NCCNClinicalPracticeGuidelinesinOncologyNCCNGuidelines?)Myeloid/LymphoidNeoplasmswithEosinophiliaandTyrosineKinaseFusionGenesrsionJulyVersion4.2021,07/09/21?2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon9/2/202110:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2021NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.NCCNGuidelinesVersion4.2021NCCNnNCCNGuidelinesVersion4.2021NCCNn KinaseFusionGenes*AaronT.Gerds,MD,MS/Chair??TCaseComprehensiveCancerCenter/UniversityHospitalsSeidmanCancerCenterandClevelandClinicTaussigCancerInstitute*JasonGotlib,MD,MS/Vice-Chair?StanfordCancerInstituteHarisAli,MD?ξCityofHopeNationalMedicalCenterPrithvirajBose,MD?TheUniversityofTexasMichaelW.Deininger,MD,PhD?HuntsmanCancerInstituteattheUniversityofUtahAndrewDunbar,MD?MemorialSloanKetteringCancerCenterAmroElshoury,MD?RoswellParkComprehensiveCancerCenterTracyI.George,MD≠HuntsmanCancerInstituteattheUniversityofUtahKrishnaGundabolu,MBBS?Fred&PamelaBuffettCancerCenterElizabethHexner,MD?ξAbramsonCancerCenterheUniversityofPennsylvaniaGabrielaHobbs,MD?MassachusettsGeneralHospitalCancerCenteresPanelDisclosuresTaniaJain,MBBS?TheSidneyKimmelComprehensiveCancerCenteratJohnsHopkinsCatrionaJamieson,MD,PhD?UCSanDiegoMooresCancerCenterAndrewT.Kuykendall,MD?TMoffittCancerCenterYazanMadanat,MD?UTSouthwesternSimmonsComprehensiveCancerCenterBrandonMcMahon,MD?UniversityofColoradoCancerCenterSanjayR.Mohan,MD?Vanderbilt-IngramCancerCenterStephenOh,MD,PhD?SitemanCancerCenteratBarnes-JewishHospitalandWashingtonUniversitySchoolofMedicineAnimeshPardanani,MBBS,PhD?MayoClinicCancerCenterNikolaiPodoltsev,MD,PhD?YaleCancerCenter/SmilowCancerHospitalErikRanheim,MD,PhD≠UniversityofWisconsineCancerCenterLindsayRein,MD?DukeCancerInstituteRachelSalit,MD?FredHutchinsonCancerResearchCenter/SeattleCancerCareAllianceBradyL.Stein,MD?TRobertH.LurieComprehensiveCancerCenterofNorthwesternUniversityMosheTalpaz,MD?UniversityofMichiganRogelCancerCenterPankitVachhani,MD?O'NealComprehensiveCancerCenteratUABMarthaWadleigh,MD??Dana-Farber/BrighamandWomen’senterKatherineWalsh,MD?TheOhioStateUniversityComprehensiveCancerCenter-JamesCancerHospitalandSoloveResearchInstituteDawnC.Ward,MD≠UCLAJonssonComprehensiveCancerCentererPhD?Hematology/HematologyoncologyTInternalmedicine?Medicaloncology≠PathologyξTransplantation*DiscussionSectionWritingCommitteeVersion4.2021,07/09/21?2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon9/2/202110:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2021NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.NCCNGuidelinesVersion4.2021Myeloid/LymphoidNeoplasmswithEosinophiliaandTyrosinedexNCCNMyeloproliferativeNeoplasmsPanelMembersSummaryofGuidelinesUpdatesOverview(MLNE/INTRO-1)InitialEvaluationandDiagnosticTip-offs(MLNE-1)Workup(MLNE-2)DiagnosticTestingAlgorithmsNCCNMyeloproliferativeNeoplasmsPanelMembersSummaryofGuidelinesUpdatesOverview(MLNE/INTRO-1)InitialEvaluationandDiagnosticTip-offs(MLNE-1)Workup(MLNE-2)DiagnosticTestingAlgorithmsforTyrosineKinaseFusionGeneRearrangements(MLNE-3)DiagnosisandStagingConsiderationsinMyeloid/LymphoidNeoplasmswithEosinophiliaandTyrosineKinaseFusionGenes(MLNE-4)Myeloid/LymphoidNeoplasmswithEosinophiliaandtheFIP1L1-PDGFRARearrangementeplasmswithEosinophiliaandPDGFRBRearrangementMLNEoplasmswithEosinophiliaandFGFRRearrangementMLNEoplasmswithEosinophiliaandplasmswithEosinophiliaandPDGFRBRearrangementMLNEoplasmswithEosinophiliaandFGFRRearrangementMLNEoplasmswithEosinophiliaandJAKRearrangementMLNEophiliaandABLorFLTRearrangementMLNENCCNCategoriesofPreference:Allrecommendationsareconsideredappropriate.CausesofSecondaryReactiveEosinophilia(MLNE-A)WHODiagnosticCriteriaforMyeloidLymphoidNeoplasmswithEosinophiliaandRearrangementofPDGFRA,PDGFRB,orFGFRorwithPCMJAK2(MLNE-B)ymphoidNeoplasmswithEosinophiliaAndFusionGenesMLNECrationSequencingNGSintheDiagnosisofMyeloidLymphoidNeoplasmswithEosinophiliaAndFusionGenesMLNEDTheNCCNGuidelinesareastatementofevidenceandconsensusoftheauthorsregardingtheirviewsofcurrentlyacceptedapproachestotreatmentAnyclinicianseekingtoapplyorconsulttheNCCNGuidelinesisexpectedtouseindependentmedicaljudgmentinthecontextofindividualstancestodetermineanypatientscareortreatmentTheNationalComprehensiveCancerNetworkNCCNmakesnorepresentationsorwarrantiesofanykindregardingtheircontentuseorapplicationanddisclaimsanyresponsibilityfortheirapplicationoruseinanywayTheNCCNationalComprehensiveCancerNetworkAllrightsreservedTheNCCNGuidelinesandtheillustrationshereinmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.?2021.Version4.2021,07/09/21?2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon9/2/202110:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2021NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.NCCNGuidelinesVersion4.2021Myeloid/LymphoidNeoplasmswithEosinophiliaandTyrosinedexionoftheNCCNGuidelinesforMLNEfromVersionincludeMLNE-5Footnote"t"modifiedasfollows:Avapritinibisapprovedforadvancedsystemicmastocytosis(SM)(aggressiveSM[ASM],SMwithanassociatedhematologicneoplasm[SM-AHN],andmastcellleukemia[MCL])andalsoforunresectableormetastaticgastrointestinalstromaltumors(GISTs)harboringaPDGFRAexon18mutation,includingD842Vmutations.ThissuggestsapossibleroleforavapritinibinpatientswithFIP1L1-PDGFRA–positivemyeloid/lymphoidneoplasmswitheosinophiliaharboringPDGFRAD842Vmutationresistanttoimatinib.Ifthismutationisidentified,aclinicaltrialofavapritinibispreferred(ifavailable),ratherthanoff-labeluse.MS-1TheDiscussionhasbeenupdatedtoreflectthechangestothealgorithm.ionoftheNCCNGuidelinesforMLNEfromVersionincludeMLNE-7"Pemigatinib"hasbeenaddedasaTKIwithactivityagainstFGFR1underotherrecommendedregimensforblastphase,withthefollowingcorrespondingfootnote,"Pemigatinib(FGFR1,2,and3inhibitor)isapprovedforthetreatmentofadultpatientswithpreviouslytreated,unresectable,locallyadvancedormetastaticcholangiocarcinomaandaFGFR2fusionorotherrearrangement,asdetectedbyanFDA-approvedtest.Pemigatinibhasreceivedorphandrugdesignationforthetreatmentofpatientswithmyeloid/lymphoidneoplasmswitheosinophiliaandFGFR1rearrangementandiscurrentlybeingevaluatedinaclinicaltrialforthisindication.Aclinicaltrialofpemigatinibispreferred(ifavailable),ratherthanoff-labeluse(HoySM.Drugs2020;80:923-929;VerstovsekS,etal.Blood2018;132:Abstract690)."MS-1TheDiscussionhasbeenupdatedtoreflectthechangestothealgorithm.ionoftheNCCNGuidelinesforMLNEfromVersionincludeMLNE-3(AlsoforMLNE-4,MLNE-8,andMLNE-9)?Thefollowingfootnoteisnewtothepage,"ThedifferentialdiagnosisofJAK2andABL1fusionswithaphenotypeofALLincludesPh-likeALL."MLNE-5?Thefollowingfootnotecorrespondingto,Ifresistancemutationfound,referforclinicaltrialisnewtothispage."Avapritinibisapprovedforadultpatientswithunresectableormetastaticgastrointestinalstromaltumors(GISTs)harboringaPDGFRAexon18mutation,includingD842Vmutations.ThissuggestsapossibleroleforavapritinibinpatientswithFIP1L1-PDGFRA–positivemyeloid/lymphoidneoplasmswitheosinophiliaharboringPDGFRAD842Vmutationresistanttoimatinib.Ifthismutationisidentified,aclinicaltrialofavapritinibispreferred(ifavailable),ratherthanoff-labeluse."MLNE-7?"Pemigatinib"hasbeenaddedasaTKIwithactivityagainstFGFR1underotherrecommendedregimens.?Thefollowingfootnotecorrespondingto,"clinicaltrial"and"pemigatinib"isnewtothispage."Pemigatinib(FGFR1,2,and3inhibitor)isapprovedforthetreatmentofadultpatientswithpreviouslytreated,unresectable,locallyadvancedormetastaticcholangiocarcinomaandaFGFR2fusionorotherrearrangement,asdetectedbyanFDA-approvedtest.Pemigatinibhasreceivedorphandrugdesignationforthetreatmentofpatientswithmyeloid/lymphoidneoplasmswitheosinophiliaandFGFR1rearrangementandiscurrentlybeingevaluatedinaclinicaltrialforthisindication.Aclinicaltrialofpemigatinibispreferred(ifavailable),ratherthanoff-labeluse(HoySM.Drugs2020;80:923-929;VerstovsekS,etal.Blood2018;132:Abstract690)."MS-1?TheDiscussionhasbeenupdatedtoreflectthechangestothealgorithm.Version4.2021,07/09/21?2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.UPDATESMLNE/INTRO-1PrintedbyMinTangon9/2/202110:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2021NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.MLNE/INTRO-1NCCNGuidelinesVersion4.2021NCCNnNCCNGuidelinesVersion4.2021NCCNn OVERVIEW1,2,3,4,5leosinophiliaassociatedwithtyrosinekinaseTKfusiongenerearrangementsPDGFRAPDGFRBFGFRJAKABLorFLTcanhavediverseclinicalpresentationsincludingPhnegativemyeloproliferativeneoplasmsMPNwitheosinophilia,myelodysplasticsyndromes(MDS)/MPNwitheosinophiliaacutemyeloidleukemia(AML),B-cellorT-celllymphomas,acutelymphoblasticleukemia(ALL),ormixedlineageleukemias/lymphomas.Adiagnosisofmyeloid/lymphoidneoplasmswitheosinophiliashouldbesuspectedinthefollowingclinicalsituations(SeeMLNE-1):?Sustainedeosinophilia(≥1.5x109/L)ortissueeosinophilia(anyeosinophilcount)inatargetorgan,withtheoccurrenceofcharacteristicgeneticbreakpoints,withsomenotalwaysvisiblebystandardcytogenetics(eg,FIP1L1-PDGFRA,ETV6-ABL1);?Clinicalfeaturessuchassplenomegaly,anemia,thrombocytopenia,leukoerythroblastosis,circulatingdysplasticcells,elevatedserumvitaminB12and/ortryptaselevels,andabnormalmastcellproliferationinthebonemarrow(BM);?Featuresofsystemicmastocytosis(SM)witheosinophiliabutwithinterstitial,notdenseaggregatesofatypicalmastcells(FIP1L1-PDGFRArearrangement);?Featuresofchronicmyelomonocyticleukemia(CMML)witheosinophilia(PDGFRBrearrangement);?PersistenteosinophiliaafterintensivetreatmentofAML,ALL,B-celllymphoma,orT-celllymphoma.MyeloidLymphoidNeoplasmswithEosinophiliaandFIPLPDGFRARearrangementaCEListhemostcommonclinicalpresentationVariantpresentationsincludeblastphaseMPNAMLwitheosinophiliaRAormyeloidsarcomaThisentityhasastrongmalepredominanceandiscommonlyassociatedwithionofserumvitaminBelevatedserumtryptaseandsplenomegalyPeripheraleosinophiliaisusuallybutnotalwaysobservedBMishypercellularwithincreasedeosinophilprecursorsgenerallywithoutdysplasiaandproliferationoflooselydistributedCD25+spindle-shapedmastcells.DenseclustersofmastcellstypicallyseeninSMwiththeKITD816Vmutationareusuallyabsent.Myeloid/LymphoidNeoplasmswithEosinophiliaandPDGFRBRearrangement:CMML,atypicalCML,MDS/MPN,MPN,juvenilemyelomonocyticleukemia(JMML),andblastphasediseaseinvolvingtheBMand/orextramedullarydisease(EMD)involvingmyeloid,lymphoid,ormixedlineages.Thisentityalsohasastrongmalepredominance.Eosinophiliaisnotinvariablypresent.MyeloidLymphoidNeoplasmswithEosinophiliaandFGFR1Rearrangement:llorTcelllymphomaALLmixedphenotypeacuteleukemiaandorEMDofmyeloidlymphoidormixedlineageThisentityhasamoderatemalepredominanceandisgenerallyassociatedwithanaggressiveclinicalcoursewithrapidprogressionofchronicphasediseasetoblastphase/secondaryacuteleukemia.Eosinophiliaisnotinvariablypresent.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version4.2021,07/09/21?2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon9/2/202110:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2021NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.NCCNGuidelinesVersion4.2021NCCNnNCCNGuidelinesVersion4.2021NCCNn OVERVIEW1,2,3,4,5MyeloidLymphoidNeoplasmswithEosinophiliaandJAK2Rearrangement:Chronicmyeloidneoplasmwitheosinophilia(MPNwitheosinophiliaorMDS/MPNwitheosinophilia)isthecharacteristicclinicalpresentation.ALLordenovoAMLhavealsobeenobserved.Thisentityhasastrongmalepredominanceandisgenerallyassociatedwithanaggressiveclinicalcoursewithrapidprogressionofchronicphasediseasetoblastphase/secondaryacuteleukemia.ThepresenceofeosinophiliaismorevariableforBCR-JAK2andETV6-JAK2variants.LymphoidNeoplasmswithEosinophiliaandFLTorABLRearrangementyeloidandorlymphoidneoplasmwitheosinophiliaconsistentwiththeWHOcategoryofCELnototherwisespecifiedCELNOSisthecharacteristicmentPeripheralTcelllymphomaorTcelllymphoblasticlymphomaTLBLhavealsobeenisthemostcommonclinicalpresentationassociatedwithABLrearrangementhowevervariousacuteleukemiaandchronicmyeloidlymphoidphenotypeshavealsobeendescribedItisgenerallyassociatedwithanaggressiveclinicalcourse,diseaseprogression,orrelapse.Eosinophiliaisnotinvariablypresent.References1ReiterA,GotlibJ.Myeloidneoplasmswitheosinophilia.Blood2017;129:704-714.2ShomaliW,GotlibJ.WorldHealthOrganization-definedeosinophilicdisorders:2019updateondiagnosis,riskstratification,andmanagement.AmJHematol2019;94:1149-1167.3SwerdlowSH,CampoE,HarrisNL.etal.WorldHealthOrganization(WHO)ClassificationofTumoursofHaematopoieticandLymphoidTissues.Revised4thed.Lyon,France:IARCPress;2017.4JawharM,NaumannN,SchwaabJ,etal.Imatinibinmyeloid/lymphoidneoplasmswitheosinophiliaandrearrangementofPDGFRBinchronicorblastphase.AnnHematol2017;96:1463-1470.5ReiterA,WalzC,WatmoreA,etal.Thet(8;9)(p22;p24)isarecurrentabnormalityinchronicandacuteleukemiathatfusesPCM1toJAK2.CancerRes2005;65:2662-2667.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version4.2021,07/09/21Version4.2021,07/09/21?2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon9/2/202110:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2021NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.NCCNGuidelinesVersion4.2021NCCNGuidelinesIndexMyeloid/LymphoidNeoplasmswithEosinophiliaNCCNGuidelinesVersion4.2021NCCNGuidelinesIndexINITIALEVALUATION?Ruleoutsecondary(reactive)eosinophiliaa(SeeMLNE-A).?Allpatientsshouldbeevaluatedandmanagedbyamultidisciplinaryteaminspecializedcenters.?Assessmentforclinicalsituationsthatmayrequireurgentinterventionisrecommendedforallpatients.Immediateinstitutionoforalorhigh-doseIVcorticosteroidsmaybenecessary.DIAGNOSTICTIP-OFFS?Primary(clonal/neoplastic)eosinophiliabmaybesuggestedbyoneormoreofthefollowing:pElevatedserumtryptaselevel;pAbnormalT-cellpopulation;pIncreasedblasts,dysplasia,cytogeneticormolecularabnormality,and/orbonemarrowfibrosis;orpSplenomegalyand/orlymphadenopathy.?ExcludethediagnosisofBCR-ABL1–positiveCML,PV,ET,PMF,CNL,andBCR-ABL1–negativeatypicalCMLbasedonWHOcriteria.?ScreenforTKfusiongenerearrangementsorothercytogeneticabnormality(SeeMLNE-3).?Immunohistochemistry(IHC)fortryptase/CD117/CD25candmolecularc?T-cellimmunophenotypingflowcytometry(preferred)and/orIHCtoestablishevidenceofabnormalT-cellphenotypeorT-cellproliferation;molecularanalysistoconfirmT-cellclonalitywhenappropriateAPDGFRBFGFR1,JAK2,ABL1,FLT3rearrangementsidentifieddminorcriteriaforSMsfiedonalcytogeneticrmolecularabnormalityorexcessblaststo<20%)TcellphenotypeationthoutdlymphoidlasmgeneticityornotyperationSeeWorkup(MLNE-2)andDiagnosticTestingAlgorithms(MLNE-3)SMSeeNCCNGuidelinesforicMastocytosistofophiliaHEphilicsyndromeHESEosinophilia-relatedorgandamageYes?IdiopathicHES?IdiopathicEaThisdiagnosticalgorithmexcludesconditionsassociatedwithsecondary(reactive)eosinophilia(seeMLNE-A);includeseosinophiliaassociatedwithnon-myeloidmalignanciessuchasT-celllymphoma,Hodgkinlymphoma,andALL.bGenerally,absoluteeosinophilcount≥1.5x10/L.cAllele-specificoligonucleotidequantitativereversetranscriptasePCR(ASO-qPCR)oralternativehigh-sensitivitymethodisrecommendedforKITD816Vmutationtesting.SeeNCCNGuidelinesforSystemicMastocytosis.dThediagnosisisbasedonthe2017WHOClassificationandrequiresacombinationofhistopathologic,clinical,laboratory,andcytogenetic/molecularanalyses.See2017WHODiagnosticCriteriaforMyeloid/LymphoidNeoplasmswithEosinophiliaandTyrosineKinaseFusionGeneRearrangement(MLNE-B).eAdditionalcytogeneticormoleculartestingmayberequiredtoconfirmthedifferentialdiagnosisofclonalhematopoiesisofindeterminatepotential(CHIP)vs.CEL-NOS.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.MLNE-1Version4.2021,07/09/21?2021NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon9/2/202110:14:44AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2021NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.NCCNGuidelinesVersion4.2021NCCNGuidelinesIndexMyeloid/LymphoidNeoplasmswithEosinophiliaNCCNGuidelinesVersion4.2021NCCNGuidelinesIndexWORKUPGeneralDiagnosticStudies?Historyandphysical(H&P)examination,includingskinexam,palpationofspleen,anddetailinganyfamilyhistoryofeosinophiliaandsigns/symptomsofimmunodeficiencytoidentifyrareprimaryimmunodeficiencydisordersandruleoutsecondary(reactive)eosinophilia(SeeMLNE-A).?CBCwithdifferential?Examinationofbloodsmear(eg,monocytosis,dysplasia,eosinophilia,circulatingblasts)?Comprehensivemetabolicpanelwithuricacid,lactatedehydrogenase(LDH),andliverfunctiontests(LFTs)?Serumtryptase,vitaminB12,erythrocytesedimentationrate(ESR),and/orC-reactiveprotein(CRP)?Quantitativeserumimmunoglobulin(Ig)levels(includingIgE)?BMaspirateandbiopsywithIHCforCD117,CD25,andtryptaseandreticulin/collagenstainsforfibrosis?Peripheralblood(PB)assessmentforPDGFRArearrangementbyfluorescenceinsituhybridization(FISH)and/ornestedquantitativeRT-PCRf(RT-qPCR)?ConfirmatoryFISH(PBorBM)ifchromosomeanalysisrevealsthefollowingbreakpoints:4q12(PDGFRA);g5q31~33(PDGFRB);h8p11~12(FGFR1);9p24(JAK2);9q34(ABL1);and13q12(FLT3)i?T-cellimmunophenotypingflowcytometry(preferred)and/orIHCandmolecularanalysistoconfirmT-cellclonalitywhenappropriate?Myeloidmutationpanel(next-generationsequencing[NGS])i,jEvaluationofTargetOrganInvolvementkBasedonclinicalpresentationrequiringengagementofothersub-specialists;organ-directedbiopsygenerallyneededtoconfirmtissueeosinophilia:?Chestx-rayECG?Symptom-directedCT/MRIscanofthebody?Cardiactroponinand/orNT-proBNPmeasurement;ifelevatedorclinicalfeaturesofcardiacinjury,echocardiogram,and/orcardiacMRI?Lunginvolvement:pulmonaryfunctiontests,bronchoscopywithbronchoalveolarlavage,andlungbiopsy?GIinvolvement:endoscopywithrelevantmucosalbiopsywithIHCforCD25,CD117,andtryptase?Liverinvolvement:liverbiopsy?Neuropathy:electromyography(EMG),nervebiopsy?ENTsymptoms:evaluationforsinusitis,nasalpolyposis,sensorineuralhearingloss,etc.?Cutaneousinvolvement:skinbiopsy?Eosinophilicfasciitis:deepbiopsythatincludesfascia,MRIiagnosticeFusionGeneiagnosistagingiderationsinhoidlasmswithinophiliaandonGenesLNEfTestingforimatinib-sensitiveTKfusiongenerearrangementsbyPBisfeasibleandappropriateincertainclinicalcircumstances.SeePrinciplesofCytogeneticandMolecularTestingforMyeloid/LymphoidNeoplasmswithEosinophilia(MLNE-C).gTheoverwhelmingmajorityofPDGFRAfusionsarerepresentedbyFIP1L1-PDGFRA,whichiscytogeneticallyoccultandrequiresFISHforthedetectionofCHIC2deletionforinitialscreening.hInrarecases,crypticPDGFRBrearrangementshavebeenfound,andFISHmaybeusedtouncover,notonlyconfirmPDGFRBrearrangements.iRT-PCRmaybeprefer