithotherNHLsubclasses(oroccasionallyotherhematologicalmalignancies);datamarkedbyasteriskareforallpatients,ratherthanthesubsetofMCLpatients.
`mib:anddexamethasone;RMC:rituximab:methotrexate:andcytarabine(Ara-C).
`R-FCM–rituximab:fludarabine:cyclophosphamide:andmitoxantrone;R-GemOx:rituximab:gemcitabine:andoxaliplatin;RGM:rituximab:gemcitabine:andmitoxantrone;RiBVD:rituximab:bendamustine:bortezo-
`mide:vincristine:andprednisone;R-hyperCVAD:rituximabandhyperfractionatedcyclophosphamide:vincristine:doxorubicin:anddexamethasonealternatingwithhigh-dosemethotrexateandcytarabine(Ara-C);
`docetaxel;GDP:gemcitabine:dexamethasone:andcisplatin;PEP-C:prednisone:etoposide:procarbazine:andcyclophosphamide;R-BAC:rituximab:bendamustine:cytarabine(Ara-C);R-CVP:rituximab:cyclophospha-
`Chemotherapyregimens:BR:bendamustineandrituximab;FCM:fludarabine:cyclophosphamide:andmitoxantrone;FFR:flavopiridol:fludarabine:andrituximab;FR:fludarabineandrituximab;GD:gemcitabineand
`spectivestudy;R/R:relapsed/refractory.
`CR:completeresponse;CRu:unconfirmedcompleteresponse;MCL:mantlecelllymphoma;NHL:non-Hodgkin’slymphoma;ORR:overallresponserate;OS:overallsurvival;PFS:progression-freesurvival;retro:retro-
`
`1(1–5)
`
`2(1to>3)
`
`29
`
`22
`
`(1–5)
`
`34;31evaluable
`
`83%(60%)
`
`79%(75%)
`
`1.8(0–5)
`
`1(1–4)
`
`30
`
`28
`
`II
`
`Notstated
`
`Retro
`
`Retro
`
`Salvagetherapy
`
`withRMTX.Ara-C[26]
`R-hyperCVADalternating
`
`Fludarabine-basedcombi-
`Fludarabine-basedregimens
`
`PEP-C[25]
`Otherregimens
`nationsb[24]
`
`R-GemOx[23]
`
`R-GemOx[22]
`
`Notreported
`
`Notreported
`
`16;15evaluable
`
`RGem-Mitox[21]
`Gemcitabine-basedregimens
`
`82%(40%)
`26%(13%)
`71%(38%)
`
`1(1–2)
`
`2(1–4)
`
`1(1to>2)a
`
`Notreported
`
`100%(73%)
`
`4(1–16)
`
`20
`
`45
`23
`24
`
`12
`
`11
`
`II
`
`II
`
`III
`
`II
`
`II
`
`median(range)
`Priorregimens,
`
`No.ofpatients
`
`Phase
`
`R-BAC[20]
`
`BR[19]
`
`BR[18]
`
`FR
`BR
`
`BR[17]
`
`Bendamustine[16]
`Bendamustine-basedregimens
`Regimen
`
`Table1.Chemotherapyandchemoimmunotherapyoptions:clinicaltrialswith10patients.
`
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`4
`
`M. DREYLING ET AL.
`
`(continued)
`
`Peripheralneuropathy(13%),fatigue(12%),
`
`up)
`(34%lymphopeniaatlong-termfollow-
`thrombocytopenia(11%),diarrhea(7%)
`
`17%),fatigue(4%versus7%)
`versus20%),neutropenia(13%versus
`cytopenia(9%versus42%),anemia(8%
`Foribrutinibversustemsirolimus:thrombo-
`
`(11%),hyperglycemia(11%)
`fatigue(25%),infection(15%),dyspnea
`(18%),anemia(15%),leukopenia(7%),
`
`Thrombocytopenia(39%),neutropenia
`19%),infection(9%,4%)
`22%),anemia(20%,11%),asthenia(13%,
`cytopenia(59%,52%),neutropenia(15%,
`Inhigh-andlow-dosegroups:thrombo-
`
`raleffusion(7%)
`(30%),anemia(12%),fatigue(9%),pleu-
`
`dyspnea(12%),fatigue(10%)
`(42%),anemia(20%),leukopenia(16%),
`
`Neutropenia(89%),thrombocytopenia
`
`Neutropenia(46%),thrombocytopenia
`
`(neutropenicsepsis).
`(42%),infection(42%)Onegrade5AE
`
`(20%),leukopenia(27%),fatigue(6%)
`
`Neutropenia(40%),thrombocytopenia
`
`Neutropenia(62%),thrombocytopenia
`
`fatigue(7%)
`(27%),anemia(11%),pneumonia(8%),
`
`Neutropenia(43%),thrombocytopenia
`
`Neutropenia(44%),thrombocytopenia
`
`(28%);4SPMs(3%)
`
`7%),leukopenia(8%versus11%)
`(18%versus28%),anemia(8%versus
`(44%versus34%),thrombocytopenia
`ForlenalidomideversusIC:neutropenia
`
`Notreported
`
`(pneumonia,probablytreatmentrelated).
`thrombocytopenia(5%)Onegrade5AE
`(5%),dyspnea(5%),pneumonia(5%),
`
`Neutropenia(11%),anemia(5%),diarrhea
`
`(13%),anemia(11%),pneumonia(6%)
`
`Neutropenia(17%),thrombocytopenia
`
`6.5/23.5
`
`6.2/21.3
`15.6/NR
`
`6/14
`1.9/9.7
`3.4/10.0
`4.8/12.8
`
`5.6/notreported
`
`3.9/10.0
`
`8.8/notreached
`
`9.2
`
`7.0
`NR
`
`N/A
`3.6
`7.1
`
`6
`
`13.7
`
`22.2
`
`16.3
`
`62-monthOS¼26%
`62-monthDFS¼37%
`
`5.7/notreported
`
`Notreached
`
`Notreported
`
`5.2/21.2
`8.7/27.9
`
`4.0/20.9
`
`4.0/20.9
`
`13.0/22.5
`
`13.9/notreached
`
`10.4
`16.1
`
`16.6
`
`16.6
`
`17.5
`
`17.5
`
`32%(8%)
`
`2%(2%)
`6%(0%)
`22%(2%)
`
`31%(8%)
`
`11%(0)
`40%(5%)
`
`28%(8%)
`
`28%(8%)
`
`MostCommonGrade3AEs
`
`months
`
`MedianPFS/OS,
`
`months
`
`MedianDOR,
`
`1(1–3)
`
`155;141evaluable
`
`47%(3%)
`77%(23%)
`
`41%(3.7%)
`
`53%(20%)
`
`2(1–9)
`2(1–9)
`
`4(1–9)
`4(2–7)
`3(2–7)
`3(2–7)
`
`4(2–7)
`
`3(2–7)
`
`35%(12%)
`
`3(1–13)
`
`42%(21%)
`
`44%(31%)
`
`67%(23%)
`
`3(1–13)a
`
`Notreported
`
`2(IQR1–3)
`2(IQR1–3)
`
`4(2–10)
`
`4(2–10)
`
`3(1–6)
`
`141
`139
`
`29;27evaluable
`
`53
`54
`54
`162
`
`15
`
`26
`
`57
`
`70
`
`84
`170
`
`134
`
`68%(21%)
`
`3(1–6)
`
`111;109eval.
`
`II
`
`III
`
`II
`
`III
`
`II
`
`II
`
`II
`
`II
`
`II
`
`II
`
`ORR(CR/CRu)
`
`median(range)
`Priorregimens,
`
`No.ofpoints
`
`Phase
`
`Bortezomib[48,49]
`Proteasomeinhibitor
`
`[46,47]
`Temsirolimus
`Ibrutinibversus
`
`Investigatorchoice
`Lowerdose
`Higherdose
`
`Temsirolimus[43,44]
`mTORinhibitor
`
`Temsirolimus[45]
`
`Lenalidomide[42]
`
`Lenalidomide[41]
`
`Long-termfollow-up[40]
`
`Lenalidomide(retro)b
`
`Lenalidomide[39]
`
`[38]
`
`LenalidomideIC[37]
`
`Long-termfollow-up[36]
`
`Lenalidomide[35]
`Immunomodulatoryagent
`
`Long-termfollow-up[34]
`
`Ibrutinib[33]
`BCRpathwayinhibitor
`Treatment
`
`Table2.Targetedmonotherapyoptions:clinicaltrialswith10patients.
`
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`EU TREATMENT: MANTLE CELL LYMPHOMA
`
`5
`
`lenalidomide,
`ibrutinib,
`treatment guidelines [1,2,12],
`and temsirolimus are approved in the EU [55–57],
`whereas three molecular-based agents are approved
`by the US Food and Drug Administration:
`ibrutinib
`[58], lenalidomide [59], and bortezomib [60].
`Ibrutinib, an inhibitor of Bruton’s tyrosine kinase
`(BTK), has been approved by the European Medicines
`Agency (EMA) for the treatment of adult patients with
`relapsed or refractory MCL and in the US for patients
`with MCL who have received at least one prior therapy
`[56,58].
`Ibrutinib was evaluated in a phase II
`trial
`involving MCL patients with a median of three prior
`regimens [33,34]. ORR and CR rates improved over
`time on therapy, reaching 68 and 21%, respectively.
`For the entire cohort, median PFS was 13.9 months
`and median OS was not reached. Response rates did
`not differ between bortezomib-naïve versus pre-
`treated patients, although trends toward longer DOR
`and PFS were observed in patients who had received
`prior bortezomib. The most common grade 3/4 toxic-
`ities were neutropenia (16%) and thrombocytopenia
`(11%). The activity of ibrutinib in patients with MCL
`progressing after bortezomib therapy was confirmed
`in another phase II trial [61].
`Both primary and secondary resistance to ibrutinib
`in relapsed/refractory MCL has been observed [33].
`Two separate retrospective reviews reported poor out-
`comes for patients with ibrutinib-resistant MCL after
`subsequent salvage therapy, with a median OS of 5.8
`[62] and 8.4 months [63] after
`ibrutinib cessation.
`Effective therapy for patients with relapsed MCL with
`ibrutinib resistance therefore represents an important
`unmet medical need.
`Multiple phase II studies have been conducted with
`lenalidomide alone and in combination with rituximab
`(R2 regimen) [35–42,64]. The pivotal phase II MCL-001
`(EMERGE) study in the US established the activity of
`lenalidomide in relapsed/refractory MCL,
`including
`patients who received prior bortezomib (median 4
`prior regimens) [35]. Lenalidomide provided an ORR of
`28% (8% CR/CRu) by independent central review, with
`a median DOR of 16.6 months. Median PFS was 4.0
`months, and median OS (longer-term follow-up) was
`20.9 months [36]. The most common grade 3/4 toxic-
`ities were neutropenia (43%) and thrombocytopenia
`(27%).
`In the phase II, multicenter, open-label MCL-002
`(SPRINT) pivotal trial in the EU, patients with relapsed
`or refractory MCL were randomized 2:1 to lenalido-
`mide monotherapy or investigator’s choice (IC) mono-
`therapy
`(rituximab,
`gemcitabine,
`fludarabine,
`chlorambucil, or cytarabine) [37]. At a median follow-
`up of 15.9 months, lenalidomide significantly improved
`
`bDatawerereportedinabstractform.
`aThesetrialsalsoincludedpatientswithotherNHLsubclasses(oroccasionallyotherhematologicalmalignancies);datamarkedbyasteriskareforallpatientsinthestudy,ratherthanthesubsetofMCLpatients.
`TFR:tumorflarereaction;VOD:veno-occlusivedisease.
`cil:orcytarabinemonotherapy;MCL:mantlecelllymphoma;ORR:overallresponserate;OS:overallsurvival;R/R:relapsed/refractory;PFS:progression-freesurvival;SAE:seriousAE:SPM:secondprimarymalignancy;
`AE:adverseevent;ALT:alanineaminotransferase;CR:completeresponse;CRu:unconfirmedcompleteresponse;DOR:durationofresponse;IC:investigator’schoiceofrituximab:gemcitabine:fludarabine:chlorambu-
`pulmonaryembolism(5%),pyrexia(5%)
`diarrhea(8%),acuterenalfailure(5%),
`monia(13%)SAEs:pneumonia(10%),
`increased(15%),anorexia(15%),pneu-
`ALTincreased(20%),diarrhea(18%),AST
`
`penia(8%)a
`sion-relatedreaction(8%),thrombocyto-
`
`Lymphopenia(15%),anemia(10%),infu-
`
`3.7/notreported
`
`2.7
`
`40%(5%)
`
`4(1–14)
`
`2.7a/notreported
`
`Notreported
`
`27%(13%)
`
`3(1–17)a
`
`(13%)
`(30%),neutropenia(20%),hypocalcemia
`
`penia(8%)
`leukopenia(12%),anemia(8%),leuko-
`Lymphopenia(35%),neutropenia(15%),
`
`Lymphopenia(35%),thrombocytopenia
`MostCommonGrade3AEs
`
`6.7a
`
`MedianPFS/OS,
`
`5.3/notreported
`months
`
`6.7a
`
`3.8
`
`MedianDOR,
`
`months
`
`25%(0)
`
`Notreported
`
`50%(17%)
`ORR(CR/CRu)
`
`2(0–4)
`
`median(range)
`Priorregimens,
`
`40;36evaluable
`
`No.ofpoints
`
`40
`
`15
`
`10
`
`I
`
`Idelalisib[54]
`
`II
`
`II
`
`II
`
`Phase
`
`Obinutuzumab[53]
`Other
`
`Bortezomib[52]
`
`Bortezomib[50,51]
`Treatment
`
`Table2.Continued
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`6
`
`M. DREYLING ET AL.
`
`PFS compared with IC (median 8.7 versus 5.2 months,
`p¼ .004). ORR was 40% (5% CR/CRu) for lenalidomide
`and 11% (0% CR/CRu) for IC. Median OS (27.9 versus
`21.2 months) also favored lenalidomide. The most
`common grade 3 or 4 AEs were neutropenia (44% ver-
`sus 34%) without increased risk of infection, thrombo-
`cytopenia (18% versus 28%),
`leukopenia (8% versus
`11%), and anemia (8% versus 7%) in the lenalidomide
`and IC groups, respectively. Analysis of subgroups and
`regression analyzes associated superior PFS with lenali-
`domide over IC therapy irrespective of prior treatment
`history [65].
`Temsirolimus, an mTOR inhibitor, was the first agent
`registered by the EMA for
`relapsed/refractory MCL
`[55].
`In a pivotal phase III study, temsirolimus was
`compared with investigator’s choice of therapy in 162
`patients with relapsed/refractory MCL who had
`received a median of
`three prior
`regimens
`[43].
`Temsirolimus was administered at a dose of 175 mg
`weekly for 3 weeks followed by either 75 or 25 mg
`weekly. In the control arm, the investigators selected
`from prospectively approved options, most commonly
`gemcitabine and fludarabine. Patients receiving the
`higher dose of temsirolimus had significantly longer
`PFS than those in the investigator’s choice arm (4.8
`versus 1.9 months; p¼ .0009); median OS did not differ
`significantly (12.8 versus 9.7 months; p¼ .35). The
`most frequent grade 3/4 toxicities with the higher
`dose of temsirolimus were thrombocytopenia (59%),
`anemia (20%), neutropenia (15%), and asthenia (13%).
`When patients were retrospectively classified accord-
`ing to the MCL International Prognostic Index, a vali-
`dated
`predictor
`of
`survival
`[66],
`the
`higher
`temsirolimus dose increased PFS by 7.9, 2.8, and 1.1
`months compared with investigator’s choice therapy
`in
`low-,
`intermediate-,
`and
`high-risk
`groups,
`respectively.
`An international, randomized, open-label, phase III
`study compared ibrutinib with temsirolimus in patients
`with relapsed or refractory MCL [46,47]. Temsirolimus
`was administered at a dose of 175 mg weekly for 3
`weeks followed by 75 mg weekly. At a median follow-
`up of 39 months, ORR was significantly improved in
`the ibrutinib group (77% versus 47%, p < .0001), as
`was PFS (15.6 versus 6.2 months, p < .0001)
`[47].
`Ibrutinib was better
`tolerated, with lower
`rates of
`grade 3 or 4 thrombocytopenia (9% versus 42%),
`anemia (8% versus 20%), neutropenia (13% versus
`17%), and fatigue (4% versus 7%) than temsirolimus,
`with fewer AEs leading to discontinuation (6% versus
`26%) [46]. Major bleeding was more frequent in the
`ibrutinib group (10% versus 6%), but after adjusting
`for longer ibrutinib exposure, event rates were similar.
`
`In the pivotal phase II PINNACLE study, the prote-
`asome inhibitor bortezomib was evaluated in patients
`with relapsed MCL who had received a median of one
`prior regimen [48]. ORR was 32% and included 8%
`with CR/CRu [49]. Median PFS was 6.5 months for all
`patients and median OS was 23.5 months. Toxicity was
`generally manageable;
`grade
`3/4
`lymphopenia
`occurred in 34% of patients. The most common grade
`3/4 non-hematologic toxicity was peripheral neur-
`opathy (13%). Four deaths occurred within 28 days of
`the last dose of bortezomib that were probably attrib-
`utable to study drug (3 due to non-neutropenic sepsis,
`1 due to respiratory failure).
`Several newer
`investigational agents are note-
`worthy, and although clinical data are limited, they
`show promise for use in combination with other
`agents based on their mechanism(s) of
`action.
`Obinutuzumab (GA101) is a glycoengineered human-
`ized anti-CD20 monoclonal antibody that exhibited
`superior activity compared with rituximab in MCL
`xenograft models [67]. In the phase II GAUGUIN study,
`obinutuzumab was administered in a subset of MCL
`patients [53]. Two different dosing regimens were eval-
`uated: 1600 mg on days 1 and 8 of cycle 1 and
`800 mg on day 1 of cycles 2–8, or 400 mg at all infu-
`sions. Best ORR with obinutuzumab for MCL patients
`was 4/15 (27%), with 2/15 (13%) reaching a CR/CRu
`and including response durations ranging from 5.5 to
`30.5þ months. Obinutuzumab exhibited an acceptable
`safety profile for all patients; grade 3/4 infusion-related
`reactions occurred in 3 (8%). Obinutuzumab may rep-
`resent an alternative to rituximab as a future option in
`combination therapies.
`Idelalisib acts via the B-cell receptor (BCR) pathway
`and is a selective inhibitor of phosphatidylinositol 3-
`kinase delta isoform (PI3Kd).
`In a phase I study,
`patients with relapsed or refractory MCL (median 4
`prior treatments) were treated with 50–350 mg oral
`idelalisib once or twice daily [54]. ORR was 40% (5%
`CR), and median PFS was 3.7 months (1-year PFS 22%).
`The most frequent grade 3/4 AEs were increased ala-
`nine aminotransferase (ALT; 20%), diarrhea (18%),
`increased aspartate aminotransferase (AST; 15%), and
`anorexia (15%), with 18% of patients discontinuing
`due to AEs. Due to limited efficacy, potential toxicity,
`and the availability of other
`targeted agents,
`the
`future of idelalisib in MCL is doubtful.
`Venetoclax (ABT-199), a selective inhibitor of the
`anti-apoptotic protein BCL-2,
`received accelerated
`approval in the US as monotherapy for patients with
`chronic lymphocytic leukemia with 17p deletion and
`at least one prior therapy [68], based on results of an
`uncontrolled phase II study [69]. Although based on a
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`small number of patients, this agent also showed a
`very high rate of response (75%) in relapsed/refractory
`MCL, comparable to the efficacy of BTK inhibitors, and
`would be an attractive option for
`this group of
`patients [70].
`
`Novel agents combined with
`chemoimmunotherapy
`
`The addition of molecular-based agents such as ibruti-
`nib,
`lenalidomide,
`temsirolimus, and bortezomib to
`chemoimmunotherapy may be appropriate for some
`patients, though careful attention for potential unex-
`pected toxicity is important during initial assessments.
`These combinations are being examined in multiple
`phase II studies (Table 3) [71–80] some of which are
`described in detail below.
`Two studies have evaluated the combination of rit-
`lenalidomide, and bendamustine (R2-B)
`uximab,
`in
`MCL [71,72]. A phase I/II study in patients age >65
`years (n¼ 51) with untreated stage II–IV MCL assessed
`induction with six cycles of R2-B followed by mainten-
`ance with 7 cycles of single-agent
`lenalidomide.
`Inclusion criteria allowed treatment with one cycle of
`chemotherapy or radiation therapy. Because of a high
`number of AEs (especially allergic and cutaneous reac-
`tions) in the phase I dose escalation, the protocol was
`amended to omit lenalidomide during the first cycle
`and to include corticosteroids and Pneumocystis carinii
`pneumonia prophylaxis in subsequent cycles.
`In the
`combined phase I and II parts of the study, 74% com-
`pleted the induction phase and 24% of patients com-
`pleted the maintenance phase. Best responses were
`80% ORR and 64% CR/CRu. At a median follow-up of
`31 months, the PFS was 42 months and the 3-year OS
`was 73%. Of concern, many patients had a grade 3–5
`infection,
`including three patients with opportunistic
`infections, and 16% had a second primary malignancy.
`In a phase II study of second-line therapy, patients
`responding to R2-B induction received R2 consolida-
`tion, and those with CR or partial response (PR) were
`then treated with lenalidomide maintenance [72].
`In
`elderly patients (median age 70 years), ORR was 79%
`(55% CR) after consolidation, and 24-month PFS and
`OS rates were 43 and 67%,
`respectively. Toxicities
`were predominantly hematologic: grade 3/4 neutro-
`penia (71% in induction/consolidation; 72% during
`maintenance) and grade 3/4 thrombocytopenia (14%
`in induction/consolidation; 7% during maintenance).
`Thirty-six percentage of responding patients achieved
`minimal
`residual disease (MRD) negativity in bone
`marrow following induction and consolidation.
`
`EU TREATMENT: MANTLE CELL LYMPHOMA
`
`7
`
`A multicenter phase Ib study of temsirolimus in
`combination with rituximab-chemotherapy in patients
`with relapsed/refractory MCL reported ORRs of 56, 42,
`and 80% for the combination of temsirolimus with
`R-CHOP, RFC (rituximab,
`fludarabine, cyclophospha-
`mide), and R-DHA (rituximab, dexamethasone, and
`high-dose cytarabine), respectively [73]. The combin-
`ation of temsirolimus with BR produced a 94% ORR
`(39% CR) and a median PFS of 22 months in a recent
`phase I/II study [74].
`In the full patient population,
`which included nine patients with follicular lymphoma,
`the most common grade 3/4 AEs were leukopenia
`(32%), neutropenia (24%), and thrombocytopenia (21%).
`Most evidence exists for chemotherapy regimens
`combined with bortezomib. Based on encouraging first
`line data [81], a multicenter, phase II study randomized
`patients with relapsed MCL who had received one
`treatment prior to CHOP or bortezomib (days 1 and 8)
`plus CHOP [75]. The addition of bortezomib improved
`ORR (83% versus 48%), CR rates (35% versus 22%),
`median PFS (16.5 versus 8.1 months), and median OS
`(35.6 versus 11.8 months). The difference in OS was
`statistically significant (p¼ .01), although higher rates
`of grade 3/4 neutropenia (30% versus. 20%)
`in the
`bortezomib-CHOP arm translated into increased febrile
`neutropenia (39% versus 17%).
`In patients unwilling or unable to receive first-line
`dose-intensive therapy, the combination RiBVD (rituxi-
`mab, bendamustine, bortezomib, and dexamethasone;
`no maintenance) in a phase II study of newly diag-
`nosed MCL patients >65 years of age has also shown
`notable efficacy (84% ORR with a 24-month PFS of
`70% at a median follow-up of 52 months), but was
`hampered by prominent infectious complications [80].
`
`Molecular-based combinations
`
`With the availability of novel agents and biologic ther-
`apy, treatment of relapsed/refractory MCL has moved
`toward a molecular-based approach rather
`than a
`high-dose, intense chemotherapy strategy. In addition
`to monotherapy as discussed above, several agents
`have been evaluated in combination mostly with ritux-
`imab (Table 4) [64,82–92].
`Ibrutinib was combined with rituximab in a single-
`center, phase II trial enrolling patients with relapsed/
`refractory MCL [82]. An 88% ORR (44% CR) was
`reported, with atrial fibrillation (12%) being the only
`grade 3/4 AE occurring in more than one patient. One
`on-study death (septic shock) may have been treat-
`ment related. Recent report of the MCL6 PHILEMON
`phase II study from the Nordic Lymphoma Group
`showed that ibrutinib combined with R2 was active
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`8
`
`M. DREYLING ET AL.
`
`aThistrialalsoincludedpatientswithotherNHLsubclasses;datamarkedbyasteriskareforallpatients,ratherthanthesubsetofMCLpatients.
`Thistabledoesnotincludestudieswith<10MCLpatients.
`predn