Rev. Bras. Hematol. Hemoter. vol.38 número4

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

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Original

article

Is

it

feasible

to

use

granulocyte-colony

stimulating

factor

alone

to

mobilize

progenitor

cells

in

multiple

myeloma

patients

induced

with

a

cyclophosphamide,

thalidomide

and

dexamethasone

regimen?

Edvan

de

Queiroz

Crusoe

,

Fabiana

Higashi

,

Gracia

Aparecida

Martinez

,

José

Carlos

Barros

_,

_Marcelo

_Bellesso

_,

_Marina

_Rossato

_,

_Ana

_Cinira

_F.

_Marret

_,

Carlos

Sérgio

Chiattone

_,

_Vania

_Tietsch

_de

_Moraes

_Hungria

a_{FaculdadedeCiênciasMédicasdaSantaCasadeSãoPaulo(FCMSCSP),SãoPaulo,SP,Brazil}

b_{UniversidadedeSãoPaulo(USP),FaculdadedeMedicina,HospitaldasClínicas,InstitutodoCâncerdoEstadodeSãoPauloOctavio}

FriasdeOliveira(ICESP),SãoPaulo,SP,Brazil

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t

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c

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e

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o

Articlehistory:

Received4April2016 Accepted6June2016 Availableonline29July2016

Keywords:

Bonemarrowtransplantation Multiplemyeloma

Granulocyte-colonystimulating factor

Cyclophosphamide

a

b

s

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t

Background:Cyclophosphamide plus thalidomide as induction for multiple myeloma patientseligibleforautologousstemcelltransplantationmaybealimitingfactorforcell mobilization.Theminimumacceptablemobilizedperipheralbloodstemcellcountto pre-ventdeleteriouseffectsduringtransplantationis2.0×106_CD34+_{cells/kg.Combiningother} treatmentstogranulocyte-colonystimulatingfactor,suchascyclophosphamide,could over-comethemobilizationlimitation.Theobjectiveofthisstudywastoassessthenumber ofCD34+ _{cellsmobilized usinggranulocyte-colony stimulatingfactor withand without} cyclophosphamideafterinductionwithcyclophosphamide,thalidomideand dexametha-sone.

Methods:Aretrospectivestudywasperformedofacohortofmultiplemyelomapatients submittedtoautologousstemcelltransplantationsattwoBraziliancentersbetweenMay 2009andJuly2013.Theoralcyclophosphamideandthalidomideinductiondosesusedwere 1500mg/monthand100–200mg/day, respectively.Mobilizationdoses were10–15mcg/kg granulocyte-colonystimulatingfactorwith2–4g/m2_{cyclophosphamide,or15–20mcg/kg} granulocyte-colonystimulatingfactoralonefor5days.Collectionof>2.0×106_CD34+_cells/kg wasconsideredsufficient.

Results:Eighty-eight patients were analyzed; only 18 received cyclophosphamide. The medianagewas58 yearsold(range:51–62)forthegranulocyte-colony stimulating fac-torgroupand56.5yearsold(range:54–60)forgranulocyte-colonystimulatingfactorplus

∗ _{Correspondingauthorat:DepartamentodeHematologiaeOncologia,FaculdadedeCiênciasMédicasdaSantaCasadeSãoPaulo}

(FCMSCSP),RuaDr.CesárioMottaJr.,61,01221-020SãoPaulo,SP,Brazil. E-mailaddress:edvancrusoe@gmail.com(E.Q.Crusoe).

http://dx.doi.org/10.1016/j.bjhh.2016.06.004

cyclophosphamidegroup.Fifty-twopatientsweremale.Eightycases(90.9%)were Durie-Salmon StagingSystem III-A/B and38 (44.7%) and20 cases (23.5%)wereInternational StagingSystem2and3,respectively.Thegroupthatreceivedcyclophosphamidecollected a highermediannumberofprogenitorcells[3.8(range:3.1–4.4)vs. 3.2(range:2.3–3.8)] (p-value=0.008).Nocorrelationwasobservedbetweenbetterresponsesornumberof induc-tioncyclesandthenumberofcellscollected.

Conclusion:Thenumberofcellsmobilizedwithgranulocyte-colonystimulatingfactorplus cyclophosphamidewashigher.However,inbothgroups,themediannumberofCD34+_cells wassufficient toperforma singleautologousstem celltransplantation;nodeleterious effectswerereportedduringharvesting.

©2016Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Theuseofhigh-dosechemotherapyplusautologousstemcell transplantation(ASCT)asconsolidationafterchemotherapy inductionhasbeenthefirstlineoftreatmentforeligible mul-tiple myeloma patients for over three decades.1 _Currently, themost commonlyemployedinductionstrategy istouse a number of cycles (4–6) with three drugs.1 _The introduc-tion of triple combinations of novel agents for induction, suchas the immunomodulators thalidomideand lenalido-mideortheproteasomeinhibitorbortezomib,hassignificantly changedasthesedrugsresultedinbetteroutcomesand tol-erability comparedto classicregimens suchas vincristine, doxorubicinanddexamethasone(VAD).1_However,the induc-tion regimens should not affect hematopoietic progenitors in the mobilization process.2–6 _{Recently, this influence on} mobilizationhasbeengainingincreasedattentionduetothe use of chemotherapy combinations involving novel agents suchasimmunomodulators(lenalidomide)and,in particu-lar,alkylatingagents(cyclophosphamide)whichcanincrease hematologictoxicity.2,6_Auneretal.2_foundthatthe combina-tionofcyclophosphamide,thalidomideanddexamethasone (CTD)intheinductionofpatientswithmultiplemyeloma sig-nificantlyreducedmobilizationofprogenitorcellscompared tothe classicVAD orVAD-likeregimens, evenwhenusing cyclophosphamide inassociation with granulocyte colony-stimulatingfactor (G-CSF)duringmobilization. In aneffort to overcome this mobilization problem, other agents have beenassociatedwithG-CSF,mostnotablyplerixafor.7 How-ever, the high cost of plerixafor limits its use in many centers. Chemotherapy associated with G-CSF can signifi-cantlyincreasethe mobilizationofprogenitorcells.Oneof themostusedchemotherapydrugsinmobilizationbasedona combinationwithG-CSFiscyclophosphamide,administered ata typicaldose of2–4g/m2_.8 _{However,thistreatment has} somedrawbacks giventhat itraises the costofthe proce-dureowingto theneed forhospitalizationofpatients and canleadtoslowerbonemarrowengraftment,greater toxic-itywithpancytopenia,neutropenia,infectionsanddeath.9–12 Thenumber ofCD34+ _{collected forASCT depends on} sev-eralfactorsthemostimportantofwhicharethenumberof transplantations planned and the leastimpact interms of

timeonthemobilizedperipheralbloodstemcells. Tradition-ally,thetargetforCD34+ _{cellcollectionforsingleASCThas} been 4–6×106_{cells/kg, with the value also hinging on the} deleteriousimpactofharvesting atcountsofbelow2×106 CD34+_{cells/kg,definedasthelowestacceptablelevel.}3_Greater numbersofCD34+_{cellshavenotbeenassociatedwithany} sig-nificantbenefitintheparametersstudied.6_{Anotherobjective} inthequantityofcellsmobilizedistoallowforacellreserve forasecond ASCTasrescueintheevent offuture disease relapse,renderingthetargetcellcountinthefirstmobilization ≥4×106_CD34+ _cells/kg.8,13 _{SomepeculiaritiesexistinBrazil} whichhampertheuseofASCTsuchaslownumberofbeds fortransplantationsand theshortageoffrozencellstorage forsecondtransplantswithintheBrazilianNational Health System(SUS).Thethree-druginductionregimenwidelyused inBrazilformultiplemyelomapatientsiscyclophosphamide, thalidomideanddexamethasone(CTD).14_Theprimary objec-tiveofthis study was todeterminewhether the collection of progenitor cells using G-CSF alone is sufficient to per-formatleastoneASCT,comparedwithagroupundergoing mobilizationwithG-CSFassociatedwithcyclophosphamide, inpatientssubmittedtotheCTDchemotherapyregimenfor induction.

Methods

(2–4g/m2_{splitin2doses)associatedwithG-CSF(10–15mcg/kg} until the collection of cells), and Group 2 received G-CSF (15–20mcg/kgfor5days)alone.Allpatientsweresubmitted toanoutpatientmobilizationprotocol.TheCD34+ _cellcount for collection was determined by flow cytometry using a FACSCaliburBDdevicewithdoubleplatformandemploying thecellquestprogramandISHAGEprotocol.Apheresiswas performedaccordingtotheCD34+_{countinperipheralblood} (≥10×103_{/mL)startingbetweenDay7and10inGroup1and} Day4and10inGroup2,withthemediandayofcollection beingDays7and4aftercommencingG-CSFforGroups1and 2,respectively.Thepatientsweresubmittedtoalargevolume leukapheresisprotocolwithamedianoffourblood volume apheresis (range: 3–6). The Cobe® _{Spectra Marc Terumo} BCTapheresissystemwasusedinbothcenters.CD34+ _cell collectionwasconsideredadequatewithacount≥2.0×106 CD34+ _{cells/kg. Asthe CD34}+ _{cells forthe transplants had} comefrompatientswhohadtheircellscollectedpreviously, itwasnotpossibletoanalyzedataonfailureofmobilization. Progression-freesurvival(PFS)andoverallsurvival(OS)were analyzed.PFSwasdefinedasthetimeelapsedbetweenthe startofinductiontreatmenttodiseaseprogressionordeath, withcensureonthedateoflastcontact.OSwasdefinedasthe timeelapsedbetweenthestartofinductiontreatmentuntil death,withcensureonthedateoflastcontact.Theunpaired

t-testwasusedtocomparemeansofvariableswithanormal distribution,whereastheMann–Whitneytestwasemployed tocomparevariableswithanon-normaldistribution. Cate-gorical variables, including response rates, were compared using the Chi-square or Fisher exact tests, as applicable. Survivalanalyseswere carried out using the Kaplan–Meier technique whilethe comparisonbetween groups was per-formedwiththelogranktest.Medianfollow-upforOSwas calculatedusingthereverseKaplan–Meiermethod.Analyses were carried out using the MedCalc software (Mariakerke, Belgium,v.11.3.3.0).Valueswithatwo-tailed p-value<0.05 wereconsidered statisticallysignificant.Thestudyprotocol wasapprovedbybothinstitutions,withdatacollectedfrom a database derived from the Grupo Brasileiro de Mieloma Múltiplo(GBRAM003)study.Thisstudywasapprovedbythe ResearchEthicsCommitteeoftheHospitaldaIrmandadeda SantaCasadeMisericórdiadeSãoPauloandaconsentform waswaivedgiventheretrospectivenatureofthestudy.

Results

Demographicandbaselineclinicalcharacteristicsof patients

Atotalof88patients withmultiplemyelomasubmitted to ASCTafterinductionusingCTDwereincluded.Regardingthe mobilization scheme, 70 patients receivedfilgrastim alone, and18receivedacombinationoffilgrastimand cyclophos-phamide.Themaindemographicandclinicalcharacteristics ofthe88patientsstratifiedbymobilizationschemeareshown inTable1.Thegroupsdidnotdifferinrespecttoage(median: 58;range:51–62years)orgenderandthegroupswerebalanced in terms ofperformance status or prognostic index using the Durie-Salmon Staging System (DSS) and International

StagingSystem(ISS).Table2depictsthedistributionofthe mainlaboratoryvariablesatthetimeofdiagnosis.No signif-icantdifferencewasfoundbetweenthegroupsforanyofthe variablesstudied.Giventheretrospectivenatureofthestudy, therewasalargeamountofmissingdataforsomevariables (totalcalcium,ionizedcalcium,creatinine,lactate dehydroge-nase(LDH),Beta-2microglobulin)inthegroupsubmittedto mobilizationusingG-CSFalone.

Mobilizationofprogenitorcells

ThedataonthenumberofCD34+_{collectedwasavailablefor} allpatients,whereasthenumberofdaysofapheresisrequired forcollectionwasavailableforonly77cases.Thegroup receiv-ingG-CSFaloneharvestedameanof3.4±1.3×106_/kganda medianof3.2×106_{/kg(range:2.3–3.8×10}6_/kg)ofCD34+_cells. Onthe otherhand,thegroupthatreceivedfilgrastim com-binedwithcyclophosphamideharvestedahighernumberof progenitorcellswithameanof6.4±7.7×106_/kgandmedian of3.8×106_{/kg(range:3.1–4.4×10}6_{/kg)(p-value=0.008).No} sig-nificantdifferenceinthenumberofdaysforcollectionwas observedbetweenthegroups(p-value=0.077).Asummaryof thenumberofcellsmobilizedanddaysofapheresisforthe twogroupsisshowninTable3.

Pre-transplantresponserates,numberofchemotherapy cycles,quantityofcellsmobilizedandadverseevents relatedtothemobilizationprotocol

The mobilizedCD34+_{-cell countwasnot influenced bythe} number of chemotherapy cycles administered, nor by the responseratepriortoASCT(Figure1andTable4).Noadverse eventswere recordedinthedatabaseregister forthegroup thatreceivedcyclophosphamideassociatedwithG-CSF.

Overallsurvivalforthetwogroups

Atthe time ofanalysis, 39 ofthe 88patients had suffered diseaseprogression,andfourhaddied.Themedianfollow-up was 28.6 months and the overall PFS was 24 months. No significant difference was found between the two groups. MedianPFSwas25.7monthsfortheG-CSFalonegroupand the PFS had notbeen attainedfor the groupthat received

40

0 2 4 6 8

P=.390

Number cycles

CD34

10 12 14

35

30

25

20

15

10

5

0

Table1–Patientcharacteristics.

Variables G-CSF G-CSFplusCyclophosphamide p-Value

Ageatstartoftreatment–years

n 80 18

Range 36–69 42–68 0.933

Mean±SD 56.2±7.3 56.4±6.5

Median(IQR) 58(53–61) 56.5(54–60)

Gender–n(%)

n 80 18

Female 31(44.3) 5(27.8) 0.284

Male 39(55.7) 13(72.2)

Igsubtype–n(%)

n 80 18

IgGK/L 30(42.8) 9(50) NS

IgAK/L 9(12.8) 4(22.2)

Light 7(10) 4(22.2)

Other/notanalyzed 24(34.2) 1(5.6)

Performancestatus–n(%)

n 44 14

0 19(43.2) 7(50.0) 0.944

1 8(18.2) 2(14.3)

2 11(25.0) 4(28.6)

3 5(11.4) 1(7.1)

4 1(2.3) 0

Osseouslesion–n(%)

n 39 6

No 8(20.5) 5(83.3) 0.005

Yes 31(79.5) 1(16.7)

DSS–n(%)

n 70 18

IIA 7(10.0) 1(5.6) 0.769

IIIA 53(75.7) 15(83.3)

IIIB 10(14.3) 2(11.1)

ISS–n(%)

n 68 17

1 23(33.8) 4(23.5) 0.678

2 29(42.7) 9(52.9)

3 16(23.5) 4(23.5)

G-CSF:granulocyte-colonystimulatingfactor;SD:standarddeviation;IQR:interquartilerange;DSS:Durie-SalmonStaging;ISS:International StagingSystem.

associatedcyclophosphamide(Figure2).Similarly,no

differ-encewasobservedbetweenthetwogroupsforOS.MedianOS hadnotbeenattainedineitherofthegroups.Thehazardratio forOSwas0.65(95%confidenceinterval:0.18–2.27)favoring thecyclophosphamideregimenbutnotreachingsignificance (p-value=0.495)(Figure3).

Discussion

Theaimofthe present study was to analyzethe quantity ofmobilized progenitorcells with the use ofG-CSF alone orincombinationwiththechemotherapyagent cyclophos-phamide,inpatientswithnewlydiagnosedmultiplemyeloma submittedtochemotherapyinductionusingtheCTDprotocol. Thisisthe firstanalysisofitskind publishedinthe litera-ture.Thetargetquantityofmobilizedcells differsbetween centersassomeplandoubleASCT,orallowforthefreezingof somecellsforasecondtransplantintheeventofrelapsewhile

Table2–Laboratoryvariables.

Variable G-CSF G-CSFplusCyclophosphamide p-Value

Hemoglobin–g/dL

n 66 18

Mean±SD 9.6±2.5 9.7±1.6 0.972

Creatinine–mg/dL

n 54 18

Mean±SD 1.2±0.8 1.5±1.4 0.443

Median(IQR) 0.9(0.7–1.5) 1.05(0.8–1.5)

Totalcalcium–mg/dL

n 49 18

Mean±SD 9.9±1.6 10.2±1.7 0.099

Median(IQR) 9.3(9.0–10.1) 9.75(9.6–10.6)

Ionizedcalcium–mol/L

n 22 17

Mean±SD 5.6±2.0 5.5±0.7 0.955

Median(IQR) 5.3(4.9–6.5) 5.3(5.2–5.6)

ˇ2-microglobulin–mg/L

n 51 17

Mean±SD 4.3±3.2 7.3±7.1 0.128

Median(IQR) 3.3(2.2–5.4) 3.8(3.0–7.5)

C-reactiveprotein–mg/dL

n 29 15

Mean±SD 13.6±25.5 22.8±50.2 0.063

Median(IQR) 2.3(0.4–11.9) 7.2(3.3–16.2)

LDH–U/L

n 27 18

Mean±SD 278±193 335±181 0.320

Albumin–g/dL

n 45 18

Mean±SD 3.6±0.7 3.5±0.6 0.840

Mcomponent–g/dL

n 25 18

Mean±SD 3.6±2.2 4.9±3.1 0.136

Plasmocytes–%

n 55 18

Mean±SD 40.7±27.0 41.0±32.4 0.960

G-CSF:granulocyte-colonystimulatingfactor;LDH:lacticdehydrogenase;Mcomponent:monoclonalcomponent.

multiplemyelomaeligibleforASCTvariesbetweencenters

worldwideintermsoftypeand combinationofthe agents

employed.Thereisastrong,almostuniversal tendencyfor

theuseofnovelagentssuchasbortezomib,lenalidomideand

thalidomide,ascombinationsorwithcorticosteroidsand/or

alkylatingagents.18–21_{Theuseofacombinationofthreedrugs}

ininductionasopposedtotwodrugsyieldsgreaterbenefitsin responseandsurvival.1_{InBrazil,theonlyagentavailablefor}

Table3–QuantityofmobilizedcellsanddaysofapheresisfortheG-CSFandG-CSFpluscyclophosphamidemobilization regimens.

Variable G-CSF G-CSF/Cyclophosphamide p-Value

Cellcount–×106_/kg

n 70 18

Mean±SD 3.4±1.3 6.4±7.7 0.008

Median(IQR) 3.2(2.3–3.8) 3.8(3.1–4.4)

Apheresis–days

n 60 17

Mean±SD 1.5±0.6 1.2±0.5 0.077

Median(IQR) 1(1–2) 1(1–1)

Table4–Relationshipbetweenresponsetypeoninductionandnumberofmobilizedcells.

Responsetypeandtimepoint Response Noresponse p-Value

Afterfourcycles≥PR

Cellcount–×106_{/kg n=74 n=14}

Mean±SD 4.2±4.1 3.1±0.8 0.176

Median(IQR) 3.35(2.7–4.0) 3.15(2.3–3.3)

Pre-aHSCT≥PR

Cellcount–×106_{/kg n=80 n=8}

Mean±SD 4.1±4.0 3.3±0.8 0.780

Median(IQR) 3.3(2.6–4.05) 3.3(2.95–3.55)

Afterfourcycles≥VGPR

Cellcount–×106_{/kg n=36 n=52}

Mean±SD 5.0±5.6 3.4±1.4 0.228

Median(IQR) 3.35(2.95–5.25) 3.3(2.35–3.8)

Pre-aHSCT≥VGPR

Cellcount–×106_{/kg n=47 n=41}

Mean±SD 4.6±5.0 3.4±1.5 0.135

Median(IQR) 3.4(3.025–4.275) 3.2(2.3–3.825)

aHSCT:autologoushematopoieticstemcelltransplantation;PR:partialresponse;VGPR:verygoodpartialresponse.

useinthepublichealthsystemisthalidomide.Thebest

com-binationidentifiedandwidelyusedinBraziliancentersisthe

CTDprotocol.Currently,centersindevelopedcountries

pre-fertouseotherdrugsforinductionhowever,combinations

withthalidomidearestillinuseinBrazilandinother

devel-opingcountries.Thisprotocolwascomparedinarandomized

phaseIIIstudyagainsttheVADpluscyclophosphamide

regi-meninover1000patientswiththeCTDarmprovidingbetter

responserates.20_{Thepatientsstudiedinthepresent}

inves-tigation were selected from two national centers that use differentprotocols forthe use ofcyclophosphamide. How-ever,the finalmonthlydose (1500mg)isthe sameinboth: Center1usesacontinuousdailyoraldoseof50mg;Center2 usesadoseof500mg/weekforthreeweeksevery28days.In theonlystudypublishedassessingtheeffectonmobilization

Progression-free survival

Number at risk Group: 1

70 48 33 10 3 1

18 14 5 3 0 0

Group: 2

Sur

viv

al probabillty

, %

Time (months) Regimen

G-CSF G-CSF/Cy

100

90

80

70

60

50

40

30

20

10

0

0 10 20 30 40 50

Figure2–Progression-freesurvivalforG-CSFand G-CSF+cyclophosphamidegroups.

inpatientsundergoingCTD,Auneretal.2_reported mobiliza-tionfailureinattemptstoperformatleastoneASCT.Failure ratesforcellnumbercut-offsof≥4×106_CD34+_cells/kgand of≥2×106 _CD34+ _{cells/kg were 39% and25% ofthe cases,} respectively.InanotherstudycomparingCTDvs.aregimen ofVAD plus cyclophosphamideasinduction,Morganet al. identifiedamobilizationfailurerateof1%ofcases.19_Inthese studies,thecombinationofG-CSFandcyclophosphamidewas usedformobilizationinallcases.Transplant centersdiffer withregardtothestandardconductforharvesting progen-itor cells. The use of cyclophosphamide, while promoting bettercellcollection,prolongsthewholeprocessduetothe waitfor cell productionrecovery.Generally, this process is performed with the patient hospitalized and is associated withincreasedriskoffebrileneutropeniaandotherinfectious

Overall survival

Number at risk Group: 1

70 53 41 23 10 1

18 16 8 4 0 0

Group: 2

Sur

viv

al probabillty

, %

Time (months) Regimen

G-CSF G-CSF/Cy

100

90

80

70

60

50

40

30

20

10

0

0 10 20 30 40 50

complications.6_{Forbothofthecentersinthepresent} analy-sis,theminimumacceptablenumberofcollectedcellswas 2×106_CD34+_{cells/kg,therebyallowingforatleastoneASCT} to becarried out.A difference betweengroups was noted forthemobilizationofprogenitorcells,withthegroupthat receivedG-CSF pluscyclophosphamideharvestingahigher meanof6.4(±7.7)×106_{/kgvs.3.4(±1.3)×10}6_{/kgforthegroup} thatreceivedG-CSFalone(p-value=0.008).However,the num-berofcellsinbothgroupswassufficienttoperformatleast oneASCT.Auneret al.reportedadifferentnumberofdays ofapheresis in cases that received CTD vs. those induced usinga VAD orVAD-likeprotocol.In the currentstudy,no differenceinthenumberofdaysofapheresiswasobserved betweenthegroups(p-value=0.07).Nostudiesexistthat sup-portanincreaseininductiontimeprecedingmobilizationto enhancesuccessfulcellcollection.22_{Inthepresentstudy,no} associationwasfoundbetweenbetterresponseandimproved survival.Thecyclophosphamideusedinmobilization,in addi-tiontoitsabilitytopromotereleaseofprogenitorcellsfrom thebonemarrowforperipheralcollection,hasareputation ofreducingthediseasefurther(debulking)duringthe collec-tionofprogenitorcells.Retrospectivestudieshavefailedto confirmthiseffectandhaveshownnoadvantageintermsof survival.22_{Similarly,inthepresent study,noadvantagesof} cyclophosphamideusewerefoundintermsofmobilization, improvedresponseorsurvival.Assessingthesituationinthe Braziliancontextwithregardstolimitationsforperforming ASCT,difficultiesinfrozenstorageofcells,andtheneedto cutcosts,thepresentstudyrevealedthatsufficientprogenitor cellscanbemobilizedtoperformatleastoneASCTwiththe useofG-CSFaloneinpatientsinducedusingtheCTDprotocol.

Conclusion

TheuseofG-CSFalonetomobilizeprogenitorcellsisfeasible in multiple myeloma patients induced with a cyclophos-phamide,thalidomideanddexamethasoneprotocol.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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