DERMATOLOGIC TOXICITIES ASSOCIATED WITH … · keranocytes. PD-L1 staining in few scaered...
Transcript of DERMATOLOGIC TOXICITIES ASSOCIATED WITH … · keranocytes. PD-L1 staining in few scaered...
DERMATOLOGICTOXICITIESASSOCIATEDWITHIMMUNOTHERAPIESANDMANAGEMENTSTRATEGIESJenniferN.Choi,MDAssociateProfessorofDermatologyChief,DivisionofOncodermatologyRobertH.LurieComprehensiveCancerCenterNorthwesternFeinbergSchoolofMedicinejennifer.choi@northwestern.eduJune30,2018
DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY
Jennifer N. Choi, MD
DISCLOSURES Biotest AG: Consultant – Honoraria
Bayer: Speaker – Honoraria Incyte: Principal Investigator – Research
Veloce Pharmaceuticals: Principal Investigator – Research
Spectrumofimmune-relatedAdverseEvents(irAEs)
AnnalsofOncology27:559–574,2016
SuozziKC,etal.JAADCaseRep.2016Jul14;2(3):264-8HofmannL,etal.EuroJCancer.60(2016):190-209
30-40%
6-16%
1-8%
DermatologicAdverseEventstoAnb-PD-1TherapiesAdverseEvent Percent(Grade3-4)
Rash 34-39%(2%)
Pruritus 17-21%(0.5-1%)
Vibligo 9-11%(0%)
NEnglJMed.2013Jul;369(2):134-44NEnglJMed.2015Jan;372(4):320-330JClinOncol2015;33NEnglJMed.2015;372:2521-2532
DermatologicAdverseEventstoAnb-PD-1TherapiesAdverseEvent Percent(Grade3-4)
Rash 34-39%(2%)
Pruritus 17-21%(0.5-1%)
Vibligo 9-11%(0%)
AdverseEvent Percent(Grade3-4)
Rash 44-65%(6-7%)
Pruritus 17-65%(0%)
Nivolumab+Ipilimumab
NEnglJMed.2013Jul11;369(2):122-33
NEnglJMed.2013Jul;369(2):134-44NEnglJMed.2015Jan;372(4):320-330JClinOncol2015;33NEnglJMed.2015;372:2521-2532
Rash
Medianbmetoonset=4-6weeks
Interface,perivascularandperiadnexallymphocybcdermabbsFewplasmacellsandeosinophils
Eczema
HwangS,etal.JAmAcadDermatol.2016Mar;74(3):455-461ShiVJ,etal.JAMADermatology.2016;152(10):1128-1136SibaudV,etal.CurrOpinOncol2016,28:254-263HofmannL,etal.EuropJCancer.2016,60:190-209BelumVR,etal.EuropJCancer.2016,60:12-25
Lichenoiddermabbs
Band-likelymphocybcinfiltratealongDEJVacuolarinterfaceCoexisbngspongiosis
Eczematous/spongiobcdermabbs
BelumVRetal.EurJCancer2016June;60:12-25.
Eczematous• Generalized• Localized
Eczematous• Generalized• Localized
Eczematous• Generalized• Localized
ClinicalPakernsofLichenoidDermabbs
DiscreteLocalizedInverseGeneralizedPalmoplantarMucosal
CD4 CD8
Lichenoid:Discrete
Lichenoid:Discrete
JAMA Dermatol. 2015;151(11):1206-1212.
Lichenoid:Localized
Lichenoid:Localized• Inverse
JAAD Case Rep. 2017 Jan; 3(1): 7–9.
Lichenoid:Generalized
Lichenoid:Generalized
Lichenoid:Palmoplantar
Lichenoid:Mucosal
• 20pabents• Timetoonset:3daysto13months• 16/20(80%):erythematouspapuleswithscale- 11/20(55%):Localizedontrunkorextremibes- 9/20(45%):Generalizeddistribubon
• 16/17(94%):lichenoidhistology• 8/16(50%):lichenoid+spongiobchistology• 4/20(20%):peripheraleosinophilia• 16/20(80%)onconcurrentmedicabonspreviouslyreportedtocauselichenoiddrugerupbons
JAMADermatology.2016;152(10):1128-1136
Association of Dermatitis after PD-1/PD-L1 Inhibitor Therapy and Progression Free Survival and Overall Survival
Lee CK et al. JAAD May 2018
ManagementofRashbyImmuneCheckpointBlockade
Grade Invesbgabons Management Follow-Up
1Macules/papules
covering<10%BSA**Asymptomabcorwithsymptoms
2Macules/papules
covering10-30%BSA**Asymptomabcorwith
symptoms
*Limibngself-careADLs
3-4Macules/papules
covering>30%BSA**Asymptomabcorwith
symptoms*Severe/life-threatening
symptoms*Generalizedexfoliabve/
ulcerated/bullousrash
• Repeatskinexam• Ifdevelops
symptoms,treatashighergrade
• Ifimprovesto<Grade1,resumeimmunotherapy
• Aoersymptomsimprove,tapersteroidsover>1month
• Ifimprovesto<Grade1,tapersteroidsover>1month
• Ifworsensin48hours,consideraddibonalimmunosuppression(infliximab,cyclophosphamide,MMF)orsupporbvemeasures
• Ifnoimprovement>12weeksfromlastdoseoftherapy,disconbnueimmunotherapy
• Mucocutane-ousclinicalexam
• Serumtesbngforliver,kidneyfuncbon
• Considerdermatologyconsult
• Considerskinbiopsy
• Conbnueimmunotherapy• Topicalcorbcosteroids
(intermediatetohighpotency)
• Oralanbhistaminesforpruritus
• Oralprednisone1mg/kg/dayorequivalent
• Oralanbhistaminesforpruritus
• Holdimmunotherapy• Oralprednisone1mg/
kg/dayorequivalent• Oralanbhistamines
forpruritus
Naidooetal.AnnOncol2015Sept14
Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review
Friedman CF, et al. JAMA Oncol. 2016;2(10):1346-1353.
TreatmentofSevereandSteroid-RefractoryImmune-RelatedAdverseEvents
PabentCourse
• Startedonprednisone80mgdailywith3-4weektaper• ClobetasolointmentBIDx2weekstogenitalareaandoralulcerabon;resolvedanddidnotrecur
• Aoerprednisonedosereached10mgQD,rashandpruritusalwaysrecurred.
• StartednarrowbandultravioletBphototherapy2-3bmesaweek–treatedfor3months
• Abletostopphototherapyandwasmaintainedonprednisone4mgdaily,thendisconbnuedprednisonecompletely2monthslater.
• Sbllonpembrolizumabwithstabledisease.• Norecurrenceofrashorpruritusforpast12months.
Anb-PD-1CutaneousErupbonsSevere/life-threatening
TEN-likereacbonassociatedwithnivolumabfollowingipilimumab
JImmunother2016,39(3):149-152
TENduetonivolumabJCutanPathol2017;00:1–4
• Diffusemorbilliformerupbon->slowprogressionoverweekstomonths
• MarkedincreaseinPD-L1stainingexpressioninepidermis
• Pembrolizumab:8SJS,2TEN
• 50yowoman,metastabcmelanoma• 3monthspriortoadmission,startedipilimumab+nivolumabx1cycle->diffusemorbilliform,grade2.
• Ipilimumabstopped.• 2morecyclesofnivolumab->slowprogression.Shortcourseofsystemicsteroidsaoereachdosewithsomeimprovement.Aoer3rddosenivolumab,treatmentheld.Startedprednisone1mg/kg.
• Biopsy:mildinterfacedermabbswithrarenecrobckerabnocytes.PD-L1staininginfewscakeredkerabnocytesandweakexpressionalongepidermis.
• Onadmission,90%BSAwith10%Nikolskysign.Extensiveconjuncbval,oral,andgenitaldesquamabon.ImmunohistochemicalanalysisdemonstratedCD8+cellsaggregatedatthedermal-epidermaljuncbonandepidermalexocytosisofCD8+cells.PD-L1expressionwasmarkedlyincreasedintheepidermis.Directimmunofluorescencewasnegabve.Dx:TEN.
• Infliximab,prednisone1mg/kg.2dayslater,startedIVIGx3doses.Developedsepbcshockandmulborganfailure.Diedonhospitalday6.
JCutanPathol2017;00:1–4
*Abilityofanb-PD-1anbbodiestoinduceTENwithouttheclassicclinicalmorphologyorbmecourseofthedisease
Immunotherapy-InducedPruritus
• Approximately30%ofpabents• Associatedwithrashandxerosis• Enhancedimmunesystemacbvabonintheskin
• Adverselyaffectsqualityoflife
76-year-oldJapanesewomanAdvancedNSCLCwithnivolumabSevererashwithmucosalinvolvementàSJSOralprednisolone1mg/kgRashresolved,butpruritusunremitngwithemollients,anbhistamines,steroidsAprepitant80mgQDx5days
80mgQDx3-5days;120mg,80mg,80mg
Vibligo• 8-25%vibligo• 52to453daystoonset
JAMADermatol.2016Jan1;152(1):45-51.
HofmannL,etal.EuropJCancer.2016,60:190-209
Association of Cutaneous AE and Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab
OR(completeorparbal)associatedwithahigheroccurrenceofvibligo:71%vs28%
JAMA Dermatol. 2016;152(1):45-51JAMA Dermatol. 2015 Nov;151(11):1206-12
Vibligoinnon-melanomacancerpabents
SOX-10
75yearoldwomanStageIVNSCLCCarboplabn+pemetrexed4monthslater,startedonnivolumab8monthsaoernivolumabinibabon:Patchofdepigmentabononrighthand
Vibligoinnon-melanomacancerpabents• 75yomanwithstage4NSCLC,treatedwithdocetaxel.Startednivolumab3monthslaterduetoprogressivedisease.
• 6dayslater,vibligoappearedonback,chest,abdomen,andextremibes
• 66yomanwithAMLinremissionaoerchemotherapyandNSCLCpreviouslytreatedwithchemotherapyandlocalradiabon
• OnnivolumabaspartofphaseIIclinicaltrialforprevenbonofAMLrecurrence
• Depigmentabonstarbng4monthsaoernivolumabinibabon:arms,chest,face,neck
LungCancer.2017Jul;109:42-44JAAD Case Reports 2017;3:90-2
Vibligoinnon-melanomacancerpabents
• Cross-reacbonwithmelanocytedifferenbabonanbgens:gp100,MelanA/MART-1,tyrosinase?
• AnothersharedanbgenbetweenNSCLCandmelanocytes?
JAMADermatol.2017Jul12.
• 13/14pabentswithlungcancer• 4=squamouscelllungcancer• 10=lungadenocarcinoma• 13/14completehairrepigmentabontobaselinehaircolor
• Nivolumab(n=11)• Pembrolizumab(n=1)• Atezolizumab(n=2)• 13/14parbalresponseorstabledisease
JAMADermatol.2017Jul12.
JAmAcadDermatol2017;76:863-70
• 8pabentsonanb-PD1therapyvs30vibligocontrols• Photoexposedareaswithspecificdepigmentabonpakernconsisbngofmulbplefleckedlesions• Nopersonalorfamilyhistoryofvibligo,thyroidibs,orotherautoimmuned/o• Bloodandskinsamples:
• IncreasedCXCmobfligand10levelsinserum• SkininfiltrabonofCD8TcellsexpressingCXCmobfreceptor3andproducingelevatedlevelsofIFN-γandTNF-α
• MeanBSA4.25%(1-9%)
JAmAcadDermatol2017;76:863-70
RepigmentabonofVibligoAssociatedwithMelanomaRelapse
NakamuraYetal.JAMADermatol.2017Sep1;153(9):942-944
Case• 83yearoldCaucasianwomanwithmetastabcmelanomatolungandspine
• Pembrolizumab2mg/kgIVevery3weeks• 2monthhistoryofworseningvaginalandinterglutealerupbon
• Onsetbetweencycles2and3• Empiricsystemicanb-fungalandanbbacterialtherapywithminimalresponse
• Consultedaoeradmissiontohospitalforrash
Anb-PD-1CutaneousErupbons
• Exacerbabonofpsoriasis• Psoriasiformerupbons
JEurAcadDermatolVenereol.2015Sep21
ActaDermVenereol.2015Aug13
JAMADermatol.2015Jul;151(7):797-9CurrOpinOncol2016,28:25-263
JEurAcadDermatolVenereol.2016Oct14JAMADermatol.2016May1;152(5):590-2
CurrentProbCancer.2017;41:407-412
Anb-PD-1InducedPsoriasis• 21pabents• 86%male• 71%withhistoryofpsoriasis• Meanbmeofonsetbetweenanb-PD1inibabonandpsoriasisflare:50days- Denovopsoriasis:90days- Preexisbngpsoriasis:33days
• 95%developedplaquepsoriasis- +gukate:n=6- +palmoplantar:n=4- +pustularpalmoplantar:n=1
• 81%topicaltreatment• 10%systemicsteroids• 5%acitrebn(5/17pabentsrequiredacitrebnassecond-linetx)• 5%phototherapy• 91%controlledbytreatment;9%worsened
BonigenJetal.Oct2016doi:10.1111/jdv.14011
• Ifknownhistoryofpsoriasis,makesurepabentsarefollowedcarefullyduringimmunotherapy.• Inibatetopicalsteroidtreatmentearlyonwithamaintenanceregimen:
E.g.TopicalsteroidsBIDx2weeks,thentopicalcalcipotrienecream/ointmentQD-BIDduringonweekdaysandtopicalsteroidsQD-BIDonweekends
• Lowthresholdtoaddonphototherapywhileonimmunotherapy.• Canconsideraddibonaltherapy:acitrebn,low-dosemethotrexate
Feb May Aug Oct
Anb-PD-1CutaneousErupbons
• Autoimmunebullousskindisorders- Bullouspemphigoid
CancerImmunolRes.2016Feb29.MelanomaRes.2015Jun;25(3):265-8.IntlJDermatolo.2018;57:664-669.
• Atleast21casesreported:pembro,nivo,durvalumab,atezolizumab• Pruritus:prominentfeature,precedingorconcurrent• Meanbmetopruritus:17weeks• Timetodevelopmentofbullae:6to80weeks(median24weeks)• Metastabcmelanoma,head/neckSCC,lungadenocarcinoma,lung
SCC,NSCLC,renalcellcarcinoma,urothelialcarcinoma• Meanage:71years• 6/21pabents=29%hadoralmucosalinvolvement
• Topicalsteroidmonotherapy• Oralsteroids+topicalsteroids• Doxycycline+niacinamide:n=1;+oralandtopicalsteroids:n=3• Rituximab:n=1• Omalizumab:n=1• 3/21pabents:prolongedcoursesofBPfor3-12monthsaoer
disconbnuabonofcheckpointinhibitor• Disconbnuabonnecessaryin16/21cases=76%• 7/19pabents=37%hadcancerprogressionorpabentdeathshortly
aoerBPdiagnosisandcheckpointinhibitordisconbnuabon
• 2theories:• AlteredregulabonofT-cellstargebngcollagenXVII/
BP180• IncreasedautoanbbodyproducbonagainstBP180
• Inpabentswithpersistentorunusualpruritus,considersubclinicalBP.
• Cantakemonthstoresolveduetoautoimmuneacbvabon
Otherreportedcutaneoussideeffectstocheckpointinhibitors
• Acneiformerupbon• Acbnickeratosis• Acutegeneralizedexanthematouspustulosis(AGEP)• Annulargranuloma• Alopeciaareata,universalis• Basalcellcarcinoma• Dermalhypersensibvityreacbon(DHR)• Dermabbsherpebformis• Dermatomyosibs• Drugrashwitheosinophiliaandsystemicsymptoms(DRESS)• Erupbvekeratoacanthoma• Erythema• Erythema-nodosum-likepanniculibs• Exfoliabvereacbon• Grover’sdisease• Hyperhidrosis
• Nailchanges• Necrobzingvasculibs• Papulopustularrosacea• Peritumoralinflammatorycellulibs• Photosensibvityreacbon• Pityriasislichenoides-likereacbon• Prurigonodularis• Pyodermagangrenosum-likeulcerabons• Radiabon-associateddermabbs• Regressionofmelanocybcnevi• Sarcoidosis• Sclerodermoidreacbon• Seborrheickeratosis• Sjögren’ssyndrome• Squamouscellcarcinoma• Sweet’ssyndrome• Tumoralmelanosis• Urbcaria• Xerosis
Erupbvekeratoacanthomas
CutaneousSCCs5/82pabents=6.1%Face,chest,armsOlderpabents(73yovs60yo)Hwangetal.JAmAcadDermatol2016;74:455-61.
Erupbvekeratoacanthomas
JAMADermatology.2017May3
• 3pabentsonpembrolizumab• Suddenonsetofmulbplelesionsonsun-exposedareasofextremibes• Median13months(4-18mos)• Pathology:Mulbloculated,crateriform,kerabn-filledlesionsSquamouscellsw/glassyappearingcytoplasmandminimalcytologicatypiaDisbnctlichenoidinfiltrateinunderlyingdermisw/CD3+Tcells• IL+topicalsteroids+/-cryotherapy
Autoimmunefasciibs• 43-year-oldwomanwithmetastabcmelanoma• Startedonnivolumab• 14monthslater:developedprogressivefabgue,widespreadmyalgiaofbilateralupperandlowerlimbs,progressivedysphagia
• Skin-musclebiopsy:focusedfascialandperifascicularinflammatoryinfiltrate
ParkerMetal.BMJCaseRep2018;Jan8
Pembrolizumab-inducedscleroderma• 66-year-oldmanwithmetastabcmelanoma.Startedonpembrolizumab.Aoercycle13,developedfabgueandswellingofjointsandankles.Progressiontoburningandmuscleweakness.Developeddiffuseskinthickeningoverbilateralextremibesandface.
• TreatedwithIVIG5daysweeklypermonthandmycophenolatemofebl1000mgBID.Symptomimprovement,then14weekslater,begantodeclineanddied2monthslater.
• 79-year-oldmanwithmetastabcmelanoma.Startedonpembrolizumab.Aoercycle5,severesbffnessofhandsandfeet.Pembrolizumabwasdisconbnued.
• Treatedwithhydroxychloroquine200mgBIDandoralprednisone.Improvementinsymptoms.
Mayo Clin Proc. 2017;92(7):1158-1163
Checkpointinhibitor-induceddermatomyosibs• Ipilimumab:n=1• Nivolumab:n=1• 42-year-oldmanwithstageIVlungadenocarcinoma.Treatedwith4cyclesofcisplabn,pemetrexed,andbevacizumab->7cyclesofpemetrexedandbevacizumab->4cyclesofdocetaxel.Startedonnivolumab(3mg/kgQ2weeks).
• Afewdaysaoercycle1:generalfabgueandminorproximallimbmuscleweakness• 6weekslater:clearproximalmuscleweaknessandskinfindings• MRIlegs:abnormallyhighintensityareasinbilateraladductorandobturatormuscles;EMGshowedmyogenicconversion.
• Treatedwithprednisolone0.6mg/kgQD->slighttemporaryimprovement• Thendiagnosedwithspinalcordandmeningealdisseminabon10dayslater->death
Intern Med. 2018 Mar 9.
Erythemanodosum-likepanniculibs
Sarcoidosis
Immunotherapy-inducedalopeciaareata
• 1-1.6%ofpabentsonimmunotherapy• Anb-CTLA-4,PD-1,andPD-L1inhibitors• Scalp,face,eyebrows,eyelashes,trunk• Areataanduniversalis• Treatmentwithintralesionalsteroids(triamcinolone)andtopicalsteroids(clobetasol)
• Resultantregrowthwithpoliosis
BrJDermatol.2017June;176(6):1649–1652.