HODGKIN LYMPHOMA - BC Cancer

HODGKINLYMPHOMADR.AMRITKAHLON

HEMATOLOGIST, BCCANCER– ABBOTSFORDCENTERFEBRUARY18, 2021

CONFLICTOFINTERESTDISCLOSUREIhavereceivededucationalgrantfundingfromJanssen

IhavereceivedspeakersfeesandadvisoryboardhonorariafromJanssen,CelgeneandSanofiGenzyme

OBJECTIVES

ReviewepidemiologyandpathogenesisofHodgkinlymphomaReviewclinicalpresentationofHodgkinlymphoma

RecognizediagnosticcriteriaSummarizekeytherapeuticoptions

Reviewpost-treatmentfollow-uprecommendations

MYQUESTIONSDoyoutakecareofHodgkinlymphomapatientsinyourpractice?

1. Yes

2. No

MYQUESTIONSWhattypeofcaredoyouprovide?

1. Makingthediagnosis

2. Discussingthediagnosis

3. Managingacutesideeffectsofchemotherapy

4. Post-treatmentfollowupcare

5. 1or2or4

6. Alloftheabove

EPIDEMIOLOGY

Overallincidenceislow◦ AnnualageadjustedincidenceinpopulationsofEuropeanancestry~2-3%per100,000

◦ HLisoneofthemostcommoncancersinyoungadults

90%10%

RISKFACTORSImmunosuppresion◦ IntheHIVpopulation,cHLisoneofthemostcommonnon-AIDSdefiningcancersandisalmostalwaysEBVpositive◦ Autoimmunedisorders

Geneticriskfactors◦ GenomewideassociationstudiesinpopulationsofEuropeanancestryhaveidentified18geneticriskvariantsprimarilyinimmunerelatedgenes

Familialrisk◦ 3-5greaterriskwithafamilyhistoryofHL◦ Veryhighincidenceinidenticaltwins(~100fold)comparedtofraternaltwins

Socioeconomicstatus◦ HighersocioeconomicstatusassociatedwithNSHLandyoungerageatdiagnosis◦ LowersocioeconomicstatusassociatedwithMCHLandLDHLandolderageatdiagnosis

EBV◦ Variesbyage,geographicregion,andimmuno-competence

Connors,JMetal.NatureReviewsDiseasePrimers.2020.6:61UpToDate.Hodgkinlymphoma:Epidemiologyandriskfactors.

EPIDEMIOLOGYTRIMODALAGESPECIFICPATTERN

• 15-35years• EBVnegativeNSHL• Associatedwithhigh

socioeconomicstatus,Europeanancestry,andslightlyhigherincidenceinfemalesex

• Twosmallerpeaksinage<15yrsandelderlyadults>50yrs• EBVpositiveMCHL• Associatedwithlow

socioeconomicstatus,non-Europeanethnicity,andmalesex

Connors,JMetal.NatureReviewsDiseasePrimers.2020.6:61

PATHOPHYSIOLOGY• HodgkinandReed-Sternbergcells

• DevelopfrommalignanttransformationofdevelopingBlymphocytes

• AberrantautocrineandparacrinesignalingbyHRScells• Attractsinflammatorytumor

micro-environment• Tumormicro-environment

• Inflammatorycellinfiltrate• Supportgrowthandsurvival

ofHRScells• Allowsimmuneevasionof

tumorcells

Connors,JMetal.NatureReviewsDiseasePrimers.2020.6:61UpToDate.PathogenesisofHodgkinlymphoma.

CLINICALPRESENTATIONLymphadenopathy◦ Supra-diaphragmaticlymphadenopathy

◦ Neck– 60-80%◦ Axillary– 30%◦ Inguinal– 10%

◦ Isolatedsub-diaphragmaticlymphadenopathyisuncommon(<10%)◦ Mediastinalmass

◦ Asymptomatic,cough,SOB,retrosternalchestpain,uncommonlypericardial/pleuraleffusionorsuperiorvenacavasyndrome

Constitutional(”B”)symptoms– 40%◦ Fevers(>38C),drenchingnightsweats,unexplainedweightlossof>/=10%ofbodyweightwithin6months◦ Pel-Ebsteinfever

◦ Uncommonbutcharacteristiccyclicriseandfallinfeverover1-2weeks

Pruritus– 10-15%

Alcoholinducedpain- <10%

Connors,JMetal.NatureReviewsDiseasePrimers.2020.6:61UpToDate:ClinicalpresentationanddiagnosisofclassicalHodgkinlymphomainadults

CLINICALPRESENTATIONSpreadiscontiguousvialymphaticchannelsbeforeinvolvingmoredistantornon-adjacentsites/organs◦ Spleen,bone/bonemarrow,lung,liver◦ Rare– GI,CNS,skin,nephroticsyndrome(minimalchangedisease)

Laboratoryabnormalities◦ Anemia◦ Hypercalcemia◦ Eosinophilia◦ Other– lymphopenia,hypoalbuminemia,thrombocytosis,leukocytosis

Diseasetempo◦ Slowbutcanbevariable

Connors,JMetal.NatureReviewsDiseasePrimers.2020.6:61UpToDate:ClinicalpresentationanddiagnosisofclassicalHodgkinlymphomainadults

DIAGNOSISLymphnodebiopsy

• Excisionalbiopsypreferredtocoreneedlebiopsy

• IdentificationofHRSorLPcellsintheproperhistologicalmicroenvironment• HRSvariants(mononuclearvariants,lacunar

cells,necroticforms,areusefulforidentifyingcHLsubtypes

• Immuno-histochemicalstaining:CD3,CD15,CD20,CD30,CD45,PAX-5,EBVbyEBERandLMP1• CD30positive,variableCD15positive,CD45

negative

DIAGNOSIS/CLASSIFICATION• CLASSICALHODGKINLYMPHOMA

(90%)• NodularsclerosingHL(NSHL)–

70%• MixedcellularityHL(MCHL)–

20-25%• LymphocyterichHL(LRHL)– 3-

5%• LymphocytedepletedHL(LDHL)

– rare• NON-CLASSICALHODGKIN

LYMPHOMA(10%)• Nodularlymphocytedepleted

HL(NLPHL)


STAGINGHistoryandphysical(lymphadenopathy,abdominalorganomegaly)

Laboratoryinvestigations:CBC,renal,calcium,albumin,liverfunctiontests,HIV,hepatitisBandhepatitisCserology

Imaging◦ CTneck,chest,abdomen,andpelvis◦ PETscan

◦ Upstages41%ofpatientsfromdetectionofextra-nodaldiseaseespeciallyboneandbonemarrowdisease◦ Downstages10%ofpatients

Bonemarrowbiopsy◦ NolongerroutinelydoneifPETscanstagingavailable◦ IfPETunavailable,bonemarrowdoneif

◦ Bsymptoms◦ WBC<4x10*9/L,HGB<120g/L(women),HGB<130g/L(men),PLT<125x10*9/L

BCCancer:CancerManagementGuidelines.HodgkinLymphoma

STAGING

MANAGEMENT– ABVDCHEMOTHERAPYOriginallydevelopedin1975◦ 4drugintravenousregimen(doxorubicin,vinblastine,bleomycin,dacarbazine)◦ Itisdeliveredasanoutpatientevery14daysin28daycycles

Alternativechemotherapyregimens◦ BEACOPPchemotherapy

◦ DevelopedbytheGermanHodgkin’sLymphomaStudyGroup(GHSG)◦ ConsistsoforalprednisoneandIVbleomycin,etoposide,doxorubicin,cyclophosphamide,vincristine,procarbazine◦ ComparedwithABVD,BEACOPPimprovesPFSbutdidnotdemonstrateaclearOSadvantage

◦ ABVDvs.BEACOPP:7yearPFS73%vs.85%(p=0.004),OS84%vs.89%(p=0.39)◦ IncreasedtoxicitywithBEACOPPcomparedtoABVD

◦ StanfordV◦ Notcommonlyused◦ Combinesabriefintensivechemotherapyregimenwithradiationtherapyusinglessdoxorubicinandbleomycin◦ NoPFSorOSdifferencecomparedtoABVD

BonadonnaGetal.Cancer1975;36(1):252.VivianiSetal.NEJM.2011;365(3):203.UpToDate.Initialtreatmentofadvanced(stageIII-IV)classicalHodgkinlymphoma

ABVD– SIDEEFFECTSNeutropenia(34%),nausea/vomiting(13%),alopecia(34%)◦ Severeinfections(2%),anemia(5%)andthrombocytopenia(3%)arerare

Bleomycininducedpulmonarytoxicity(20-30%)◦ Developssubacutelywhileontherapyoruptosixmonthsposttreatment

◦ Mortalityrateof4.2%anddecreased5yearOS(63%vs.90%)

◦ Acutereactions:fever,hyperpyrexiasyndrome,anaphylactoidreactions◦ Latebleomycin-relatedpulmonarytoxicity– pulmonaryfibrosis

◦ Riskfactorsincludeage>40yrs,mediastinalradiation,useofGCSF,exposuretohighFiO2,cigarettesmoking◦ Symptomsincludedrycoughandshortnessofbreathonexertion◦ PulmonaryfunctiontestingcanshowasignificantdeclineinDLCO

Doxorubicinassociatedcardiomyopathy◦ Associatedwithtotaldose>400mg/m2(ABVD6cycles300mg/m2)◦ 7.8xhigherriskofmyocardialinfarctioncomparedtoageadjustednormalpopulation

Vinblastineassociatedperipheralneuropathy

Fertilityisgenerallypreserved◦ Moststudiesshowalowimpactonovarianreserveandfertility◦ Azoospermiaandoligospermiatendtorecovertonormalvaluesposttreatment◦ Fertilitypreservationshouldstillbediscussedinhigherriskpatients

.UpToDate.Initialtreatmentofadvanced(stageIII-IV)classicalHodgkinlymphoma

MANAGEMENT– TRADITIONALAPPROACH


PETADAPTEDAPPROACH• FDGavidPETisusedtomeasurethe

responseafterinitialbriefchemotherapytoidentifypatientswithahighqualityresponsetopermitde-escalatingintensityoftherapytoreducetoxicity• Omitradiation• De-intensifychemotherapy

• InterimFDGavidPETfollowing2cyclesofchemotherapyareusedinlimitedandadvancedstagedisease

• FDGavidPETisusedattheendoftreatmenttodistinguishbetweenfibronecroticdebrisandactivelymphomainresidualmasses


PETADAPTEDAPPROACHLIMITEDSTAGEDISEASE2cyclesABVD

PETpositive

Radiation

PETnegative

2cyclesAVD

InterimFDG-PET

• AdoptedbyBCCancerin2005

• Rationalewastominimizethelong-termtoxicityofradiationforpatientswithchemosensitivedisease

• RetrospectivereviewofBCdatafromJuly2005-April2016publishedDecember2018

Villaetal.Haematologica2018;103:e590

• 239prospectivelydiagnosedlimitedstageHL• 88%werePET2negativepost2cyclesABVD• Medianfollowupof5.5years(10mo– 12yrs)

• 22relapsesatamediantimetorelapseof14mo(5mo– 5.3yrs),9%ABVDaloneand12%ABVD+RT

• NostatisticallysignificantdifferenceinPFSorOSinPET2positiveandPET2negativegroups

5yrPFS84.9%(PET2+)vs.89.5%(PET2-)P=0.366

5yrOS96.6%(PET2+)vs.97.3%(PET2-)P=0.932

PETADAPTEDAPPROACADVANCEDSTAGEDISEAE2cyclesABVD

PETpositive

4cyclesABVD

PETpositive-radiation

PETnegative– noradiation

PETnegative

4cyclesAVD

EndoftreatmentPET

InterimFDGPET• Rationalewastominimizelong-term

toxicityofbleomycinandradiationforpatientsdemonstratingchemosensitivedisease

• ApproachbasedonevidencefromResponseAdaptedTherapyinHodgkinLymphoma(RATHL)trial(2016)

Johnsonetal.NEJM2016;374:2419-29

• ProspectivetrialtotestaresponseadaptedapproachbasedonPET2after2cyclesABVDandmodifyingtreatmentbasedonresults

• 83.7%ofpatientshadanegativePET2

3yrPFSwas85.7%(ABVD)vs.84.4%(AVD)

3yrOSwas97.2%(ABVD)vs.97.6%(AVD)

PROGNOSISOverallapproximately90%ofpatientsintheagerangeof16-70yearscananticipatebeingcured◦ 50%ofrelapsingpatientswillbecuredwithHDT/ASCT

Limitedstagedisease◦ Cureratesare90-95%fornon-bulkystageIAorIIAdisease◦ Ariskstratificationmodelforlimitedstagediseaseisnotcommonlyused

Advancedstagedisease◦ Cureratesare70-80%foradvancedstagedisease◦ InternationalPrognosticScore(IPS)providesvalidatedestimatesofprobablePFSandOS


• IPSisthemostwidelyusedriskstratificationindexforHL• InitiallypublishedinNEJMin1998

• Isbasedonpatientstreatedbefore1992withavarietyofchemotherapyregimens+/- radiation

• Predicted5yrFFPandOSrangingfrom42%-84%and56%-89%respectively

• BCCancervalidatedthescoreinamorerecentlytreatedpatientpopulationandpublishedresultsin2012• Included740patientstreatedbetween1980to2010• TheIPSremainedprognosticforbothFFPandOS• 5yrFFPandOSrangedfrom62%-88%and67%-98%

respectively

RELAPSEDHODGKINLYMPHOMAEligiblefor

ASCT

YES

Salvagechemotherapy

HDT/ASCT

MaintenanceBrentuximab

vedotin

NO

-SingleagentBrentuximabvedotin-Pembrolizumab/nivolumab-Radiotherapyforlocalizeddisease-Palliativechemotherapy(singleagentorcombination)-Clinicaltrial

AUTOLOGOUSSTEMCELLTRANSPLANTELIGIBLEHL• Salvageregimen(GDP,ICE,DHAP)

• Gemcitabine/dexamethasone/cisplatinmostcommonlyusedinBC

• Noheadtoheadtrialstoestablishsuperiorityofoneregimenoveranother

• 2-3cyclesdeliveredpriortoproceedingwithtransplanttodemonstratechemo-sensitivedisease

• MaintenanceBrentuximabvedotin• BrentuximabisgivenIVin3weekcyclesfor

16cycles• AETHERAtrial:maintenanceBrentuximab

postASCTcanpreventapproximately1/3ofrelapsesexpectedtooccurpostASCT

Connors,JMetal.NatureReviewsDiseasePrimers.2020.6:61Moskowitzetal.Blood.Dec2018.132(25),2639.

HIGHDOSETHERAPYANDAUTOLOGOUSSTEMCELLTRANSPLANT

• AnumberofHDTregimensareinuse• BEAM,CBV– nonehasemergedassuperior

• WithcurrentsupportivecareASCTrelatedmortalityisexpectedbe<5%

• Long-termtoxicities• Infertilityinwomen>25yearsandmenof

anyage• 5-10%riskofdevelopingsecondneoplasms• Hypothyroidism

• Fiveindependentfactorsassociatedwithoutcome• Timetorelapse<3mo,stageIVdiseaseat

relapse,performancestatus(ECOG>!),largestindividualtumor> 5cm,lackofCRtosecond-linechemotherapy


ANTIBODYDRUGCONJUGATESBRENTUXIMABVEDOITIN

• Approved2011forrelapsepostASCT• ORR75%andCR34%

• Maintenancetherapyposttransplant• AETHERAtrial

• Newer1stlinecombinationAVD-BvforstageIII/IVCHL• ECHELON-1trialdemonstrated

improved2yrPFSof82.1%(AVD-Bv)vs.77.2%(ABVD)

• GreatestbenefitforpatientswithstageIVor2ormoresitesofextra-nodalinvolvement

• Maintoxicities– peripheralneuropathy

Domingo-Domenech,EVAandAnnaSureda.JClinMed.2020May;9(5):1384.

IMMUNECHECKPOINTINHIBITORS• Nivolumabandpembrolizumabavailablefor

useinCanada• Pembrolizumabapprovedforuseupto

2years• Nivolumabapprovedforuseuntil

diseaseprogressionorunacceptabletoxicity

• Nivolumabbeingtrialedin1stlinetreatmentwithAVDandincombinationwithbrentuximabandAVDandincombinationwithbrentuximabaloneinrelapsed/elderlysetting

• Maintoxicities:autoimmunecomplications


ALLOGENEICSTEMCELLTRANSPLANTLimitedroleinHodgkinlymphoma◦ Highernon-relapseassociatedmortality(NRM)(>15%)

◦ Acuteandchronicgraftvs.hostdisease(GVHD)◦ SevereopportunisticinfectionsinthecontextofGVHD

Remainsareasonableoptionforselectedfitpatients◦ OnlycurativestrategyforpatientswithHLthatrelapseafterauto-SCT◦ Diseasestatusattransplantationplaysthemostimportantrole

◦ 4yrPFSandOSwas18%and41%intheglobalpopulation◦ 4yrPFSandOSimprovedto40%and60%respectivelyforpatientsallograftedwith

chemosensitivedisease

Neweragentssuchasbrentuximabvedotinandtheimmunecheckpointinhibitorshaveprovidednewoptionsforbridgingpatientstopotentiallycurativeallogeneicstemcelltransplant

Thetimingofallogeneictransplantafterbrentuximabvedotinandimmunecheckpointinhibitortherapyremainsatopicofdiscussion


SURVIVORSHIPCARERELAPSESURVEILLANCE

MANAGEMENTOFLONGTERMCOMPLICATIONS

RELAPSESURVEILLANCERelapseSurveillance◦ 5yearriskofrelapsefromdiagnosisforallpatientsis18.1%

◦ 72%ofrelapsesoccurwithinthefirst2yearsofdiagnosis◦ Theriskofrelapsediminishesto5.6%at2yearsfromdiagnosis◦ Foradvancedstagepatientsremainingrelapsefreeat2years,the5yearriskofrelapse

is7.6%andforthreeyearspostdiagnosisiscomparabletolimitedstagepatientsat4.1%

◦ Patientsarenowbeingtransitionedtosurveillancefollowupthroughtheirprimarycareproviderat2yearspostcompletionoftreatment◦ Clinicvisitsevery6monthsforyear2-5posttreatmentandannuallyafteryear5

◦ History◦ Physicalexamincludinglymphnodeandspleenexam◦ Bloodtests(CBC,LFTs,creatinine,LDH,calcium,albumin)◦ Chestx-ray(forpatientswiththoracicdisease)everyvisitfor2yearsandthenevery

othervisit(BCrecommendation)

Hapgoodetal.JClinOncol.2016.34:2493-2500BCCancer.Cancermanagementguidelines.Hodgkinlymphoma

LATECOMPLICATIONSOFTHERAPYSecondarymalignancies– leadingcauseofdeathinsurvivorsofHodgkinlymphoma◦ Increasedriskofsolidtumorsappearsapproximately5yearsaftercompletingtherapyandcontinuestoriseforatleast20years◦ Lung,colonandbreastaremostcommonsecondarymalignancies◦ Skin,thyroid,esophagus,colon,andsarcomasoccurtypicallyintheareasofradiation◦ Solidtumorsaremorefrequentthanhematologicmalignancies

◦ TheriskofAMLpeaksat5-9yearsposttreatment◦ Screening

◦ Nogeneralconsensusregardingoptimalscreeningprogram◦ BCrecommendations

◦ “Although uncommon,certainsecondaryneoplasmsoccurwithincreasedfrequencyinpatientswhohavebeentreatedforHodgkinlymphoma.Theseincludeacutemyelogenousleukemia,thyroid,breast,lunganduppergastrointestinalcarcinomaandmelanomaandcervicalcarcinoma-in-situ.Itisappropriatetoscreenfortheseneoplasmsfortherestofthepatient'slifebecausetheymayhavealengthyinductionperiod.”

◦ Annually◦ TSHlevel(onlyifthyroidirradiated)◦ Mammographyforwomenbeginning10yearsafterdiagnosisofHodgkinlymphomaoratage40years,whichevercomesfirst◦ Papsmear

UpToDate.ApproachtotheadultsurvivorofclassicalHodgkinlymphoma.BCCancer.Cancermanagementguidelines.Hodgkinlymphoma

LATECOMPLICATIONSOFTHERAPYCardiovasculardisease– mostcommonnon-malignantcauseofdeath◦ Coronaryarterydisease,valvulardisease,pericardialdisease,arrhythmia,cardiomyopathy,andperipheralarterydisease

◦ Increasedriskemergessoonaftercompletionoftreatmentandremainselevatedforthesurvivorslifetime

◦ Riskfactors◦ Pre-existingheartdiseaseisthemostsignificantpredictorofpost-HLtherapycardiaccomplications◦ Others:chemotherapy(doxorubicin),radiationtherapy,traditionalcardiacriskfactors

◦ Screening◦ Cardiacexamandauscultationforheartmurmurs,carotidbruits◦ Screeningandmanagementofcardiacriskfactors

◦ Bloodpressuremonitoring,screeningfordiabetes,dyslipidemia◦ Smokingcessation◦ Nutritionalcounselling/obesitycontrol

◦ Counselpatientstoreportsymptomssuchasfatigue

UpToDate.ApproachtotheadultsurvivorofclassicalHodgkinlymphoma.

LATECOMPLICATIONSOFTHERAPY◦ Significantpsychosocialimpactwhichcanbepersistentandsevere◦ Cognitive◦ Emotionalfunctioning◦ Rolefunctioning◦ Socialfunctioning◦ Fatigue◦ Dyspnea◦ Sleepdisturbance◦ Financialproblems

◦ Impactcanbeinfluencedbybaselineimpactandage◦ Highertumorburdenatassociatedwithimpairedbaselinescores◦ Impactisindependentofchemotherapytype

◦ Moreliteratureisrequiredtobetterassessthelong-termpsychosocialimpactofcancertreatment

Kreissl,Setal.JCO.2020.38(25).2839.

HODGKIN LYMPHOMA - BC Cancer

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