慢性髓細胞白血病2022.v3（英文）-NCCN腫瘤臨床實踐指南

NCCNClinicalPracticeGuidelinesinOncologyNCCNGuidelines?)ChronicMyeloidLeukemiaersionJanuarytientsavailableatwwwnccnorgpatientsVersion3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:34:38AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.idLeukemiadex*NeilP.Shah,MD,PhD/Chair?UCSFHelenDillerFamilyComprehensiveCancerCenter*RaviBhatia,MD/Vice-Chair?O'NealComprehensiveCancerCenteratUABJessicaK.Altman,MD?RobertH.LurieComprehensiveCancerCenterofNorthwesternUniversityMariaAmaya,MD,PhD?UniversityofColoradoCancerCenterEllinBerman,MD??TMemorialSloanKetteringCancerCenterRobertH.Collins,Jr.,MD?UTSouthwesternSimmonsComprehensiveCancerCenterPeterT.Curtin,MD??ξCityofHopeNationalMedicalCenterDanielJ.DeAngelo,MD,PhD??Dana-Farber/BrighamandWomen’senterJasonGotlib,MD,MS??StanfordCancerInstituteGabrielaHobbs,MD??MassachusettsGeneralHospitalCancerCenteresPanelDisclosuresLoriManess,MD?FredandPamelaBuffettCancerCenterMonicaMead,MD?UCLAJonssonComprehensiveCancerCenterLelandMetheny,MD?ξCaseComprehensiveCancerCenterUniversityHospitalsSeidmanCancerCenterandClevelandClinicTaussigCancerInstituteSanjayMohan,MD,MSCI?Vanderbilt-IngramCancerCenterJosephO.Moore,MD?DukeCancerInstituteVivianOehler,MD?FredHutchinsonCancerResearchCenter/SeattleCancerCareAllianceMrinalPatnaik,MD?MayoClinicCancerCenterKeithPratz,MD?AbramsonCancerCenterheUniversityofPennsylvaniaIskraPusic,MD,MSCI?SitemanCancerCenteratBarnes-JewishHospitalandWashingtonUniversitySchoolofMedicineMichalG.Rose,MD?YaleCancerCenter/SmilowCancerHospitalB.DouglasSmith,MD?TTheSidneyKimmelComprehensiveCancerCenteratJohnsHopkinsKendraL.Sweet,MD,MS??TMoffittCancerCenterMosheTalpaz,MD?UniversityofMichiganRogelCancerCenterTiffanyN.Tanaka,MD?UCSanDiegoMooresCancerCenterJamesThompson,MD,MS?RoswellParkComprehensiveCancerCenterJenniferVaugh,MD,MSPH?TheOhioStateUniversityComprehensiveCancerCenter-JamesCancerHospitalandSoloveResearchInstituteJeannaWelborn,MD?UCDavisComprehensiveCancerCenterDavidT.Yang,MD≠UniversityofWisconsineCancerCenterξ?T?≠BonemarrowtransplantationHematology/HematologyoncologyInternalmedicineMedicaloncology*DiscussionSectionWritingCommitteeVersion3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.MyeloidLeukemiaPanelMembersryofGuidelinesUpdatesrkupCMLMLCMLEarlyTreatmentResponseMilestonesClinicalConsiderationsandRecommendationsCMLMyeloidLeukemiaPanelMembersryofGuidelinesUpdatesrkupCMLMLCMLEarlyTreatmentResponseMilestonesClinicalConsiderationsandRecommendationsCMLvancedPhaseCMLCMLTreatmentRecommendationsBasedonBCRABLMutationProfile(CML-5)eneicHematopoieticCellTransplantationCMLatedPhaseandBlastPhaseCMLBringPregnancyCMLCeriaforResponseandRelapseCMLDrapyandMutationalAnalysisCMLEKITherapyCMLFMLGofMLGofLGofMLGofyCMLGofMLGofteractionsofTKIsCMLGofidLeukemiadexlievesthatthebestmanagementforanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.FindanNCCNMemberInstitution:/home/member-institutions.ofEvidenceanddationsotherwisedNCategoriesofEvidenceandConsensus.NCCNCategoriesofPreference:Allrecommendationsareconsideredappropriate.SeeNCCNCategoriesofPreference.TheNCCNGuidelinesareastatementofevidenceandconsensusoftheauthorsregardingtheirviewsofcurrentlyacceptedapproachestotreatment.AnyclinicianseekingtoapplyorconsulttheNCCNGuidelinesisexpectedtouseindependentmedicaljudgmentinthecontextofindividualclinicaltancestodetermineanypatientscareortreatmentTheNationalComprehensiveCancerNetworkNCCNmakesnorepresentationsorwarrantiesofanykindregardingtheircontentuseorapplicationanddisclaimsanyresponsibilityfortheirapplicationoruseinanyway.TheNCCNbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.?2022.Version3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.UPDATESVersion3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:34:38AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.idLeukemiadexrsionoftheNCCNGuidelinesforChronicMyeloidLeukemiafromVersioninclude?Thediscussionsectionwasupdatedtoreflectthechangesinthealgorithm.rsionoftheNCCNGuidelinesforChronicMyeloidLeukemiafromVersioninclude?AsciminibaddedtotheTableforTreatmentRecommendationsBasedonBCR-ABL1MutationProfile?Footnotexadded:AsciminibisatreatmentoptionforCP-CMLpatientswiththeT315Imutationand/orCP-CMLwithresistanceorintolerancetoatleasttwopriorTKIs.CML-F?Footnote1modified:ThefeasibilityofTFRfollowingdiscontinuationofbosutiniborponatinibTKIsotherthandasatinib,imatinib,ornilotinibhasnotyetbeenevaluatedinclinicalstudies.CML-G6of9?Bulletonemodified:Vascularocclusion:Arterialandvenousthrombosisandocclusions,includingfatalmyocardialinfarctionandstroke,haveoccurredataconsiderablerateArterialocclusiveevents(AOEs;includingfatalmyocardialinfarctionandstroke)andvenousthromboembolicevents(VTEs),haveoccurredinpatientstreatedwithponatinib.CML-G7of9?NewpageaddedfortheManagementofAsciminibToxicityPrintedbyMinTangon3/14/20227:34:38AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.idLeukemiadexrsionoftheNCCNGuidelinesforChronicMyeloidLeukemiafromVersionincludelogiesmodifiedtobemoreinclusiveofsexualandgenderidentities.CML-2mentImatinib?FootnoteaachangedfromalinktotheDiscussiontothefollowingreferences:CarpenterPA,etal.Bloodlogiesmodifiedtobemoreinclusiveofsexualandgenderidentities.CML-2mentImatinib?Footnotefmodified:Iftreatmentisneededduringpregnancy?Footnotefmodified:Iftreatmentisneededduringpregnancy,itispreferabletoinitiatetreatmentwithinterferons(interferonalfa-2aorpeginterferonalfa-2a).Interferonalfa-2a/2bandpeginterferonalfa-2bhavebeendiscontinued.Peginterferonalfa-2amaybesubstitutedforotherinterferonpreparations.TKItherapy,particularlyduringthefirsttrimester,shouldbeavoided.SeeManagementofCMLDuringPregnancy(CML-C).?Footnotegmodified:Basedonfollow-updatafromtheBFORE,pIftreatmentisneeded,itispreferabletoinitiatetreatmentwithinterferons.Bothinterferonalfa-2aorpeginterferonalfa-2ahavebeenusedduringpregnancy.Mostofthedatausinginterferonsduringpregnancyhavebeenreportedinpatientswithessentialthrombocythemia.Ifintroducedearlier,theuseofinterferonalfa-2a/2borpeginterferonalfa-2acanpreservemolecularremissionafterdiscontinuationofTKI.Interferonalfa-2a/2bandpeginterferonNandENESTndtrialssecondgenerationTKIsalfa-2bhaveNandENESTndtrialssecondgenerationTKIsbosutinibdasatinibornilotinibarepreferredforbosutinibdasatinibornilotinibarepreferredforpatientswithanintermediateorhigh-riskscore.Second-generationTKIstoestablishtheuseofpeginterferonanintermediateorhigh-riskscore.Second-generationTKIsshouldalsobeconsideredforspecificsubgroups(basedontheinpregnancyshouldalsobeconsideredforspecificsubgroups(basedontheassessmentoftreatmentgoalsandbenefitassessmentoftreatmentgoalsandbenefitrisksforexample,youngerpatientswhoareinterestedinultimatelyyoungerpatientswhoareinterestedinultimatelydiscontinuingtreatmentandespeciallyforyoungtreatmentandespeciallyforyoungwomenpatientsassignedfemaleatbirthwhosefemaleatbirthwhosegoalistoachieveadeepandrapidmolecularonseandeventualdrugdiscontinuationofTKItherapyfor?TitleonseandeventualdrugdiscontinuationofTKItherapyforfamilyplanningpurposes.familyplanningpurposes.FootnotehaddedInnovatorandgenericdrugsapprovedbyFootnotehaddedInnovatorandgenericdrugsapprovedbythetoryauthoritiesbasedonpharmacokineticequivalencecanpAnysignoflosstoryauthoritiesbasedonpharmacokineticequivalencecanAapprovedgenericversionisanappropriatesubstituteforaninnovatordrug(imatinib).Genericappropriatesubstituteforaninnovatordrug(imatinib).GenericversionsofotherTKIsarelikelytobemarketedinthenearversionsofotherTKIsarelikelytobemarketedinthenearfuture.lsoappliestoCMLCMLdefinedasanincreaseinlsoappliestoCMLCMLClinicalConsiderationsLightGreen,TKI-sensitivediseasep1-logincreaseinClinicalConsiderationsLightGreen,TKI-sensitivediseaseshouldpromptbonemarrowevaluationforlossofCCyRbutisnot?Nilotinib:G250EremovedasacontraindicatedmutationCML-6NotinCCyRorinrelapsechangedto?Nilotinib:G250EremovedasacontraindicatedmutationCML-6NotinCCyRorinrelapsechangedtoLessthanCCyRorinrelapseFollowupFollowupTherapyPCR,PositiveisbasedonpriortherapydependingonpriorTKI,tolerance,BCR-ABL1mutationprofile,andpost-HCTmorbidities)Version3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.atitisBpanelcPrintedbyMinTangon3/14/20227:34:38AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.atitisBpanelcidLeukemiadexWORKUPCLINICALPRESENTATIONADDITIONALEVALUATION?H&P,includingspleensizebypalpation(cmbelowcostalmargin)?CBCwithdifferential?Chemistryprofile?Bonemarrowaspirateandbiopsyicevaluationaformorphologicicevaluationa?QuantitativeRT-PCR(qPCR)usingABL1(blood)bInternationalScale(IS)ABL1(blood)bPhpositiveorBCR-ABL1PhnegativeandBCR-ABL1negativeL)alculationdvancedAcceleratedphasededestingifngallogeneicestingifngallogeneice?ConsidereSeeCML-4ordiseasesotherthanCMLCNGuidelinesfortiveNeoplasmsaBonemarrowevaluationshouldbedonefortheinitialworkup,toprovidemorphologicreview,andalsotodetectchromosomalabnormalitiesinadditiontothePhchromosome.Fluorescenceinsituhybridization(FISH)canbeusedifcytogeneticevaluationisnotpossible.bConsiderqualitativeRT-PCRforthedetectionofatypicalBCR-ABL1transcripts.SeeDiscussion.Referraltocenterswithexpertiseinthemanagementofrarehematologicmalignanciesisrecommended.cHepatitisBvirusreactivationhasbeenreportedinpatientsreceivingTKItherapy.However,itisnotalwayspossibletoreliablyestimatethefrequencyorestablisharelationshiptodrugexposurebecausetheseincidencesarereportedvoluntarilyfromapopulationofuncertainsize.dSeeDefinitionsofAcceleratedPhaseandBlastPhase(CML-B).eConsidermyeloidmutationpanelforpatientswithacceleratedphaseorblastphase.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.CML-1PrintedbyMinTangon3/14/20227:34:38AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.idLeukemiadexCLINICALPRESENTATIONChronicTreatmentconsiderationsindependentofriskscore?Comorbiditiesleof?Possibledruginteractions?PatientpreferenceLow-riskscore)(SeeRiskCalculation)TableCML-AeorhighscoreeRiskCalculationPRIMARYTREATMENTf,gPreferredregimensFirst-generationTKI(Imatinib400mgSecond-generationTKI(alphabeticalorder)(Bosutinib400mgQD[category1] satinibrar100mgQD[category1] lotinibir300mgBID[category1])ClinicaltrialPreferredregimensSecond-generationTKI(alphabeticalorder)(Bosutinib400mgQD[category1] satinibrar100mgQD[category1] lotinibir300mgBID[category1])tgenerationTKItgenerationTKIImatinibmgQDhirialponseonsCMLjonsCMLjkponseonsCMLjonsCMLjkfIftreatmentisneededduringpregnancy,itispreferabletoinitiatetreatmentwithinterferons(interferonalfa-2aorpeginterferonalfa-2a).Interferonalfa2a/2bandpeginterferonalfa-2bhavebeendiscontinued.Peginterferonalfa-2amaybesubstitutedforotherinterferonpreparations.TKItherapy,particularlyduringthefirsttrimester,shouldbeavoided.SeeManagementofCMLDuringPregnancy(CML-C).gBasedonfollow-updatafromtheBFORE,DASISION,andENESTndtrials,second-generationTKIs(bosutinib,dasatinib,ornilotinib)arepreferredforpatientswithanintermediate-orhigh-riskscore.Second-generationTKIsshouldalsobeconsideredforspecificsubgroups(basedontheassessmentoftreatmentgoalsandbenefit/risks),forexample,youngerpatientswhoareinterestedinultimatelydiscontinuingtreatmentandespeciallyyoungpatientsassignedfemaleatbirthwhosegoalistoachieveadeepandrapidmolecularresponseandeventualdiscontinuationofTKItherapyforfamilyplanningpurposes.hInnovatorandgenericdrugsapprovedbytheregulatoryauthoritiesbasedonpharmacokineticequivalencecanbeusedinterchangeably.AnFDA-approvedgenericversionisanappropriatesubstituteforaninnovatordrug(imatinib).GenericversionsofotherTKIsarelikelytobemarketedinthenearfuture.iImatinibmaybepreferredforolderpatientswithcomorbiditiessuchascardiovasculardisease.jSeeCriteriaforResponseandRelapse(CML-D).kSeeMonitoringResponsetoTKITherapyandMutationalAnalysis(CML-E).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.CML-2PrintedbyMinTangon3/14/20227:34:38AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.idLeukemiadexEARLYTREATMENTRESPONSEMILESTONESj,kRABLISs12monthsl>10%mYELLOWYELLOW≤0.1%CLINICALCONSIDERATIONSRECOMMENDATIONSesistant?Evaluatepatientcomplianceanddruginteractions?ConsidermutationalanalysisSwitchtoalternateTKICMLandevaluateforallogeneicHCTYELLOW?Evaluatepatientcomplianceanddruginteractions?Considermutationalanalysis?ConsiderbonemarrowcytogeneticanalysistoassessforMCyRat3moorCCyRat12moSwitchtoalternateTKI(CML-5)orContinuesameTKI(otherthanimatinib)(CML-G)norIncreaseimatinibdosetoamaxof800mgandConsiderevaluationforallogeneicHCTensitive?Iftreatmentgoalislong-termsurvival:≤1%optimal?Iftreatmentgoalistreatment-freeremission:≤0.1%optimal?Ifoptimal:continuesameTKI?Ifnotoptimal:shareddecisionensitiveonitorresponseCMLEandsideeffectsContinuesameTKI(CML-G)qjSeeCriteriaforResponseandRelapse(CML-D).kSeeMonitoringResponsetoTKITherapyandMutationalAnalysis(CML-E).lBCR-ABL1≤0.1%at12monthsisassociatedwithaverylowprobabilityofsubsequentlossofresponseandahighlikelihoodofachievingasubsequentdeepmolecularresponse(MR4.0;≤0.01%BCR-ABL1IS),whichisaprerequisiteforatrialoftreatment-freeremission(TFR).mPatientswithBCR-ABL1onlyslightly>10%at3monthsand/orwithasteepdeclinefrombaselinemayachieve<10%at6monthsandhavegenerallyfavorableoutcomes.Therefore,itisimportanttointerpretthevalueat3monthsinthiscontextbeforemakingdrasticchangestothetreatmentstrategy.nAchievementofresponsemilestonesmustbeinterpretedwithintheclinicalcontext.Patientswithmorethan50%reductioncomparedtobaselineorminimallyabovethe10%cutoffcancontinuethesamedoseofdasatinib,nilotinib,orbosutinibforanother3months.Continuationofimatinib400mgisnotrecommended.oSwitchingfromimatinibtoasecond-generationTKIimprovesresponse,butisassociatedwithincreasedtoxicity.pConsiderreferraltoaspecializedCMLcenterand/orenrollmentinaclinicaltrial.qDiscontinuationofTKIwithcarefulmonitoringisfeasibleinselectedpatients.SeeDiscontinuationofTKITherapy(CML-F).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.CML-3rations?DiseaseprogressingtoadvancedphasewhileonTKItherapyhasworseprognosisthandenovoadvancedphaseCML.?Evaluationforallogeneiccceleratedphased,sAllogeneic?Omacetaxineuhaveanegativerations?DiseaseprogressingtoadvancedphasewhileonTKItherapyhasworseprognosisthandenovoadvancedphaseCML.?Evaluationforallogeneiccceleratedphased,sAllogeneic?OmacetaxineuhaveanegativeprognosticimpactonsurvivalPatientswhopresentwithacceleratedphaseatdiagnosisshouldbetreatedwithaTKI,followedbyevaluationforidLeukemiadexCLINICALPRESENTATIONTREATMENTfClinicaltrialorPreferredregimensFirstgenerationTKIImatinibh,tincircumstances?Second-generationorthird-generation TKI(alphabeticalorder)(BosutiniborDasatiniborNilotiniborFirstgenerationTKIImatinibh,tincircumstancesTasindicatedrTasindicatedroidSeeNCCNGuidelinesforAcuteMyeloidoidSeeNCCNGuidelinesforAcuteMyeloidAllogeneic ukemiaer)+TKIh(CML-G)HCT(CML-6)dSeeDefinitionsofAcceleratedPhaseandBlastPhase(CML-B).TKIh(CML-G)fIftreatmentisneededduringpregnancy,itispreferabletoinitiatetreatmentwithinterferons(interferonalfa-2aorpeginterferonalfa-2a).Interferonalfa2a/2bandpeginterferonalfa-2bhavebeendiscontinued.Peginterferonalfa-2amaybesubstitutedforotherinterferonpreparations.TKItherapy,particularlyduringthefirsttrimester,shouldbeavoided.SeeManagementofCMLDuringPregnancy(CML-C).hInnovatorandgenericdrugsapprovedbytheregulatoryauthoritiesbasedonpharmacokineticequivalencecanbeusedinterchangeably.AnFDA-approvedgenericversionisanappropriatesubstituteforinnovatordrug(imatinib).GenericversionsofotherTKIsarelikelytobemarketedinthenearfuture.sThepresenceofmajorrouteadditionalchromosomalabnormalitiesinPh-positivecells(ACA/Ph+;trisomy8,isochromosome17q,secondPh,andtrisomy19)mayrConsiderevaluationsThepresenceofmajorrouteadditionalchromosomalabnormalitiesinPh-positivecells(ACA/Ph+;trisomy8,isochromosome17q,secondPh,andtrisomy19)mayallogeneicHCT,basedonresponsetotherapy.Itrnsii.phaseCML.OmacetaxineisnotatreatmentoptionforpatientswhopresentwithacceleratedphaseCML.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.CML-4Version3.2022,01/27/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon3/14/20227:34:38AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.idLeukemiadexTREATMENTRECOMMENDATIONSBASEDONBCR-ABL1MUTATIONPROFILE?Patientswithdiseaseresistanttoprimarytreatmentwithimatinibshouldbetreatedwithbosutinib,dasatinib,ornilotinibinthesecond-linesetting,takingintoaccountBCR-ABL1mutationstatus.?Patientswithdiseaseresistanttoprimarytreatmentwithbosutinib,dasatinib,ornilotinibcanbetreatedwithanalternateTKI(otherthanimatinib)inthesecond-linesetting,takingintoaccountBCR-ABL1mutationstatus.Thedurabilityoftheseresponsesisfrequentlylimited.?ThetablebelowliststheBCR-ABL1mutationsthatshouldNOTbetreatedwithbosutinib,dasatinib,ornilotinibinthesecond-linesetting.APYT315I,V299L,G250E,orF317LwTIAF317L/V/I/C,orV299LT315I,Y253H,E255K/V,orF359V/C/IAsciminib,xPonatinib,yOmacetaxine,zallogeneicHCT(CML-6),orclinicaltrialvMutationscontraindicatedforimatinibaretoonumeroustoinclude.Therearecompoundmutationsthatcancauseresistancetoponatinib,butthoseareuncommonfollowingtreatmentwithbosutinib,dasatinib,ornilotinib.wBosutinibhasminimalactivityagainstF317Lmutation.Nilotinibmaybepreferredoverbo