ccr focus - clinical cancer researchchemo-free approaches represent a valuable option, as long as...

Are We Nearing an Era of Chemotherapy-Free Managementof Indolent Lymphoma?

Emmanuel Bachy1,2 and Gilles Salles1,2

AbstractIndolent B-cell lymphomas are heterogeneous, comprising three grades of follicular lymphoma, small

lymphocytic lymphoma, Waldenst€om macroglobulinemia, marginal zone lymphoma, and most recently,

possibly low proliferative mantle cell lymphoma. These lymphomas are characterized by a high respon-

siveness to chemotherapyor immunochemotherapy; however, inmost cases, conventional therapymightnot

offer a cure. Furthermore, the patient’s age at diagnosis, at time to first or subsequent relapses, as well as

potential comorbidities often preclude the use of chemotherapy. Recent progress has been made in our

understanding of dysregulated pathways and immunologic antitumor responses in indolent lymphoma.

Major therapeutic advances have been achieved in the development of nonchemotherapeutic agents,making

"chemo-free" treatment a near-future reality. In this article, we highlight these promising approaches, such as

the combination of anti-CD20 antibodies with immunomodulatory drugs, withmAbs directed against other

surface antigens such as CD22, with immunomodulatory antibodies such as PD-1, or with inhibitors of key

steps in the B-cell receptor pathway signaling. However, the cost of such therapies and potential, albeit

manageable, toxicity should be considered. Phase III trials will confirm the benefit of these new treatment

strategies that do not require a chemotherapeutic drug and help us identify their exact place in the therapeutic

armamentarium for indolent lymphoma. Here we focus on follicular lymphoma, which is themost frequent

subtype of indolent lymphoma and for which an increasing body of evidence has emerged that supports the

dawn of a new era of chemotherapy-free treatment.

See all articles in this CCR Focus section, "Paradigm Shifts in Lymphoma."

Clin Cancer Res; 20(20); 5226–39. �2014 AACR.

IntroductionA major step forward in the treatment of indolent lym-

phoma was the development and broad use of a mAbtargeting the CD20 antigen on the surface of B cells. Onepivotal study and three randomized trials demonstrated asignificant, prolonged, progression-free, event-free, or over-all survival (PFS, EFS, or OS, respectively) with the use of arituximab-containing first-line regimen comparedwith che-motherapy alone (1–5).

However, the short- and long-term toxicities of such achemotherapy-based regimen cannot be underestimated.Short-term toxicity usually includes cytopenias, withincreased infectious disease risk, whereas secondary neo-plasia (either of solid or hematopoietic types) is the mainconcern for long-term toxicity (6, 7). Therefore, new strat-egies with a chemotherapy-free regimen aimed at preclud-ing such toxicities while providing an equivalent or higher

response rate and response duration are eagerly awaited forindolent lymphomas.

In this CCR Focus section, we discuss how anti-CD20antibodies—alone or in association with other mAbs, withimmunomodulatory agents, or with molecules targetingcritical signaling pathways (Fig. 1)—might replace conven-tional therapy in the near future, moving us into a new"chemo-free" era. The impact of these therapies on the estab-lished "watch and wait" approach for appropriate patientswill be a subject for future discussion (see Text Box 1).

Single-Agent Anti-CD20 in Indolent LymphomasRituximab

Rituximab is a monoclonal chimeric antibody (Fig. 2A)directed against the CD20 antigen that is expressed on thesurface of B-cell lymphomas (Table 1). It mediates comple-ment and antibody-dependent cell-mediated cytotoxicity(CDC and ADCC, respectively) in addition to exerting adirect antiproliferative and proapoptotic effect (Fig. 2B).Rituximab displayed an impressive overall response rate(ORR) of 48% in a pivotal study performed by McLaughlinand colleagues (8) in relapsed anti-CD20 na€�ve patients witha history of indolent lymphoma of more than 15 years. Onehundred and sixty patientswere enrolled from31centers andtreated with four weekly doses of 375 mg/m2 of rituximab.The projected median time to progression was 13 months

1Hospices Civils de Lyon, Service d'H�ematologie, Pierre B�enite Cedex,France. 2Universit�e Claude Bernard, Facult�e de M�edecine Lyon-SudCharles M�erieux, Universit�e de Lyon, Pierre B�enite Cedex, France.

Corresponding Author: Gilles Salles, Lyon Sud Hospital, 165 Chemin duGrandRevoyet, 69495Pierre B�enite Cedex, France. Phone: 33-478-86-43-02; Fax: 33-478-86-43-75; E-mail: [email protected]

doi: 10.1158/1078-0432.CCR-14-0437

�2014 American Association for Cancer Research.

CCRFOCUS

Clin Cancer Res; 20(20) October 15, 20145226

on May 20, 2020. © 2014 American Association for Cancer Research. clincancerres.aacrjournals.org Downloaded from

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in responders. In the study by Maloney and colleagues (9),which was a similarly designed phase II trial, single-agentrituximab yielded an ORR of 46%. Importantly, the toxicitywas mild and mostly limited to infusion-related reactions(IRR; Table 2). Several studies confirmed the potency ofthe mAb in relapsed or refractory indolent lymphomas(10, 11; Table 1). The use of rituximab as a single agent wasfurther evaluated in the first-line setting and similarly pro-duced a high ORR of 70% to 75% with approximately 30%of cases with complete response (CR) and an extended timeto treatment failure of 2 years (12–16; Table 1).Maintenance of rituximab after rituximab monotherapy

induction has shown interesting results in two randomizedstudiesby theUKIntergroupand theU.S.-basedECOGgroup(RESORT study) by demonstrating prolonged PFS (17–18).However, no consistent benefit in terms of time to nextchemotherapy, time to treatment failure,orOSwasobserved.

Other anti-CD20 antibodiesGiven the potency of rituximab, other anti-CD20 anti-

bodies have been developed to increase the CDC, ADCC, ordirect toxicity (Fig. 2B).

Ofatumumabwas the first anti-CD20mAb to be approvedin the United States and European Union (EU) for patientswith chronic lymphocytic leukemia (CLL) refractory to flu-darabine and alemtuzumab. Ofatumumab as monotherapyalso demonstrated some efficacy in follicular lymphoma andWaldenstr€om macroglobulinemia. Ofatumumab was eval-uated in 40 refractory/relapsed follicular lymphoma patientsin a phase I/II dose-escalation trial and produced a prom-ising 41% ORR across all doses (300, 500, 700, and 1,000mg) at week 19 and a 60% ORR in the 1,000-mg cohort atweek 26 (19). The antibody was further tested in a phase IIstudy of 116 pretreated patients with follicular lymphomarefractory to previous rituximab therapy and resulted in amodest 11% ORR and a median response duration of 6months (20). Ofatumumab was well tolerated in bothstudies with mainly grade 1/2 IRR at first infusion (Table 2).

Obinutuzumab is a type II anti-CD20 antibody thatresults in a lower CDC but in a significantly higher ADCCand direct cell death compared with type I anti-CD20antibodies (like rituximab andofatumumab), characterizedby their ability to stabilize CD20 on lipid rafts and henceto induce high CDC (21, 22). Obinutuzumab has been

© 2014 American Association for Cancer Research

Monoclonal antibody

Drug targeting a specific component

of a signaling pathway

Immunomodulatory drug

Antitumoral response

Ligand

BCR

Lymphoma cell

Signaling

pathway

Ag

1

2

3

4

Coreceptor

Various components of the

targeted signaling pathway

Figure 1. Nonchemotherapeuticagents in the treatment of indolentlymphoma. mAbs can be directedagainst B-cell surface antigenssuch as CD20, which is expressedby tumor cells and mediatescomplement, antibody-dependentcell-mediated cytotoxicity or directcell death (part 1). Antibodiescan also be directed againstcoreceptors withimmunomodulatory functionssuch as PD-1, which is expressedon antitumor cells (NK or CD8T cells) and impairs the ligand/receptor axis to foster an immuneresponse (part 2). The antitumorresponse might be strengthenedby a nonantibodyimmunomodulatory agent such aslenalidomide as well (part 3).Finally, tumor cell death might alsobe promoted by targeted agentsthat impede critical signalingpathways, such as ibrutinib, whichimpedes BTK, a step in the B-cellreceptor (BCR) signaling pathway(part 4). Ag, antigen.

Chemotherapy-Free Approaches in Indolent Lymphoma

www.aacrjournals.org Clin Cancer Res; 20(20) October 15, 2014 5227



approved recently both in the United States and the Euro-peanUnion in combinationwith chlorambucil for first-linetreatment of patients with CLL. Two phase I studies wereconducted in patients with relapsed/refractory CD20þ non-Hodgkin lymphoma with no dose-limiting toxicities andmainly grade 1/2 IRR (23, 24). Notably, rare cases of tumorlysis syndrome and grade 3/4 reactions were observed. Thefirst single-arm phase II studies indicated an appealingbenefit of obinutuzumab monotherapy in heavily pre-treated patients with indolent non-Hodgkin lymphoma, ofwhom 55% were rituximab refractory. The final treatment

response rate was 55% (with a 11.3monthsmedian PFS) inthe higher-dose cohort, with an impressive 50% of ORR inthe rituximab-refractory subcohort of patients (25). A ran-domized phase II trial comparing head-to-head obinutu-zumabwith rituximab induction treatment followed by a 2-year maintenance for indolent lymphoma demonstrateda significantly increased ORR for patients receiving obinu-tuzumab after induction (43% vs. 28% as assessed by acentral review), but there was no difference in the PFS(ref. 26; Table 1).

Veltuzumab is a humanized anti-CD20 mAb with acomplementary determining region that is identical torituximab (27). Phase I/II studies showed excellent tolera-bility and encouraging response rates in patients withpreviously treated follicular lymphoma and good bioavail-ability after delivery either by the intravenous or subcuta-neous route (28, 29; Tables 1 and 2).

At present, rituximab remains the only FDA- and Euro-pean Medical Agencies approved anti-CD20 mAb forrelapsed follicular lymphoma, and in addition to its wideuse in combination with chemotherapy, monotherapy iscommonly used both in the relapse and first-line setting.Until clinical trials evaluating newer anti-CD20mAbs (suchas those approved in CLL) head to head against rituximabdemonstrate equivalence or superiority, it remains hypo-thetical to foresee their approval as single agents in the nearfuture. However, further development of anti-C20 mAbs incombinations, as discussed below, is under way to increasethe rate and durability of responses.

Armed mAbsArmed antibodies, either as radiolabeled antibodies or as

antibody drug conjugates, also play a role in the manage-ment of patients with indolent lymphoma. While the latter(still in clinical development) can be viewed as a smarterway to deliver cytotoxic drugs (30), radioimmunotherapy(RIT) can be considered as one of the chemo-free optionsalready available. Essentially represented by two anti-CD20radiolabeled antibodies (131I-tositumomab or 90Y-ibritu-momab tiuxetan), RIThas been shown tobeoneof themostactive therapies in indolent lymphoma, providing a highresponse rate in relapsed/refractory or previously untreatedpatients (31).Whenused as single agents, short-term revers-ible hematologic toxicities represent the prominent sideeffect and are easily manageable, whereas long-term toxi-cities (including the risk of myelodysplastic syndromes) arerare and do not seem to exceed those encountered withchemotherapy regimens (31). Although anecdotal reportsof prolonged responses have appeared, especially in thefirst-line setting (32), few pivotal randomized studies havebeen conducted. When a single infusion of 90Y-ibritumo-mab tiuxetan was compared head to head with rituximab(4 weekly infusions), time to progression was not statisti-cally different between the two options, although responseduration was much longer with RIT (33). In summary, RITstill represents a very efficient way to achieve a clinicalresponse in patients with indolent lymphoma, but despitea development startedmore than 10 years ago, its role in the

TextBox1. Expert opinion:Did "watchandwait"become obsolete with chemo-free options?Because of the indolent clinical course of follicular

lymphoma, its frequent asymptomatic presentation,and considering data obtained in prospective studieshaving evaluated its safety, watchful waiting has repre-sented a well-validated management option in use forseveral decades, especially in newly diagnosed patients.One may then ask whether the chemo-free approacheswill lead to abandonment of its use. In the first-linesetting, despite a significant delayed time to progression,there is still no data indicating that early therapeuticintervention with rituximab (either as a short course oras prolonged treatment) results in short- or long-termimprovement of overall survival.In one randomized trial (17) comparing watchful wait-

ing with rituximab, patients who were allocated afterrandomization to the watch and wait arm of the studyappeared to have presented more anxiety than those treat-ed. However, these results have a certain degree of bias,given patient participation in such a study and the detailedinformation provided to patients before randomization.It is, however, true that for some patients, feeling

anxious about living with an untreated cancer despiteadequate information, or for those who experienceasymptomatic (but sometimes palpable) progression,chemo-free approaches represent a valuable option, aslong as they are not associated with clinically relevanttoxicities. However, all experienced hemato-oncologistsrecommending watchful waiting do know that a sub-stantial proportion of patients will feel comfortablewith simple clinical surveillance and can remain free oftherapeutic intervention for years. Likewise, delaying anew intervention in patients who have experiencedmultiple relapses may also be acceptable.Of note, with increasing concerns about health care

costs, and the rising prices of new drugs, this is a strategyobviously using fewer resources. Hence, until chemo-free approaches eventually demonstrate at least animprovement in overall survival in patients with indo-lent lymphoma, watchful waiting in selected casesshould still be considered as one of the managementoptions to be discussed with patients.

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Clin Cancer Res; 20(20) October 15, 2014 Clinical Cancer Research5228



current clinical practice has not been firmly established(31, 34).

Other antibody-based therapy in indolent lymphomasSuccessful development of anti-CD20 antibodies pro-

mpted the use of other tumor cell surface antigens as thetarget of mAb (Table 1 and Fig. 3A).CD22 is widely expressed on the surface of B cells. Naked

humanized CD22 mAb epratuzumab yielded a limited ORRof 18% in recurrent indolent non-Hodgkin lymphoma across

all subtype histologies and dose levels (35). Concurrentadministration of rituximab and epratuzumab, used first linefor patients with follicular lymphoma, produced an ORR of88% andCRof 42% aswell as a prolonged response duration(60% of patients still in remission after 3 years; ref. 36).

Other mAbs, such as anti-CD37 (otlertuzumab) or anti-CD74 (milatuzumab) antibodies, are currently in early-phase development. CD37 is expressed at a high concen-tration on the surface of B cells. Properly speaking, otler-tuzumab is not an mAb; instead, it is an anti-CD37 protein

1

2

3

Mouse

A

B

Mouse

Human

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Constant

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CR3

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Humanized Fully human Glycosylated

Defucosylated

Figure 2. Evolution andmechanisms of action of mAb.A, evolution of mAbs over time.First murine mAbs were obtainedin 1975 before development ofchimeric (1984), humanized(1988–1991), and fully humanmAbs (1994–1999) optimizingpotency and tolerance of mAb.Recently, posttranscriptionalmodifications of the constantregion and selection ofglycosylated or defucosylatedisoforms of mAb were shown toenhance mAb efficiency. B,mechanisms of action of mAb:1) ADCC, 2) CDC, or 3) directinduction of programmed celldeath. CR3, complementreceptor 3; C1q, complementcomponent 1q. Panel B isreprinted from ref. 89. Reprintedwith permission fromMassachusetts Medical Society(Copyright � 2008).





Tab

le1.

Che

mothe

rapy-free

trea

tmen

tsat

vario

usstag

esof

dev

elop

men

tin

thetrea

tmen

tof

indolen

tB-celllym

pho

mas

Drug/m

Abna

mes

Targeted

Ag/m

olecu

lePredominan

tmec

hanism

ofac

tion

Referen

cesofclinical

stud

iesin

relapse

d/

refrac

tory

settingsa

Referen

cesofclinical

stud

iesin

thefirst-lin

ese

ttinga

Anti-CD20

sing

leag

ent

Ritu

ximab

CD20

ADCC/C

DC

(8–11

)(12–

18)

Ofatumum

ab(19,

20)

Obinutuz

umab

(23,

26)

Veltuzu

mab

(27–

29)

Other

cellsu

rfac

e–dire

cted

mAb

Epratuzu

mab

CD22

(35,

36)

Otle

rtuz

umab

CD37

(37)

Milatuzu

mab

CD74

(38,

39)

Galixim

abCD80

(40–

42)

Blinatum

omab

CD19

/CD3

Eng

ages

CD3þ

T-ce

llkilling

ofCD19

þB-cell

tumor

cells

(43)

Bs2

0�22

CD20

/CD22

Bispe

cificmAbreco

gnizing2B-celle

pito

pes

Vac

cine

Tumor

B-cell

idiotype

ADCC/C

DC

(45–

47)

(45)

Immun

omod

ulatory

mAb

Pidilizu

mab

/nivolum

ab/

lambo

lizum

abPD-1

Block

ingmAb(preve

ntsT-ce

llex

haus

tion)

(52)

NCT0

2038

946

NCT0

1953

692

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ingmAb(preve

ntses

capefrom

phag

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is)

Urelumab

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nistic

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sesADCC)

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n)

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Lena

lidom

ide

Multip

leMultip

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stersT-ce

llan

dNKce

llkilling

amon

gothe

rs)

(62–

66)

(67)

NCT0

1307

605

NCT0

1650

701

Other

targeted

therap

ies

Ibrutin

ibBTK

BCRpa

thway

inhibition

(71,

72)

NCT0

1779

791

NCT0

1829

568

Idelalisib

PI3Kd

BCRpa

thway

inhibition

(73,

74)

NCT0

1732

913

Bortezo

mib

26Sproteas

ome

Proteas

omeinhibition

(75–

79)

Bcl2

Rev

ersing

inhibition

ofap

optosis

(80)

Abbreviations

:Ag,

antig

en;B

CR,B

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luster

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n;IM

iD,immun

omod

ulatorydrug.

aEith

eras

asing

leag

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inco

mbination(m

ainlywith

aritux

imab

-con

tainingregimen

).

CCRFOCUS




Table 2. Main toxicities of chemotherapy-free therapeutic agents

Drug/mAbnames

(Reference),settings, andphase of trial

Most frequent AE of anygrade (approximate %)

Most frequent grade3/4 AE (approximate %)

Anti-CD20 singleagentsa

Rituximab (12)First-linePhase II

Headache (45)Fever (40)Pain (30)Asthenia (20)Pruritus (20)Hypotension (15)

Hypotension (<5)Hypertension (<5)

Ofatumumab (20)Rituximab-refractoryPhase II

Infection (30)Rash (15)Urticaria (15)Fatigue (15)Pruritus (10)Nausea (10)

Neutropenia (10)Infection (<5)Cough (<5)Urticaria (<5)

Obinutuzumabb (25)Relapsed/refractoryPhase II

Infection (50)Asthenia (35)Nausea (20)Pyrexia (15)Peripheral edema (15)Neutropenia (15)

Infection (15)Neutropenia (15)Lymphopenia (10)Infusion-related reaction (10)Anemia (5)Febrile neutropenia (5)

Veltuzumab (28)Relapsed/refractoryPhase II

Fatigue (25)Fever (15)Pruritus (15)Asthenia (10)Headache (10)Dyspnea (10)

Anemia (<5)Back pain (<5)

Other cell surface–directed mAbs

Epratuzumab (35)Relapsed/refractoryPhase II

Nausea (20)Fatigue (20)Back pain (20)Anemia (15)Limb pain (15)Rigors (15)

Infusion-related reaction(1 patient, grade 3 AE)

Otlertuzumab (37)Relapsed/refractoryPhase II

Fatigue (30)Nausea (30)Diarrhea (30)Neutropenia (25)Cough (20)Chills (20)

Neutropenia (20)Fatigue (10)Thrombocytopenia (5)Anemia (5)Dyspnea (<5)Back pain (<5)

Milatuzumabc (38)Phase I

NR Infusion-related reaction for1 patient (DLT)

No DLT at highest doses

Galiximab (41)Relapsed/refractoryPhase II

Fatigue (30)Nausea (15)Headache (10)Lymph node pain (5)Dyspepsia (5)Dysgeusia (5)

Deep venous thrombosis (5)Axillary pain (<5)

(Continued on the following page)





Table 2. Main toxicities of chemotherapy-free therapeutic agents (Cont'd )

Drug/mAbnames

(Reference),settings, andphase of trial

Most frequent AE of anygrade (approximate %)

Most frequent grade3/4 AE (approximate %)

Blinatumomab (43)Phase I

Pyrexia (75)Lymphopenia (75)Leukopenia (57)Headache (45)Thrombocytopenia (40)Fatigue (35)

9 of 52 patients developedCNS events (tremor,speech impairment,apraxia, and seizure)

(2 DLT)

ImmunomodulatorymAbs

Pidilizumab (52)Relapsed/refractoryPhase II

Fatigue (50)Anemia (45)Leukopenia (35)Thrombocytopenia (35)Dyspnea (20)Neutropenia (20)

None

IMiDs Lenalidomided (62)Relapsed/refractoryPhase II

Neutropenia (60)Fatigue (50)Thrombocytopenia (40)Anemia (40)Diarrhea (30)Leukopenia (30)

Neutropenia (50)Thrombocytopenia (20)Leukopenia (10)Anemia (10)Asthenia (5)Pneumonia (5)

Other targetedtherapies

Ibrutinib (88)f

Phase IIIDiarrhea (50)Respiratory tract infection (20)Fatigue (30)Cough (30)Arthralgia (25)Rash (25)

Neutropenia (15)Hypertension (5)Sinusitis (5)Pyrexia (5)Fatigue (5)Diarrhea (<5)

Idelalisib (74)Relapsed/refractoryPhase II

Increased ALT or AST (40)Diarrhea (40)Nausea (30)Fatigue (30)Cough (30)Dyspnea (20)

Neutropenia (30)Increased ALT or AST (15)Diarrhea (10)Pneumonia (5)Thrombocytopenia (5)Dyspnea (5)

Bortezomib (79)e

Relapsed/rituximab-naïve or-sensitive

Phase III

Diarrhea (50)Nausea (35)Pyrexia (25)Fatigue (22)Constipation (20)Neutropenia (20)

Neutropenia (10)Infection (10)Diarrhea (5)Herpes zoster (5)Peripheral neuropathy (5)Thrombocytopenia (5)

Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CNS, central nervous system;DLT, dose-limiting toxicity; IMiD, immunomodulatory drug; NR, not reported.aMost of toxicities are infusion-related reactions.bIn the 1,600/800-mg arm of treatment.cToxicities in indolent lymphoma were extrapolated from a phase I study in multiple myeloma as no study of the mAb in monotherapyhas been published in indolent lymphoma.dConcerns about secondary malignancies have been suspected, especially in association with melphalan in multiple myeloma (seecorresponding paragraph in the text).eToxicities were extrapolated from the rituximab þ bortezomib arm of treatment of the randomized phase III trial.fToxicities in indolent lymphoma were extrapolated from a phase III study in CLL as no sufficient data about indolent lymphoma arecurrently available.

CCRFOCUS




© 2014 American Association for Cancer Research

BCR

CD20

CD20

CD19

A

B

CCD79B

CD79A

NF-κB activation

PLCγ

BTKSYK

PI3K

LYN

CD20

PDL1/2HLA-C

CD22 CD37CD74

CD80

Lymphoma cell

FcγRFcγR

PD1

KIR

NK cellCD8 T cell

Lymphoma cell

Lymphoma cell

1

1

1

2

2

2

3

3

3

4

5Figure 3. A, mAbs directed againstcell surface antigenson the surfaceof the tumor cell. CD20 is theprototype of the targeted surfaceantigen and has revolutionizedthe management of B-cellmalignancies with rituximab, thefirst-in-human anti-CD20, andother anti-CD20 mAbs that arecurrently in development, such as1) ofatumumab, obinutuzumab,and veltzumab. 2) CD22 mightconstitute another promisingtarget in the treatment of indolentB-cell lymphoma. Other mAbs,such as 3) anti-CD37(otlertuzumab) and 4) anti-CD74(milatuzumab) antibodies, arecurrently in the early phase ofdevelopment, whereas the 5)anti-CD80 mAb (galiximab)provided modest results and hasnot been further developed.B, immunomodulation in indolentB-cell lymphoma. Therapeuticimmunomodulation of the T-cellresponse can be obtained bymany mechanisms, including1) inhibition of the PD-1/PD-L1/2receptor/ligand axis or 2) theKIR–HLA matched inhibitory axis.The biologic mechanisms oflenalidomide action are not yet fullyunderstood, but the drug isanother approach to fostering anantitumor response and has beenfound to 3) enhance NK- and T-cellkilling of tumor cells. C, intracellulartargeted therapy in indolentlymphoma. Advances in theunderstanding of dysregulatedpathways in B-cell malignancieshave paved the way for thedevelopment of new, targetedtherapies, such as inhibitors of theB-cell receptor (BCR) pathway.Both 1) ibrutinib, a first-in-humanBTK inhibitor, and 2) idelalisib,a PI3K d inhibitor, inhibit criticalkinases in this BCR signalingpathway, leading to cell death inlymphoma. HLA, human leukocyteantigen; Syk, spleen tyrosinekinase; Lyn, Lck/Yes-relatednovel tyrosine kinase; PLCg ,phospholipase C gamma.





therapeutic consisting of an IgG1 variable region and asmall, engineered constant region, allowing for bettertumor penetration. Otlertuzumab was well tolerated butproduced modest activity as a single agent in CLL in arecently published phase I study (37). CD74 is the invari-ant chain of the MHC class II molecule and is expressed innon-Hodgkin lymphoma. A phase I study evaluated thesafety of the anti-CD74 humanized antibody milatuzu-mab as a single agent in multiple myeloma (38), and aphase I study showed a safe profile and a 22% ORRin heavily pretreated patients with various non-Hodgkinlymphoma histologies who were treated with an associa-tion of milatuzumab and veltuzumab (including indolentand aggressive lymphomas; ref. 39).

The anti-CD80 mAb galiximab provided modest results,both as a single agent and in association with rituximab, infollicular lymphoma [72% of ORR with 48% of CR/CRu(unconfirmed CR) in de novo follicular lymphoma], and itsdevelopment was further placed on hiatus (40–42).

Bispecific antibodies, such as blinatumomab (an anti-CD19/anti-CD3 antibody that engage T cells andmalignantB cells) or Bs20�22 (a bispecific antibody against CD20and CD22 composed of epratuzumab conjugated with4 Fab regions from veltuzumab), are at the very early stagesof development for indolent lymphoma. Blinatumomabhas shown promising results albeit with notable toxicity(of the central nervous system; ref. 43). Preclinical data onBs20�22 demonstrated that it has more tumoricidal activ-ity than does the parent antibody alone (44). Toxicities ofthose mAb are presented in Table 2.

It remains to be determined whether or not clinical trialswill demonstrate that these new naked antibodies are ableto provide a substantial clinical benefit for patients withindolent lymphoma. Until then, they will remain investi-gational agents in the field.

Vaccine approachIdiotype vaccination consists in an immunization with

the tumor B-cell idiotype (i.e., the unique variable region ofthe B-cell receptor at the surface of the tumor B cell). Infollicular lymphoma, both humoral and cellular immuneresponses have been observed following idiotype vaccinestrategies. However, three phase III trials in follicular lym-phoma had disappointing results wherein the primaryendpoint was not achieved (45–47) except for one trialwith a significant disease-free survival coprimary endpointas per protocole (47). An interesting correlation betweenthe immune response against the tumor B-cell idiotype andthe PFS was demonstrated in one of these trials (46).

Immunomodulation in Indolent LymphomaTreatmentAntibody-based immunomodulation

Most therapeutic mAbs target surface antigens that areexpressed on the surface of the tumor cells and mediateCDC or ADCC.However, increasing numbers of antibodiesare now also designed to foster the antitumor immuneresponse (Fig. 3B and Table 1).

Indolent lymphomas are characterized by an importantinterplay between malignant cells and their microenviron-ment (48, 49). PD-L1 (programmeddeath ligand1) ishighlyexpressed by histiocytes within the T-cell–rich zone of thetumor follicles and is thought to play a crucial role in T-cellexhaustion (50, 51). The programmed cell-death 1 (PD-1)–PD-L1/2 axis was considered an attractive target, and dis-rupting this axis by anti–PD-1-blocking antibodies has pro-ducedpromising results.Westin and colleagues (52) recentlypublished the results of a phase II study on pidilizumab, ananti-PD1 antibody, combined with rituximab in relapsedfollicular lymphoma. The combination provided a highORR of 66% (19 of 29 patients) and CR rate of 52% (15of 29) with a median PFS of 18.8 months. Other anti–PD1-blocking antibodies, such as nivolumab or lambrolizumab(MK-3475), which demonstrated encouraging activity inmelanoma, are currently under scrutiny for the treatmentof indolent lymphoma (clinicaltrials.gov identifiers:NCT02038946 and NCT01953692).

Although no trials have either been published or arecurrently recruiting for evaluating the other immunomod-ulatory axes, blocking or agonistic antibodies that modifythe interaction of receptors, such as CD47, CD137, or killerimmunoglobulin-like receptor (KIR), with their ligands areemerging as promising tools in the treatment of indolentlymphoma (Table 1). CD47 is highly expressed on non-Hodgkin lymphoma tumor cells and inhibits phagocytosisthrough activation of signal regulatory protein a expressedon the surface of macrophages and dendritic cells. Thecombination of the blocking anti-CD47 antibody andrituximab was shown to increase Fc receptor (FcR)–depen-dent and –independent stimulation of phagocytosis andprolonged survival of mice transplanted with human lym-phoma cell lines (53). Anti-CD47 antibody has been testedas a single agent in a phase I dose-escalating study foradvanced ormetastatic solid tumors, but it has not yet beenused to treat hematologicmalignancies. CD137 is expressedand upregulated by natural killer (NK) cells upon bindingthe anti-CD20–covered non-Hodgkin lymphoma cells dur-ing activation. Agonistic anti-CD137 antibodies stimulateNK cells that have been activated by a tumor-specific mAb,resulting in increasedADCC(54–57). Trials evaluating anti-CD137 have been completed in solid tumors, but studies inindolent non-Hodgkin lymphoma in combination withrituximab are still needed. Similarly, MHC class I antigensexpressed on the surface of lymphoma cells decreaseNK cellantitumoral response via their interaction with KIR. There-fore, immunomodulation with blocking anti-KIR antibo-dies aimed at fostering the NK cell antitumor response iscurrently under development. Trials in myeloma, acuteleukemia, or solid tumors with anti-KIR antibody (lirilu-mab) are ongoing, and preclinical models in lymphomashow encouraging results (58).

Immunomodulatory drugs in indolent lymphomaFirst successfully used in multiple myeloma, immuno-

modulatory drugs (IMiD) such as lenalidomide havenow entered the armamentarium against indolent

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lymphomas (Table 1 and Fig. 3B). Whereas somewhatdisappointing results in indolent lymphoma wereobserved with the use of thalidomide as a single agent(59, 60), encouraging response rates were observed withlenalidomide. A defect in the ability of tumor-infiltratingT cells to form an immune synapse with tumor cells wasdemonstrated in patients with follicular lymphoma, andthis defect was reversed by treatment with the IMiDlenalidomide (61).A pilot phase II trial was conducted in relapsed/refractory

indolent non-Hodgkin lymphoma with lenalidomide. Thistreatment yielded amoderate ORR of 23%with a 7%CR orCRu but a prolonged response duration (RD) amongresponders (median RD was at least 16.5 months; ref. 62).As expected, grade 3/4 adverse events included neutro-penia and thrombocytopenia. Encouraging results withlenalidomide prompted several cooperative groups world-wide to use the drug in combination with chemotherapy(which is beyond the spectrum of this review) and/orrituximab. Three phase II studies confirmed the efficacy oflenalidomide when used with rituximab in relapsed andrefractory patients with an ORR ranging from 49% to 86%,except in grade 3 follicular lymphoma cases in which only a25% response was observed (63–65). Preliminary resultsfroma randomized study comparing lenalidomide alone orin combinationwith rituximabdemonstrated a clear benefitof the combination with an ORR of 75% and 32% CR/CRucompared with 49% and 13%, respectively, with the use oflenalidomide as a single agent. The EFS was also signifi-cantly prolonged in the combination treatment arm (2.0 vs.1.2 years, P ¼ 0.0063; ref. 66).In de novo indolent lymphoma, a phase II study

assessed the safety and efficacy of lenalidomide andrituximab for 110 patients with advanced-stage diseaseand various histologies [small lymphocytic lymphoma(SLL), n ¼ 30; follicular lymphoma, n ¼ 50; marginalzone lymphoma, n ¼ 30]. The ORR for evaluable patientswas 90% for all patients and an impressive 98% infollicular lymphoma (87% CR/CRu). As an indicator ofthe depth of response, nearly all patients with follicularlymphoma experienced a molecular response, as assessedby PCR, at the end of therapy (6 courses of a 28-day cycle)and 93% achieved a metabolic response, as assessed byPET scanning (42 of 45 with an initial PET scan evalu-ation; ref. 67).To confirm these excellent results with a chemo-free

regimen combining lenalidomide and rituximab, two ran-domized trials are currently ongoing. The trial from theSwiss and Nordic lymphoma groups (clinicaltrials.govidentifier: NCT01307605) enrolled patients with advanced-stage follicular lymphoma in need of therapy. This trialcompared four courses of weekly rituximab at weeks 1, 2, 3,and 4 followed by four more weekly infusions (in case of aresponse at week 10) at weeks 12, 13, 14, and 15 with thesame regimen in combination with lenalidomide at a 15-mgdose without interruption. A study conducted by the Lym-phoma Study Association group and U.S. investigators(clinicaltrials.gov identifier: NCT01650701) aims to com-

pare an immunotherapy-based induction regimen followedby a 2-year rituximabmaintenance dosing as designed in thePRIMA trial (experimental arm of treatment; ref. 68) with alenalidomide plus rituximab regimen (induction andmaintenance).

However, the long-term safety profile of lenalidomideusemust be carefully followed given concerns about secondarymalignancies that have emerged in patients with multiplemyeloma, but particularly when lenalidomide is used inassociationwith alkylating agents such asmelphalan (Table2; ref. 69).

Targeted Therapy Other than mAbsBTK and PI3K inhibitors

Ibrutinib (formerly PCI-32765), a first-in-human Bru-ton’s tyrosine kinase (BTK) inhibitor, was specified as a"breakthrough therapy" by the FDA in 2013 (Fig. 3C). Itdisplayed impressive preclinical activity both in vitro andin vivo in animal models (70), and already achieved FDAand EMA approval for mantle cell lymphoma and CLL. Aphase I trial evaluated escalating doses of ibrutinib with-out reaching an MTD. Six of 16 patients with follicularlymphoma, 3 of 4 with Waldenst€om macroglobulinemia,and 1 of 4 with mantle cell lymphoma achieved a clinicalresponse (71). The FLR2002 study a phase II single-armstudy of ibrutinib, aims to enroll 110 patients withrelapsed/refractory follicular lymphoma and is ongoing(clinicaltrial.gov identifier NCT01779791; ref. 72). Othertrials testing ibrutinib in combination with rituximab(clinicaltrial.gov identifier NCT01980654) and lenalido-mide (clinicaltrial.gov identifier NCT01829568) are cur-rently accruing (Table 1).

Idelalisib (formerly CAL-101 or GS-1101), a PI3K dinhibitor (Fig. 3C), was recently approved by the U.S. andEuropean Union drug agencies for CLL (in combinationwith rituximab) and for follicular lymphoma. In a phase Istudy, idelalisib showed no major toxicity with an encour-aging 47% response rate in patients with indolent lympho-ma (73). Full FDA approval in CLL was based on a ran-domized trial in combination with rituximab versus ritux-imab with placebo, whereas in follicular lymphoma, accel-erated approval was based on a phase II single-arm, open-label study. Among the 125 patients (follicular lymphoma,n ¼ 72; SLL, n ¼ 28; Waldenst€ommacroglobulinemia, n ¼10; mantle zone lymphoma, n¼ 13) enrolled, the ORRwas57%with a CR rate of 6%, themedian duration of responsewas 12.5months, and themedian PFS was 11months (74).Other PI3K inhibitors and combinations of idelalisib withother agents (clinicaltrial.gov identifier NCT01732913),including rituximab, are under investigation (Table 1).

Although ibrutinib and idelalisib are well tolerated(Table 2), no long-term follow-up is currently available.

Other agentsProteasome inhibitors, such as bortezomib, provided

encouraging results as a monotherapy (75–77) or in asso-ciation with rituximab (78), and drug exposure seemed to





play a role in the activity. Although the PFSwas significantlyprolonged in combination with rituximab in a phase IIIrandomized trial for relapsed rituximab-na€�ve or rituximab-sensitive patientswith follicular lymphoma (P¼0.038), thelimited median PFS improvement (12.8 months vs. 11months) was considered as being clinically irrelevant inthis chronic disease (79; Table 1). Data on the preclinicalefficacy and clinical safety of carfilzomib in lymphoma areemerging (80, 81).

Emerging preliminary clinical data with the bcl-2inhibitor ABT/GDC-199 showed 28% of response in 13patients with follicular lymphoma, 75% in 4 patients withWaldenst€om macroglobulinemia, and 67% in 3 patientswith marginal zone lymphoma, respectively (82). Thiscompound will be rapidly evaluated, as a single agent orin combination, further expanding the chemo-free appro-aches in indolent lymphoma.

ConclusionsIn a matter of only a few years, targeted therapies have

changed the landscape for lymphoma treatment in generaland indolent lymphoma treatment in particular. A briefoverview of such treatments is presented in this review,whereas new directions in other lymphoma subtypes arepresented in this edition of CCR Focus (83–87). Amongother promising approaches, combining anti-CD20 anti-bodies with IMiDs, mAbs directed against other surfaceantigens such as CD22, immunomodulatory antibodiessuch as PD-1, or inhibitors of the B-cell receptor (BCR)pathway is of paramount interest. Among inhibitors of theBCR pathway, PI3K inhibitors such as idelalisib mightrapidly be a key treatment of indolent lymphoma due toits high potency and favorable toxicity profile.

Off-target effects of such therapies must not be under-estimated. Chemo-free treatments are not "toxicity-free"

treatments, and significant side effects might be IRR withmAbs, cytopenias with lenalidomide, or cytolytic hepatitiand diarrhea or pneumonitis with idelalisib. Furthermore,no sufficient long-term follow-uphas beenprovided to fullyaddress the question of detrimental side effects such assecondary neoplasia. The benefit–cost ratio of such thera-pies will have also to be fully appraised because the price ofthose new agents is high.

With the use of rituximab as a single agent in routinepractice for selectedpatients,wehave already entered the eraof chemo-free regimens for the management of patientswith indolent lymphoma.However, at least for high–tumorburden follicular lymphoma, nodal and extra-nodalmantlezone lymphoma, Waldenst€ommacroglobulinemia, or SLL,immunochemotherapy-based treatments are still the stan-dard of care for first-line treatment, and chemo-free regi-mens cannot be recommended outside of clinical trials. It isof utmost importance for the design of these studies enableus to evaluate the true clinical benefit of these agents andtheir long-term safety, to allow the regulatory approval ofthe new agents and establish their use in therapeutic algo-rithms for clinical practice.

Disclosure of Potential Conflicts of InterestE. Bachy is a consultant/advisory board member for Roche. G. Salles

reports receiving a commercial research grant from Roche and is a consul-tant/advisory board member for Amgen, Gilead, Janssen, Mundipharma,and Roche. No other potential conflicts of interest were disclosed.

Authors' ContributionsConception and design: E. Bachy, G. SallesDevelopment of methodology: E. Bachy, G. SallesWriting, review, and/or revision of the manuscript: E. Bachy, G. SallesStudy supervision: G. Salles

ReceivedMay 19, 2014; revised August 3, 2014; accepted August 19, 2014;published online October 15, 2014.

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2014;20:5226-5239. Clin Cancer Res Emmanuel Bachy and Gilles Salles Indolent Lymphoma?Are We Nearing an Era of Chemotherapy-Free Management of

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