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'sfinaleditedversionofthisisavailableatBiolBloodMarrowTransplantSeeothersinPMCthatcitethepublished.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.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/oractivediseaseatthetimeoftransplantationisst...