Clinical Case Vignettes

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ClinicalCaseVignettes

AssociationofNorthernCaliforniaOncologists(ANCO)HematologicMalignanciesUpdate

November12,2016

GregKaufmanMD,fellow(Stanford)[email protected]

Disclosures

• Nothingtodisclose• Ihaveattemptedtohighlight“off-label”useifapplicableincases

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OutlineofClinicalCaseVignettes

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• 4clinicalcaseshighlightingcommontreatmentandmanagementissuesinhematologicalmalignancies• Takeaway“learningpoints”highlightedineachcase• Audiencequestionswelcomeatanytime,expertopiniononeachcase• Feelfreetodiscussyourownvariationsofcaseswithourexperts

Case1– 53yearoldmale

• Followedforprogressiveanemiaandreferredforpancytopenia• PMHlimitedtoHTN,activewithgoodPS.• Exam– Fitgentleman.Otherwiseunremarkable.

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2.4 848.1 EPOunknown

ANC900TSH/B12/folate nmlIronstudiesnml138

4.2 22

109 16

0.891

Peripheralblood– noblastsorhemolysis

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Case1– Bonemarrowbx

• Initialbonemarrowbiopsy

• 1weeklaterFISHstudiesreturned• 66%ofcellswith16q22rearrangement

5 Source:ASHimagebank

Case1– InitialManagement

• Whatwouldyourecommendasinitialtherapyandwhy?a.)Erythropoietinstimulatingagents+/- G-CSFb.)Azacitidine/decitabinec.)7+3d.)7+3+midostaurine.)7+3+sorafenibf.)otherinductionchemotherapyregimen

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Case1– DiagnosisofAML

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Case1– CoreBindingFactorLeukemia

- Heterodimerictranscriptionfactorsthatinfluencemultipledifferentiationpathways

- AlphasubunitbindsDNAandthebetasubunitenhancesalphasubunitbinding

- inv(16)(p13q22)andt(16;16)(p13;q22)occurasthebetasubunitofCBFistransposedfrom16q22tothemyosinheavychainat16p13creatingafusiontranscript

- Morefrequentlyseeninyoungerpatients

Mrozek,K.etal."PrognosticSignificanceOfTheEuropeanLeukemianetStandardizedSystemForReportingCytogeneticAndMolecularAlterationsInAdultsWithAcuteMyeloidLeukemia".JournalofClinicalOncology 30.36(2012):4515-4523.

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Case1– CoreBindingFactorLeukemiaAge<60

Mrozek,K.etal."PrognosticSignificanceOfTheEuropeanLeukemianetStandardizedSystemForReportingCytogeneticAndMolecularAlterationsInAdultsWithAcuteMyeloidLeukemia".JournalofClinicalOncology 30.36(2012):4515-4523.

Case1– TreatmentofCoreBindingFactorLeukemia

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Case1– TreatmentofCoreBindingFactorLeukemia

• FLAG-IDAx2à consolidationwithHIDACx2cycles• (fludarabine,cytarabine,idarubicin,withGCSFpriming)

• SupportedbydatafromMRCAML15trialandMDAndersonpublisheddata

Burnett,A.K.etal."OptimizationOfChemotherapyForYoungerPatientsWithAcuteMyeloidLeukemia:ResultsOfTheMedicalResearchCouncilAML15Trial".JournalofClinicalOncology

31.27(2013):3360-3368.

Case1– Outcome

• Underwent2cyclesofazacitadine (7daycycles)beforediagnosisofELNfavorableAMLwasclarifiedatBMTappointment• Bonemarrowbiopsyperformedafter2cyclesofAZAshowedmorphologicandcytogeneticcompleteremission• FLAG-IDAx2à consolidationwithHIDACx2cycles

• fludarabine,cytarabine,idarubicin,withGCSFpriming• Cytarabine1.5mg/m2

• NowcompletedtreatmentandremainsinCRp for>6months

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Case1– TakeAways

• Persistentcytogeneticabnormalitiesincludingt(15;17),t(8;21),t(16;16),andinv(16)definethediagnosisofacutemyeloidleukemiaregardlessofbonemarrowblastpercentage.• CBFleukemiainpatients<60areconsideredELNfavorablerisk• DatasuggestgoodoutcomeswithFLAG-ida andconsolidationwithintermediate/highdosecytarabine(MRCAML15trial)

Case2– 47yearoldmale

• 1monthoffatigue,weightloss,bonepain• Foundtohavepancytopeniawithcirculatingatypicalcells• NosignificantPMH;appearsfitonexam

26.8 538.6

Phos 5.6Uricacid10.2LDH1443Coags/fibrinogennml

138

4.3 24

105 10

1.3116

Peripheralblood– 52%blasts

Source:ASHimagebank

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Case2– Bonemarrowbx

• Initialbonemarrowbiopsy

Case2– Ph+ALL– initialmanagement

• TreatedsupportivelyforTLS• CNS1statusconfirmed• Initialtreatmentoncooperativegroupprotocol• Dasatanib140mgdaily+dexamethasone10mg/m2days1-7• CNSprophylaxisbuiltinwithIVandITMTXaswellas4dosesofIVvincristine• ThoseinmorphologicCRgotoallo HCT

• RepeatbonemarrowbiopsiesdocumentmorphologicCR;p210transcriptpositivebut3logreduction(MMRlike)

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Case2– Ph+ALL– initialmanagement

• 2evolvingmainstrategiesinPh+ALL• TKIswithminimalChemoRx &standardchemo+TKI• MorphologicCRrates90-100%witheach• Completemolecularresponserates20vs80%• Allo HCTrequired?debatable

Jabbour,E.LancetOncology16;1547.&Jabbour,EpresentationatSOHOannualmeeting2016.

Case2– Ph+ALL– initialmanagement• MatchedrelateddonorHCT3monthsintotreatmentcourse

• Diseasestatus– CR(bcr-abl p210transcriptdetectablebut>3logreduction)• Reducedintensity– Fludarabine/melphalanconditioning• GVHprophylaxis– alemtuzumabandtacrolimus

• ComplicatedbyBKcystitisandCMVviremia

• Overalldoeswell,resumesdasatanibperprotocolatreduceddoseatday+30

• Bonemarrowbiopsyconfirmsfullengraftment,continuedmorphologicCRandcompletemolecularresponse

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Case2– 47yearoldmanwithPh+ALL– ongoingfollowup

• Continuesonmaintenancedasatanib• MaintainsCMRviaperipheralbloodx15months• PeripheralbloodandbonemarrowmolecularstudiesshowlossofCMRanddetectabilityofp210transcript

• Patientswitchedfromdasatanibtoponatinib15mgdailyperprotocol

ChoiceofTKIinPh+ALL– MDAndersonretrospectivenon-randomizeddata

Sasaki,Kojietal."Hyper-CVADPlusPonatinibVersusHyper-CVADPlusDasatinib AsFrontlineTherapyForPatientsWithPhiladelphiaChromosome-PositiveAcuteLymphoblasticLeukemia:APropensityScore

Analysis".Cancer (2016)EliasJabbour – SOHO2016figure

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Case2– 47yearoldmanwithPh+ALL– ongoingfollowup

• Changestoponatinib• Bonemarrowmorphologicallyandcytogeneticallynegativefordisease• 2monthslaterpresentswithblurryvision• CSFshowsnumerousblasts• Peripheralbloodnegativebypcr (re-establishingCMRat3months)andbonemarrownegativebymorphology/cyto;noconfirmedmarrowCMRatthispoint

Case2– 47yearoldmanwithPh+ALL– ongoingfollowup

• Ponatinib increasedto30mgdaily• 6weeksoftwiceweeklyITchemo;failstoclearCSF• Craniospinal radiation2400cGy tocranium;1800cGy tospine• LatestCSFcytologypending• Furthersystemictreatment?

Originalflowfromdiagnosis

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Case2– 47yearoldmanwithPh+ALLwithsystemicMRDandfrankCNSrelapse

• ThiscasedemonstratesrelapsefromCMRpostallo inthesettingofmaintenanceTKI• Depthofresponseisimportant• But20%of“MRD”negativeptsstillrelapseinALL

• CMRleveltranscriptsinperipheralbloodre-establishedwithchangeinTKItoponatinib• FrankCNSrelapse,ofcoursedifficulttotreat• Questions/comments

Case3– 33yearoldwoman

• 2010- fevers,sweats,weightloss,foundtobepancytopenic• PMHincludesWHOclassIIIobesityanddiabetesmellitus• Exam– acanthosis nigricans,obese,limitedexambutnopalpableadenopathy

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2.9 1997.1 ESR109

Albumin2.1LDH538ALC290/uL127

4.2 25

94 9

0.8204

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Case3– 33yearoldwoman

CT– 11cmrenalmass

LargecellswithIHCshowingCD20+,CD30+,PAX5+,CD15andCD5negative,EBV+

StagingPETconfirmedFDGavidsupraclavicular,splenic,retroperitoneal,gastrohepatic,pericardial,azygoesophageal disease.

WhatisthesignificanceofherCD20positivity?

Case3– 33yearoldwoman

• StageIVXEBSCD20positivenodularsclerosisclassicalHodgkinLymphoma(IPS4)

• ABVDx2cycles– PET/CTdemonstratesmetabolicCR

Wouldthispatientqualifyforomittingbleomycin (eg RATHL)?

• ABVDx4additionalcycles– PETconfirmscompletemetabolicCR• Bonemarrowbiopsyatcountrecoveryconfirmsnoevidenceoflymphoma• ESRnormalizes• RTto30Gy tobulkysites,spleen,aortocaval andparaaortic region

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Case3– StageIVXEBSnscHL treatedwith6cABVDtoCR

1yearposttherapyPET/CT

- SUV4.1rightcervicalnodelikelyinflammatory

Patientthenlosttofollowupx3years

Case3– StageIVXEBSnscHL treatedwith6cABVDtoCR

4yearsposttherapy

NoBsymptoms,nocytopenias,ESRelevated75

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Case3– StageIVXEBSnscHL treatedwith6cABVDtoCR

Rightaxillarylymphnodeexcisionalbiopsy

BiopsyshowsPTGCandnolymphoma

Howwouldyoumanagethepatientatthistime?

Case3– StageIVXEBSnscHL treatedwith6cABVDtoCR

CD20expressionincHL?- HistoricalcaseseriesaredifficulttointerpretgivenclarityastowhetherCD20expressedonRScellsorinfiltrativebackground.Noapparentprognosticsignificance.CasereportsofrituximabuseincHL butnotinfirstlinesetting.

WhoiseligibleforRATHL?

RATHLincludedalladvancedstagepatientsIIBtoIVwithDeauville3orlessresponseafter2cyclesofABVDeligibletocomplete4additionalcyclesofAVD.

FollowupofHodgkinpatients?

Johnson,Peteretal."AdaptedTreatmentGuidedByInterimPET-CTScanInAdvancedHodgkin’SLymphoma".NewEnglandJournalofMedicine 374.25(2016):2419-2429.

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Case3– StageIVXEBSnscHL treatedwith6cABVDtoCR

FollowupofHodgkinpatients?

AtStanfordwedoconsideronetimefollowupPET/CTifDeauville3atcompletionoftherapy.

Case3– StageIVXEBSnscHL treatedwith6cABVDtoCR

• Continueclinicalfollowupin3monthswithoutimaging,consideringrepeatingaPET/CTin6months• ConcernistransformationtoTcellrichdiffuselargeBcelllymphomaornodularlymphocyte-predominantHodgkinlymphoma

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Case3– AdvancedstageclassicalHodgkinLymphoma

Brentuximabvedotin – currentFDAapprovalinHodgkinlymphoma

- TreatmentofclassicalHodgkinlymphomaafterfailureofatleast2priormultiagentchemotherapyregimens(inpatientswhoarenotautologoushematopoieticstemcelltransplantcandidates)orafterfailureofautologoushematopoieticstemcelltransplant

- Treatment(maintenancetherapy)ofclassicalHodgkinlymphomainpatientsathighriskofrelapseorprogressionaspost–autologoushematopoieticstemcelltransplantconsolidation

FrontlinePhIIIBv +AVDtrialinadvancedstagecHL,fullyaccrued,awaitingresults.(NCT01712490)

Case3– AdvancedstageclassicalHodgkinLymphoma

Ongoingupfrontadvancedstagetrials

1.“Chemotherapyfree”frontlinePhIIolderadults>60(allstagesabove1A)nivolumab andbrentuximabvedotin- NCT02758717- Multicentertrial,onlycenterinCalifornia

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Case4– 43yearoldmale

• Presentswith6wks ofanalpainandbleeding• MSM,treatedforanalfissure• PMHincludesDM2,HTN,OSA• Exam– slightlyoverweight

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6.0 27814.0 HIVnegative

TSH/B12/folate nmlIronstudiesnml

136

3.9 26

100 12

1.1198

Case4– 43yearoldmale

• EUAwithbiopsy• PET– distalrectumSUV13.3,otherwise

unremarkable

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Case4– 43yearoldmale

• Possibleextramedullary solitaryplasmacytoma• Monoclonalproteinstudies(noCRAB/MDEs)• SPEP/IFE– IgG lambdatoolowtoquantify• sFLC nml• LDH/B2Mnml• Calciumnml• MRIadditionallyperformed

• – noabnormalbonyuptake/lesions• Bmbx performed- negative

Case4– 43yearoldmale,rectalplasmacytoma

• Treatedwithradiation40Gy (25fractions)• Complicatedbyfissure,treatmentinterruptedx1weekbutcompleted

• Symptomsimprove;PETandEUAwithbiopsynegativeat3months

• 9monthspostcompletionofRTrepeatPETperformedforsurveillance• Residualuptakeindistalrectum,SUV10

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Case4– 43yearoldmale,locallyrecurrentanalplasmacytoma

• RepeatEUAandbiopsyconfirmsclonalplasmacellpopulation• Repeatmonoclonalproteinstudiesnegative• PeripheralbloodMYD88mutationalscreen(p.Leu265Pro)negative• Repeatbonemarrowbiopsynegativebymorphologyandflowforincreasedclonalplasmacellpopulation

Case4– 43yearoldmale,locallyrecurrentanalplasmacytoma

• Surgeryevaluated– resectionwouldrequireanAPR/necessitateanostomy• Patientasymptomaticatthisrecurrence• Recommendations?

• Ruleoutreactiveplasmacytoma,marginalzonelymphoma• Systemictherapy

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Extramedullary plasmacytoma• EMPlesscommonthanSBP• MajorityofcasesintheH&Nregion• Localcontrolratesareexcellentwithradiationalone(typically40-50Gy)• Relapseistypicallyseensystemically(eg myeloma)

Kilciksiz,Sevil etal."AReviewForSolitaryPlasmacytomaOfBoneAndExtramedullaryPlasmacytoma".TheScientificWorldJournal 2012(2012):1-6.

Weber,D.M."SolitaryBoneAndExtramedullary Plasmacytoma".Hematology 2005.1(2005):373-376.

Case4– 43yearoldmale,locallyrecurrentanalplasmacytoma

• PatientseenatbothStanfordandUCSF• RecommendedMRDtestingonbonemarrowtodetectclonalPCsbeneathlevelofmorphology/typicalflowmarkers• Consideringsystemicregimensà lenalidomide/dexamethasone

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Thankyou!

Questions/comments

Othercases?

GregKaufmanMD,fellow(Stanford)[email protected]