Rev. Bras. Hematol. Hemoter. vol.37 número4

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w w w . r b h h . o r g

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Original

article

Unrelated

hematopoietic

stem

cell

transplantation

in

the

pediatric

population:

single

institution

experience

Daniela

Hespanha

Marinho

∗

_,

_José

_Zanis

_Neto,

_Carmem

_Maria

_Sales

_Bonfim,

Vaneuza

Araujo

Moreira

Funke,

Lisandro

Lima

Ribeiro

UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received4December2014

Accepted9February2015

Availableonline3June2015

Keywords:

Hematopoieticstemcell

transplantation

Bonemarrowtransplantation

Cordbloodstemcelltransplantation

Unrelateddonors

Child

a

b

s

t

r

a

c

t

Objective:Hematopoieticstemcelltransplantationhasbeensuccessfullyusedtotreatthe

pediatricpopulationwithmalignantandnon-malignanthematologicaldiseases.Thispaper

reportstheresultsupto180daysaftertheprocedureofallunrelatedhematopoieticstem

celltransplantationsinpediatricpatientsthatwereperformedinoneinstitution.

Methods:A retrospective review was performed of all under 18-year-old patients who

receivedunrelatedtransplantationsbetween1995and2009.Datawereanalyzedusingthe

log-ranktest,Coxstepwisemodel,Kaplan–Meiermethod,FineandGraymodelandFisher’s

exacttest.

Results:Thisstudyincluded118patients(46.8%)whoreceivedbonemarrowand134(53.2%)

whoreceivedumbilical cord blood transplants. Engraftmentoccurred in 89.47% ofthe

patientsthatreceivedbonemarrowand65.83%ofthosethatreceivedumbilicalcordblood

(p-value<0.001).Bothneutrophilandplateletengraftmentswerefasterinthebonemarrow

group.Acutegraft-versus-hostdiseaseoccurredin48.6%ofthepatientswithoutstatistically

significantdifferencesbetweenthetwogroups(p-value=0.653).Chronicgraft-versus-host

diseaseoccurredin9.2%ofthepatientswithahigherincidenceinthebonemarrowgroup

(p-value=0.007).Relapseoccurredin24%ofthe96patientswithmalignantdiseasewith

2-yearcumulativeincidencesof45%inthebonemarrowgroupand25%intheumbilicalcord

bloodgroup(p-value=0.117).Five-yearoverallsurvivalwas47%,withanaveragesurvival

timeof1207days,andnosignificantdifferencesbetweenthegroups(p-value=0.4666).

Conclusion:Despitedelayedengraftmentintheumbilicalcordbloodgroup,graft-versus-host

disease,relapseandsurvivalweresimilarinbothgroups.

byElsevierEditoraLtda.Allrightsreserved.

∗ _{Corresponding}_author_at_:_Rua_General_Carneiro,_181,_Alto_da_Glória,_80060-900_Curitiba,_PR,_Brazil.

E-mailaddress:dhmarinho@hotmail.com(D.H.Marinho).

http://dx.doi.org/10.1016/j.bjhh.2015.05.004

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Introduction

Allogeneichematopoieticstemcelltransplantation(HSCT)is

anacceptedtreatmentforanumberofinheritedandacquired

hematopoietic diseases in children, especially diseases for

whichanalternativetreatmentisnotavailableornolonger

effective.1,2

Humanleukocyte antigen(HLA)-matchedsibling donors

areavailableonlyforaround25%ofsuchchildren.However,

therehasbeensubstantialprogressoverthelastfourdecades

intheuseofalternativedonors,includingunrelatedvolunteer

donors.3–5

Theknownadvantagesofunrelatedumbilicalcordblood

(UCB) over unrelated bone marrow (BM) are well

docu-mentedandinclude:significantlyfasteravailabilityofbanked

cryopreservedUCBunits,norisktothedonor,reduced

trans-missionofviralillnessessuchascytomegalovirus(CMV)and

EpsteinBarrvirus(EBV),toleranceofHLAdisparitybetween

the donor and recipient, and reduced risk and severity of

acutegraft-versus-host disease(GVHD). However,the main

problemofusingUCBfortransplantationisthelownumber

ofhematopoieticprogenitorcells,whichresultsinincreased

riskofgraftfailure,delayedhematopoieticengraftmentand

delayedimmunereconstitution.6,7

HLAmatching,theuseofhigh-dosechemotherapyand/or

radiotherapyandtheneedofimmunosuppressivedrugs

rep-resentthecausesofonsetofmanycomplicationsfollowing

HSCT.8,9

GVHD is a common complication, mainly in unrelated

HSCTorinthepresenceofanyHLAallelemismatch.10_At_an

incidenceof40%,acuteGVHDoccursintheearlyperiodafter

transplantwiththeskinbeingthemostcommonlyaffected

tissue.RiskfactorsforthedevelopmentofGVHDincludethe

recipient’sage,CMVserostatus,HSCdonorsourceand HLA

disparity.11,12_Chronic_GVHD_is_observed_in_30–90%_of

recipi-entsofHSCT.3

Inpatientswithmalignantdiseases,GVHDisassociated

withthegraft-versus-leukemiaeffect(GVL),thusresultingin

adecreasedincidenceofrelapse.13,14

Inrecentdecades,theoverallsurvival(OS)inchildrenwho

receivedHSCTismuchhigher,about 60%onetotwoyears

aftertransplant,dependingonthedisease,clinicalconditions

priortotransplantandcomplicationsafterthetransplant.2,6

Therefore,thisstudyaimedtoanalyzetheresultsofunrelated

HSCTinpediatricpatientsupto180daysaftertheprocedure

andtocomparethestemcellsourcesused.

Methods

Patients

This is a retrospective study. Between January 1995 and

December2009,261under18-year-oldpatientsreceived

unre-latedHSCTattheHospitaldeClínicas,UniversidadeFederaldo

Paraná(UFPR),Brazil.Ofthe261patients,ninewereexcluded

fromtheanalysisforthefollowingreasons:sevenpatientshad

insufficientdataforanalysisandtwopatientswererecipients

ofperipheralblood transplants.Onehundred andeighteen

Table1–Featuresofpatientsandtreatment.

Variable

Age–mean(range)years 8(0.2–18.0)

Diagnoses–n(%)

Malignantdisease 96(38.1)

Marrowfailure 95(37.7)

Immunedeficiency 42(16.7)

Metabolicdisorders 19(7.5)

Sourceofstemcell–n(%)

Bonemarrow 118(46.8)

Umbilicalcordblood 134(53.2)

DegreeofHLAmatch–n(%)

Withoutincompatibility(BM) 71(60.2) One/moreincompatibility(BM) 47(39.8) Withoutoroneincompatibility(UCB) 76(56.7) Two/moreincompatibility(UCB) 58(43.3)

Conditioningregimen–n(%)

CFA+FLU 106(42.4)

CFA+TBI 47(18.8)

CFA+BU 58(23.2)

CFA+BU+MEL 8(3.2)

Others 31(12.4)

ATG 174(69.0)

GVHDprophylaxis–n(%)

CsA+MTX 144(57.1)

CsA+steroids 91(36.1)

Others 17(6.7)

CFA:cyclophosphamide;FLU:fludarabine;TBI:totalbody irradia-tion;BU:busulfan;MEL:melphalan;ATG:anti-thymocyteglobulin; CsA:cyclosporine;MTX:methotrexate.

patientsreceivedBMand134UCBgrafts.Thecharacteristics ofthe252casesthatwereassessedarelistedinTable1.

HLAtypingandunrelateddonorselection

TheunitswereselectedonthebasisofbestHLAmatchingand

acriticalminimumcelldoseatthediscretionofthetreating

physiciansandsourcefromNationalandInternationalPublic

Banks.ClassItypingwasperformedbyserologicalor

molecu-lartechniquesandClassIItypingbymoleculartechniques;it

wasonlyin2008thattheanalysisofthelocusCwasfrequently

performed.

Conditioningregimenandprophylaxisagainst graft-versus-hostdisease

Theconditioning regimenand prophylaxisforacuteGVHD

variedaccordingtotheunderlyingdisease,stemcellsource

andHLAincompatibilities(Table1).

Transplantation

The units ofBM grafts used for transplantation contained

an average of4.39×108 total nucleatedcells (TNC) (range:

0.3–10.8 cells)per kilogramofrecipient’sbody weightafter

thawing.TheunitsofUCBgraftsusedfortransplantation

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1.3×105CD34cells(range:0.1–11.4cells)perkilogramof

recip-ient’sbodyweightafterthawing.

Supportivecare

Central venous catheters were inserted in all patients.

Patients received acyclovir for antiviral prophylaxis,

flu-conazoleoramphotericin-Bforantifungalprophylaxis,and

trimethoprim-sulfamethoxazoleforprophylaxisagainst

Pneu-mocystiscarinii. Empiricalbroadspectrumantibiotictherapy

wasstartedatthefirstsignoffever.

Hematopoieticrecoveryandengraftment

Hematologic recovery was defined as the time when the

absolute neutrophil count was equal to or greater than

0.5×109cells/L in three consecutive laboratory counts on

different days and platelet count equal to or greater

than 20×109cells/L (after seven days without transfusion

support).6

Graft-versus-hostdisease

Patients were evaluated and considered at risk for acute

GVHDwhentherewasevidenceofneutrophilrecovery.

Diag-nosis of acute GVHD was based on clinical criteria, with

histopathologicconfirmationwhenpossible.Overallstaging

was assessed according to previously published criteria.15

Only those patients with sustained engraftment of donor

hematopoiesissurvivingformorethan90 daysafter

trans-plantwereassessedforchronicGVHDaccordingtothecriteria

describedinpreviousstudies.16

Othermeasurements

Relapse was characterized by morphological evidence of

malignant disease atany site. Transplant-related mortality

(TRM)wasdetermined tobeevery causeofdeaththatwas

notdeathbyrelapse.OSwasthetimebetween

transplanta-tionanddeathduetoanycauseorbetweentransplantation

andthedayofthelastfollow-up.

Statisticalanalysis

AllstatisticalanalyseswerecarriedoutusingtheSTATAv.12.0

computerprogram.Survivalrateswerecalculatedusingthe

Kaplan–Meiermethod.Thelog-rank testwasusedfor

test-ingdifferencesinsurvivalbetweengroupsintheunivariate

analysis.Cumulativeincidencecurveswereusedfor

engraft-mentand GVHDendpoints withdeathasacompeting risk

factor.TheCoxproportional hazards modelwithbackward

eliminationwasusedformultivariatetestingofco-variables

(statisticalsignificancewasbasedonp-values≤0.05).

Differ-encesbetweensubgroupswerecomparedusingtheFineand

Gray testwith death asa competing risk. Theassociation

betweendichotomousvariableswascalculatedusingFisher’s

exacttest.

Results

Patientcharacteristics

From1995to2009,252patientsweretreatedwithunrelated

HSCT.Themeanageofthepatientswaseightyears(range:

0.2–18 years) with 34 patients being one year old or less.

Mostpatientsweremale(61.1%).Atotalof96patientswere

transplantedformalignantdiseaseswith64(66.7%)beingat

anearlystage.Atotalof150(59.5%)donor-graftpairs were

matchedforABOand124(49.8%)werematchedforgender.

BMwasusedforHSCTin118patients(46.8%)andUCBin134

patients(53.2%).Thepatientsaswellastreatmentarelisted

inTable1.

Neutrophilandplateletengraftment

Neutrophil engraftment occurred in 181 ofthe 234 (77.4%)

avaliable(18patientsdiedbefore)cases(BM:89.47%andUCB:

65.83%). Inthe BMgroup,102 ofthe118 patientsachieved

neutrophilengraftmentinanaveragetimeof24days(range:

11–1696days).ThecumulativeincidencebyDay30was80%.

IntheUCBgroup,79ofthe134patientsachievedneutrophil

engraftmentinameantimeof32days(range:14–4037days).

The cumulative incidenceby Day 42 was 62%. Inthe

uni-variateanalysis, neutrophil engraftmentwas influencedby

cellsource(p-value<0.001)andpatientage(p-value=0.002).

Inthemultivariateanalysisonlycellsource(p-value<0.001)

wasasignificantlyfavorablefactorforneutrophilengraftment

(Table2andFigure1).

IntheBMgroup,patientsachievedplateletengraftmentin

anaverageof25days(range:10–96days).Thecumulative

inci-dencebyDay30was50%.IntheUCBgroup,patientsachieved

plateletengraftmentinameantimeof43days(range:19–158

days).ThecumulativeincidencebyDay42was38%.Inthe

uni-variateanalysis,plateletengraftmentwasinfluencedbycell

source(p-value<0.001),patientage(p-value=0.022)andHLA

match(p-value=0.027).Inthemultivariateanalysiscellsource

(p-value<0.001)andHLAmatch(p-value=0.013)were

signifi-cantlyfavorablefactorsforplateletengraftment(Table2and

Figure2).

1

.8

.6

.4

.2

0

0 30 60 90 120 150 160

Days

Cumulative incidence

P<0.001

Umbilical cord blood Bone marrow

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Table2–Multivariateanalysis.

Variable Hazardratio 95%Confidenceinterval p-Value Favorablefactor

Neutrophilengraftment

Stemcellsource 0.37 0.25–0.54 <0.001 Bonemarrow

Age 0.99 0.96–1.03 0.744

Plateletengraftment

Stemcellsource 0.36 0.24–0.54 <0.001 Bonemarrow

Age 0.52 0.94–1.03 0.520

HLA 0.63 0.43–0.90 0.013 Withoutmismatch

AcuteGVHD

HLA 1.74 1.20–2.52 0.003 Withoutmismatch

ATG 0.58 0.40–0.86 0.006 Use

Relapse

Diseasestatus 3.27 1.44–7.42 0.005 CR1/2

Overallsurvival

Age(years) 1.11 1.04–1.18 <0.001 Young

GVHD 2.55 1.29–5.04 0.007 Without

ATG 1.99 1.07–3.72 0.029 Use

HLA:humanleukocyteantigen;GVHD:graft-versus-hostdisease;ATG:anti-thymocyteglobulin;CR1/2:completeremission1/2.

1

.8

.6

.4

.2

0

0 30 60 90 120 150 180 210 240 270 300 330 360

Days

P<0.001

Figure2–Cumulativeincidenceofplateletengraftment overtime.

Graft-versus-hostdisease

AcuteGVHDoccurred in88 (48.6%)patients ofthetotal of 181(onaveragewithin90days)andwasscoredasGradeII (54.5%)andGradeIII–IV(45.5%).ByDay100after transplanta-tion,thecumulativeincidencewas44%intheBMgroupand 43%intheUCBgroup(p-value=0.653–Figure3).HLAmatch

(p-value=0.004)andATG(p-value=0.005)weresignificantin

theunivariateanalysis;thiswasthesameinthe

multivari-ateanalysis(p-value=0.003andp-value=0.006,respectively–

Table2).

ChronicGVHDoccurredin13(9.2%)patientsoutofthetotal

of142(onaveragewithin90days).Thediseasewasclassified

aslimitedinsixcases(46.2%)andextensiveinsevencases

(53.8%).Atoneyearaftertransplantation,thecumulative

inci-dencewas14%intheBMgroupand2.5%intheUCBgroup

(p-value=0.053).

1

.8

.6

.4

.2

0

0 90 180 270 360 450 540 630 720

Days

P=0.653

Figure3–Cumulativeincidenceofacutegraft-versus-host diseaseovertime.

Relapse

Hematologicalrelapsewasdetectedbetween21and1228days

(mean: 181 days; 95% confidence interval:94.0–670.0) after

transplantationin23of96patientstreatedformalignant

dis-ease.Relapsewasobservedin29.31%ofthepatientsinthe

BMgroupand15.79%intheUCBgroup(p-value=0.117).The

cumulativeincidencesofrelapsewere45%intheBMgroup

and25%intheUCBgroupattwoyears(Figure4).Thestageof

thediseasewasfoundtobesignificant(p-value=0.005)

how-evercellsource,GVHD,CMVandABOincompatibilitywerenot

(Table2).

Overallsurvivalandcausesofdeath

Withanaveragefollow-uptimeofsurvivingpatientsof1207

days (3.3 years), the cumulative proportions of surviving

patientsatoneyearandfiveyearswere55%and47%,

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1

.8

.6

.4

.2

0

0 365 730 1095 1460 1825

Days

P=0.117

Figure4–Cumulativeincidenceofrelapseovertime.

yearandfiveyearsafterunrelatedHSCTwithBMwere55%and

45%,respectivelyandforUCBtheywere52%and45%,

respec-tively(p-value=0.466)(Figure5).Inamultivariateanalysis,the

factors thatmostinfluenced ofnegativeformtheOS were

higherages(p-value<0.001),non-useofATG(p-value=0.029),

andGVHD(p-value=0.007–Table2).

Inthisseries,131(52.0%)patientsdied,59(50.0%)intheBM

groupand72(53.73%)intheUCBgroup(p-value=0.614).Death

was associated with infection (n=47), graft failure (n=29),

GVHD(n=25),relapse(n=18)andothers(n=12).

Discussion

Thisretrospectivestudycomparedaheterogeneouspediatric

populationwithdifferentdiagnosestransplantedoveralong

period oftime using two different stem cell sources. This

studyaimedtoevaluatetheoutcomesofunrelatedHSCTin

thepediatricpopulationcomparingtheuseofBMandUCB;

only25%ofpatientswhoneedtransplantsfindsuitablefamily

donors.

Thecumulativeincidence(80%byDay30intheBMgroup,

and62%byDay42intheUCBgroup)andspeedofneutrophil

engraftment(onaveragebyDay24intheBMgroupandDay

0.00 0.20 0.40 0.60 0.80 1.00

0 500 1000 1500 2000 2500 3000 3500 4000 4500 5000

Time (days)

Survival

P=0.466

Figure5–Cumulativeincidenceofoverallsurvivalover time.

32 in theUCB group)were similar tothe results ofBarker

et al.17 _In_other _studies_on_UCB_{transplantations}6,18,19

neu-trophilengraftmentwasfoundhigherandfasterthaninthe

currentstudy.Inthisstudy,neutrophilengraftmentwasnot

influencedbyHLAmatchingsimilartothestudyofPetterson

etal.6_even_though_Kurtzberg_et_al.18_found_that_HLA_matching

influencedneutrophilengraftment.Itisknownthat,during

thetimeofthisstudy,HLAtypingtechniqueswereimproved.

Manystudies1,6,19_demonstrated_that_the_dose_of_infused_CD34

cells influencesneutrophilengraftment,however no

differ-ence wasseen inthecurrentstudyperhapsduetothelow

meancellcountinfused.

Thecumulativeincidence(50%byDay30intheBMgroup,

and 38% byDay 42 inthe UCBgroup)and speed (on

aver-age,Day25intheBMgroupandDay43intheUCBgroup)of

plateletengraftmentweresimilartoBarkeretal.12_Petterson

etal.,6_who_analyzed_patients_who_received_UCB

transplanta-tion,foundthatplateletengraftmentwassimilartothisstudy.

Theauthorsreportedthatengraftmentwasnotinfluencedby

theinfusedTNCorCD34celldoseorHLAmatching.However

inthecurrentstudy,plateletengraftmentwasinfluencedby

HLAmatching.ItisagainimportanttonotethatHLAtyping

techniqueswereimprovedduringthisperiod.

Acute GVHD remains a major cause of morbidity and

mortality after HSCT. The incidence of Grade II–IV GVHD

is between 20 and 50%. The recipient’sage, CMV

serosta-tus,donorsourceandHLAdisparityhaveconsistentlybeen

foundtoberiskfactorsforthedevelopmentofacuteGVHD.12

This study demonstrates that 48.6% ofthe patients

devel-opedacuteGVHDwithGradeIIbeingfoundin54.5%ofthe

cases.Somestudies12,18,19_demonstrated_similar_incidences,

howeverothers2,10_found_lower_incidences,_and_Faraci_et_al.20

foundanincidenceof75%.Inthisreport,aswellinBarker

etal.17_and_Hwang_et_al.,21_there_was_no_difference_in_the

inci-denceofacuteGVHDbetweentheBMandtheUCBgroups;

however,Wangetal.22_reported_that_the_incidence_was_lower

intheUCBgroup.

TheincidenceofchronicGVHDrangesbetween30%and

50%andthusisamajorcauseofnon-relapsemortalityand

morbidity in long-termsurvivors.Chronic GVHD is

associ-atedwithagraft-versus-leukemiaeffect(GVL)resultingina

decreasedincidenceofrelapse.13_In_this_study,_the_incidence

was9.2%versus25.0%asreportedbyZeccaetal.13_However_in

thisstudythefollow-upwasonlyupto180daysafter

trans-plant. Similar toother reports,21,22 _chronic_GVHD _occurred

moreintheBMgroup(p-value=0.007).Barkeretal.17_reported

nodifferencebetweenthetwogroups.

Relapseoccurredin24%ofthepatientswhoreceivedHSCT

for malignant diseaseswith the incidencebeing similarin

bothgroups.Wang etal.22_stated _that_relapse_was_lower_in

theUCBgroup.GVHDdidnotshowaGVLeffect,similartothe

reportbyLeeetal.23_;_however_Yi_et _al.24 _believe_that_GVHD

hasanimportantprotectiverole.Thestageofthediseasewas

importantforprognosisinthisstudyandinothers.18,25

Theestimatedone-yearOSafterHSCTintheBMandthe

UCBgroupswere58%and52%,respectively(p-value=0.466).

Thesedatawerefoundtobesimilartotheliterature.3,6,17_In

the multivariateanalysis,the resultsassociatedwitha

sig-nificantlyworseOSincludedhigherage,non-useofATGand

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hadworsesurvival,andWagneretal.1_stated_that_HLA

mis-matchinfluencedsurvivaltoo.Infectionwasthemaincause

ofdeathasinotherpublications.2,25

Conclusion

OurfindingsconfirmthatunrelatedHSCTwithBMandUCB

resultsinsimilarcomplicationsandsurvivalinthepediatric

population.Therefore,UCBisasafecellsourceforpatients

whodonothaveasiblingdonorforHSCT.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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