NCCNClinicalPracticeGuidelinesinOncologyNCCNGuidelines?)HairyCellLeukemiaVersion1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dex*WilliamG.Wierda,MD,PhD/Chair??TheUniversityofTexas*JenniferBrown,MD,PhD/Vice-Chair?Dana-Farber/BrighamandWomen'sCancerCenterJeremyS.Abramson,MD,MMSc??MassachusettsGeneralHospitalCancerCenterFarrukhAwan,MD??TUTSouthwesternSimmonsComprehensiveCancerCenterSyedF.Bilgrami,MD?YaleCancerCenter/SmilowCancerHospitalGregBociek,MD,MSc?ξFred&PamelaBuffettCancerCenterDanielleBrander,MD?DukeCancerInstituteRandallS.Davis,MD?O'NealComprehensiveCancerCenteratUABHerbertEradat,MD,MS??UCLAJonssonComprehensiveCancerCenterChristopherD.Fletcher,MD?UniversityofWisconsineCancerCenteresPanelDisclosuresSamehGaballa,MD?MoffittCancerCenterArminGhobadi,MD?TξSitemanCancerCenteratBarnes-JewishHospitalandWashingtonUniversitySchoolofMedicineMuhammadSaadHamid,MD?St.JudeChildren'sResearchHospital/TheUniversityofTennesseeHealthScienceCenterFranciscoHernandez-Ilizaliturri,MD?RoswellParkComprehensiveCancerCenterBrianHill,MD,PhD?CaseComprehensiveCancerCenter/UniversityHospitalsSeidmanCancerCenterandClevelandClinicTaussigCancerInstitutePaulKaesberg,MD?TUCDavisComprehensiveCancerCenterManaliKamdar,MD?UniversityofColoradoCancerCenterLawrenceD.Kaplan,MD?UCSFHelenDillerFamilyComprehensiveCancerCenterNadiaKhan,MD?FoxChaseCancerCenterThomasJ.Kipps,MD,PhD?UCSanDiegoMooresCancerCenterShuoMa,MD,PhD?RobertH.LurieComprehensiveCancerCenterofNorthwesternUniversityAnthonyMato,MD,MSCE?MemorialSloanKetteringCancerCenterClaudioMosse,MD,PhD≠Vanderbilt-IngramCancerCenterStephenSchuster,MD??AbramsonCancerCenterheUniversityofPennsylvaniaTanyaSiddiqi,MD?CityofHopeNationalMedicalCenterDeborahM.Stephens,DO?HuntsmanCancerInstituteattheUniversityofUtahChaitraUjjani,MD?FredHutchinsonCancerResearchCenter/SeattleCancerCareAllianceNinaWagner-Johnston,MD?TheSidneyKimmelComprehensiveCancerCenteratJohnsHopkinsJenniferA.Woyach,MD?TheOhioStateUniversityComprehensiveCancerCenter-JamesCancerHospitalandSoloveResearchInstituteJ.ChristineYe,MD,MSc?UniversityofMichiganRogelCancerCenterξBonemarrowtransplantation?Hematology/HematologyoncologyTInternalmedicine?Medicaloncology≠Pathology/Hematopathology*DiscussionWritingCommitteeMemberVersion1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexelievesthattheanagementelievesthattheanagementforanypatientwitherisinaclinicaltrialclinicaltrialsisespeciallyencouraged.FindanNCCNMemberInstitution:/home/member-institutions.ofEvidenceandsusAllrecommendationsareherwiseindicatedNCategoriesofEvidenceandConsensus.NCCNCategoriesofPreference:Allrecommendationsareconsideredappropriate.SeeNCCNCategoriesofPreference.aryoftheGuidelinesUpdatesDiagnosisandWorkup(HCL-1)IndicationsforTreatment,InitialTreatment,andRelapsed/RefractoryTherapy(HCL-2)SuggestedTreatmentRegimens(HCL-A)HCLResponseCriteria(HCL-B)SupportiveCareforPatientswithHCL(HCL-C)SpecialConsiderationsfortheUseofMoxetumomabPasudotox(HCL-D)SpecialConsiderationsfortheUseofSmallMoleculeInhibitors(HCL-E)UseofImmunophenotyping/GeneticTestinginDifferentialDiagnosisofMatureB-CellandNK/T-CellNeoplasms(SeeNCCNGuidelinesforB-CellLymphomas)Abbreviations(ABBR-1)TheNCCNGuidelinesareastatementofevidenceandconsensusoftheauthorsregardingtheirviewsofcurrentlyacceptedapproachestotreatmentAnyclinicianseekingtoapplyorconsulttheNCCNGuidelinesisexpectedtouseindependentmedicaljudgmentinthecontextofindividualclinicalcircumstancestodetermineanypatientscareortreatmentTheNationalComprehensiveCancerNetwork?(NCCN?)makesnorepresentationsorwarrantiesofanykindregardingtheircontent,useorapplicationanddisclaimsanyresponsibilityfortheirapplicationoruseinghtsreservedTheNCCNGuidelinesandtheillustrationshereinmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.?2022.Version1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.UPDATESVersion1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexrsionoftheNCCNGuidelinesforHairyCellLeukemiafromVersioninclude?WorkuppUsefulundercertaincircumstances,10thbulletrevised:Discussionoffertilityissuesandspermbankingpreservation.Correspondingfootnotegadded:Fertilitypreservationoptionsinclude:spermbanking,semencryopreservation,invitrofertilization(IVF),orovariantissueoroocytecryopreservation.?Footnotearevised:ThisguidelineappliestohistologicallyconfirmedcHCL,notHCLv.?Initialtherapy,vemurafenib+obinutuzumabwasaddedascategory2A,UsefulinCertainCircumstancesrecommendationwiththequalifier:considerforpatientswhoareunabletotoleratepurineanalogsincludingfrailpatientsandthosewithactiveinfection).?Progressivediseaseafterrelapsed/refractorytherapy,Vemurafenib±rituximabrevisedbyadding:ifnotpreviouslygiven.?Footnotearevisedbyadding:TreatmentrecommendationsapplytohistologicallyconfirmedcHCL,notHCLv.rutinibAdverseeventsofspecialinterestupdatedbasedonRogersKAAndritsosLAWeiLetalPhasestudyofibrutinibinclassicandvarianthairycellleukemia.Blood2021;137:3473-3483.ABBR1Newsectionadded:Abbreviations.PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexDIAGNOSISaWORKUP?Bonemarrowbiopsy±aspirate:pPresenceofcharacteristichairycellsuponmorphologicexaminationofperipheralbloodorbonemarrowandcharacteristicinfiltratewithincreasedreticulininbonemarrowbiopsysamples.Drytapisfrequent.?AdequateimmunophenotypingisessentialforestablishingthediagnosisandfordistinguishingvariantHCLvbcdbetweenclassicalhairyvariantHCLvbcdpImmunohistochemistry(IHC)orflowcytometryfor:CD19,CD20,CD5,CD10,CD11c,CD22,CD25,CD103,CD123,cyclinD1,andCD200USEFULUNDERCERTAINCIRCUMSTANCES:?Molecularanalysistodetect:IGHV4-34rearrangemente?IHCormolecularanalysistodetectBRAFV600Emutationforcasesthatdonothave?Historyandphysicalexamwithattentiontonode-bearingareasandthemeasurementofsizeofliverandspleenpPresenceofenlargedspleenand/orliver;presenceofperipherallymphadenopathy(uncommon)?Performancestatus?Peripheralbloodsmearexamination?CBCwithdifferential?Comprehensivemetabolicpanelwithparticularattentiontorenalfunction?Lactatedehydrogenase(LDH)?HepatitisBfandCtesting?HepatitisBfandCtestingiftreatmentcontemplated?Chest/abdominal/pelvicCTwithcontrastofdiagnosticqualityscussionoffertilitypreservationg?PregnancytestinginpatientsofchildbearingagescussionoffertilitypreservationgSeeInitialTreatment(HCL-2)therapyandgenerallyhaveapoorerprognosis.ThereisevidencethatHCLvandeTenpercentto20%ofB-celllymphoproliferativeneoplasmswithacHCLphenotypepossessIGHV4-34rearrangementsandtypicallylackBRAFV600Emutations.Thesediseasesbehavemoretherapyandgenerallyhaveapoorerprognosis.ThereisevidencethatHCLvandIGHV-34–mutantHCLoftenshowmutationsinMAP2K1.fHepatitisBIGHV-34–mutantHCLoftenshowmutationsinMAP2K1.fHepatitisBtestingisindicatedbecauseoftheriskofreactivationduringtreatment(eg,immunotherapy,chemoimmunotherapy,chemotherapy,targetedtherapy).SeeTreatmentandViralReactivation(NCCNGuidelinesforCLL/SLL).TestsincludehepatitisBsurfaceantigenandcoreantibodyforapatientwithnoriskfactors.ForpatientswithriskfactorsorprevioushistoryofhepatitisB,adde-antigen.Ifpositive,checkviralloadandconsultwithgastroenterologist.gFertilitypreservationoptionsinclude:spermbanking,semencryopreservation,invitrofertilization(IVF),orovariantissueoroocytecryopreservation.bTypicalimmunophenotypeforcHCL:CD5-,CD10-,CD11c+,CD20+(bright),CD22+,CD25+,CD103+,CD123+,cyclinD1+,annexinA1+,andCD200+(bright).Monocytopeniaischaracteristic.cHCLvischaracteristicallyCD25-,CD123-,annexinA1-,andnegativeforBRAFV600Emutations.ThishelpstodistinguishthevariantformfromcHCL.dSeeUseofImmunophenotyping/GeneticTestinginDifferentialDiagnosisofMatureB-CellandNK/T-CellNeoplasms(NCCNGuidelinesforB-CellLymphomas).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.HCL-1Version1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.ortreatmentemicsymptomsns?Recurrentinfection?Hemoglobin<11g/dL?Platelets<100,000/mcL?Absoluteneutrophilcount(ANC)<1000/mcL?Symptomaticorganomegaly?Progressivelymphocytosisorlymphadenopathyortreatmentemicsymptomsns?Recurrentinfection?Hemoglobin<11g/dL?Platelets<100,000/mcL?Absoluteneutrophilcount(ANC)<1000/mcL?Symptomaticorganomegaly?ProgressivelymphocytosisorlymphadenopathydexINDICATIONSFORINDICATIONSFORINITIALTREATMENThTREATMENTiTOTHERAPYTHERAPYiTHERAPYipy≥2yearshRelapsepy≥2yearsh indicationfortreatment<2<2yearshSeeInitialTherapy(HCL-A)eapsedractoryTherapyHCLA-LessthanpleteresponseerinitialatmentORRelapseeessiveapyhGreverMR,etal.Blood2017;129:553-560.iSeeSupportiveCareforPatientswithHCL(HCL-C).jSeeHCLResponseCriteria(HCL-B).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.HCL-2PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexENSaINITIALTHERAPYb,c,d,ePreferredRegimens?PurineanalogspCladribine±rituximabUsefulinCertainCircumstances(considerforpatientswhoareunabletotoleratepurineanalogsurafenibfobinutuzumabincludingfrailpatientsandurafenibfobinutuzumabRituximabRituximabifunabletoreceiveRELAPSED/REFRACTORYTHERAPYb,d,eLessthancompleteresponseafterinitialLessthancompleteresponseafterinitialtreatmentORensecommendedRegimens?Peginterferon-alfa2ah?Alternativepurineanalog?Clinicaltrialemurafenibfgrituximab?emurafenibfgrituximab?Retreatwithinitialpurineanalog+rituximab?Alternativepurineanalog+rituximabn/aRituximabifunabletoreceivePROGRESSIVEPROGRESSIVEDISEASEAFTERRELAPSED/REFRACTORYTHERAPYd,ePreferredRegimensOtherRecommendedRegimens?Clinicaltrial?Ibrutinibf?Moxetumomabpasudotoxi?Vemurafenibi±rituximab(ifnotpreviouslygiven)aTreatmentrecommendationsapplytohistologicallyconfirmedcHCL,notHCLv.SeeSuggestedTreatmentRegimenReferences(HCL-A2of2).bStandard-dosepurineanalogsshouldnotbeadministeredtopatientswithactivelife-threateningorchronicinfection.Treatactiveinfectionpriortoinitiatingtreatmentwithstandard-dosepurineanalogs.Ifitisnotpossibletocontrolinfection,considerinitiatingtreatmentwithlow-dosepentostatinbeforeusingstandard-dosepurineanalogstosecureadurableresponse.cCladribineandpentostatinhavenotbeencomparedhead-to-headinclinicaltrials,butappeartoshowcomparabletherapeuticactivity.dRituximabandhyaluronidasehumaninjectionforsubcutaneoususemaybeusedinpatientswhohavereceivedatleastonefulldoseofarituximabproductbyintravenousroute.AnFDA-approvedbiosimilarisanappropriatesubstituteforrituximab.eSeeSupportiveCareforPatientswithHCL(HCL-C).fSeeSpecialConsiderationsfortheUseofSmallMoleculeInhibitors(HCL-E).gStudiedforprimaryrefractorydiseaseandearlyrelapse(1–2y)afterfirstcourseofpurineanalog.iSeeSpecialConsiderationsfortheUseofMoxetumomabPasudotox(HCL-D).hInterferonalfahasbeendiscontinued.Peginterferonalfa-2amaybesubstitutedforotheriSeeSpecialConsiderationsfortheUseofMoxetumomabPasudotox(HCL-D).Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.HCL-AOF2PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexREFERENCESPurineanalogmonotherapyFlinnIW,KopeckyKJ,FoucarMK,etal.Long-termfollow-upofremissionduration,mortality,andsecondmalignanciesinhairycellleukemiapatientstreatedwithpentostatin.Blood2000;96:2981-2986.GoodmanGR,BurianC,KoziolJA,SavenA.Extendedfollow-upofpatientswithhairycellleukemiaaftertreatmentwithcladribine.JClinOncol2003;21:891-896.ZinzaniPL,TaniM,MarchiE,etal.Long-termfollow-upoffront-linetreatmentofhairycellleukemiawith2-chlorodeoxyadenosine.Haematologica2004;89:309-313.ChadhaP,RademakerAW,MendirattaP,etal.Treatmentofhairycellleukemiawith2-chlorodeoxyadenosine(2-CdA):long-termfollow-upoftheNorthwesternUniversityexperience.Blood2005;106:241-246.RobakT,JamroziakK,Gora-TyborJ,etal.Cladribineinaweeklyversusdailyscheduleforuntreatedactivehairycellleukemia:finalreportfromthePolishAdultLeukemiaGroup(PALG)ofaprospective,randomized,multicentertrial.Blood2007;109:3672-3675.ElseM,DeardenCE,MatutesE,etal.Long-termfollow-upof233patientswithhairycellleukaemia,treatedinitiallywithpentostatinorcladribine,atamedianof16yearsfromdiagnosis.BrJHaematol2009;145:733-740.ZenhausernR,SchmitzSF,SolenthalerM,etal.Randomizedtrialofdailyversusweeklyadministrationof2-chlorodeoxyadenosineinpatientswithhairycellleukemia:amulticenterphaseIIItrial(SAKK32/98).LeukLymphoma2009;50:1501-1511.DeardenCE,ElseM,CatovskyD.Long-termresultsforpentostatinandcladribinetreatmentofhairycellleukemia.LeukLymphoma2011;52Suppl2:21-24.GreverM,KopeckyK,FoucarMK,etal.Randomizedcomparisonofpentostatinversusinterferonalfa-2ainpreviouslyuntreatedpatientswithhairycellleukemia:anintergroupstudy.JClinOncol1995;13:974-982.TallmanMS,HakimianD,VariakojisD,etal.Asinglecycleof2-chlorodeoxyadenosineresultsincompleteremissioninthemajorityofpatientswithhairycellleukemia.Blood1992;80:2203-2209.KrautEH,GreverMR,BouroncleBA.Long-termfollow-upofpatientswithhairycellleukemiaaftertreatmentwith2'-deoxycoformycin.Blood1994;84:4061-4063.PurineanalogswithrituximabElseM,OsujiN,ForconiF,etal.Theroleofrituximabincombinationwithpentostatinorcladribineforthetreatmentofrecurrent/refractoryhairycellleukemia.Cancer2007;110:2240-2247.ElseM,DeardenCE,MatutesE,etal.Rituximabwithpentostatinorcladribine:aneffectivecombinationtreatmentforhairycellleukemiaafterdiseaserecurrence.LeukLymphoma2011;52Suppl2:75-78.ChiharaD,KantarjianH,O'BrienS,etal.Long-termdurableremissionbycladribinefollowedbyrituximabinpatientswithhairycellleukaemia:updateofaphaseIItrial.BrJHaematol2016;174:760-766.ChiharaD,AronsE,Stetler-StevensonM,etal.RandomizedphaseIIstudyoffirst-linecladribinewithconcurrentordelayedrituximabinpatientswithhairycellleukemia.JClinOncol2020;38:1527-1538.LauriaF,LenociM,AnninoL,etal.Efficacyofanti-CD20monoclonalantibodies(Mabthera)inpatientswithprogressedhairycellleukemia.Haematologica2001;86:1046-1050.NievaJ,BethelK,SavenA.Phase2studyofrituximabinthetreatmentofcladribine-failedpatientswithhairycellleukemia.Blood2003;102:810-813.ThomasDA,O'BrienS,Bueso-RamosC,etal.Rituximabinrelapsedorrefractoryhairycellleukemia.Blood2003;102:3906-3911.ZenhausernR,SimcockM,GratwohlA,etal.Rituximabinpatientswithhairycellleukemiarelapsingaftertreatmentwith2-chlorodeoxyadenosine(SAKK31/98).Haematologica2008;93:1426-1428.Vemurafenib+obinutuzumaborrituximabParkJH,WinerES,HuntingtonSF,etal.Firstlinechemo-freetherapywiththeBRAFinhibitorvemurafenibcombinedwithobinutuzumabiseffectiveinpatientswithHCL[abstract].Blood2021;138:Abstract43.DietrichS,PircherA,EndrisV,etal.BRAFinhibitioninhairycellleukemiawithlow-dosevemurafenib.Blood2016;127:2847-2855.TiacciE,ParkJH,DeCarolisL,etal.TargetingmutantBRAFinrelapsedorrefractoryhairy-cellleukemia.NEnglJMed2015;373:1733-1747.TroussardX,MontanéL,TiabM,etal.Vemurafenibinadvancedpatientswithhairycellleukemia(HCL):ResultsoftheAcséphaseIItrial[abstract].Blood2017;130:AbstractciECarolisLDSimonettiEetalVemurafenibplusrituximabinrefractoryorrelapsedhairy-cellleukemia.NEnglJMed2021;384:1810-1823.KAAndritsosLAWeiLetalPhasestudyofibrutinibinclassicandvarianthairycellleukemia.Blood2021;137:3473-3483.MoxetumomabpasudotoxKreitmanRJ,DeardenC,ZinzaniPL,etal.Moxetumomabpasudotoxinrelapsed/refractoryhairycellleukemia.Leukemia2018;32:1768-1777.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.Version1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.HCL-A2OF2PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexHCLRESPONSECRITERIAaponseNearnormalizationofperipheralbloodcounts:hemoglobin>11g/dL(withouttransfusion);platelets>100,000/mcL;ANC>1500/mcL.Regressionofsplenomegalyonphysicalexamination.AbsenceofmorphologicevidenceofHCLonboththeperipheralbloodsmearandthebonemarrowexamination.fresponsentThebonemarrowexaminationforevaluatingresponseinpatientstreatedwithcladribineshouldnotbedonebefore4monthsaftertherapy.Inthosepatientsbeingtreatedwithpentostatin,thebonemarrowcanbeevaluatedafterthebloodcountshavenearlynormalizedandthephysicalexaminationshowsnosplenomegaly.CRwithorwithoutminimalresidualdisease(MRD)InpatientswhoachievedaCRanimmunohistochemicalassessmentofthepercentageofMRDwillenablepatientstobeseparatedintothosewithCRwithorwithoutevidenceofMRD.APRrequiresnearnormalizationoftheperipheralbloodcount(asinCR)withaminimumof50%improvementinorganomegalyandbonemarrowbiopsyinfiltrationwithHCL.lediseaseSDPatientswhohavenotmetthecriteriaforanobjectiveremissionaftertherapyareconsideredtohaveSD.BecausepatientswithHCLaretreatedforspecificreasons,includingdisease-relatedsymptomsordeclineintheirhematologicparameters,SDisnotanacceptableresponse.sePDPatientswhohaveanincreaseinsymptomsrelatedtodisease,a25%increaseinorganomegaly,ora25%declineintheirhematologicparametersqualifyforPD.Aneffortmustbemadetodifferentiateadeclineinbloodcountsrelatedtomyelosuppressioneffectsoftherapyvs.PD.apseisdefinedasthereappearanceofHCLintheperipheralbloodthebonemarrowbiopsyorbothbymorphologicstainsintheabsenceofhematologicrelapse.HematologicrelapseisdefinedasreappearanceofcytopeniasbelowthethresholdsdefinedaboveforCRandPR.Whereasnotreatmentisnecessarilyneededincaseofmorphologicrelapsetreatmentdecisionsforahematologicrelapsearebasedonseveralparameters(eg,hematologicparameterswarrantingintervention,reoccurrenceofdisease-relatedsymptoms).ritsosLAetalConsensusguidelinesforthediagnosisandmanagementofpatientswithclassicalhairycellleukemiaBlood2017;129:553-560.Note:Allrecommendationsarecategory2Aunlessotherwiseindicated.ClinicalTrials:NCCNbelievesthatthebestmanagementofanypatientwithcancerisinaclinicaltrial.Participationinclinicaltrialsisespeciallyencouraged.HCL-BVersion1.2023,08/30/22?2022NationalComprehensiveCancerNetwork(NCCN),Allrightsreserved.NCCNGuidelinesandthisillustrationmaynotbereproducedinanyformwithouttheexpresswrittenpermissionofNCCN.PrintedbyMinTangon10/4/20226:51:13AM.Forpersonaluseonly.Notapprovedfordistribution.Copyright?2022NationalComprehensiveCancerNetwork,Inc.,AllRightsReserved.dexSUPPORTIVECAREFORPATIENTSWITHHCLAnti-infectiveProphylaxis?Considerherpesvirusprophylaxiswithacyclovirorequivalentforaminimumof3monthsanduntilCD4+T-cellcounts≥200cells/μL.?Considerpneumocystisjiroveciipneumonia(PJP)prophylaxiswithsulfamethoxazole/trimethoprimorequivalentforaminimumof3monthsANDuntilCD4+T-cellcounts≥200cells/μL.?Considerbroad-spectrumprophylacticantibacterialcoverageduringperiodofneutropenia.?HepatitisBvirus(HBV)prophylaxisandmonitoringisrecommendedforhigh-riskpatients.SeeTreatmentandViralReactivationintheNCCNGuidelinesforCLL/SLL(CSLL-C1of4).RareComplicationsofMonoclonalAntibodyTherapy?Rarecomplicationssuchasmucocutaneousreactionsincludingparaneoplasticpemphigus,Stevens-Johnsonsyndrome,lichenoiddermatitis,vesiculobullousdermatitis,andtoxicepidermalnecrolysiscanoccur.Consultationwithadermatologistisrecommendedformanagementofthesecomplications.Re-challengewiththesamemonoclonalantibodyinsuchsettingsisnotrecommended.RituximabRapidInfusionandSubcutaneousAdministration?Ifnosevereinfusionreactionswereexperiencedwithpriorcycleofrituximab,arapidinfusionover90minutescanbeused.?Rituximabandhyaluronidasehumaninjectionforsubcutaneoususeisareasonablealternativeforpatientswhohavereceivedatleast