异基因造血干细胞移植预后与白舒非剂量相关分析解析.docx
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异基因造血干细胞移植预后与白舒非剂量相关分析解析.docx
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异基因造血干细胞移植预后与白舒非剂量相关分析解析
BiolBloodMarrowTransplant.Authormanuscript;availableinPMC2014Jun11.
Publishedinfinaleditedformas:
BiolBloodMarrowTransplant.2013Mar;19(3):
474–480.
Publishedonline2012Dec7.doi:
10.1016/j.bbmt.2012.12.001
PMCID:
PMC4052712
NIHMSID:
NIHMS580149
DoseintensificationofBusulfaninthepreparativeregimenisassociatedwithimprovedsurvival:
APhaseI/IIControlled,RandomizedStudy
SParmar,1GRondon,1MdeLima,1PThall,2RBassett,2PAnderlini,1PKebriaei,1IKhouri,1PGanesan,1RChamplin,1andSGiralt3
1DeptofStemCellTransplantationandCellularTherapy,TheUniversityofTexasatMDAndersonCancerCenter,Houston,TX77030
2DeptofBiostatistics,TheUniversityofTexasatMDAndersonCancerCenter,Houston,TX77030
3MemorialSloanKetteringCancerCenter,NewYork
CorrespondingAuthor:
SimritParmar,MD,AssistantProfessor,MDAndersonCancerCenter,1515HolcombeBlvd.,Houston,TX77030,Email:
gro.nosrednadm@ramraps
Authorinformation▼CopyrightandLicenseinformation►
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Thepublisher'sfinaleditedversionofthisarticleisavailableatBiolBloodMarrowTransplant
SeeotherarticlesinPMCthatcitethepublishedarticle.
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Abstract
Doseintensityisimportantfordiseasecontrolinpatientsundergoingallogeneicstemcelltransplantation.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.
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INTRODUCTION
Reducedintensityconditioning(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.
PatientsandMethods
Patientsunder75yearsofageundergoingAlloSCTfromHLAA,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,http:
//ctep.cancer.gov/reporting/ctc.html).
Treatmentplan
Fludarabinewasadministeredatadoseof30mg/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.
Table1A
IVBUSULFANDosingschedule:
SupportiveCare
PatientsreceivedGVHDprophylaxisusingtacrolimustargetingabloodlevelof5–15ng/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.
Statisticaldesignandanalysis
ThiswasaphaseI/IIBayesianadoptivelyrandomizeddosefindingstudythattookintoaccountbothtoxicityandefficacy.Patientswereevaluatedbasedonage,organfunctionanddonor-match.
StudyEndPoints
Themajorendpointsassessedduringthestudywereengraftment(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.
DoseFindingStrategy
Basedonfactorsinfluencingtoxicityoccurringfromthepreparativeregimen;includingpatientage,organfunctionanddegreeofdonormatch;patientswereseparatedintotwostratainconsiderationforthetoxicityforphaseIendpoints:
“good”riskasdefinedbygood
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