异基因造血干细胞移植预后与白舒非剂量相关

BiolBloodMarrowTransplant.Authormanuscript;availableinPMC2014Jun11.Publishedinfinaleditedformas:BiolBloodMarrowTransplant.2013Mar;19(3):474–480.Publishedonline2012Dec7.doi:

10.1016/j.bbmt.2012.12.001PMCID:PMC4052712NIHMSID:NIHMS580149DoseintensificationofBusulfaninthepreparativeregimenisassociatedwithimprovedsurvival:APhaseI/IIControlled,RandomizedStudySParmar,1GRondon,1MdeLima,1PThall,2RBassett,2PAnderlini,1PKebriaei,1IKhouri,1PGanesan,1RChamplin,1andSGiralt31DeptofStemCellTransplantationandCellularTherapy,TheUniversityofTexasatMDAndersonCancerCenter,Houston,TX770302DeptofBiostatistics,TheUniversityofTexasatMDAndersonCancerCenter,Houston,TX770303MemorialSloanKetteringCancerCenter,NewYorkCorrespondingAuthor:SimritParmar,MD,AssistantProfessor,MDAndersonCancerCenter,1515HolcombeBlvd.,Houston,TX77030,Email:gro.nosrednadm@ramrapsAuthorinformation▼CopyrightandLicenseinformation►Thepublisher'sfinaleditedversionofthisarticleisavailableatBiolBloodMarrowTransplantSeeotherarticlesinPMCthatcitethepublishedarticle.\o"Gotoothersectionsinthispage"Goto:AbstractDoseintensityisimportantfordiseasecontrolinpatientsundergoingallogeneicstemcelltransplantation.WeconductedaphaseI/IIcontrolledadoptiverandomizedstudytodeterminetheoptimaldosingscheduleofi.v.busulfan.Patientswithadvancedhematologicmalignancies,≤75yearswithHLA-compatibledonorwereeligible.Allpatientsreceivedfludarabineat30mg/m2/dfor4daysandbusulfanwasadministeredindifferentdosesinoralori.v.formulations.AsdeterminedbythephaseItrial,i.v.busulfanatadoseof11.2mg/kg/dwasutilizedforthephaseIIexpansioncohort.Altogether,80patientswithamedianageof56yearswereenrolled.Fortypercenthadactivediseaseatthetimeoftransplant.Engraftmentoccurredin91%andacompleteresponsewasachievedin79%ofpatientspost-transplant.Atamedianfollowupof91monthsinthesurvivingpatients,theoutcomesfori.v.busulfandoseof11.2mg/kg/dvs.otherdoseswere:non-relapsemortality:34%vs.23%(p=0.4);cumulativeincidenceofrelapse:43%vs.68%(p=0.02);relapse-free-survival(RFS):25%vs.9%(p=0.017);overall-survival(OS):27%vs.9%(p=0.02).Weconcludethatoptimizingintravenousbusulfandoseintensityinthepreparativeregimenmayovercomediseaseassociatedpoorprognosticfactors.\o"Gotoothersectionsinthispage"Goto:INTRODUCTIONReducedintensityconditioning(RIC)regimenisassociatedwithlownon-relapsemortality(NRM)andhasmadeitpossibletoofferallogeneicstemcelltransplant(alloSCT)totheolderpopulation.SeverallargeregistrystudieshaveshownthatthelowerNRMseeninRICcomesatthecostofincreasedrelapsedrate1–3.Althoughmyeloablativedosesofi.v.busulfanincombinationwitheitherfludarabineorcyclophosphamidehavebeenassociatedwithfavorableoutcomes,significanttoxicitiesandtreatmentrelatedmorbidityandmortalityremainamajorconcern4–6.Slavinetalfirstreportedthesuccessfulcombinationoforalbusulfanwithfludarabine,whichresultedin100%engraftmentandwasassociatedwithlong-termdiseasecontrolin77.5%7.Sincethen,i.v.busulfanhaslargelyreplaceditsoralformulationaspartofthepreparativeduetomorepredictablepharmacokineticsandabilitytoperformdoseadjustmentstoavoidexcesstoxicities4,6,8.Bypassingtheoralroutetoachieve100%bioavailabilityhastranslatedintoimprovedcontroloverdrugadministration,withincreasedsafetyandreliabilityinordertomaximizetheanti-leukemicefficacy.Arecentreportrevealedapromisingassociationwithuseofthei.v.formofbusulfanandalowerNRM,eveninsickerorolderpopulations9.However,high-riskdiseaseand/oractivediseaseatthetimeoftransplantationisstillassociatedwithpooroutcomes10–14.Levineetalhavedemonstratedpooroutcomeassociatedwithlowerdosesofbusulfaninconditioningregimen,especiallyinpatientswithadvanceddisease12.Inaretrospectiveanalysisof31patients,busulfandoseof8mg/kgwasassociatedwithbetterdiseasecontrolwhencomparedtoalessintenseregimenof4mg/kg15.However,otherstudieshavenotfoundanadvantagewithhigherdosebusulfancontainingregimens.Hamadanietalreported(inaretrospectiveanalysis)thattherewasnodifferenceintheoutcomesbetweenRICbusulfan/fludarabine(6.4mg/kgtotaldoseofbusulfan)comparedwithamoreintenseregimen(130mg/m2ofbusulfanfor4days-roughlyequivalentto12.8mg/kgcumulativedose)16.However,thereweremajordifferencesinthepatientprofilesoftwostudyarmswithmoreacuteleukemiasintheintensetherapyarmandmoreindolentdiseaseslikechroniclymphocyticleukemiainthelessintensearm.Therefore,optimizationofbusulfancontainingconditioningregimensisneededforimprovementclinicallyrelevantpatientoutcomes.WeconductedaprospectivephaseI/IIBayesianadoptivelyrandomizedstudytodeterminethebestdose,dosingscheduleandefficacyofi.v.busulfanincombinationwithfludarabineasapreparativeregimenforAlloSCT.PatientsandMethodsPatientsunder75yearsofageundergoingAlloSCTfromHLAA,BandDRmatchedunrelateddonorsor≥5/6matchedrelateddonorswiththefollowingdiagnoseswereeligible:chronicmyeloidleukemia(CML),thatwaseithertransformedorInterferon-resistant;acutemyeloidleukemia(AML);intermediateorhigh-riskmyelodysplasticsyndrome(MDS)asdefinedbytheInternationalPrognosticScoringSystem(IPSS);lymphomaormyelomabeyond1stremission.Eligiblepatientswereconsideredunqualifiedtoundergoablativepreparativeregimenbecauseofadvancedageorthepresenceofco-morbidities.PatientshadtobeinZubrodPerformancestatus(PS)≤2withadequatehepatic(bilirubin<3mg/dL),andrenal(creatinine<2.5mg/dL)function.Thegoalwastoidentifytheoptimaldoseandscheduleofi.v.busulfanincombinationwithafixeddoseoffludarabineasaRICregimen.ThestudywasreviewedandapprovedbytheInstitutionalReviewBoardoftheUniversityofTexas-MDAndersonCancerCenter.Informedconsentwasobtainedfromthepatientsanddonors.UnrelateddonorswereconsentedaccordingtotheNationalMarrowDonorRegistryPolicies.Graftvs.hostdisease(GVHD)assessmentwasperformedaccordingtotheconsensuscriteria17.ToxicitieswereassessedaccordingtotheNCIcommontoxicitycriteria(NCICTCversion3,/reporting/ctc.html).TreatmentplanFludarabinewasadministeredatadoseof30mg/m2/daypriortobusulfanondays-5,-4,-3and-2toallpatients.Equineanti-thymocyteglobulin(ATG10mg/kg/d×4,ondays-4,-3,-2,and-1)wasaddedforpatientsreceivingmismatchedrelated(MMR)ormatchedunrelateddonor(MUD)transplants.Inthephase1portionofthestudy,7doselevelsofbusulfanwereexplored,witheachlevelbeingdeliveredeitheronceaday(m1)orevery6hour(m2)infusions(Table1A).Drugsweredosedaccordingtoadjustedbodyweightinpatientswhoseactualweight≥120%oftheidealbodyweight.Actualweightwasusedfortherestofthepatients.Atthetimeofperformingthistrial,theresourcesforperformingbusulfanpharmacokineticswerenotavailable.Table1AIVBUSULFANDosingschedule:SupportiveCarePatientsreceivedGVHDprophylaxisusingtacrolimustargetingabloodlevelof5–15ng/mlandmethotrexate(5mg/m2days1,3,6and11).PatientswereallowedtobeonanyactiveGVHDprophylaxisprotocols.Infectiousdiseaseprophylaxisgenerallyincludedfluconazole,acyclovir,andciprofloxacin.Ganciclovirwasusedonapre-emptivebasisforpatientswithcytomegalovirus(CMV)antigenemiaorviremiawhichwasmonitoredonaweeklybasis.PatientsreceivedG-CSF5mcg/kgsubcutaneouslydailyfromDay+7onwardsuntilachievementofanabsoluteneutrophilcountof>1.5×109/Lforthreedays.Filteredandirradiatedbloodproducttransfusionsweregiventomaintainhemoglobin>8g/dLandplatelets>20,000/cmm3.StatisticaldesignandanalysisThiswasaphaseI/IIBayesianadoptivelyrandomizeddosefindingstudythattookintoaccountbothtoxicityandefficacy.Patientswereevaluatedbasedonage,organfunctionanddonor-match.StudyEndPointsThemajorendpointsassessedduringthestudywereengraftment(definedasabsoluteneutrophilcount>0.5×109/L,for3daysinarow),plateletrecovery(plateletrecovery>20×109/L,independentofplatelettransfusions),infectiouscomplications,achievementofcompleteremission(CR)(<5%blastsinthebonemarrowwithtrilineagedifferentiationandfreedomfromplatelettransfusionandANC>0.5×109/L),developmentandgradeofacuteGVHD,chimerismovertime,andtoxicity.OverallSurvival(OS)timewascalculatedasthetimefromthedateoftransplanttothedateofdeathorcensoredatthedateoflastfollow-up.Non-relapsemortality(NRM)100wasdefinedasthebinaryindicatorofdeathwithinthefirst100dayswithoutrelapse.Relapsefreesurvival(RFS)timewascalculatedasthetimefromthetransplantdatetothedateofdiseaserelapseordeath,whicheverwasearlier.Patientswhowerealivewithoutrelapseatendofthestudywerecensoredatthedateoflastfollow-up.Therewerefourcovariatesofinterest:age,cytogeneticriskcategory(good,intermediate,orbad),doseofbusulfanreceivedandthepercentofbonemarrowblasts.DoseFindingStrategyBasedonfactorsinfluencingtoxicityoccurringfromthepreparativeregimen;includingpatientage,organfunctionanddegreeofdonormatch;patientswereseparatedintotwostratainconsiderationforthetoxicityforphaseIendpoints:“good”riskasdefinedbygoodorganfunction,age<60yearsforpatientswithsiblingmatcheddonorsandage<50yearsforMUDand“poor”riskgroupasdefinedbyallotherpatientswhomettheeligibilitycriteria:Asdescribedearlier,2deliverymodesm1(dailydose)andm2(every6hourdosing)wereexamined.Withineachmode,amaximumtolerateddose(MTD)wasdeterminedamongdifferentintravenousbusulfandoselevelsusingthecontinualreassessmentmethod(CRM18,19)withaprobability20%forgrade3–4organtoxicity.PhaseIIportionofthestudyPhaseIIwasconductedusingtheMTDselectedinphaseIwiththeaimtokeepthefailureratebelowthehistoricalrateof0.05andreducethedeathrateby0.20usingthemonitoringmethoddescribedbyThall,SimonandEstey20.StatisticalMethodsTheCRM18,19,asdescribedabove,wasusedfordose-findingonphaseI.ThemethodofThall,SimonandEstey20wasusedforsafetymonitoringinphaseII.Bayesianregressionmodels21werefittoassesstheeffectsofthecovariatesofinterestonthefollowingoutcomemeasurements:OS,RFS,andNRMat100days(NRM100).Forthetime-to-eventoutcomes(OSandRFS),goodnessoffittestswereperformedusingtheBayesianInformationCriterion(BIC)22tochoosethebestfittingmodelfromamongtheWeibull,normal,lognormal,logistic,loglogistic,exponential,andgammadistributions.ForthedichotomousoutcomeNRM100,Bayesianlogisticregressionmodelswerefit.Foreachmodelfit,weassumedthateachparameterinthelineartermfollowedanon-informativenormalpriorwithmean0andvariance10.AllcalculationswereperformedinRversion2.12.0andOpenBUGSversion3.1.2rev668.ThecumulativeincidenceofrelapseandNRMwereanalysedinacompetingrisksframework23anddistributionswerecomparedusingmethodologyofFineandGray24.\o"Gotoothersectionsinthispage"Goto:ResultsEightypatientswithmedianageof56years(range,10–71years)andactivediseasein32(40%)patientswereenrolledinthestudyfromMarch2000tillOctober2004.(Enrollmentdiagram,Table1B).Medianfollowupforsurvivorswas91months(25.5–125.7months).Patientcharacteristicsaredescribedintable2.Fortypatientshadamatchedrelateddonorand35patientshadmismatchedrelatedorunrelateddonorasasourceofstemcellsforthealloSCT.Fivepatients(mismatchrelateddonor=1;MUD=4)receivedfludarabine,busulfanandalemtuzumab(12%).Fortytwopatientsreceivedperipheralblood(PB)progenitorcellsand38receivedbonemarrow(BM)transplants.ThemediannumberofinfusedCD34+cellswas4.7×106/kgandthemedianTNCinfusedwas4.1×108cells/kg.GVHDprophylaxiswastacrolimusandmethotrexatein69(87%)patients,tacrolimusalonein3while1patientreceivedadditionalextracorporealphotopheresis,and7receivedadditionalpentostatin25Sixcohortsoftwopatientseach(n=2)weretreatedwitheachofthe2modalitiesofschedulem1orm2,foratotalof12patientspermodalityand24patientsoverall.Table1BEnrollmentDiagramTable2APatientcharacteristicsGoodRiskCohort(n=31)Threedoselevelsofi.v.busulfanwereexaminedinthiscohort:9.6mg/kg,11.2mg/kg,and12.8mg/kg.Thestartingdosewaschosenbasedonourexperienceandthepublishedliteratureatthetimeofthestudy7.PoorRiskCohort(n=49)Fourdoselevelsoni.v.busulfanwereexaminedinthiscohort8.0mg/kg,9.6mg/kg,11.2mg/kg,and12.8mg/kg.Thepatientcharacteristicsandtheirdistributionisshownintable2A.TheMTDestablishedfromthephaseIstudyforbothgoodandhighriskcohortswasi.v.busulfanat11.2mg/kg.Afterthecompletionofenrolmentof32patientsinthephaseIportion,thesubsequent48patientswereenrolledintothephaseIIpartofthestudyoni.v.busulfandoselevel11.2mg/kg(doselevel5).Sincethemajority(73%)ofpatientsinthetrialreceivedthedoselevel5,thisdosewasre-codedasadichotomousvariable:doselevel5vs.allotherdosescombined(Table2B)foroutcomeanalysis.Allpatientswereincludedinthefinalplannedanalysis.Table2BPatientcharacteristics:doselevel5vsothersToxicityThemostcommon(≥20%)adverseeventsofanygrade,regardlessoftherelationshiptothepreparativeregimenwereincreasedcreatinine(33.7%),diarrhea(35%),infection(32.5%),mucositis(51%),nausea(57.5%),skinrash(37.5%)andtransaminitis(35%).Regimen-relatedgrade3orhighertoxicityincludedbleeding(2.5%),diarrhea(2.5%),increasedbilirubin(2.5%),hematuria(1.2%),highbloodpressure(1.2%),mucositis(1.2%),neutropenia(1.2%),skinrash(1.2%).OnepatientdevelopedVeno-occlusivedisease(VOD)at67dayspost-transplantandwasassociatedwithalteredmentalstatus,hepaticencephalopathy,raisedtransaminitis.Liverbiopsyshowedmildincreaseinperiportalfibrosiswithnoevidenceofcirrhosisandseverelyincreasedirondeposition.Patientwassubsequentlyfoundtohavesevereironoverloadandimprovedwithphlebotomy.Ultimately,thepatientdiedofsteroid-refractoryGVHD.Overall57%haddocumentedinfections.Isolatedorganismsincluded:alpha-hemolyticstreptococci(1),BKvirus(2),C-difficile(1),CMVreactivation(6),Coagulasenegativestaphylococcus(4),E.Coli(1),Klebsiella(1),Parainfluenza(1),pseudomonasaeruginosa(7),rhizopus(1),vancomycin-resistantenterococcus(3).Onepatienthadwestnilevirusencephalitis.Engraftment,chimerismandGVHDEngraftmentoccurredin73patients(91%).Nodifferenceswereseenintheengraftmentratebetweeni.v.busulfandoselevel11.2mg/kgandothergroups(91.4%vs.91%,respectively;p=NS).Therewere3earlydeathsandfourgraftfailures.Therewassignnificantcorrelationbetweengraftfailureandpersistentdiseaseintheposttransplantsetting(chisquare,p<0.0001).Amongthosewhoengrafted,37(50%)hadfulldonorchimerism.Routinelyperformedchimerismstudiesrevealedthedevelopmentofmixedchimerism(<99%donorcellsdetectedinperipheralbloodonmorethan1occasion)in32patients.Amongthesepatients,>90%donorchimerismwasseenin12patients(38%).Themediandegreeofchimerisminthesepatientswas86.5%(12%–98%)andawassignificantcorrelationwasdemonstratedbetweentheincidenceofmixedchimerismandpersistentdiseaseinthepost-transplantsetting(chisquare,p<0.0001).Themediantimetoneutrophilengraftmentwas13daysandtoplateletengraftmentwas17days.Theengraftmentdataforthewholecohortisshownintable3A.Therewerenodifferencesinthedoselevel5vs.othersintermsofgraftfailure,timetoneutrophilengraftmentdaysortimetoplateletengraftment(Table3B).Table3ATransplantoutcomesinthewholecohortTable3BTransplantOutcomesDoseLevel5vs.OthersAmongtheengraftedpatients,grade2–4aGVHDoccurredin26patients(35.6%)andgrade3–4aGVHDoccurredin8patients(11%).ThemediantimetoonsetofacuteGVHDwas43.5days(13–208days).ThedistributionoftheaGVHDwasprimarilytotheskin(n=34)followedbyGItract(n=10)andliver(n=2).TheaGVHDdistributionforthewholecohortisshownintable3A.TherewerenodifferencesintheaGVHDratesbetweendoselevel5vs.others(Table3).ChronicGVHDoccurredin22patients(27.5%)involvingskin(n=11),GItract(n=7),liver(n=3)andeyes(n=2).Again,nosignificantdifferenceswereseenbetweendoselevel5patientsvs.others.Non-RelapseMortality(NRM)Table4demonstratestheresultsofmultivariateanalysisofNRM100.Advancedageatthetimeoftransplantwastheonlysignificantfactorpredictingworseoutcome.NRM100was10%forthewholecohort(duetoinfections=3,aGVHD=2,graftfailures=2,alveolarhaemorrhage=1).The1-yearNRMwas23.8%(duetoGVHD=10,Infection=4,GraftFailure=2,Haemorrhage=2,Unknown=1).At8yearfollowup,nosignificantdifferencewasseenforNRMof34%fori.v.busulfandoselevel11.2mg/kgand23%seeninallothers(p=0.4,figure1A)Figure1Figure1A:CumulativeIncidenceofNRMwithcompetingriskofrelapseTable4SummaryofBayesianLogisticRegressionModelforTRMbyDay100,RFSandOSRelapseandSurvivalThe8-yearcumulativeincidenceofrelapseof43%wassignificantlylessinthepatientsreceivingbusulfanat11.2mg/kgascomparedto68%relapseseeninotherdoselevels(p=0.02,figure1B).Inmultivariateanalysis,RFSwassuperiorforpatientsreceivingi.v.busulfanat11.2mg/kg(table4).The5yearRFSwas25%fordoselevel5patientsvs.9%forallothers(p=0.017;Figure1B).DiseaserelatedpoorprognosticfactorsincludingbadcytogeneticsandincreasedbonemarrowblastswerealsoassociatedwithworseRFS.Atamedianfollowupof91monthsinthesurvivingpatients,thefiveyearOSforpatientstreatedwithiv.Busulfan11.2mg/kgdoselevelwas27%comparedto9forpatientstreatedattheotherdoselevels(p=0.02;figure2B).Inmultivariateanalysis,improvedOSwasseenindoselevel5patients(table4).Olderage,unfavorablecytogenetics,andincreasedbonemarrowblastswerealsoassociatedwithworseOS(Table4).Figure2Figure2A:OverallSurvivalSinceindicationforAlloSCTwasAML/MDSin75%ofthepatientsinourstudy,wespecificallystudiedoutcomesinthispopulation.The5-yearOSforthewholecohortwas18%.SignificantimprovementinOSwasseeninpatientsreceivingi.v.busulfanat11.2mg/kgdosewhencomparedtoothers:23%vs.5%(p=0.019).Thecausesofdeathsforthewholecohortwereprogressivediseasein39(48.8%),GVHDin12(15%),infectionin5(6.3%),graftrejectionin2(2.5%),haemorrhagein2(2.5%),myocardialinfarctionin1,andunknownin2.Potentialcandidatesforhighdosebusulfan:ImpactoftransplantriskfactorsAmongthepatientsreceivingi.v.busulfanat11.2mg/kg,wesoughttoexaminewhetherthetransplantprognosticriskfactorswouldaffecttheoveralloutcomes.Inthiscategory,significantlyimprovedmedianoverallsurvivalof12.3monthswasobservedinthepatientswithgoodprognosticriskfactorsvs.6.3monthsseeninthepatientswithpoorriskfactors.(p=0.04;logrank).Similarly,atrendtowardsimprovedRFSof9.4monthswasseeninthepatientswithgoodprognosticriskfactorscomparedto4.6monthsinpatientswithpoorprognosticriskfactors(p=0.08,logrank).QIDvs.DailydosingNosignificantdifferenceswereseenintermsofmortality,overallsurvivalorPFSwhencomparingdailydosevs.fourtimedailydoseofBusulfan.\o"Gotoothersectionsinthispage"Goto:DiscussionWereporttheresultsofaphaseI/IIstudyofi.v.busulfancontainingreducedintensitypreparativeregimen,withoutpharmacokineticmonitoring,forolderormedicallyinfirmpatientswithadvancedhematologicmalignancies,nototherwiseconsideredeligibleformyeloablativeconditioning.Thistrialfurthervalidatedasetoffavourabletransplantriskfactors(independentofthediseasestatus)thatinclude:i)goodorganfunction,ii)age<60yearsforsiblingmatcheddonortransplantandiii)age<50yearsforMUDtransplantthatareassociatedwithimprovedoutcomeswitha5-yearOSof40%andRFSof36%.Alargeproportionofourstudypopulationwereolderthan60yearsofage(38%)andharboredhighrisk.Asshownpreviously,asimilarpatientpopulationwithactivediseaseatthetimeoftransplantareunlikelytoachievedurableremissionsandareassociatedwithpooroutcomes26,27.However,inourstudy,remissionwasachievedin63patients(79%)afterthetransplantinthewholecohortandin84%forthosereceivingbusulfanat11.2mg/kg.Specifically,improvedsurvivalwasassociatedwithi.v.busulfan11.2mg/kgdoseamongpatientswithdiagnosisofAML/MDS,whichisahardtotreatpopulation.Furthermore,improvedrelapseratesof43%wereassociatedwiththei.v.busulfandoseintensificationbutnotatthecostoftoxicity.InfactNRMratesexceeding40%havebeenreportedinayoungerpopulationascomparedtoourpatients,withrelativelylessadvanceddiseasebutacomorbidityindexof≥328,whereasinourstudy,theNRMwas31%forthewholecohort.Eventhoughamajorityofthepatientswereheavilypre-treated,wedidnotseeanyincreaseinlivertoxicityandspecifically,onlyonepatientdevelopedVOD.Asexpected,increasedbonemarrowblastsandpoorcytogeneticsstillremainedaspoorpredictorsofoutcomeandnovelpost-transplanttherapiesincludingdemethylatingagentscontinuetobeexploredasapost-transplantstrategy29,30.Inourstudy,theengraftedpatientsdemonstratedmixedchimerismin44%patients.Thisisnotsurprisingsincemixedchimerismratesofupto65%havebeenshowninthesettingofRICusingbusulfan/fludarabine