rev bras hematol hemoter. 2017;39(3):193–196
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Scientific
Comment
New
agents
in
relapsed/refractory
Hodgkin’s
lymphoma
夽
Irene
Biasoli
∗,
Nelson
Spector
UniversidadeFederaldoRiodeJaneiro(UFRJ),RiodeJaneiro,RJ,Brazil
Hodgkin’slymphoma(HL)isaB-cellmalignancythataffects 9000newpatientsannuallyintheUSA,representing approx-imately11%ofalllymphomas.1Inthelastdecades, random-izedclinicaltrialsconductedbycooperativegroupsinNorth AmericaandEuropehaveidentifiedtreatmentschedulesthat providehigherefficacyandlowertoxicitywithcurrent treat-mentbeingexpectedtocureover80%ofpatients.2The three-andfive-yearprogression-freesurvival(PFS)ratesrangefrom 82%to94%3–5inpatientswithlocalizeddiseaseandfrom71% to86%inpatientswithadvanceddisease.6–14
Autologous stem cell transplantation (auto-SCT) has
becomethestandardofcareforrelapsedorrefractoryHL.15,16 It leads to long-term PFS rates of approximately 50% in relapsed patients and of 30–40% in patients with primary refractoryHL.6,15–20
ThetreatmentofrelapsedorrefractoryHLpatientswith treatmentfailureafteranauto-SCTisatherapeuticchallenge. Diseaserelapse orprogressionafterauto-SCT isassociated withapoorprognosis,withamedianoverallsurvivalof2.4 years.21,22 While allogeneic stem cell transplantation (allo-SCT)representstheonlypotentiallycurativeoption,itsroleis stillcontroversial.6,23,24Datafromretrospectiveand prospec-tivestudiessupporttheuseofallo-SCTinparticularsettings. Moreover,arecentanalysisfromtheCenterforInternational Blood and Marrow Transplant Research (CIBMTR) reported encouraging resultswiththe useofreduced-intensity con-ditioninghaploidenticaltransplantation,whencomparedto matched-unrelated donor transplantation.25 Briefly, when recommendingtheprocedure,otheraspectsshouldbetaken into account, such as age, the use of non-myeloablative
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2017.03.008.
夽
SeepaperbyRochaetal.onpages216–22.
∗ Correspondingauthorat:DepartamentodeMedicina,HospitalUniversitárioeEscoladeMedicinadaUniversidadeFederaldoRiode
Janeiro(UFRJ),RuaProfessorPauloRoccon◦255,4.andar–sala4A12,IlhadoFundão,21941-590RiodeJaneiro,RJ,Brazil.
E-mailaddress:irene.biasoli@gmail.com(I.Biasoli).
approaches, donor factors (availability, typeand matching) comorbiditiesandthesubstantialrisksoftreatment-related morbiditiesandmortality.6,23,24
Forpatientswhoarenotcandidatesforallo-SCT,thegoal oftherapyisdiseasecontrolwithminimaltoxicity.6,22,23,26,27 Multiple options are available in this setting, including
single agent chemotherapy, combination chemotherapy,
radiotherapy,antibody–drugconjugates,immunecheckpoint inhibitors, immunomodulatory agents and small molecule inhibitors.
Overallresponserates ofsingleagents, including gemc-itabine, etoposide, vinorelbine, liposomal doxorubicin, vin-blastine and bendamustine, range from 22% to 72%, with completeresponseratesof12%to51%andmedianduration ofresponsesrangingfrom5to8months.28–32Several combi-nationchemotherapyregimensbasedeitherongemcitabine, platinumdrugsorifosfamidehavebeenemployed.Fewdata ontheuseoftheseregimensinthe settingofrelapseafter auto-SCTareavailable,withoverallresponseratesof approxi-mately70%andcompleteremissionratesrangingfrom19%to 50%.33–36Mostcombinationregimenshaveahighfrequency ofgrade3–4myelosuppression.
WiththegrowingknowledgeofHLbiology,novel therapeu-ticagentsaimedatspecificmoleculartargetsandpathways havebeenidentified.Relevantpublishedstudiestestingthese agentsinpatientswithactivediseaseafterauto-SCTare sum-marizedinTable1.23,26
Brentuximabvedotinisanantibody–drugconjugatethat selectivelytargetstumorcellsexpressingCD30.Inthepivotal phaseII multicentertrialof102patientstreatedforfailure
http://dx.doi.org/10.1016/j.bjhh.2017.05.003
194
revbrashematolhemoter.2017;39(3):193–196Table1–Clinicalstudieswithnovelagentsinpatientswithrelapsed/refractoryHLafterautologousstemcell transplantation.
Studies Treatment n Response Mediandurationofresponse Progression-freesurvival
Younesetal.37 Brentuximab,PhaseII 102 ORR=75%
CR=34%
9.7months At5years: 22% Anselletal.40 Nivolumab,PhaseI 23 ORR=87%
CR=17%
Notreported At24weeks: 86%. Younesetal.42 Nivolumab,PhaseII 80 ORR=66%
CR=9%
7.8months At6months: 77% Armandetal.41 Pembrolizumab,Phase 31 ORR=65%
CR=16%
70%of patientsmore than6 months
At24weeks: 69%.
Fehringeretal.43 Lenalidomide,PhaseII 38 ORR=19%
CR=16%
6months Median:4 months Johnstonetal.47 Everolimus,PhaseII 19 ORR=47%
CR=5%
7.2months Median:6.2 months Younesetal.45 Panobinostat,PhaseII 129 ORR=27%
CR=4%
6.9months Median:6.9 months
CR:completeresponse;ORR:overallresponserate.
afteran auto-SCT, 75% had a response, and 34% achieved completeremission(CR).37Atfiveyears,overallsurvival(OS) was41%andPFSwas22%.Patientswhoachievedacomplete remissionhadsuperioroutcomes(OS:64%;PFS:48%).38 Thir-teenpatients(38%ofallCRpatients)remainedinremission. Amongthese13patients,fourreceivedaconsolidative allo-SCT,andnine(9%ofallenrolledpatients)remaininCRwithout receivinganyfurthertreatment.Brentuximabwasalsotested asconsolidationtreatmentafterauto-SCTinpatientswitha highriskofrelapse.Inthisstudy(AETHERA),patientsgiven brentuximabhadamedianPFSof42monthscomparedwith 24monthsintheplacebogroup.39
Inrecentyears,theactiveroleofneoplasticcellsin down-regulating the patient’s immune response has been better understood.InHL,Reed-SternbergcellsexpressPD-1ligands (PD-L1 and PD-L2), which interactwith PD-1 expressedon activatedT-cells,thus leadingtotumortolerance. Antibod-iesagainstPD1andPD-L1havebeenshowntohamperthis downregulationinvarious types ofcancer.Nivolumab and pembrolizumab,twomonoclonalantibodiesdirectedagainst PD-1,haveshowngoodresultsinheavilypretreatedpatients withrelapsedorrefractoryHL.40,41InaphaseIbtrial,23such patientsreceivednivolumabuntilcompleteresponse,tumor progression,orexcessivetoxiceffects.Mostofthepatientshad beentreatedwithanauto-SCT,and78%hadreceived bren-tuximab.Anobjectiveresponsewasfoundin87%,including 17%withacompleteresponse.Progression-freesurvivalatsix monthswas86%.Furthermore,thedrugpresentedacceptable safety.40TheseresultsledtoaphaseIItrialofnivolumabin80 patientswithHLafterfailureofauto-SCTandbrentuximab.42 Anobjectiveresponsewasachievedin66%ofpatientsand9% ofcompleteremission.Themediantimetoresponsewas2.1 months.Follow-upisongoingtoassessthelong-term dura-bilityofnivolumabinthissetting.Anotherstudyincluded31 heavilypretreatedHLpatientstreatedwithpembrolizumab. The overall response rate was 65%, with 16% in complete remission.Progression-freesurvivalat24weekswas69%.41
Lenalidomidehasbeentestedinafewstudiesinpatients with relapsedor refractoryHL.43,44 Ina phase II trial that
included 38 patientswitha medianoffour previous treat-ments,87%ofwhomhadreceivedanauto-SCT,theobjective overall responserateandcomplete responseratewere 19% and16%,respectively.Duetotheacceptabletoxicityprofile, furtherstudiestooptimizedosesandinvestigatetheuseof lenalidomideincombinationwithotherdrugsareneeded.43
Drugsthattargethistonedeacetylasesmayalsobe effec-tiveinHL.Themosteffectiveinhibitorofhistonedeacetylase inHLappearstobepanobinostat.AphaseIIstudywith129 HL patients treatedpreviously witha medianoffour regi-menswasreported.Objectiveresponseswereachievedin27%, including 30(23%)partialresponsesandfive(4%) complete responses.Themediandurationofresponsewas6.9months andmedianPFSwas6.1months.45
SignalingthroughthePI3-kinase/mTORpathwayhasbeen demonstratedtobeactiveinHL.Everolimusisanoralagent that specificallytargetsthe mTOR complex1(mTORC1).23,46 A phase II trial was conducted in nineteen patients with relapsedHL,whohad receivedamedianofsixprior thera-pies,including84%withapriorauto-SCT.Theoverallresponse
rate was 47% and only one patient achieved a complete
remission.47 InthecurrentissueoftheBrazilianJournalof HematologyandHemotherapy,aretrospectiveanalysisof33 relapsed/refractoryHLpatientswhoreceivedeverolimusina compassionateuseprograminBrazilisreported.48 Patients had receivedamedianoffivepriortherapiesand88% had undergoneanauto-SCT. Theoverallresponseratewas45%; two(6%)patientsachievedcompleteremissionand13(39%) hadapartialresponse.ThemedianPFSandOSwere9months and36months,respectively,somewhatsimilartothefindings inthepreviousphaseIItrial,inwhichthemedianPFSandOS were6monthsand25months,respectively.Itisnoteworthy thatthirteenpatientsreceivedtreatmentformorethanone year,andthreepatientshadbeenreceivingitformorethan fouryears,despiteprogressionofthedisease.
revbrashematolhemoter.2017;39(3):193–196
195
into clinical practice in many countries. However, the therapeuticchallengeiscompoundedbythehighcostofthese newdrugs.Thecomplexitiesofallo-SCTalsolimitits availabil-ityinthepublichealthsystem.Asbetterdataonthelong-term resultsofthesenoveltreatmentsaccumulate,wewill hope-fully,beabletobetterdefinethebestapproaches,andoffer themtoeverypatientinneed.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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