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:s.araag.mdaodnr.on.orgAutha.iafa.notiaa▼CopyrightandLicenseinformation►Thepublisher'sfinaleditedversionofthisarticleisavailableatBiolBloodMarrowTransplantSeeotherarticlesinPMCthatcitethepublishedarticle.Goto:AbstractDoseintensityisimportantfordiseasecontrolinpatientsundergoingallogeneicstemcelltransplantation.WeconductedaphaseI/IIcontrolledadoptiverandomizedstudytodeterminetheoptimaldosingscheduleofi.v.busulfan.Patientswithadvancedhematologicnolisaoacimg,≤75ymo.gwithHLA-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.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,BandDRnotchmdua.mlotmddaaa.ga.≥5/6notchmd.mlotmddaaa.gwiththmfollowingdiagnoseswereeligible:chronicmyeloidleukemia(CML),thatwaseithertransformedorInterferon-resistant;acutemyeloidleukemia(AML);intermediateorhigh-riskmyelodysplasticsyndrome(MDS)asdefinedbytheInternationalPrognosticScoringSystem(IPSS);lymphomaormyelomabeyond1stremission.Eligiblepatientswereconsideredunqualifiedtoundergoablativepreparativeregimenbecauseofadvancedageorthepresenceofco-morbidi