New horizons in the treatment of chronic lymphocytic leukemia

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Review/Praca poglądowa

New horizons in the treatment of chronic lymphocytic leukemia

Nowe horyzonty w leczeniu przewlekłej białaczki limfocytowej

Tadeusz Robak *

DepartmentofHematology,MedicalUniversityofLodz,CopernicusMemorialHospital,Head:prof.drhab.n.med.

TadeuszRobak,Lodz,Poland article info

Articlehistory:

Received:18.03.2014 Accepted:31.03.2014 Availableonline:13.04.2014

Keywords:

ABT-199

Ibrutinib

Idelalisib

Obinutuzumab

Otlertuzumab

CART

Słowakluczowe:

ABT-199

Ibrutinib

Idelalisib

Obinutuzumab

Otlertuzumab

CART

abstract

Chroniclymphocyticleukemia(CLL)isthemostcommonadultleukemiainthewestern world,accountingforapproximately30%ofallleukemiasinEuropeandNorthAmerica.

Recently,significantprogressin thecharacterization and understandingofthe biology andprognosisofCLLhasprovidednewopportunitiesforthedevelopmentofinnovative, moreeffectivetherapies.Severalnewanti-CD20monoclonalantibodiesdirectedagainst lymphoidcellshave been developed andare underinvestigationin preclinical studies andclinicaltrials.Currently,themostpromisingisobinutuzumab,anovelthirdgenera- tionanti-CD20monoclonalantibodythatexhibitssuperiorcaspase-independentapopto- sis and antibody-dependent cellular cytotoxicity than rituximab. The antibody has showna safety profilesimilar tothat ofrituximab and promisingefficacy in patients withCLL.The CD37antigenmaybeadvantageous overCD20in diseasesinwhichthe levelofCD37 expressionis higher thanthatofCD20. The resultsof recentpreclinical andearly clinical studies suggest thatanti-CD37antibodies and relatedagents canbe usefulinthetreatmentofCLL,andmanysmallmoleculeinhibitorstargetingB-cellanti- gen receptor (BCR) signaling pathways have recently been under investigation in patients. Promising clinical results have been observed with a Btk inhibitor, ibrutinib, anda selectiveinhibitorofPI3Kd,idelalisib.Severalotheragentsincludingimmunomo- dulatingagentsandthosetargetingtheantiapoptoticbcl-2familyofproteinsalsoshow promiseintreatingCLL.Moreover,immune-basedtreatmentstrategiesintendedtoaug- mentthecytotoxicpotentialofTcellsofferexcitingnewtreatmentoptionsforpatients withCLL.

*Correspondenceto:KatedraiKlinikaHematologiiUniwersytetuMedycznegowŁodzi,ul.Ciołkowskiego2,93-510Łódź,Poland.

Tel.:+48426895191;fax:+48426895192.

E-mailaddress:robaktad@csk.umed.lodz.pl.

ContentslistsavailableatScienceDirect

Acta Haematologica Polonica

journal homepage:www.elsevier.com/locate/achaem

http://dx.doi.org/10.1016/j.achaem.2014.04.008

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Introduction

Chronic lymphocytic leukemia (CLL) is a B-cell malignant disease with a progressive accumulation of B cells in the blood, bonemarrow and lymphatic tissue, and follows an extendeddisease course.Itisthe mostprevalentleukemia intheWesternWorldwithanestimated15,720newcases in2014 andalmost4600attributabledeaths peryearinthe United States[1]. Themedianage at diagnosis is72 years and90% of patientsare olderthan 50 years.Thediagnosis of CLL requires the presence of at least 5000 leukemic Blymphocytespermicroliterintheperipheralblood[2].The managementofCLLisdeterminedbythestageandactivity of the disease, as well as age and comorbidities. Rando- mized studies and a meta-analysis indicate that early initiation of chemotherapy does not show beneﬁt in CLL and may increase mortality. There is no evidence that cytotoxictherapy basedon alkylatingagentshas beneﬁcial effectsinpatientswiththeindolentformof thedisease[3].

Thestrategyof watchfulwaitingor observation,i.e.closely monitoring patient status without giving any treatment until progression, may be adopted [4]. However, patients with symptomatic and/or progressive disease should be immediatelytreated.

CLLis typicallysensitivetoavariety of cytotoxic drugs, butthe diseaseisconsidered incurable.Therehasbeen an important increase in the range of available therapeutic options in recent years, and many drugs are now in the process of making the transition to the clinic [5]. The approval of rituximab-based immunochemotherapy can be viewedasasubstantialtherapeuticadvanceinCLL.Alarge phase III randomized trial demonstrated that rituximab combined with ﬂudarabine and cyclophosphamide (RFC) increasedthe overallresponse(OR) andcomplete response (CR)rates,andprolongedprogressionfreesurvival(PFS)and overallsurvival (OS) compared withﬂudarabine and cyclophosphamide (FC) in previously untreated and relapsed/

refractory patients[6, 7]. Forthe last twenty years, signiﬁ- cantprogressinmolecularandcellularbiologyhasresulted in a better characterization and understanding of the biology and prognosis of CLL. These achievements have providednewopportunitiesforthedevelopmentofinnova- tive,moreeffectivetherapiesinthisdisease.

Monoclonal antibodies and related agents

Several new anti-CD20 monoclonal antibodies directed against lymphoid cells have been developed and investi- gatedinpreclinicalstudiesandclinicaltrials[8].Theresults ofpreclinicalandclinicalstudiessuggestthattherapywhich uses monoclonal antibodies (mAbs) directed at a target other than CD20 can be useful in treating CLL [9]. Such treatments include lumiliximab (anti-CD23), epratuzumab (anti-CD22), apolizumab (anti-MHC-II), galiximab (anti- CD80), anti-CD40 monoclonal antibodies and TRU-016, a small modular immunopharmaceutical (SMIP) derived from the fusion of key domains of an anti-CD37 antibody withahumanprotein.

Novelanti-CD20antibodies

Several new anti-CD20 monoclonal antibodies directed againstlymphoidcellshavebeendevelopedandinvestigated in preclinical studies and clinical trials [8]. Obinutuzumab (Gazyva^TM, GA-101,RO5072759, Roche)isa novelthirdgen- erationmonoclonalantibodywhichisdistinctfromrituximab [10].The antibody isbased onproprietaryGlycoMAb^®technology, whichincorporates glycoengineered antibodies that speciﬁcallyincreaseantibody-dependentcellularcytotoxicity (ADCC) and thereby increase immune-mediated target cell death,andisobtainedbyhumanizationoftheparentalB-Ly1 mouse antibody followed by a glycoengineering process developedbyGlycArtBiotechnology(laterRocheGlycartAG).

Comparedtorituximab,obinutuzumabtreatmentleadsto5– 100 times greaterinductionof ADCC,as it bindswith high afﬁnity to the CD20 epitope, and also exhibits superior caspase-independent apoptosis induction [11, 12]. However, reductionincomplement-dependentcytotoxicity(CDC)upon bindingtoCD20wasobserved.Basedonthisdata,obinutuzu- mabmAbisapromisingtherapeuticagentforCD20positive B-celllymphoidmalignancies,includingCLL.

InaphaseI/IIastudy,obinutuzumabwasadministeredas asingleagentto24patients,atdosesfrom50to2000mg[13].

The antibody hasshown a safety profile similar to that of rituximab and promising efficacy in patients with CLL and other CD20⁺ malignant disease, for whom no therapy of higher priority was available [14]. The results of a large randomized phase III trial testing three first-line chemoimmunotherapy regimes, i.e. combined obinutuzumab and chlorambucil, combined rituximab and chlorambucil and chlorambucil monotherapy, in patients with comorbidities havebeenrecentlyreported(CLL11)[15,16].Inthistrial781 patients with previously untreated CLL and a score higher than 6 on the Cumulative Illness Rating Scale (CIRS)or an estimatedcreatinine clearanceof 30–69mlperminute were included. Treatment with obinutuzumab–chlorambucil, as compared with rituximab–chlorambucil, resulted in higher rates of complete response (20.7% vs. 7.0%) and molecular response. The primary end point was investigator-assessed PFS. Treatment with obinutuzumab–chlorambucil or rituximab–chlorambucil increased response rates and prolonged PFS as compared with chlorambucil monotherapy. Median PFSwas26.7monthswithobinutuzumab–chlorambucil,15.2 months for rituximab–chlorambucil, and 11.1 months for chlorambucil alone (P<0.001). In addition, patients treated with obinutuzumab–chlorambucilhadlonger OS thanthose treated with chlorambucil alone (P=0.002). However, infusion-related reactions and neutropeniawere morecommon in patients treated with obinutuzumab–chlorambucil than with rituximab–chlorambucil. Obinutuzmab–chlorambucil treatment was associated with more grade 3–4 adverse events, mainlyinfusion-relatedreactionsthat occurreddur- ingthefirstinfusion.Infusion-relatedreactionswerenotedin 20%ofpatientstreatedwithobinutuzumab–chlorambuciland 4% of patientstreated withrituximab–chlorambucil.Incon- trast,theriskofinfectionwassimilarinbotharms.TheU.S.

FoodandDrugAdministration(FDA)approvedobinutuzumab for use with chlorambucil in patients with previously untreatedchroniclymphocyticleukemia[17].

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Ofatumumab (HuMax-CD20; Arzerra^TM, GlaxoSmithKline plc/Genmab A/S) is a fully human, IgG1 mAb recognizing a different CD20 epitope to rituximab, and demonstrating ahighercytotoxicpotentialthanrituximab[18].Ofatumumab ismoreeffectivethanrituximabatCDCinductionandkilling targetcells[19].Theclosebindingproximityofofatumumab tothecellmembranelikelyresultsinhighlyefﬁcientcomple- mentdepositiononB-cellmembranes,withouthighlevelsof systemic releaseof activated complement components[20].

Ofatumumab, in comparison to rituximab, demonstrates greater CDC in B-cells and does not induce cell death by apoptosis.

TheresultsofaphaseIIIstudydemonstratethatofatumu- mabmonotherapy showspromisingefficacyin heavilypre- treated patients with fludarabine- and alemtuzumab- refractoryCLL[21].Inthisstudy,patientsreceivedeightonce- weekly infusions of ofatumumab followed by four once- monthly infusions during a 24-week period. The OR rates were 58% and 47% in the fludarabine- and alemtuzumab- refractory groups and fludarabine-refractory CLL with bulky lymphadenopathygroups, respectively.TheORratesamong patients refractorytoRFC were50% and44% inthe fludarabine- and alemtuzumab-refractory groups, respectively.

MedianPFS and OStimes were 5.7and 13.7monthsin the fludarabine-andalemtuzumab-refractorygroups,and5.9and 15.4 months, respectively, in the fludarabine-refractory patients with bulky lymphadenopathy. In 2009, the FDA granted accelerated approval to ofatumumab for the treat- mentofpatientswithfludarabine-andalemtuzumab-refrac- toryCLL, based onaclinicallymeaningfulanddurableORR observed in the above trial (Hx-CD20-406). In 2010, the European Medicines Agency (EMA) granted a conditional marketingauthorization for ofatumumab,for the treatment offludarabine-andalemtuzumab-refractoryCLLpatients.

In a recent randomized trial (Complement 1), ofatumumab+chlorambuciltherapywascomparedwithchlorambucil alone inpatients with CLL who requiredtherapy andwere considered inappropriate for ﬂudarabine-based therapy due toadvancedageand/orco-morbidities[22].Theresultsofthis study indicate that ofatumumab+chlorambucil is superior than chlorambucil alone in this patient population. The ofatumumab+chlorambucil armdemonstrated a higher OR ratethan the chlorambucilarm(82%vs. 69%)(P=0.001), as well as a superior CR rate (12% vs. 1%). PFS was also signiﬁcantly prolonged in the ofatumumab+chlorambucil arm (22.4 months) compared to chlorambucil alone (13.1 months, P<0.001). Witha median follow-upof 29months, medianOSwasnotreachedforboththegroups.

Anti-CD37antibodies

CD37 isa heavilyglycosylated 40–52kDa tetraspanintrans- membrane family protein, which consists of 4 potential membrane-spanningregions,2extracellularloopsand2short intracytoplasmictails[23].Thismoleculemayplayarolein immunecellproliferationandinﬂuencessignalingviatheAkt pathway[24].CD37isselectivelyexpressedonmatureBcells, with its highest expressionon peripheralblood B cells. Its signiﬁcant expression was found on neoplastic cells of patients with CLL, hairy cell leukemia and non-Hodgkin's

lymphoma(NHL)[25].TherelativelineagerestrictionofCD37 toBcellsmakesitasuitabletargetforimmunotherapy.CD37 internalizes and has modest shedding in the malignant B cellswhichexpressit.ItmaybeadvantageoustotargetCD37 overCD20indiseasesinwhichthelevelofCD37expressionis higher than that of CD20. The predominant expression of CD37onCLLcellsmakesitanidealcandidateasatherapeutic target fortreatmentofCLLandhasarousedgreatinterestin theinvestigationofanti-CD37antibodies[26,24].

Theresultsofrecent preclinicalandearlyclinicalstudies suggest that anti-CD37 antibodies can be useful in the treatmentofCLL[27].BI836826(MAb37.1)isachimericIgG1 typeofanti-CD37moleculewhichhasbeenFc-engineeredto improve ADCC activity and enhance afﬁnity for Fc-gRIIIa.

BothmAb37.1anditshumanisedversion,MAb37.2,deplete CLLcellsinvitromoreeffectivelythanrituximabandalemtu- zumab[28].BI836826isunderinvestigationinCLLinaphase Iclinicaltrial(ClinicalTrials.govIdentiﬁer:NCT01296932).

Otlertuzumab (TRU-016) is produced using ADAPTIR^TM Modular Protein Technology and has shown activity in preclinical studies andclinical trials [29]. ADAPTIRproteins haveadifferentiatedstructurefrom classicalmAbsandcan generateauniquesignalingresponse.Inaddition,theymay mediateCDCandFc-dependentcytotoxicityinasimilarway tomAbs.Otlertuzumabisanengineeredproteinthatincludes anti-CD37 variable regions linked to an immunoglobulin constant domain, produced by humanizing the precursor agent SMIP-016, a single chain monospeciﬁc protein that retains Fc-mediatedeffectorfunctions[29,30].Inpreclinical studies this agent was found to employ a mechanism of apoptosis distinct from those of other agents used for CLL treatment. In addition, otlertuzumab has demonstrated a signiﬁcantly greater ability to directly kill CLL cells than rituximabandgreaterFc-mediatedcellularcytotoxicityofCLL cellsthaneitheralemtuzumaborrituximab[31].TRU-016also mediates greater NK cell mediated killing of CLL cells as comparedtoeitheralemtuzumaborrituximabandmediates superior direct apoptosis of CLL andother B-cellmalignan- cies. Moreover,otlertuzumabacts synergisticallywith bendamustine.

AphaseIstudyinvestigatedotlertuzumabinpatientswith relapsed/refractory CLLor SLL [32]. TRU-016was well tolerated with minimalinfusional toxicity.Responseoccurred in 19of83treatedpatients(23%)accordingtoNCI-96criteria.All responses were partial, and occurred more commonly in patients with symptomatic, untreated CLL. Recently, the resultsofarandomizedtrialofotlertuzumab+bendamustine vs. bendamustine alone were reported [33]. Patients with relapsedCLLwhohadundergone1–3priortherapiesreceived otlertuzumab (20mg/kg)weekly byi.v. infusion for two28- day cycles then every 14 days for four 28-day cycles, and bendamustine (70mg/m²) was administered i.v. on days 1and2ofeachcycleforuptosix28-daycycles.Inthecontrol arm,bendamustine(70mg/m²)wasgiveni.v.ondays1and 2ofeachcycleforuptosix28-daycycles.Among65patients included inthe study, 32 received otlertuzumabplus bend- amustineand33weretreatedwithbendamustinealone.The responserateobservedinpatientstreatedwithotlertuzumab +bendamustine washigher than thatinthosetreated with bendamustine alone.According to theNCI assessment,the

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ORrate in the otlertuzumab+bendamustine arm was 75%, with aCRrateof 48%,comparedtoanORrateof 52%and a CR rate of 9% in the bendamustine arm. No increase in serious adverse events were noted in the otlertuzumab +bendamustinearmversusthebendamustinearm.Ahigher rate of neutropenia was observed, but no greater rate of infectionwasseeninthecombinationarm.Neutropeniawas notedin50%ofpatientsfromtheotlertuzumab+bendamus- tinegroupand39%inthecontrolarm.Infectionswerenoted in50% of the patients inthe otlertuzumab+bendamustine armcompared to 55% in the bendamustine arm, similarly, pneumonia wasobserved in9% and15% of patientsin the combinedandmonotherapygroups,andgrade3/4thrombo- cytopenia was observed in 19% and 12%. These results suggestthatotlertuzumabcanbeavaluabledruginCLL,but itssuccesswilldependonitdemonstrating superiorityover available monoclonal antibodies and other emerging thera- piesinachievingandsustainingCRsandimprovingsurvival.

Futurephase II andIII clinical trials inthe developmentof otlertuzumab should also evaluate combinations with chemotherapy and/or other targeted therapies in comparison withwhatisconsideredstandardofcare,especiallyR-FC,in CLLpatients.

Theclinicaldevelopmentofanti-CD37mAbsandrelated agentsfor the treatment of CLL ischallenging, and future phaseIIandIIIclinicaltrialsofotlertuzumabandBI836826 inCLL patientsshouldbeinformative.Although thedevel- opment of these agents into a clinically useful therapy is probably many years away, its progress will be followed

with great interest by laboratory investigators and clini- cians.

B-cell receptor inhibitors

TheuseofB-cell antigenreceptor(BCR)signaltransduction inhibitors also represents a promising new strategy for targeted CLL treatment. Recently, many small molecule inhibitors targeting BCR signaling pathways have been underinvestigationinpatientswithCLL,includingBruton's tyrosinekinase(Btk)inhibitors,spleentyrosinekinase(Syk) inhibitorsandphosphatidylinositol3-kinase-d(PI3Kd)inhibitors[34].Theseagentsinducerapidresolutionoflymphade- nopathy and a transient increasein lymphocytosis dueto mobilization of CLL cells into the peripheral blood. BCR inhibitors are highly active and well tolerated in CLL patients, irrespective of high-risk genomic abnormalities and suggest that these drugs may be an important new targetedtreatmentapproachforthisdisorder[34].

PromisingclinicalresultshavebeenobservedwithaBtk inhibitor, ibrutinib (PCI-32765, Pharmacyclics), and a selective inhibitor of PI3Kd, idelalisib (CAL-101, GS-1101, Calistoga Pharmaceuticals/Gilead) (Fig. 1). These drugs are available in oralpreparations and are given ascontinuous treatment.Theyseemtobeactiveintraditionallypoorrisk disease groups,includingﬂuarabine-refractory patientsand patientswithbulkylymphadenopathy.Thesedrugsarepart of apromising new strategyfor targeted treatmentof CLL

Fig.1–ChemicalstructuresofnewsmallmoleculespotentiallyusefulinthetreatmentofCLL

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and are currently undergoing clinical development. These agents induce rapid resolution of lymphadenoapathy and atransientincreaseoflymphocytosisduetomobilizationof CLL cells into the peripheral blood. However, after several monthsofcontinuoustherapy,responsecanbeachievedin asubstantialnumberofpatients[35,36].

Ibrutinib

Ibrutinib (PCI-32765; Imbruvica, Pharmacyclics, Inc./Johnson

& Johnson) is an irreversible covalent inhibitor of the Btk, a critical enzyme in the BCR signaling pathway that is essential for B-cell proliferation, survival, migration, and tissue homing [34, 37]. It is a ﬁrst-in-class, oral covalent inhibitor of Btk designed for treatment of B-cell lymphoid malignancies.Initialreportsontheuseofibrutinibasasingle agentfoundthatitwaswell-toleratedandparticularlyactive inpatients with refractory/relapsedCLL patients. The most commonadversereactionsreportedintheCLLclinicaltrials werethrombocytopenia,diarrhea,bruising,neutropenia,ane- mia,fatigue,musculoskeletalpain,rash,pyrexia,constipation andarthralgia.

Byrd et al. conducted a phase Ib/II multicenter study to assessthesafety,efﬁcacy,pharmacokinetics,andpharmaco- dynamics of ibrutinib in relapsed CLL [38]. A total of 85 patientsweretreatedwithibrutiniborallyoncedaily,including 51 who received 420mg, and 34 who received 840mg.

Ibrutinib was associated with a high frequency of durable remissions inpatients with relapsed or refractoryCLL. The ORrate wassimilar between patients who received 420mg and those who received 840mg (71%). In addition, CR was notedin20%and15%ofpatients,respectively.Theresponses wereindependentofclinical andgenomicriskfactorsnoted before treatment, including advanced-stage disease, the number of previous therapies, and 17p13.1 deletion. At 26 months,theestimatedPFSratewas75%andtheOSratewas 83%. Toxic effects included transient diarrhea, fatigue, and upper respiratory tract infections. Hematologic toxic effects were minimal and the patients could receive extended therapy. O'Brien et al. assessed the safety and activity of ibrutinib in 29 treatment-naive patients with CLL, aged 65 years and older, in open-label phase Ib/II trial [39]. After a median follow-up of 22 months, 22 of 31 patients (71%) achievedanobjective response,including4CR(13%),1(3%) nodular PR, and17 (55%) PR.In 21 (68%) patients, diarrhea wasobservedincludinggrade2inthreepatients,andgrade 3infourpatients.

Ibrutinib in combination with rituximab is well tolerated anddisplayssigniﬁcantactivityinhigh-riskCLL[40].Inupdated phaseIIsingle-centerclinicaltrial,withamedianfollow-upof 14months,40patientsweretreatedwithibrutinib420mgp.o.

daily continuously throughout the study with rituximab 375mg/m²administeredweeklyfortheﬁrstfourweeksincycle 1andthenmonthlyuntilcycle6.Twentypatientshaddel17p orTP53mutationand13patientshaddel11q.Intheupdated analysis,34(87%)patientsachievedaPR,andthree(8%)aCR, accountingforanORrateof95%.TheORrateinthe20patients withdel17porTP53mutationwas90%.

Acombinationofibrutinibandbendamustine(BR)isalso highly activeand well tolerated inpatients with relapsed/

refractory CLL[41].Inthe studyperformed byBrownetal., 30 patients with refractory/relapsed CLL and a median of 2 prior therapies received up to 6 cycles of BR with acontinuousﬁxedibrutinibdoseof420mg/dayuntildisease progression or toxicity. The OR rate was 93%, including 5 CRs and 3 nodular PR (nPR), and one additional patient achievedaPRwithlymphocytosis.Theestimated12month PFS was 90%.Themostfrequentlyreportedadverse events (AEs) were diarrhea (70%), nausea (66.7%), fatigue (46.7%), neutropenia (40%) and upper respiratory tract infection (36.7%).Themostfrequentlyreportedgrade3orhigherAEs were neutropenia,maculopapular rash, fatigue and thrombocytopenia.

A randomized, multicenter, open-label, phase III study basedonarandomizedgroupof previouslytreatedpatients with CLL or SLL who were not considered candidates for treatment with purine analog-based treatments, was initiated in June 2012 (ClinicalTrials.gov Identiﬁer:

NCT01578707). Ofatumumab was administered over 24 weeks for12dosesoruntildiseaseprogressionorunaccep- tabletoxicityat 300mginitialdoseand then2000mgonce weekly in week 2 through 8, and then every 4 weeks on week 12, 16, 20 and 24. Ibrutinib was given at a dose of 420mg(3140-mgcapsules)orallyoncedailyuntildisease progression orunacceptabletoxicity.After interimanalysis, the trial was stopped earlybecause of an improvementin PFS and OS in the ibrutinib arm. In February 2014, FDA granted accelerated approval toibrutinib for the treatment of patients withCLL who have received at leastone prior therapy. Therecommendeddose and schedule of ibrutinib for patients with CLL is 420mg taken orally once daily.

However,ibrutinibwillbeanexpensivedrug.Someanalysts estimatethatitwillcost$98000ayear[37].

Idelalisib

Idelalisib (CAL-101, GS-1101, Calistoga Pharmaceuticals/

Gilead) is an oral, ﬁrst-in-class speciﬁc inhibitor of PI3Kd with potent apoptotic activity against leukemic CLL cells.

PI3Kdsignaling ishyperactive inmanyB-cell malignancies, including CLL. Idelalisib used in monotherapy has shown substantialclinical activityandafavorable safetyproﬁlein heavily pretreated, refractory and high-risk patients with CLL.

InaphaseIstudy,patientswithrelapsed/refractoryCLL were treated continuously with oral idelalisib as a single agentatadoseof50mg(QDorBID)[42].Theﬁnalresultsof this study were recently reported [43]. Fifty-four patients weretreatedcontinuouslywithsingle-agentidelalisibat50– 350mg/dose(QDorBID).Theoverallresponseratewas56%

including2CRand28PR.Themediantimetoﬁrstresponse was 1.9monthsandmedianPFSwas17months.Themost common grade 3 AEs included fatigue, diarrhea, pyrexia, rash, upper respiratory tract infection and pneumonia.

Coutreetal.reportthatidelalisibasasinglesalvagetherapy offered impressive response rates in heavily pretreated patientswithrelapsed/refractoryCLL[44].Idelalisibshowed robust activity independent of high-risk features,including del(17p)/TP53 mutation, del(11q), IGHV mutation, and NOTCH1mutation.

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Barrientosetal.presentedtheresultsof aphaseIstudy of idelalisib in combination with rituximab and/or bendamustine in patients with relapsed or refractory CLL [45].

Theoverall response rate was 81%, including a CR in one patient.Themediantimetoresponsewas1.9months,and the2-yearPFS andOSwere62%and85%,respectively.The mostcommongrade3AEswerepyrexia,diarrhea,cough, fatigue andnausea. Theseresultsindicatethat acombina- tion of idelalisib with rituximab and/or bendamustine is tolerable and highly active in patients with relapsed or refractoryCLL.O'Brienetal.recentlyreportedtheresultsof anup-fronttherapywithidelalisibandrituximabinpatients over 64 years old with CLL [46]. They were treated with rituximabgivenatadoseof 375mg/m²weeklyfor8weeks and idelalisib 150mg BID continuously for 48 weeks.

Patientscompleting48weeksoftreatmentwithoutprogres- sioncontinued to receive idelalisibon an extension study.

Theoverallresponseratewas96%for theﬁrst50ofthe64 enrolledpatientsandPFSwas91%at24months.Ofnote,all six patients with del(17p) responded, including one with aCR,andtherehavebeennoon-studyrelapses.

The results of a recently published multicenter, randomized, double-blind, placebo-controlled, phase III study indicate that a combination of idelalisib and rituximab significantlyimprovedORrate, PFSandOSinpatientswith relapsedCLLcomparedwithrituximabalone[47].Thestudy was stopped prematurely, after the first interim analysis, due to the advantage of combination therapy over monotherapy withrituximab.Patients receivingidelalisib+rituximab hadORrate81%and thosereceiving rituximabalone hadORrate13%(P<0.001).ThemedianPFSwas5.5months intherituximab groupand wasnotreachedinthe idelalisib+rituximab group (P<0.001) and overall survival at 12 months (92% vs. 80% (P=0.02), respectively. Serious AEs were similar in both arms and occurred in 40% of the patientsreceivingidelalisib+rituximabandin35%ofthose receiving rituximab. Another phase III, randomized study evaluatingtheefficacyandsafetyofidelalisibincombination withbendamustineandrituximabforpreviouslytreatedCLL was initiated in June 2012 [48]. In addition, a phase III, randomized, controlled study evaluating the efficacy and safety of idelalisib in combination with ofatumumab for previouslytreatedCLLhasalsobeeninitiated(NCT01659021).

Bcl-2 inhibitors

Bcl-2 proteins play a central role in enhancing cell death activityandarethoughttoimpacttumorformation,growth and resistance.They are expressedat high levels inB-cell NHL,CLLandotherB-cellneoplasms.Overexpressionofthe prosurvivalproteinBcl-2isacharacteristicfeatureofmany B-lymphoid malignancies and contributes to resistance to many commonly used chemotherapeutic agents. ABT-199 (GDC-0199, RG7601) is a novel, orally bioavailable, small molecule with a high-afﬁnity Bcl-2-selective BH3 mimetic, recently developed by Abbott Laboratories [49]. This agent speciﬁcally causes Bax/Bak-mediated apoptosis triggered principally by the initiator BH3-only Bim protein. ABT-199 can trigger apoptosis in vitro, even in del(17p) CLL cells.

Leukemic cells isolated from patients with CLL as well as normal B-cells are also highly sensitive to ABT-199 both in vitroandinvivo [50]. Theresultsof anearlyclinicaltrial showthatABT-199haspromisingpotentialinthetreatment ofCLL[51].IncontrasttotheBH3mimeticABT-737andthe related orally available compound ABT-263 (navitoclax), ABT-199 iseffectiveinprolongingthe survivalof immuno- competenttumor-bearingmiceandsparedhumanplatelets invitroanddogplateletsinvivowithoutcausingthrombocy- topenia[52].

The resultsof a phaseI, dose-escalation studyof ABT- 199 in high-risk relapsed/refractory CLL was recently pre- sented [53]. Cohorts received a single dose of ABT-199 on week 1, day 3 (W1D-3) or day 7 (W1D-7), followed by continuous once-daily dosing from W1D1, until disease progression or unacceptable toxicity, at doses from 150 to 1200mg.Fifty-sixpatientswereenrolled,including17(38%) with del(17p) and 18 (32%) with fludarabine-refractory disease. The OR rate was 84%, including 20% CR/CRi. Four patientshadnodetectableMRD,includingonepatientwith fludarabine-refractorydiseaseanddel(17p)andtwopatients with fludarabinerefractory disease. The responserate was 82% in patients with del(17p), and 78% in patients with fludarabine-refractory disease. Notably, 3 of the 4patients who had no detectable MRD and achieved a CR/CRi were high-risk disease patients. Twenty-two patients discontin- ued treatment: 12 due to progressive disease or other reasons,and8duetoAEsincludingdiarrhea (46%),neutropenia(43%),fatigue(34%)andinfection(29%).Grade3/4AEs included neutropenia (41%), TLS(11%) and thrombocytopenia(10%).

Immunomodulating agents

Immunomodulating agents are a new class of drugs that changetheexpressionof variouscytokines andcostimulate immune effector cells. Lenalidomide (Revlimid, Celgene) is asecondgenerationthalidomideanalogwithpossibleimmu- nomodulatingandantiangiogenicproperties,whichmayalso modulate cytokine activityinthe tumormicroenvironment.

Lenalidomideisorallyavailableandhassigniﬁcantactivityin multiplemyelomaandmyelodysplasticsyndrome,andmost recentlyithasbeenshowntobeeffectiveinthetreatmentof various lymphoproliferativedisorders such as CLLand NHL [54]. A characteristic AE of treatment with lenalidomide in CLListumorﬂarereaction,aswellasanimmune-modulatory effectwhichleadstoasensationofheatandburninginthe lymphnodes.Chanan-Khanetal.investigatedtheantileuke- miceffectsoflenalidomidein45CLLpatientswithrelapsed orrefractorydisease[55].Thedrugwasadministeredorallyat adoseof25mgonceadayfor21daysona28-dayschedule.

Duetotheoccurrence oftumorlysissyndrome(TLS)intwo oftheﬁrst29patients,thetreatmentprotocolwasrevisedto allowslowdoseescalationinsubsequentpatients,inwhom theinitialdosewas5mg,whichwasincreasedby5mgevery 1–2weekstoamaximum25mg.Twenty-ninepatientswere assessableforresponseandall45patientswereevaluatedfor toxicity.ThemostcommonnonhematologicAEswerefatigue (83%) and ﬂare reaction (58%). Grade 3–4 thrombocytopenia

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wasnotedin45%ofthepatientsandgrade3–4neutropenia in70%ofthepatients.Majorresponseswere observedin21 patients(41%)with4CRs(9%)and17(38%)achievingaPRin intent-to-treat analysis. The medianPFS time hasnot been reached.

Ferrajoli et al. reportthe resultsof a phase II study in which lenalidomidewas administeredat 10mgper day by continuous dailydosing with dose escalation up to 25mg, basedonpatienttolerabilityandresponse[56].Patientswho had stable disease continued treatment until disease progression.Forty-fourpatientswithrelapsedorrefractoryCLL were included. Three patients (7%) achieved a CR, one nodularPRand10patientsaPR,atanORrateof 32%.The treatmentwaseffectivein31%ofthepatientswithhighrisk cytogenetic abnormalities (del11q or del 17p), 24% of the patients with un-mutated VH and 25% of the patients refractorytofludarabine. Thirteenpatients(30%) developed tumorflarereaction.Despiteamediandoseof10mgdaily, significant hematologic toxicity was frequently observed.

Grade3–4neutropeniawasnotedin41%ofthecoursesand grade3–4thrombocytopeniain16%ofthepatients.

Subsequently, Andritsos et al. reported four consecutive patientswithCLLwhoweretreatedwithlenalidomideandall hadseriousadverseevents[57].Thedrugwasadministered atadoseof25mg/dayfor21daysofa28-daycycle.Tumor ﬂarewasobservedinthreepatientsandwascharacterizedby painful lymph node enlargement, with one fatal outcome.

Another patient developed sepsis and renal failure. The efﬁcacyoflenalidomidemaybeincreasedwiththeaddition of rituximab. Badoux et al. reported an OR rate of 66%

(including 12% CR) and an estimated 36-month survival of 71%inrelapsed orrefractory CLL patientstreated with this combination[58].Inanother phaseIIclinicaltrialtreatment with lenalidomide and rituximab as the ﬁrst-line therapy induced ORinmore than90%of the patients,including an ORrateof53%(CR13%)inpatientswith(17p)deletion[59].

The ORIGIN trial compares the safety and efﬁcacy of lenalidomide with those of chlorambucil in patients with CLL, 65 years and older (NCT00910910). Interim analysis showed higher rates of death in patients treated with lenalidomidecompared tothose treatedwithchlorambucil, and the recruitment for the study was stopped. Currently, lenalidomideisunderevaluationfor maintenanceinphase III study in patients with CLL following ﬁrst-line therapy (CLLM1)(NCT01556776).

Autologous CD19-targeted CAR-modiﬁed T cells

Immune-basedtreatmentstrategiestoaugmentthecytotoxic potentialof Tcellsofferexcitingnewtreatmentoptionsfor patients with CLL [60]. Chimeric antigen receptors (CARs) combinetheantigenrecognitiondomainofanantibodywith intracellularsignalingdomainsintoasinglechimericprotein.

In CLL, the CD19 antigen is an ideal target for CARs since expressionisrestrictedtonormaland malignant Bcells. In CLLpatients,Tcellsmay begenetically modiﬁedtoexpress CARstargetedtoCD19antigenexpressedontumorcells[61, 62]. In a pilot clinical trial, autologous T cells genetically engineeredtoexpress ananti-CD19CAR were usedtotreat

3patientswithrefractoryCLL.Inthisstudyalentiviralvector expressingachimericantigenreceptorwithspeciﬁcityforthe B-cell antigen CD19 was coupledwith CD137 and CD3-zeta signalingdomainsandautologouschimericantigenreceptor- modiﬁed T cells were reinfused into patients [63]. Two patients achieved aCRlastinglongerthan 2yearsand one patienthadastablePR.

In anotherstudy, 8patients,including4with B-cellNHL and4withCLL,weretreatedwithcyclophosphamidedailyfor 2daysfollowedbyﬂudarabinedailyfor 5daysandoneday after the last dose of ﬂudarabine, received a single i.v.

infusion of anti-CD19-CAR-transduced T cells [64]. Three hours after the T-cell administration, IL-2 infusion was initiated. Six of the 7 evaluable obtained strictly defined remissions. Recently, Park et al.reported a phase I clinical trial in previously untreated CLL patients with high-risk disease featuresand residualdisease followingthefirst-line chemotherapy [65]. Patients received CD19-targeted CAR⁺ T cells as consolidative therapy. Autologous T cells were collected by leukapheresisand transduced with a retroviral vector encoding the anti-CD19 scFv linked to CD28 co- stimulatory andCD3z signalingdomains. CAR⁺ T cellswere infused twodaysaftercyclophosphamideconditioningther- apy. Among 6 patients who received the CAR⁺ T cells, 2patientswhohadaPRfollowingthefirst-linechemotherapy achievedaCRaftertheTcellinfusion,2patientsmaintained PR and 2 patients had progressive disease. Another group recentlyreported theresultsof astudy on14 patientswith relapsed,refractoryCLLtreatedwiththeCD19-targetedCAR⁺ Tcells[66],whichindicatethatCAR⁺Tcellscaninducepotent andsustainedresponsesforpatientswithadvanced,relapsed and refractory CLL regardless of p53 mutation status. The overallresponseratewas57%,threepatients(21%)achieved aCR,five(36%)achievedaPRandsix(43%)hadnoresponse, foranoverallmajorresponserateof57%.Twoof5patients with a PR progressed4monthsafter infusionwith CAR⁺ T, andnopatientwithaCRhasrelapsedsofar.Allresponding patientsdevelopedadelayedcytokinereleasesyndromeman- ifested by fever, and variable degrees of nausea, anorexia, myalgia, and transient hypotension. A randomized, phase II doseoptimizationstudyofCAR⁺TcellsdirectedagainstCD19 inCLLpatientswithrelapsed,refractorydiseaseisongoing[67].

Authors' contributions/Wkład autorów

Accordingtoorder.

Conﬂict of interest/Konﬂikt interesu

Nonedeclared.

Financial support/Finansowanie

This work was supported in part by the grant from the Medical Universityof Lodz(No.503/1-093-01/503-01)andby the Foundation for the Development of Diagnostics and Therapy,Warsaw,Poland.

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Ethics/Etyka

Thework describedin this article has been carriedout in accordance with TheCode of Ethics of the World Medical Association(Declaration of Helsinki)for experimentsinvol- ving humans; EU Directive 2010/63/EU for animal experi- ments; and Uniform Requirements for manuscripts submittedtoBiomedicaljournals.

references/pi smiennictwo

[1] SiegelR,MaJ,ZouZ,JemalA.Cancerstatistics,2014.CA CancerJClin2014;64:9–29.

[2] HallekM,ChesonD,CatovskyD,etal.Guidelinesforthe diagnosisandtreatmentofchroniclymphocyticleukemia:

areportfromtheinternationalWorkshoponChronic LymphocyticLeukemiaupdatingtheNationalCancer Institute-WorkingGroup1996guidelines.Blood 2008;111:5446–5456.

[3] DighieroG,MaloumK,DesablensB,etal.Chlorambucilin indolentchroniclymphocyticleukemia.French

CooperativeGrouponChronicLymphocyticLeukemia.N EnglJMed1998;338:1506–1514.

[4] EichhorstB,DreylingM,RobakT,MontserratE,HallekM.

Chroniclymphocyticleukemia:ESMOclinicalpractice guidelinesfordiagnosis,treatmentandfollow-up.Ann Oncol2011;22:50–54.

[5] RobakT,JamroziakK,RobakP.Currentandemerging treatmentsforchroniclymphocyticleukaemia.Drugs 2009;69:2415–2449.

[6] HallekM,FischerK,Fingerle-RowsonG,etal.Additionof rituximabtoﬂudarabineandcyclophosphamideinpatients withchroniclymphocyticleukaemia:arandomised,open- label,phase3trial.Lancet2010;376:1164–1174.

[7] RobakT,DmoszynskaA,Solal-CélignyP,etal.Rituximab plusﬂudarabineandcyclophosphamideprolongs progression-freesurvivalcomparedwithﬂudarabineand cyclophosphamidealoneinpreviouslytreatedchronic lymphocyticleukemia.JClinOncol2010;28:1756–1765.

[8] RobakT,RobakE.Newanti-CD20monoclonalantibodiesfor thetreatmentofB-celllymphoidmalignancies.BioDrugs 2011;25:13–25.

[9] RobakT.Howtoimprovethetreatmentoutcomeinchronic lymphocyticleukemia?LeukRes2010;34:272–275.

[10] RobakT.GA-101,athird-generation,humanizedandglyco- engineeredanti-CD20mAbforthetreatmentofB-cell lymphoidmalignancies.CurrOpinInvestigDrugs 2009;10:588–596.

[11] PatzM,IsaevaP,ForcobN,etal.Comparisonoftheinvitro effectsoftheanti-CD20antibodiesrituximabandGA101on chroniclymphocyticleukaemiacells.BrJHaematol 2011;152:295–306.

[12] BolognaL,GottiE,ManganiniM,etal.Mechanismofaction oftypeII,glycoengineered,anti-CD20monoclonalantibody GA101inB-chroniclymphocyticleukemiawholeblood assaysincomparisonwithrituximabandalemtuzumab.J Immunol2011;186:3762–3769.

[13] SallesG,MorschhauserF,LamyT,etal.Phase1study resultsofthetypeIIglycoengineeredhumanizedanti-CD20 monoclonalantibodyobinutuzumab(GA101)inB-cell lymphomapatients.Blood2012;119:5126–5132.

[14] GoedeV,FischerK,BuschR,etal.Chemoimmunotherapy withGA101pluschlorambucilinpatientswithchronic lymphocyticleukemiaandcomorbidity:resultsofthe

CLL11(BO21004)safetyrun-in.Leukemia2013;27:1172–

1174.

[15] GoedeV,FischerK,BuschR,etal.Obinutuzumabplus chlorambucilinpatientswithCLLandcoexisting conditions.NEnglJMed2014;270:1001–1010.

[16] GoedeV,FischerK,BuschR,etal.Head-to-head comparisonofobinutuzumab(GA101)pluschlorambucil (CLB)versusrituximabplusclbinpatientswithchronic lymphocyticleukemia(CLL)andco-existingmedical conditions(comorbidities):ﬁnalstage2resultsoftheCLL11 trial.Blood(ASHAnnualMeetingAbstracts)2013;122 [Abstract6].

[17] CameronF,McCormackPL.Obinutuzumab:ﬁrstglobal approval.Drugs2014;74:147–154;ĆTraynorK.

ObinutuzumabapprovedforCLL:monoclonalantibody productisﬁrstFDA-approvedbreakthroughtherapy.AmJ HealthSystPharm2013;70:2162.

[18] RobakT.Ofatumumab,ahumanmonoclonalantibodyfor lymphoidmalignanciesandautoimmunedisorders.Curr OpinMolTher2008;10:294–309.

[19] HerterS,HertingF,MundiglO,etal.Preclinicalactivityof thetypeIICD20antibodyGA101(obinutuzumab)compared withrituximabandofatumumabinvitroandinxenograft models.MolCancerTher2013;12:2031–2042.

[20] BarthMJ,CzuczmanMS.Ofatumumab:anovel,fully humananti-CD20monoclonalantibodyforthetreatment ofchroniclymphocyticleukemia.FutureOncol2013;9:1829–

1839.

[21] WierdaWG,KippsTJ,MayerJ,etal.Ofatumumabassingle- agentCD20immunotherapyinﬂudarabine-refractory chroniclymphocyticleukemia.JClinOncol2010;28:1749–

1755.

[22] HillmenP,RobakT,JanssensA,etal.Ofatumumab +chlorambucilversuschlorambucilaloneinpatientswith untreatedchroniclymphocyticleukemia(CLL):resultsof thephaseIIIstudyComplement1(OMB110911).Blood(ASH AnnualMeetingAbstracts)2013;122[Abstract28].

[23] ClassonBJ,WilliamsAF,WillisAC,SeedB,StamenkovicI.

Theprimarystructureofthehumanleukocyteantigen CD37,aspecieshomologueoftheratMRCOX-44antigen.J ExpMed1989;169:1497–1502.

[24] LapalombellaR,YehYY,WangL,etal.TetraspaninCD37 directlymediatestransductionofsurvivalandapoptotic signals.CancerCell2012;21:694–708.

[25] BarrenaS,AlmeidaJ,YuntaM,etal.Aberrantexpressionof tetraspaninmoleculesinBcellchroniclymphoproliferative disordersanditscorrelationwithnormalB-cellmaturation.

Leukemia2005;19:1376–1383.

[26] JonesEL,DemariaMC,WrightMD.Tetraspaninsincellular immunity.BiochemSocTrans2011;39:506–511.

[27] RobakT,RobakP.Anti-CD37antibodiesforchronic lymphocyticeukemia.ExpertOpinBiolTher2014;14:651–

661.

[28] HeiderKH,KieferK,ZenzT.AnovelFc-engineered monoclonalantibodytoCD37withenhancedADCCand highproapoptoticactivityfortreatmentofB-cell malignancies.Blood2011;118:4159–4168.

[29] RobakT,RobakP,SmolewskiP.TRU-016,ahumanizedanti- CD37IgGfusionproteinforthepotentialtreatmentofB-cell malignancies.CurrOpinInvestigDrugs2009;10:1383–1390.

[30] ZhaoX,LapalombellaR,JoshiT,etal.TargetingCD37- positivelymphoidmalignancieswithanovelengineered smallmodularimmunopharmaceutical.Blood

2007;110:2569–2577.

[31] ZhaoXB,TruptiJ,LapalombellaR,etal.NKcellscontribute signiﬁcantlytotheinnateimmuneeffectorroleofCD37- speciﬁcSMIPinCLLandNHL.Blood(ASHAnnualMeeting Abstracts)2006;108[Abstract135].

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[32] ByrdJC,PagelJM,AwanFT,etal.APhase1studyevaluating thesafetyandtolerabilityofotlertuzumab(TRU-016),an anti-CD37mono-speciﬁcADAPTIRTMtherapeuticprotein inchroniclymphocyticleukemia.Blood2013;123:1302–

1308.

[33] RobakT,HellmanA,KloczkoJ,etal.Phase2studyof otlertuzumab(TRU-016),ananti-CD37ADAPTIRTMprotein, incombinationwithbendamustinevsbendamustinealone inpatientswithrelapsedchroniclymphocyticleukemia (CLL).Blood(ASHAnnualMeetingAbstracts)2013;122 [Abstract2860].

[34] RobakT,RobakE.Tyrosinekinaseinhibitorsaspotential drugsforB-celllymphoidmalignanciesandautoimmune disorders.ExpertOpinInvestigDrugs2012;21:921–947.

[35] BinderM,MüllerF,FrickM,etal.CLLB-cellreceptorscan recognizethemselves:alternativeepitopesandstructural cluesforautostimulatorymechanismsinCLL.Blood 2013;121:239–241.

[36] RobakT,RobakP.BCRsignalinginchroniclymphocytic leukemiaandrelatedinhibitorscurrentlyinclinicalstudies.

IntRevImmunol2013;32:358–376.

[37] GarberK.KinaseinhibitorsoverachieveinCLL.NatRev DrugDiscov2014.http://dx.doi.org/10.1038/nrd4259.

[38] ByrdJC,FurmanRR,CoutreSE,etal.TargetingBTKwith ibrutinibinrelapsedchroniclymphocyticleukemia.NEngl JMed2013;369:32–42.

[39] O'BrienS,FurmanRR,CoutreSE,etal.Ibrutinibasinitial therapyforelderlypatientswithchroniclymphocytic leukaemiaorsmalllymphocyticlymphoma:anopen-label, multicentre,phase1b/2trial.LancetOncol2014;15:48–58.

[40] BurgerJA,KeatingMJ,WierdaWG,etal.Ibrutinibin combinationwithrituximab(iR)iswelltoleratedand inducesahighrateofdurableremissionsinpatientswith high-riskchroniclymphocyticleukemia(CLL):new, updatedresultsofaphaseiitrialin40patients.Blood(ASH AnnualMeetingAbstracts)2013;122[Abstract675].

[41] BrownJR,BarrientosJC,BarrPM,etal.Ibrutinibin combinationwithbendamustineandrituximabisactive andtolerableinpatientswithrelapsed/refractoryCLL/SLL:

ﬁnalresultsofaphase1bstudy.Blood(ASHAnnual MeetingAbstracts)2013;122[Abstract525].

[42] CoutreSE,ByrdJC,FurmanRR,etal.Phase1studyofCAL- 101,anisoform-selectiveinhibitorofphosphatidylinositol3 kinaseP110,inpatientswithpreviouslytreatedchronic lymphocyticleukemia.JClinOncolASCOAnnualMeeting Abstracts2011;29:63.

[43] BrownJR,FurmanRR,FlinnI,etal.FinalresultsofaphaseI studyofidelalisib(GS-1101)aselectiveinhibitorofPI3Kd,in patientswithrelapsedorrefractoryCLL.JClinOncolASCO AnnualMeetingAbstracts2013;31[Abstract7003].

[44] CoutreSE,FurmanRR,BarrientosJC,etal.Clinicalactivity ofidelalisib(GS-1101),aselectiveinhibitorofPI3Kd,in phase1and2trialsinchroniclymphocyticleukemia(CLL):

effectofdel(17p)/TP53mutation,del(11q),IGHVmutation, andNOTCH1mutation.Blood(ASHAnnualMeeting Abstracts)2013;122[Abstract1632].

[45] BarrientosJC,Wagner-JohnstonND,DeVosS,etal.Chemo- immunotherapycombinationofidelalisibwith

bendamustine/rituximaborchlorambucil/rituximabin patientswithrelapsed/refractoryCLLdemonstrates efﬁcacyandtolerability.Blood(ASHAnnualMeeting Abstracts)2013;122[Abstract4176].

[46] O'BrienSM,LamannaN,KippsTJ,etal.AphaseIIstudyof theselectivephosphatidylinositol3-kinasedelta(PI3Kd) inhibitoridelalisib(GS-1101)incombinationwithrituximab (R)intreatment-naivepatients(pts)65yearswithchronic lymphocyticleukemia(CLL)orsmalllymphocytic

lymphoma(SLL).JClinOncolASCOAnnualMeeting Abstracts2013;31[Abstract7005].

[47] FurmanRR,SharmanJP,CoutreSE,etal.Idelalisiband rituximabinrelapsedchroniclymphocyticleukemia.N EnglJMed2014;370:997–1007.

[48] EradatHA,CoutreSE,BarrientosJC,etal.APhaseIII, randomized,double-blind,placebo-controlledstudy evaluatingtheefﬁcacyandsafetyofidelalisib(GS-1101)in combinationwithbendamustineandrituximabfor previouslytreatedchroniclymphocyticleukemia(CLL).J ClinOncolASCOAnnualMeetingAbstracts2013;31 [Abstract7131].

[49] VoglerM,DinsdaleD,DyerMJ,CohenGM.ABT-199 selectivelyinhibitsBCL2butnotBCL2L1andefﬁciently inducesapoptosisofchroniclymphocyticleukaemiccells butnotplatelets.BrJHaematol2013;163:139–142.

[50] KhawSL,MérinoD,AndersonMA,etal.Bothleukaemic andnormalperipheralBlymphoidcellsarehighlysensitive totheselectivepharmacologicalinhibitionofprosurvival Bcl-2withABT-199.Leukemia2014.http://dx.doi.org/

10.1038/leu.2014.1.

[51] SouersAJ,LeversonJD,BoghaertER,etal.ABT-199,apotent andselectiveBCL-2inhibitor,achievesantitumoractivity whilesparingplatelets.NatMed2013;19:202–208.

[52] VandenbergCJ,CoryS.ABT-199,anewBcl-2-speciﬁcBH3 mimetic,hasinvivoefﬁcacyagainstaggressiveMyc-driven mouselymphomaswithoutprovokingthrombocytopenia.

Blood2013;121:2285–2288.

[53] SeymourJF,DavidsMS,JohnM,etal.Bcl-2InhibitorABT- 199(GDC-0199)monotherapyshowsanti-tumoractivity includingcompleteremissionsinhigh-riskrelapsed/

refractory(r/r)chroniclymphocyticleukemia(CLL)and smalllymphocyticlymphoma(SLL).Blood(ASHAnnual MeetingAbstracts)2013;122[Abstract872].

[54] SherT,MillerKC,LawrenceD,etal.Efﬁcacyoflenalidomide inpatientswithchroniclymphocyticleukemiawithhigh- riskcytogenetics.LeukLymphoma2010;51:85–88.

[55] Chanan-KhanA,MillerKC,MusialL,etal.Clinicalefﬁcacy oflenalidomideinpatientswithrelapsedorrefractory chroniclymphocyticleukemia:resultsofaphaseIIstudy.J ClinOncol2006;24:5343–5349.

[56] FerrajoliA,LeeBN,SchletteEJ,etal.Lenalidomideinduces completeandpartialremissionsinpatientswithrelapsed andrefractorychroniclymphocyticleukemia.Blood 2008;111:5291–5297.

[57] AndritsosLA,JohnsonAJ,LozanskiG,etal.Higherdosesof lenalidomideareassociatedwithunacceptabletoxicity includinglife-threateningtumorﬂareinpatientswith chroniclymphocyticleukemia.JClinOncol2008;26:2519–

2525.

[58] BadouxXC,KeatingMJ,WenS,etal.PhaseIIstudyof lenalidomideandrituximabassalvagetherapyforpatients withrelapsedorrefractorychroniclymphocyticleukemia.J ClinOncol2013;31:584–591.

[59] JamesDF,BrownJR,WernerL,etal.Lenalidomideand rituximabfortheinitialtreatmentofpatientswithchronic lymphocyticleukemia(CLL)AmulticenterstudyoftheCLL researchconsortium.Blood2011;118:291.

[60] BrentjensRJ.CARsandcancers:questionsandanswers.

Blood2012;119:3872–3873.

[61] BrentjensRJ,RivièreI,ParkJH,etal.Safetyandpersistence ofadoptivelytransferredautologousCD19-targetedTcells inpatientswithrelapsedorchemotherapyrefractoryB-cell leukemias.Blood2011;118:4817–4828.

[62] BrentjensRJ,CurranKJ.Novelcellulartherapiesfor leukemia:CAR-modiﬁedTcellstargetedtotheCD19 antigen.HematologyAmSocHematolEducProgram 2012;143–151.

[63] PorterDL,LevineBL,KalosM,BaggA,JuneCH.Chimeric antigenreceptor-modiﬁedTcellsinchroniclymphoid leukemia.NEnglJMed2011;365:725–733.

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[64] KochenderferJN,DudleyME,FeldmanSA,etal.B-cell depletionandremissionsofmalignancyalongwith cytokine-associatedtoxicityinaclinicaltrialofanti-CD19 chimeric-antigen-receptor-transducedTcells.Blood 2012;119:2709–2720.

[65] ParkJH,RivièreI,WangX,etal.PhaseItrialofautologous CD19-targetedCAR-modiﬁedTcellsasconsolidationafter purineanalog-basedﬁrst-linetherapyinpatientswith previouslyuntreatedCLL.Blood(ASHAnnualMeeting Abstracts)2013;122[Abstract874].

[66] PorterDL,KalosM,FreyNV,etal.Chimericantigenreceptor modiﬁedTcellsdirectedagainstCD19(CTL019cells)have long-termpersistenceandinducedurableresponsesin relapsed,refractoryCLL.Blood(ASHAnnualMeeting Abstracts)2013;122:4162.

[67] PorterDL,KalosM,FreyNV,etal.Randomized,phaseII doseoptimizationstudyofchimericantigenreceptor modiﬁedTcellsdirectedagainstCD19(CTL019)inpatients withrelapsed,refractory.CLLBlood(ASHAnnualMeeting Abstracts)2013;122:873.