Rev. Bras. Hematol. Hemoter. vol.38 número1

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

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Review

article

Hematopoietic

progenitor

cell

mobilization

for

autologous

transplantation

–

a

literature

review

Marco

Aurélio

Salvino

,

Jefferson

Ruiz

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received17April2015 Accepted17July2015

Availableonline19August2015

Keywords:

Hematopoieticprogenitorcell mobilization

Autologoustransplant Plerixafor

Multiplemyeloma Non-Hodgkinlymphoma

a

b

s

t

r

a

c

t

Theuseofhigh-dosechemotherapywithautologoussupportofhematopoieticprogenitor cellsisaneffectivestrategytotreatvarioushematologicneoplasms,suchasnon-Hodgkin lymphomasandmultiplemyeloma. Mobilizedperipheralblood progenitorcellsare the mainsourceofsupportforautologoustransplants,andcollectionofanadequatenumber ofhematopoieticprogenitorcellsisacriticalstepintheautologoustransplantprocedure. Traditionalstrategies,basedontheuseofgrowthfactorswithorwithoutchemotherapy, havelimitationsevenwhenremobilizationsareperformed.Granulocytecolony-stimulating factoristhemostwidelyusedagentforprogenitorcellmobilization.Theassociationof plerixafor,aC-X-CChemokinereceptortype4(CXCR4)inhibitor,togranulocytecolony stim-ulatingfactorgeneratesrapidmobilizationofhematopoieticprogenitorcells.Aliterature reviewwasperformedofrandomizedstudiescomparingdifferentmobilizationschemes inthetreatmentofmultiplemyelomaandlymphomastoanalyzetheirlimitationsand effectivenessinhematopoieticprogenitorcellmobilizationforautologoustransplant.This analysisshowedthattheadditionofplerixafortogranulocytecolonystimulatingfactoris welltoleratedandresultsinagreaterproportionofpatientswithnon-Hodgkinlymphomas ormultiplemyelomareachingoptimalCD34+_{cellcollectionswitha smallernumberof}

apheresiscomparedtheuseofgranulocytecolonystimulatingfactoralone.

©2015Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.Allrightsreserved.

High-dose chemotherapy with autologous hematopoietic stemcelltransplantationisaneffectivestrategytotreat vari-oushematologicneoplasms,suchaschemosensitiverelapsed Hodgkin’slymphomas,1,2 _{non-Hodgkinlymphomas(NHL)}3,4

and multiple myeloma (MM).5 _{Several clinical guidelines}

andconsensusrecommendtheprocedureasstandard treat-ment in these conditions.6–11 _{According to the Center for}

∗ _{Correspondingauthorat:RuaAugustoViana,s/n,Canela,40110-060Salvador,BA,Brazil.}

E-mailaddress:marcohemato@hotmail.com(M.A.Salvino).

International Blood and Marrow Transplant Research (CIBMTR), 12,047autologoushematopoieticstemcell trans-plantations(AHSCT)werecarriedoutintheUnitedStatesin 2011,withMMandNHLbeingthemainindications.12_InBrazil,

datafrom theBrazilianTransplant Registryshowthat1144 AHSCTwereperformedin2013,slightlyhigherthantheyear before.13

http://dx.doi.org/10.1016/j.bjhh.2015.07.011

TheCIBMTRshowsthatperipheralbloodprogenitorcells arethemainsourceusedtosupportautologoustransplants.12

In addition to the possible chemoresistance of the can-cer,mobilizationofhematopoietic progenitorcells(HPC) is anotherpotentiallylimitingstepforAHSCT,withhighfailure rates(between5%and40%)associatedwithhistoricallyused mobilizationstrategies.14

AconsensuspublishedbytheAmericanSocietyforBlood andMarrowTransplantation(ASBMT)recommendscollecting aminimumdoseof2×106_CD34+_{cells/kgtoperformAHSCT,}

butthedecisiontoacceptcollectionsofbetween1×106_and

2×106_CD34+ _{cells/kgcanbeindividualizedaccordingtothe}

circumstancesofeachpatient.Ontheotherhand,largertarget numbersareneededifmultipletransplantsareplanned.15

Although the minimum dose of progenitor cells to be collectediswelldefined,theidealtargetorthedesirable max-imum dose isless clear. Some data show that the use of

≥5×106_CD34+_{cells/kgleadstoquickerandmorepredictable}

grafting, achieving platelet transfusions independence sig-nificantly earlier with potential reductions in transplant costs.16,17_{Thus,adequateprogenitorcellmobilizationisakey}

stepwhenplanninganAHSCT.

Biology

related

to

mobilization

of

hematopoietic

progenitor

cells

and

therapeutic

targets

Although mature hematopoietic cells are physiologically releasedfromthebonemarrowtotheperipheralblood, imma-turecellsarefoundinthecirculationataverylowfrequency. About 0.05% or less of the total circulating leukocytes are HPC and express the CD34+ _{surfacemarker.}18 _{HPC adhere}

tothebonemarrowmicroenvironmentbyavarietyof adhe-siveinteractions.19 _{Furthermore,theyexpressawiderange}

ofsurfacereceptors,suchasadhesionmoleculesassociated withangiopoietin-1lymphocytes,verylateantigen4(VLA4), andMac-1,C-X-Cchemokine receptorstype4(CXCR4)and type2(CXCR2), thesurfaceglycoproteins CD44and CD62L, andtyrosinekinasereceptorc-kit.19_{Thebonemarrowstroma}

containsstromalcell-derivedfactor1(SDF-1),CXCchemokine GRO-␤,vascularcelladhesionmolecule(VCAM-1),KIT-ligand, P-selectin glycoprotein ligand and hyaluronic acid, all of which are ligands for the stem cell adhesion molecules.20

Preclinicaldatashowthatinhibitionofthesereceptor–ligand interactions resultsinincreasedmobilization ofprogenitor cells.19–21

Growth factors [granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF)] are the most widely used agents for progeni-tor cell mobilization; they have two main mechanisms of action. The first is the production of proteases by hyper-plasticmyelomonocytic series, which inducesthe cleavage ofSDF-1bypreventingitsbindingtoCXCR4.Themost stud-iedproteaseismatrixmetallopeptidase9(MMP-9),although dipeptidase CD26 seems to have a greater role in this process.22,23 _{Thesecond mainmechanismisalso}

proteoly-sisinduced and isresponsible for degradation ofVCAM-1, osteopontinandfibronectin,leadingtoreducedadhesionof progenitorcellsthroughitsVLA-4receptorinbonemarrow stroma.23

Theadditionofachemotherapeutic agenttoacytokine inthemobilizationregimenhaseffectswhichare notfully elucidated.19_{Itisspeculatedthattheadditionof}

cyclophos-phamide togrowth factors has a synergistic effect on the release ofgranulocyticproteasesinthebonemarrowasits administrationinisolationleadstocleavageofSDF-1,CXCR4 andc-kitadhesionmolecules.19_{Furthermore,thetoxicityof}

chemotherapeuticagentsonbonemarrowstromacanrelease HPCasaresultofdamagetothefunctionalabilityofstromal cellsinsupportingthem.19

Plerixafor(AMD3100)isareversiblybicyclaminhibitorof CXCR4 that breaks the binding betweenSDF-1 and CXCR4 receptors, blocking the chemotactic signaling with stromal cells.23_{Amongthehypothesesforitsmobilizationmechanism}

isthelossofsensitivityofprogenitorcellstoSDF-1caused by the inhibition of CXCR4. Consequently, these cells are attractedtothecirculationthroughsignalingprobablyrelated tosphingosine-1-phosphate(S1P),asphingolipidimplicated inthechemotaxiscontrolofprogenitorcellsfrombone mar-row, blood and other tissues.23 _{Studies also suggest that}

plerixafor keeps the progenitor cells in the circulation by binding to CXCR4,leading toa loss of chemoattraction to SDF-1, decreasing HPC homing, which also contributes to mobilization.24

Mobilization

of

hematopoietic

progenitor

cells

for

multiple

myeloma

and

lymphoma:

results

of

the

historically

most

used

strategies

show

limitations

Traditionally, the most widelyused mobilization strategies have beenthe use ofgrowth factorsalone (G-CSF/GM-CSF) or in combination with chemotherapeutic agents. Among the available growth factors, the most commonly used is recombinant G-CSFfilgrastim, whileothers,suchas, G-CSF pegfilgrastim,G-CSFlenograstimandGM-CSFmolgramostim, areusedlessfrequently.14

G-CSFaloneasfirst-linemobilizationisanattractiveoption owingtothepredictablemobilizationkinetics,whichinturn allows predictable apheresis scheduling and staffing while decreasingcostsofgrowthfactorsandthecollection proce-durecomparedwithcyclophosphamide(CY).25–27

GM-CSFhasbeenshowntobeinferiortoG-CSFinterms ofnumberofstemcellscollectedandinpost-transplantation outcomesrelatedtohematopoieticrecovery,transfusionand antibioticsupport,febrileepisodesandhospitalizations.28,29

Itis mostoftenused inremobilizationstrategies, alone or in combination with other cytokines or chemotherapy.28,29

Data on the use of pegfilgrastimin steady-state mobiliza-tionarebothlimitedandmixed,butonestudydemonstrated predictable mobilization kinetics and similar collection yieldsandapheresis dayscomparedwithaseparate G-CSF cohort.30

CYmaybeincorporatedintotheinitialinductionor sal-vagetherapycycles,ormaybeadministeredasastandalone cycle separatelyfrom standardtherapy. Themostcommon stand-aloneregimensincludecyclophosphamideatarangeof dosesbetween2and7g/m2_{.CYisassociatedwithhighercell}

engraftmentkinetics,35–40 _{but alsomay resultinmore}

tox-icity,febrile neutropenia,transfusions,hospitalizationsand highercosts.14,34,41_{ThepublishedliteratureonthevariousCY}

approachesisvast.Ingeneral,studiesdemonstratethatCY willmobilizemorestemcellsthanG-CSFaloneandhelpin theroleofmobilizingtraditionallydifficultpatients,suchas thosewithlymphoma.42,43

Theprimarygoalofmobilizationistocollectasufficient numberofprogenitorcellsforthepatienttoundergoAHSCT. Theoptimalmobilization,however, requirescollection ofa targetnumberofcellsandalsostrategiestominimizethetime andnumberofapheresis,reducingthecostoftheprocedure andavoidingcomplicationsrelatedtomobilization,suchas hospitalizationduetofebrileneutropenia.15

Asystematicreviewofrandomized clinical trials evalu-atedtheresultsof28studiescomparingdifferentmobilization schemes. Eighteen included onlypatients with MMand/or lymphomas14 _{and only four of these were multicenter.} Table1showsthecharacteristicsofinterventionsandresults observedinstudies includedinthissystematicreviewthat recruited≥10patientsineacharmand compareddifferent regimensofgrowthfactorswithandwithoutchemotherapy (Table1).

Thesestudiesshowthat,ingeneral,strategieswithhigher dosesofG-CSFaloneorchemotherapywiththeadditionof growth factors (G-CSF and/or GM-CSF) result in increased numberofCD34+ _{cellscollected.Furthermore,some}

strate-giesreducedthenumberofapheresisneededtoachievetarget collection.14

Althoughthissystematicreviewhaslimitations suchas restrictedsamplesizeofstudies,theirmoderatequalityand variabilityinthepopulation,itdemonstratesthelimitations oftechniqueshistoricallyusedinHPCmobilization.Amajor retrospective analysis, involving 2177 patients undergoing attemptedmobilizationinthreeItaliancentersbetween1999 and2007,showedarateofpoormobilizers(definedasa collec-tionof<2×106_CD34+_{cells/kg)ofonly15%corroboratingdata}

fromrandomizedtrials.44

Insufficientinitialmobilizationleadstonewmobilization procedures(remobilization),whichcannegativelyinfluence disease progression and significantly increase the use of resources.41_{Severalstudiesevaluatedthesuccessof}

remobi-lizationwithtraditionalmeasuresbasedontheuseofgrowth factors.Aretrospectiveanalysisassessedtheresultsof remo-bilizationofregimenscontainingG-CSFand/orGM-CSF,alone orcombined withchemotherapyin251 patientswith lym-phomaorMM.41_{Afterremobilization,only18.4%ofpatients}

whousedG-CSForGM-CSFand26.5%ofthosewhoreceiveda growthfactorassociatedwithchemotherapyachieved collec-tionsof≥2×106_CD34+ _{cells/kg.Whencellscollected inthe}

firstmobilization werepooled, thefailurerates were28.1% inthegroupremobilizedwithgrowthfactoraloneand47.1% inthegroupremobilizedwithgrowthfactorassociatedwith chemotherapy(Table2).41

Publisheddatasuggestthat,althoughremobilizationwith growthfactorscanrescuepatientswhofailedthefirst mobi-lization,theproportionofpatientsnotmeetingtheminimum collectionofHPCrequiredtoperformAHSCTishigh(around 30%),confirmingtheneedtoevaluatemoreeffective mobiliza-tionstrategies.

Challenges

for

the

identification

and

prospective

characterization

of

poor

mobilizers

after

strategies

based

on

the

use

of

growth

factors

The possibility ofpredicting mobilization failure based on patient’s characteristicsintheearlymobilizationprocessis highlydebatable.15_{Eachstudyproposesdifferentdefinitions}

ofpoormobilizers,limitingtheuniformityofthe characteris-ticsthatprospectivelyidentifythesepatients.18

Someidentifiablecharacteristicsbeforemobilizationhave often been associated with a higher risk of failure of procedures inpatients withlymphoproliferativediseases.29

Althoughsomeofthesefactorsareunanimouslypointedout inthe literatureaspredictiveofpoormobilization,suchas theintensityofpriorexposuretochemotherapyorradiation, theuseofchemotherapeuticagentsandfailureinaprevious attemptofmobilizationothers,suchaspatientage,havea morecontroversialrelationshipwithpoormobilization.47

The Italian working group, Gruppo Italiano Trapianto di MidolloOsseo(GITMO),recentlyproposedadefinitionfor‘poor mobilizers’forpatientswithlymphomaormyeloma.48_This

definitioncamefromaconsensusofexpertsand considers thefactorsdescribedinTable3.

Theconcept ofproved poormobilizer basedon the cir-culating CD34+ _{cell countafter 4–6 daysofmobilization is}

very relevantgiventhe availabilityofpreemptivestrategies withpotentialforreducingriskofcomplicationsrelatedtothe necessityofagreaternumberofapheresisorhigherneedfor remobilizationsandpossiblereducedcost.

Use

of

plerixafor

to

mobilize

hematopoietic

progenitor

cells:

randomized

clinical

trials

showing

its

effectiveness

Plerixaforhasprovedtobeanagentthatgeneratesrapid mobi-lizationofHPCinmurinemodelsandsubsequentlyinhealthy humanvolunteers.49_{ThephaseIandIIstudiesattestedthe}

mobilizing effect and safety of the G-CSF plus plerixafor combination inpatients withNHL and MM. Therapidand significantincreaseinwhitebloodandCD34+_cellcountsin

peripheralblood,includedpatientswhosefailuretomobilize withG-CSFalonewasproven.49–51_{Thecombination}

guaran-teedcollectionsof≥2×106_CD34+_{cells/kgin95.9%ofpatients}

with77.6% achievingacollectionof≥5×106_CD34+ _cells/kg

(22.4%ofpatientsachievedthisdoseafteronlyoneapheresis). Tworandomized,comparative,double-blind,placebo con-trolled and prospective multicenter studies evaluated the use ofG-CSFplusplerixafor versusG-CSF aloneinthe ini-tialmobilizationstrategyofpatients.Thesestudiesrecruited 298 patientswithNHL52 _{and 302patients withMM.}53 _NHL

patientstreatedwiththecombinedtherapyobtained65.6% of successful collections of ≥5×106_CD34+ _{cells/kg versus}

24.2%intheG-CSFarm.Collectionof≥2×106_CD34+_cells/kg

wasachievedby90%withthecombinationagainst59.8%in theG-CSFgroupwithinfourapheresisdays(p-value<0.001) (Figure1).ThemediannumberofCD34+ _{cellscollectedwas}

Table1–Randomizedclinicaltrialsevaluatingdifferentmobilizationstrategiesincludinggrowthfactorswith/without chemotherapy.14

Study Interventions(n) Collected

CD34+_cells

(median/×106₎

Numberof apheresis

(median)

Patients failedto mobilize(%)

Cyclophosphamideassociatedwithgrowthfactor

Faconetal.,1999 CY4g/m2_{+filgrastim5mcg/kg/d+ancestim}

20mcg/kg/d(n=55)

12.4a ₁a _14.5

CY4g/m2_{+filgrastim5mcg/kg/d(n=47) 8.2 2 19.1}

Gazittetal.2000 CY3g/m2_{+molgramostim250mcg/m}2_{(n=10) NR 2 40.0}

CY3g/m2_{+filgrastim10mcg/kg/d(n=13) NR 3 23.0}

CY3g/m2_{+molgramostim250mcg/m}2_+filgrastim

10mcg/kg/d(n=12)

NR 1 41.7

Narayanasamietal.2001 Filgrastim10mcg/kg/d(n=23) 2.5 Nodifference NR CY5g/m2_{+filgrastim10mcg/kg/d(n=24) 7.2}* _{Nodifference NR}

Pavoneetal.2002 DHAP+filgrastim5mcg/kg/d(n=38) 5.9 2 13.2 CY+filgrastim5mcg/kg/d(n=34) 7.1 2 11.8 Vela-Ojedaetal.2000 IFO+molgramostim5mcg/kg/d(n=28) 3.1 3 14.3 CY4g/m2_{+molgramostim5mcg/kg/d(n=28) 5.3 3 10.7}

Growthfactoralone

Stiffetal.2000 Filgrastim10mcg/kg/d(n=51) 3.6 NR 26.0 Filgrastim10mcg/kg/d+ancestim20mcg/kg/d(n=56) 2.4 NR 16.4

Otherchemotherapycombinationsassociatedwithgrowthfactors

Copelanetal.2009 R+VP-16+filgrastim10mcg/kg/d(n=28) 9.9* _{3 3.6}

VP-16+filgrastim10mcg/kg/d(n=27) 5.6 4 14.8 Hartetal.2009 IEE+filgrastim5mcg/kgb.i.d+EPO(n=14) 15.4 1.3 0

IEE+filgrastim5mcg/kgb.i.d(n=12) 12.6 1.8 16.7 Ozceliketal.2009 CE+filgrastim10mcg/kg/d(late)(n=23) 10.8 1 13.0 CE+filgrastim10mcg/kg/d(early)(n=25) 10.5 1 16.0

CY:cyclophosphamide;IFO:ifosfamide;DHAP:dexamethasone+cytarabine+cisplatin;IEE:ifosfamide+epirubicin+etoposide;EPO: erythro-poietin;CE:cyclophosphamide+etoposide;NR:notreported.

a _{Statisticallysignificantdifference.}

1.98×106_cells/kg).52_{Incidenceofadverseevents,mostlymild}

tomoderate,wassimilarbetweengroupswithonly5.3%of seriouseventsinthecombinationgroupand6.9%intheG-CSF groupduringthemobilization period.52_{Themostcommon}

non-seriousadverseeventswerediarrhea(38%),injectionsite erythema(29.3%),nausea(17.3%),headache(11.3%)andbone pain(10.7%),allofwhichwereeasilymanageable.52

MMpatientstreatedwithG-CSFplusplerixaforobtained

≥6×106_CD34+_{cells/kgwithintwoapheresisdays,with86.8%}

achievingthistargetversus55.9%intheG-CSFgroup(p-value <0.0001).Thecombinationwasalsomoreeffectivetocollect

≥6×106_CD34+_{cells/kgwithinfourapheresisdays(75.7%vs.}

51.3%;p-value<0.001)and≥2×106_CD34+_{cells/kgdays(95.3%}

vs.88.3%;p-value=0.031)36_{(Figure2).Themediannumberof}

Table2–ResultsobtainedwithremobilizationwithG-CSFand/orGM-CSFwithorwithoutchemotherapy.

Studyanddisease Remobilization regimen(n)

MobilizedCD34+_cells

(median/failurerate)

Apheresis days(median)

Apheresisdays consideringall mobilizations

(median)

Failurerate consideringall mobilizationsafter

cellspooled(%)

Pusicetal.,200841

–lymphomas(n=NR) –multiplemyeloma(n=NR)

G-CSF/GM-CSF (n=217)

1.2×106_{/81.6% 3 6 28.1}

G/C(n=34) 0.9×106_{/73.5% 2 6 47.1}

Lefrereetal.200445_:

–lymphomas(n=64) –myeloma(n=28) –acuteleukemia(n=27) –solidtumors(n=19)

G-CSF+chemotherapy (cyclophosphamidein 57%)

(n=138)

3.5×106_{/35% 2 NR 22.5}

Boeveetal.200446_:

–lymphoma –myeloma Othercancers

G-CSFinhighdosesor G-CSF+GM-CSF (n=86)

2.1×106_/65%for

lymphoma 3.5%formyeloma 31.5%forothercancers

3 NR 26.7after2 mobilizations and15after3 mobilizations

Table3–Definitionsforpatientswithlymphomaormyelomawhohavepredictionorevidenceofpoormobilization. Predictedpoormobilizer Atleastonemajorcriterionortwominorcriteria:

•Majorcriteria:

Failureofpreviousattempttomobilize;

Priorradiotherapyinvolvinglargeareascontainingbonemarrow;

Completecoursesofpriortherapyincludingmelphalan,fludarabineorothertherapiesthatpotentiallyaffect progenitorcellmobilizationsuchascarmustine,dacarbazine,cladribine,lenalidomide,andplatinum

compounds.

•Minorcriteria:

Atleasttwopreviouslinesofcytotoxictherapy;

Refractorydisease;

Lymphomaisahigherriskfactorthanmyeloma

Extensiveinvolvementofbonemarrowinfiltrationbytumorcells;

Bonemarrowcellularity<30%inmobilization;

Lowplateletcountbeforedeployment.

Age>65years.

Provedpoormobilizer •Havingreceivedadequatemobilization(G-CSFdoses≥10mcg/kgifusedaloneor≥5mcg/kgifusedafter chemotherapy)andpresent:

apeakofcirculatingCD34+_{cells<20/␮Londays4–6afterthestartofmobilizationwithG-CSFaloneorwithin}

20daysafterchemotherapywithG-CSF

OR

•CollectionofCD34+_cells<2×106_{/kginuptothreeapheresis}

AdaptedbyJantunenetal.47_{andGruppoItalianoTrapiantodiMidolloOsseo.}48

CD34+_{cellscollectedwasalsohigherinthecombinationgroup}

(12.97vs.7.31×106_{cells/kg).Theincidenceofadverseevents}

wassimilarbetweenstudygroups.Themostcommon non-seriousadverseeventsoccurredwereinjectionsiteerythema (20.4%),diarrhea(18.4%),nausea(16.3%),bonepain(9.5%)and fatigue (8.2%), all ofwhich were easily manageable.53 _The

majorityoftheseeventsoccurred intheperiodafter mobi-lizationandwereunrelatedtothestudydrug.53

Thesestudiesshowthatthecombinationofplerixaforwith G-CSF iswell tolerated and resultsin agreater proportion ofNHLorMMpatientsachievingCD34+ _{cellcollections}

con-sideredoptimal fortransplant withinasmaller number of apheresisdayswhencomparedwithG-CSFalone.

Strategies

for

preemptive

use

of

plerixafor

Manystudies,including phaseIIIstudies,haveshownthat theuseofplerixaforreducesriskofpoorprogenitorcell mobi-lizationandriskoffailurefromupto40%tolessthan10%. However,thecostofplerixaformaybealimitingfactorforits unrestricteduseintheinitialmobilization.54

An alternative strategy discusses the use of plerixafor as rescue treatment in patients failing prior mobilization. Micallefetal.analyzed52patientswithNHLwhofailedthe ini-tialmobilizationwithG-CSFinaphaseIIIstudy.Theanalysis showedthatpatientswhoreceivedremobilizationwithG-CSF associatedwithplerixaforpresentedamediancollectionof 2.9×106_CD34+ _{cells/kg inremobilizationaftera medianof}

threeapheresis.55 _{Inthis study,63.5% ofpatients achieved}

acollectionof≥2×106_CD34+ _{cells/kg inuptofour}

aphere-sisdaysinthesecondmobilizationand88.75%wereableto undergothetransplant.

Somecentersdevelopedalgorithmsforthepreemptiveuse ofplerixaforinwhichpatientsinitiallyreceivecustomary regi-mensformobilization.Inthiscase,plerixaforisindicated,if

necessary,toimmediatelyrescuepatientswithverifiedpoor mobilizationbeforecollectionofprogenitorcells.17,56

Onestudyevaluated314patientswithmyeloma, amyloid-osisorlymphomaundergoingmobilizationwithG-CSF and testedtwoalgorithmsforplerixaforuse.Oneusedplerixafor onlyinpatientswithaCD34+_{cellcountinperipheralblood}

of<10/␮LonDay4ofmobilizationoronanydayof aphere-sis,withcollectionsof<0.5×106_CD34+ _{cells/kg(plerixafor-1}

algorithm –including 216patients). Theother used plerix-afor ifCD34+ _{cellcountinperipheralblood reached<10/␮L}

onDay4ofmobilization(<20/␮Lifmultipletransplantswere planned) or if collection was <1.5×106_CD34+ _{cells/kg on}

Day 1ofapheresis or <0.5×106_CD34+ _{cells/kg inany}

sub-sequentapheresisday(plerixafor-2algorithm–including98 patients). The target was the collection of ≥4×106_CD34+

cells/kg (optimalcollection)or≥2×106_CD34+ _cells/kg

(min-imum collection). The results were compared with those obtainedinanothercohortof278patientsmobilizedbefore theintroductionofplerixafor,andwithdatafromthesame prospectivedatabaseoftransplant(MayoClinic),presenting similarcharacteristics.57 _{Someotherstudiesevaluating}

dif-ferentalgorithmsforthepreemptiveuseofplerixaforshowed lowercollectingfailureratesof0–7%.57,58

A reviewofpharmacoeconomicstudiespresentedsome algorithmsforthepreemptiveuseofplerixaforthatresulted inreducedconsumptionofseveralhealthresources, includ-ingthepossibilityofreducingthetotalcostofmobilization procedures.54

Cost

effective

analyses

Therearesomeanalysesrelatedtoplerixaforcost–benefitin frontlineandinremobilizationscenarios,56,59–62_buttheywere

HR=3.64 95% IC: 2.39-5.45 p<0.0001

49.1%

57.7%

65.6%

Plerixafor + G-CSF

24.2% 21.6%

Placebo + G-CSF 14.2%

4.2% 27.9%

70

60

50

40

30

20

10

0

100

90

80

70

60

50

40

30

20

10

0 1 2 3 4

1 2 3 4

Apheresis day

Apheresis day

20.4%

35.3%

56.9% 59.8%

Placebo + G-CSF Plerixafor + G-CSF

90.0% 87.9%

81.0%

56.5% HR=2.50 95% IC: 1.86-3.36 p<0.0001

Estimated percentage of patients reaching

≥

5 x 10

5 CD34 + cells/kg

Estimated percentage of patients reaching

≥

2 x 10

5 CD34 + cells/kg

A

B

Figure1–Percentageofpatientswithnon-Hodgkin

lymphomaachievingcollectiontargetsof≥5×106CD34+

cells/kg(A)andof≥2×106CD34+cells/kg(B)after

mobilizationwithG-CSFplusplaceboorG-CSFplus

plerixafor.

AdaptedfromDiPersioetal.52

HR=2.54 p<0.001

77.9%

86.8% 86.8%

55.9% 48.9%

35.3%

17.3% 54.2%

Plerixafor + G-CSF Placebo + G-CSF

5 4

3 2

1 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

Days

Percentage reaching target

Figure2–Percentageofpatientswithmultiplemyeloma

achievingcollectiontargetsof≥6×106CD34+cells/kgafter

mobilizationwithG-CSFplusplaceboorG-CSFplus

plerixafor.

AdaptedfromDiPersioetal.53

Table4–Costanalysis.

Baseline Plerixafor-1 Plerixafor-2 pvalue

Patients 280 219 98

Totalcostperpatienta

Median $12,500 $12,500 $20,000 Minimum $3000 $5000 $5500

Maximum $146,750 $93,000 $89,750 0.01 Mean $17,150 $21,532 $20,617

AdaptedfromMicaleffetal.56

a _{Costanalysisincludesremobilizationcostsandhasbeenadded}

totheoriginalmobilizationregardlessofwhentheremobilization occurred.

these analysesis thatthe calculated costs didnotinclude supportivecarecosts,includingtransfusions,antimicrobials, hospitalization,cryopreservation,nursingandmedicalcosts, patient’spersonalcosts,logistics,orevencostswithprevious failures,remobilization56,59–62_{and,specifically,theworse}

out-comeinlymphomaandmyelomapatientsfailuretoundergo AHSCT.41,63,64,65

InthestudyofMicallefetal.,56_{althoughtheearlier}

identi-ficationofpoormobilizersandadditionofplerixaforresults in higher per-patient costs over baseline, it is associated withhigherapheresisyields,fewerdaysofmobilizationand collection, and lower failure rates. The median total costs of mobilization per patient, including any remobilization attempt,wasUS$12,500inthebaselinegroup,US$12,500in theplerixafor-1group,andUS$20,000intheplerixafor-2group (Table 4). Althoughboth the medianand mean costswere higherintheplerixafor-2group,themobilizationfailurerate was1%,withfewerdaysofapheresis,fewerdaysofplerixafor, andfewertotaldaysofmobilizationandcollectioncompared totheplerixafor-1algorithm.56_{Thereisanurgencytohave}

moreaccuratepharmacoeconomicmatrixestocalculatethe otherimportantandneglectedcostsmentionedaboveandto decideabouttherealcost–benefitineachinstitution.

Consensus recommendations suggest the use of plerix-aforasamobilizationstrategyparticularlyinpatientswitha highertargetforcollectionofprogenitorcells,asapreemptive approachbasedonthemonitoringoftheCD34+_cellcountand

incasesofremobilization.15 _{TheEuropeanGroupforBlood}

Apheresis (target cell count = 2.0 Mio CD34+ _{cells/kg BW)}+

Pre-emptive plerixafor <10 cells/μL CD34+ _{cell count prior to apheresis}

10-20 cells/μL >20 cells/μL∗

Dynamic approach based on the patient’s disease characteristics and

treatment history

Figure3–EuropeanGroupforBloodandMarrow

Transplantationpositionregardingmobilization.

andMarrowTransplantation(EGBMT)recommends preemp-tiveuseofplerixaforinpatientswithCD34+_{cellcounts<10/␮L}

beforeapheresis31_{(Figure3).Eachcentershoulddevelopand}

implementitsownalgorithmsforapplyingdifferent mobiliza-tionstrategies,withthegoalofoptimizingcollectionyields andcosts–benefits.

Conclusion

Collectionofadequate numbersofHPCisacritical stepin autologoustransplantationprocedures.Traditionalstrategies, basedontheuseofgrowthfactorswithorwithout chemother-apy, havesome limitations even whenremobilizations are performed.

Theadditionofplerixaforshowsaconsistentincreasein collectionratesuccess,reducingthenumberofapheresisand notincreasingtoxicity.Strategiesofpreemptiveuseof plerix-aforhavebeenconsideredapromisingwaytooptimizeand rationalizethe useofthisagentinpatientswhohavehigh chanceoffailurewithclassic mobilizationbased onG-CSF withor withoutchemotherapy. Thisstrategywould reduce failureinmobilization,especiallyinpoormobilizers,ensuring collectionandtransplantationaswellasreducingtimeand costsofthemobilizationprocedure.However,external valid-ityofthesealgorithmsislimited,soitisrecommendedthat eachinstitutionsetsupastrategyappropriatetoitsstandards forthepreemptiveuseofplerixafor.

Funding

PublicationsupportprovidedbySanofi.

Conflicts

of

interest

Dr.MarcoAurelioSalvinoreceives consultingand speaking fees.HeismemberofSanofiHematologyAdvisoryBoard.

Dr.JeffersonRuizworksashematology/oncologyscientific advisorforSanofi,Brazil.

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