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

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►

CopyrightnoticeandDisclaimer

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