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Successful_0

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    Successful

?772?ChinMedJ2005;118(9):772776

    ;Briefreport

    ;SuccessfultranspIantationof

    ;fromunrelateddonorsinhigh

    ;doubleunitumbilica1..cordblood

    ;riskleukemiawithalongfollowup

    ;WANGFengrong,HUANGXiaojun,ZHANGYaochen,CHENYuhongandLUDaopei ;Keywords:cordbloodstemcelltransplantation?unrenteddonor?doub~?leukemia

    ;Umbilical?cordblood(UCB)isasourceofhematopoieticstemcellsthathasbeen

    ;successfullyusedfortransplantati0n,primarilyin ;children.Butthelowcelldoseseverelylimitsthe ;applicationofunrelatedumbilical-cordblood ;transplantati0n(UCBT)inadultpatients, ;particularlyinthosewithhighbodyweight.We ;hypothesizedthatthecombinedtransplantationof ;twopartiallymatchedUCBunitswouldimprove ;engraftmentwithoutcrossedimmunological ;rejection.SinceMay2000.sixadultpatientswith ;highriskleukemiahavebeentransplantedinthis ;study.

    ;METHODS

    ;Patients

    ;Pre-transplantclinicalfeaturesofthesixpatientsare ;showninTable1.AIlpatientswereadultsaged14 ;

    ;32years.weighting4795kg.withadiagnosis

    ;ofhighriskacuteleukemia.exceptonewomanwith ;chronicmyelogenousleukemiainblastcrisis.AIl ;patientsdidnothavepotentialdonorswith ;acceptableHLAcompatibility.Allpatientsgavethe ;wri~eninformedconsentbeforeparticipatinginthis ;study.

    ;Selectionofgrafts

    ;Preliminan,searchesofumbilical-cord-bloodbanks ;wereperformedusingthepatient’sHLAphenotype,

    ;asdeterminedbyserologictypingforclassI ;HLA-Aand-Bantigensandlow.resolutionDNA ;typingforclassIIHLAalleles.High-resolution ;moleculartypingforHLA-DRB1alleleswas

    ;performedasconfirmatorytyping.Preferredcord- ;bloodunitswerethosematchedatthreeormoreof ;sixHLAloci.containingahighernumberof ;nucleatedcells.TengraftsofUCBfor5patients ;wereobtainedfr0mthePlacentalBloodBankof ;PekingUniversityInsititueofHematology,the ;remainingtwograftsofUCBwereobtainedfr0mthe ;GuangzhouPlacentalBloodBank.Allumbilical-cord ;bloodunitsweretestedforinfectiousagentsasa ;routine.

    ;Preparativeregimens

    ;Threepatientswereconditionedwitharegimen ;basedontotalbodyirradiation.consistingoftotal ;bodyirradiationwith770cGyjnasignaldoseata ;doserateof5cGy/min,cyclophosphamide ;1.8/mx2days.Simustine(MeCCNU)250

    ;mg/kg,andtwopatientswereconditionedwitha ;regimenbasedonbusulfan.containingAra-C ;2g/mx1day.cyclophosphamide1.8/mx2

    ;days.busulfan12mg/kgadministeredorallyin12 ;dosesover3days.MeCCNU250mg/kg.AIIfive ;patientsreceivedatotaldoseof4560ma0f

    ;antithymocyteglobulinperkilogramforthreetofour ;daysbeforetheinfusionofumbilical-cordblood. ;Thefinalpatient.whohadmycosisincentralnerve ;systemandexperiencedhemiplegia,was

    ;conditionedwithfludarabine30ma/mx5days. ;andATG80mg/kgover4daysfTable1).

    ;Prophylaxisagainstgraft?-versus?-hostdisease ;Prophylaxisagainstgraft?-versus.?hostdisease ;(GVHD)consistedofcyclosporineA.

    ;methotrexate,methylprednis0nel0neand ;mycOphenOIatem0fetiI(MMF).Thedosageof ;cyclosporineAwas2.5mg/kgperday

    ;intravenouslyfr0mday9beforetransplantationuntil ;PekingUniversityPeople’sHospital,InstituteofHematology,

    ;Beijing100044,China(WangFR,HuangXJ,ZhangYC,Chen ;YHandLuDP)

    ;Correspondenceto:Dr.HUANGXiaojun,PekingUniversity ;People’sHospital,InstitsuteofHematology,

    ;Beijing100040,

    ;China(Tel:86108314422ext3914.Fax:86.1068314422ext

    ;3914.Email:xihrm@medmail.con.cn)

    ;

;ChineseMedicalJournal2005:118(9):772776.773.

    ;AML:acutemyeloidleukemia;ALL:acutelymphoblasticleukemia;ATG:antithymocyteglobulin;BC

    :blastcrisis;BU:busulfan;CML:chronic ;myelogenousleukemia;CNSL:centralnewoussystemleukemia;CR:completeremission;CY:cyclop

    hosphamide;F:female;M:male:REL:

    ;relapse;TBI:totalbodyirradiation.

    ;bowelfunctionwasnorma1.atthetimewhenthe ;patientwasswitchedtooralcyclosporineAathalf ;thedose.WholebloodcyclosporineAconcentration ;wasmonitoredweeklyusingafluorescence ;polarizationimmunoassay.Thelevelofcyclosporine ;Awasadjustedtobetween150and250na/m1. ;Fromdays40to50,thedosewasreduced

    ;graduallyandwasstoppedaroundday180.Ifthere ;wasnoevidenceofchronicGVHD.Thedoseof ;methotrexatewas15mg/mintravenouslyonday1 ;anddecreasedto1Omg/mintravenouslyondays ;3.6.and11aftertransplantation.Fromday1tO ;day30aftertransplantation,thepatientswere ;administeredwithMMF(0.5gper12hoursorally) ;andmethylprednisonelone(20mqperday

    ;intravenously).ThediagnosisandgradingofGVHD ;wasestablishedaccordingtothepublished ;criteria.’

    ;1.8X10/kg.1.54X10/kgand2.21X10/kg

    ;with1HLAlOCUSmismatchedtorecipients. ;respectively;astheunitwhichrejectedhad ;nucleatedcellsof0.8X107/kg.

    ;1.21X107/kgand

    ;2.67X10/kgwith1HLAlOCUS(inpatient1)or2. ;1OCi(inpatients2and6)mismatched.Ourresults ;showedthattheunitwithahighercelldoseormore ;HLAcompatibilitymayhaveapriorityengraftment. ;TranSplantatiOnprocedureandsupportivecare ;CryopreservedunitsofCOrdbloodweretransported ;tothetransplantationcenterinliquidnitrogenand ;weremaintainedinthevaporphaseuntiI

    ;transplantation.Thetwounitswereinfused ;immediatelyafterthawingviafemoraloneafter ;anotherwithaten-minutesinterva1.Afterthawing, ;thefollowingtestswereperformedontheblood: ;nucleatedcellcount,CD34cellcount.cellviability ;andassaysforcolonyformingunits.

    ;AsshowninTable2,theunitwhichengraftedin

;patients1,2and6,hadnucleatedcellsofSupportivecareincludedtheadministrationof5Ug

    ;Table2.HLAcompatibilityandcellcontentdataoftransplantedproducts

    ;

    ;?

    ;774?ChinMedJ2005;118(9):772776

    ;OfG?CSFperkilogramperdaysubcutane0uslyfrOm ;day6aftertransplantationuntildurablerecoveryof ;nuetrophilswasachieved.Thepatientsreceived ;standardbloodproducts,andtbiotics,antifungal ;agents,andnutritionalsupportaccordingtothe ;protoco1.

    ;Hematopoieticrecovery

    ;Thetimeofrecoveryofmyeloidcellswasdefinedas ;thefirstofthreeconsecutivedaysafter ;transDlantati0nduringtheperiodwhentheabsolute ;neutrophilcount(ANC)wasabove0.5x10/L ;Thetimeofrecoveryofplateletswasdefinedasthe ;firstofsevendayswhentheplateletscountwasat ;least20x10/Lwithouttransfusingsupport.Bone ;marrowaspirationandcytogeneticstudieswere ;done1,2,and3monthsaftertransplantatiOnt0 ;assessengraftment.Meanwhile.HLADNAtyping ;andPCR.DNAfingerprintingweredonetoconfirm ;donorchimera.Monitoringwascontinuedifclinically ;indicated.Foreachpatient.atleasttwomethods ;wereusedtoconfirmdonorchimerism.

    ;RESULTS

    ;Characteristicsofthegraftsofumbilicalcord

    ;blood

    ;EachpatientreceivedtwoHLA.mismatchedUCB ;unitsfrOmunrelateddonors.Table2shows ;histocompatibility.cellcontentandcellviabilitydata ;forthegrafts.Therangeofthenucleatedcellsin ;thegrafts.measuredafterthawingwas0.8×10 ;

    ;2.67x10/kgoftherecipient’sbodyweight.and

    ;therangeofCD34progenitorcellswas0.06x10. ;

    ;0.75x10./kg.Cellviabilitywas81%95%.

    ;ThetotalnumberofnucleatedcellsandCD34cells ;foronerecipientwas1.8x105.05x10/kgand

    ;0.3x10.0.96x10./kg.respectively.

    ;Hematopoieticrecovery

    ;AsmaybeseeninTable3,fourofsixpatients

    ;achievedhematopoieticrecoveryaftertransplanted ;withtwoUCBunits.Thetimeforsustainedmyeloid ;engraftmentandplateletengraftmentwerefr0m ;days21to31andfr0mdays28t072.respectively. ;1nthesefourpatients.DNAanalysisshowedthree ;patients(patients1.2and6)hadcordblood ;engraftmentandonlyonedonor’sDNAwas

    ;detectableafterengraftment,theotherone(patient ;5)hadautologousrec0nstituti0n.Primarvgraft ;failureoccurredinonepatient(patient4).andthen ;hereceivedanotherunitofUCBonday30.Hegot ;anANC>0.5x10/Londay50.andtheonly ;donorDNAdetectedbelongedtothethirdUCBunit. ;1nallfivepatients.therewasnomixedchimerism ;detectable.Anotherpatient(patient3)diedonday ;21aftertransDlantati0nbeforemyeloidrecovery. ;Graft-versus-hostdisease

    ;Amongthefourpatientsinwhomengraftmentofthe ;transplantedUCBcellsoccurredandwhosurvived ;for28daysormore,twohadgradeIacuteGVHD ;(aGVHD),oneshowedgradeIIaGVHDlimitedto ;theskinandgastrointestinaltractandwascontrolled ;byashortcourseofme廿1ylprednis0nel0ne,the

    ;remainingoneshowednosignsofaGVHD.There ;wasnosevereaGVHD.Anotherpatientwith ;autologousrecovery,whohadskinrashonday6 ;aftertransplantation.wasdiagnosedasgradeI ;superacuteGVHD.Amongthe4patientswho ;survivedformorethan100daysafter

    ;transplantati0n,nochronicGVHDdeveloped. ;TranspIantation-relatedevents

    ;Onlyoneofsixpatients(patient3)hasinfectious ;complicationduringtheperiodofpost?transplant ;neutropenia.Thispatienthadoralinfectionbefore ;transplantation,andhadhighfever,coughon ;day1.andradiographshowedinfectioninthelung ;onday7.noinfectiousagentwasfoundinblood ;andsputumculture.Althoughshereceiveda ;combinationtreatmentofantibioticsandantifungal ;agents,shediedonday21.

    ;Afterengraftment,themainclinicalproblemsin ;Table3.Patients’post—transplantationcourse

    ;GVHD:graft—versus’hostdisease;:thispatientreceivesanotherunitofUCBonday30whenprimarygr

    aftfailureOccurs.

;

    ;ChineseMedicalJournal2005;II8(9):772776?775?

    ;threepatientshavebeenrelatedtocytomegalovirus ;(CMV).forthosewhoreceivedtherapywith ;gancyclovirand/orfoscarnet.garlicoiland ;immunoglobulins.Threepatientsreceivedpre- ;emptivecoursesupondetectionofCMV

    ;antigenemia.Theevolutionhasbeenfavourblein ;patients1and6.Forpatient5.rapidlyevolving ;CMVinterstialpneumoniaresultedindeathonday ;62.

    ;Relapseandsurvival

    ;onSeptember30.2004.twoofsixpatients ;(patients1and2)whounderwenttransplantation ;werealiveanddisease-free.withafollow-upof52 ;and48months.andamongthempatient2whowith ;CMLinblastcrisisgotmolecularremission.too. ;TWopatients(patients5and6)hadrelapses7and ;6monthsaftertransplantation,respectively.As ;describedabove.1patient(patient3)diedof ;infection21daysaftertransplantation.another ;(patient4)diedofcytomegalovirusinterstial ;pneumonia62daysaftertransplantation. ;DISCUSSION

    ;Sincethefirstsuccessfultransplantationofumbilical- ;cordbloodinapatientwithFanconi’sanemia.

    ;umbilical-cordblood(UCB)hasbeenwell ;establishedasasourceofhaematopoieticstemcells ;forallogeneictransplantationtotreatavarietyof ;malignantandunmalignanthematologicdisorders. ;Althoughithasseveraladvantagesoverbone ;marrowtransplantation(BMT),forexample.the ;absenceofrisktothedonor.1essriskofsevere ;graft-versus-hostdisease.thelimitednumberof ;nucleatedcellsinUCBisacriticaIdeterminantOf ;hematopoieticrecorveryandsurvivalafter ;transplantation.Thecelldoseisamajorlim.1ationof ;theprocedureinadults.particularlyinwhomwith ;highbodyweight.Analternativetotheexvivo ;expansionofcells.whichisefficacious.isthe ;combinedtransplantationoftwocloselyHLA- ;matchedunitsofumbilicalcordblood.ButitisstilI

    ;unknownthatwhetherthetwoimmunologically ;distinctunitswillincreasetheincidenceofreiection

;andGVHD.

    ;SinceMay2000,sixadultpatientswithhighrisk ;Ieukemiahavebeentransplantedwithtwounitsof ;UCB.Exceptthatonepatientdiedbeforemyeloid ;recovery,three(patients1.2and6)offivehad ;cordbloodpermanentengraftmentwhiletheother ;twodidnot.Theneutrophilandplateletrecovery ;occurredondays21,22,28anddays51,28.71 ;aftertransplantationrespectively.whichissimilarto ;thatofsingleunitumbilical-cordblood ;transplantationfr0munrelateddonor.

    ;Nonetheless.thedurabilityofthesegraftsofUCBis ;clear:uptonow,therehavebeennolategraft ;failuresinthesurvivingpatientsfwithafollow-upof ;52and48months).Thesedatasupportthe

    ;principlethattransplantationoftwoimmunologically ;distinctUCBunitscanproducestableand ;permanentengraftment,andisnotassociatedwith ;thecrossedimmunologiclrejectionandengraftment ;delay.

    ;BarkeretalreportedapatientwithCMLwho ;receivedtwoUCBunits,bonemarrowbiopsieson ;days21and55revealed97%and98%donorcells ;respectively,andthecontributionofeachgraftto ;hematopoiesiswas76%,71%and21%.27%.

    ;respectively.FernandezMNetalalsofounda ;doublechimerainearlytimeafterthetransplantation ;OfUCBfr0mtwounrelateddonors.butonlyone ;donorDNAcouldbedetectedfrOmseveraldays ;beforeengraftment.Butourresultscontrastedwith ;thosepreviousstudies,wefoundtherewasno ;mixedchimerismdetectedofthetwoUCBunitsorof ;therecipientandtheUCBunit.Wehypothesized ;thateachunitmightcontributetohematopoiesis ;duringearlystageaftertransplantation,butwhen ;oneunitwaspredominantlyengrafted,theother ;wasrejectedgradually.

    ;1naseriesof65patientswhoreceivedUCBfrOm ;unrelateddonors.GluchmanEetalfoundthata ;graftnucleatedcelldosehigherthan3.7x10/kg ;wasassociatedwithshortertimetoneutrophiland ;plateletrecovery.AndtheyalsofoundHLA ;mismatchingbetweendonorandrecipientincreased ;theriskofdelayedengraftment.RubingsteinPetal

    ;reportedsimilarresultsin562patientswhoreceived ;unrelatedCBT.

    ;Therelativeimmatur_tVoflymphocytesincordblood ;mayreducetheriskandseverityofGVHD.whichin ;turncouldpermitmoreHLAmismatchingbetween ;thetowdonorsordonorandrecipient.Asin ;previouslypublishedseries,theincidenceof ;moderateandsevereaGVHDinpatientswho

    ;receivedHLAmatchedor1-locusmismatchedcord- ;bloodtransplantationfr0munrelateddonorsranged ;fr0m27%tO41%andfrom9%tO22%.

    ;respectively.Inourdata.GVHDislowerthan ;expected.OnlyonepatientexperiencedgradeU ;

    ;?776?ChinMedJ2005;118(9):772776

    ;aGVHD.withnosevereacuteGVHDandchronic ;GVHDoccurrence.Theremarkablymild

    ;man_festatiOnsOfGVHDobservedinourpatients ;mightsuggestthattheco-transplantedunitsofUCB ;couldaffectthereactivityoftheengraftedUCBcells ;againstthehostbyimmunologicalmechanisms. ;Theresultsinthisstudydemonstratethatdouble ;unitsHLAmismatchedumbilical-cordbloodfrOm ;unrelateddonorsisafeasiblealternativesourceof ;hematopoieticstemcellsfortransDIantatiOnin ;adults.particularlyinthosewithhighbodyweight. ;Hematopoieticreconstitutionoccurredinmost ;patients.andtheincidenceandseverityofGVHD ;werelowinspiteofHLAmismatchingand

    ;immunologicaldistinctionbetweentwoUCBunits. ;Ourfindingsshouldassistfurtherinvestigationofthe ;transDlantatiOnofumbilical-cordbloodfrOmtwo ;partiallyHLAmatcheddonorsasamethodof

    ;increasingthedoseofcells.particularlyforadult ;Patientswhoneedallogeneictransplantation. ;2

    ;3

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    ;TransplantationofunrelateddonorumbilicaIcordblood ;in1O2patientswithmalignantandnonmalignant ;diseases:influenceofCD34celldoseandHLA ;disparityontreatment-relatedmortalityandsurviva1. ;BIood2002:1OO:1611-1618.

    ;LaughlinMJ,EapenM,RubinsteinP,eta1.Outcomes ;aftertransplantationofcordbloodorbonemarrowfrOm ;unrelateddonorsinadultswithIeukemia.NEngIJMed ;2004:351:2265-2275.

    ;RochaV.LabopinM.SanzG.eta1.Transplantsof ;umbilical-cordbloodorbonemarrowfrOmunrelated ;donorsinadultswithacuteIeukemia.NEnI. ;qJMed

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