Updated recommendations on the management of gastrointestinal disturbances during iron chelation therapy with Deferasirox in transfusion dependent patients with myelodysplastic syndrome - Emphasis on optimized dosing schedules and new formulations

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ContentslistsavailableatScienceDirect

Leukemia

Research

jo u r n al ho me p ag e :w w w . e l s e v i e r . c o m / l o c a t e / l e u k r e s

Review

Updated

recommendations

on

the

management

of

gastrointestinal

disturbances

during

iron

chelation

therapy

with

Deferasirox

in

transfusion

dependent

patients

with

myelodysplastic

syndrome

–

Emphasis

on

optimized

dosing

schedules

and

new

formulations

Florian

Nolte

a,∗

_,

_Emanuele

_Angelucci

b

_,

_Massimo

_Breccia

c

_,

_Norbert

_Gattermann

d

_,

Valeria

Santini

e

_,

_Norbert

_Vey

f

_,

_Wolf-Karsten

_Hofmann

a

a_Department_of_Hematology_and_Oncology,_University_Hospital_Mannheim,_Medical_Faculty_Mannheim_of_the_University_of_Heidelberg,_Germany b_Hematology_and_Bone_Marrow_Transplant_Unit,_and_Medical_Oncology_Department,_Ospedale_Oncologico_“Armando_Businco”,_Cagliari,_Italy c_Department_of_Cellular_{Biotechnologies}_and_Hematology,_“La_Sapienza”_University,_Rome,_Italy

d_{Comprehensive}_Cancer_Center_and_Department_of_Hematology,_Oncology,_and_Clinical_Immunology,_Heinrich_Heine_University,_Düsseldorf,_Germany e_Division_of_Hematology,_University_of_Florence,_Florence,_Italy

f_Department_of_Hematology,_Institute_Paoli_Calmettes,_Marseille,_France

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received19March2015

Receivedinrevisedform4June2015 Accepted16June2015

Availableonline20June2015

Keywords: Myelodysplasticsyndrome Transfusion Ironoverload Chelation Gastrointestinaldisturbances Deferasirox

a

b

s

t

r

a

c

t

Myelodysplasticsyndromes(MDS)areoligoclonalhematopoieticdisorderscharacterizedbyperipheral cytopeniaswithanemiasbeingthemostprevalentfeature.Themajorityofpatientswilldependon regulartransfusionsofpackedredbloodcells(PRBC)duringthecourseofthedisease.Particularlypatients withMDSandlowriskfortransformationintoacutemyeloidleukemiaandlowriskofearlydeathwill receivePRBCtransfusionsonaregularbasis,whichputsthemathighriskfortransfusionalironoverload. Transfusiondependencehasbeenassociatedwithnegativeimpactonorganfunctionandreducedlife expectancy.

Recently,severalretrospectivebutalsosomeprospectivestudieshaveindicated,thattransfusion dependentpatientswithMDSmightbenefitfromconsequentironchelationwithregardtomorbidityand mortality.However,lowtreatmentadherenceduetoadverseeventsmainlygastrointestinalinnatureis animportantobstacleinachievingsufficientironchelationinMDSpatients.Here,wewillsummarizeand discusstheexistingdataonDeferasiroxinlowriskMDSpublishedsofarandproviderecommendations foroptimalmanagementofgastrointestinaladverseeventsduringironchelationaimingatimproving treatmentcomplianceand,hence,sufficientlyremovingexcessironfromthepatients.

Contents

1. Introduction...1029

2. PotentialbeneﬁtsofironchelationintransfusiondependentpatientswithMDS...1029

3. GastrointestinaldisturbancesduringDeferasiroxtreatment...1029

4. Managementofgastrointestinaladverseevents...1030

5. AlternativeironchelatorsandnewformulationsofDeferasirox...1031

6. Briefsummaryandpracticaladvice...1032

Acknowledgement...1032

References ... 1032

∗ Correspondingauthorat:DepartmentofHematologyandOncology,UniversityHospitalMannheim,MedicalFacultyoftheUniversityofHeidelberg,Theodor-Kutzer-Ufer 1-3,D-68167Mannheim,Germany.

E-mailaddress:ﬂorian.nolte@medma.uni-heidelberg.de(F.Nolte).

http://dx.doi.org/10.1016/j.leukres.2015.06.008

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1. Introduction

Myelodysplasticsyndromes (MDS)are bonemarrowfailures

that show an increasing incidence in the elderly [1]. They are

recognizedasoligoclonalhematopoieticdisorders characterized

byperipheralcytopeniaswithanemiasbeingthemostprevalent

cytopenicfeature.Themajorityof patientsiseithertransfusion

dependentforredbloodcellsorbecomestransfusiondependent

duringthecourseofthedisease.ParticularlypatientswithMDS

andlowriskfortransformationintoacutemyeloidleukemiaand

lowriskofearlydeathwillreceivepackedredbloodcell(PRBC)

transfusionsonaregularbasis,whichputsthemathighriskfor

transfusionalironoverload(IOL)sincethehumanorganismhasno

naturalmeansofremovingexcessiron.Transfusiondependence

hasbeenassociatedwithnegativeimpactonorganfunctionand

reducedlifeexpectancy[2,3],thoughdataareconﬂicting[4].

IOLleadstodepositionofironinorganssuchastheliver,the

heartandtheendocrineglands.Inpatientswithinheritedanemias

suchaspatientssufferingfromthalassemiaorsicklecelldisease,

repetitivetransfusionsandconsecutiveIOLcancauseorgan

dam-ageleadingtolivercirrhosis,cardiacfailureordiabetesmellitus

[5–7].

InadditiontotransfusionassociatedIOL,somepatientswith

MDSexhibithighferritinlevelsalthoughtheyhaveneverreceived

anytransfusions,indicatingadisturbedironmetabolism.Advances

intheunderstandingofironphysiologyandpathophysiology

sug-gest, that insufﬁcient erythropoiesis in MDS patients leads to

decreasedhepcidinlevelsand consecutivelyincreasedintestinal

ironabsorption.Infact,therecentlydiscoverederythroidregulator

erythroferronelinksaberranterythropoiesistohepcidin

suppres-sionwithconsecutiveincreaseddietaryironabsorption[8].Ofnote,

erythroidprogenitors in MDSpatientsshowa particularlyhigh

expressionoferythroferrone,whichprovidesaplausible

explana-tion,thatIOLcanbeevidentinMDSpatients,whoneverreceived

anytransfusionsofPRBC[9].

Theintroduction of efﬁcaciousiron chelation with

deferiox-amine(DFO)improvedtheoutcomeofpatientswithtransfusion

dependentanemiassuchasthalassemiaandsicklecelldisease

dra-matically[5,6].Thismightbemainlyduetotheeliminationofthe

so-calledlabileplasmairon(LPI),whichcatalyzesthegeneration

ofreactiveoxygenspecies(ROS).ROSexertahighreactivitywith

cellularorganellesandstructuressuchastheplasmamembrane,

mitochondria,intracellularenzymesandnucleicacidsinducing

cel-lulardysfunctionandcelldeath[10].

AlthoughDFOhasdemonstratedhighefﬁcacyintreatmentof

IOLcontinuousandsubcutaneousadministrationisnecessaryto

providesufﬁcientcoverageofLPIduetotheshortplasmahalf-life

ofDFO.Ithasbeenshownthatthiswayofapplicationisamajor

obstacleforprovidingasufﬁcientironchelation(IC).Patientsare

affectedbytheinconvenientadministration,whichsubsequently

leadstoloweradherencetothetreatmentandinsufﬁcientIC

result-inginincreasedmorbidityandmortality[5,6].Interestingly,IChas

beenshowntoimprovehematopoiesisinsomepatients[11–13].

Althoughtheexact mechanismis notclearyetimprovementof

hematopoiesismightbeduetoareductionofoxidativestressin

hematopoieticprogenitorsingeneralanderythropoietic

progeni-torsinparticular[10].

Deferasirox(DFX)isanorallyadministeredironchelator,which

hasdemonstrated highefﬁcacy in reduction of iron burden in

patients withtransfusional IOL. The plasma half-life of DFX is

approximately 13h, which allows a once daily administration

providing24hcoverageofLPI[14].It showeda similarefﬁcacy

in lowering iron burden as compared to DFO in MDS patients

[15,16].

Recently,severalretrospectivebutalsosomeprospective

stud-ieshaveindicated,thattransfusiondependentpatientswithMDS

mightbeneﬁtfromconsequentironchelationwithregardto

mor-bidityand mortality[17–24].However,gastrointestinaladverse

eventsleadingtoreducedqualityoflifeinthesepatientsare

asso-ciated with low treatment adherenceand are considered as a

majorobstacleinachievingconsequentandeffectiveiron

chela-tionwithDFX.Here,wewillupdateourrecommendationsonthe

managementofgastrointestinaldisturbancesduringtreatmentof

iron-overloadedpatientswithMDSusingDFX[25].

2. Potentialbeneﬁtsofironchelationintransfusion dependentpatientswithMDS

ItiswellestablishedthatIOLhasadeleteriouseffectinpatients

withinheritedanemia,i.e.thalassemiaandsicklecelldisease.

Intro-ductionofironchelationsigniﬁcantlyimprovedsurvivalinthose

patientsbypreventingparticularlycardiacfailure,butalsohepatic

andpancreaticdamageandpituitaryinsufﬁciency[5,6].Theeffect

ofIOLinMDSpatients,however,iscontroversial.Theprosandcons

forandagainstironchelationrangefromconsiderationofexcess

iron asa toxinthatneedstoberemovedontheonehandand

regardingtheironissueasaparanoiaontheotherhand[26–28].

Advocatesforinitiationofironchelationrefertotheusuallyolder

ageofMDSpatientspresentingwithclinicalsigniﬁcant

comorbidi-ties,whichrenderthemmorepronetoiron-relatedorgantoxicity.

Incontrast,theopponentsconsidertheeffectofIOLclinicallyless

relevantduetothereducedlifeexpectancyinanemicpatientswith

MDSascomparedtopatientswithotheranemias.

Thereisevidence,that transfusiondependencyand

develop-mentofIOLmighthaveanegativeimpactonpatientsurvival[2,29].

Consequently,severalretrospectiveandobservationalstudieshave

suggestedabeneﬁcialinﬂuenceofironchelationonmortalityand

morbidityinMDSpatientswithtransfusionalIO[17–24].

DFXhasshownitsefﬁcacyinsufﬁcientlyreducingserum

fer-ritinintransfusiondependentpatientswithMDSandIOL[30–34].

Althoughmainlyobtainedfromretrospectivetrials,dataindicate

that DFXmight improvesurvival and reducemorbidityin such

patients. Moreover, improvement of hematopoiesis during DFX

treatmentwasreportedby severalgroups witherythroid,

neu-trophilandplateletresponsesseenin6–21%,3–17%,and15–30%

ofthepatients,respectively,includingtransfusionindependency

forPRBCat12monthsofDFXtreatmentof12%inatrialfromthe

ItalianGIMEMAgroup[33–35].

However,sinceitislikelythatphysiciansestimateapatient’s

prognosisnotonlyonthebasisofdisease-relatedriskscoresbut

alsoaccordingtothepatient‘sgeneralﬁtness,there mightbea

systematicbiasinalloftheaforementionedstudies,becauseit

can-notbeexcludedthatinpatientswithabetterperformancestatus

ironchelationmayhavebeenmorelikelytobeinitiated.This

cir-cumstancehasrecentlybeenemphasizedinaCochraneanalysis,

which alsounderlined theneed forwellcontrolledrandomized

trials[36].

3. GastrointestinaldisturbancesduringDeferasirox treatment

AlthoughDFXishighlyeffectiveinremovingexcessironfrom

ironoverloadedMDSpatients,highdropoutratesofapproximately

50%ofpatientswithinoneyearwereobservedinthemajorityof

clinicalstudies[30,32–34].Themainreasonsfordiscontinuation

wereadverseevents,gastrointestinalinnatureinthemajorityof

patientsasdiscussedbelow.

Gattermannetal.reported,thatof327MDSpatients66%

expe-riencedadverseevents,thatwereconsideredtobedrugrelated.

Gastrointestinal eventswere the mostfrequent AEs with

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13%, 8%, and 8%, of the patients, respectively. Of 341enrolled

patients,25patientsdiscontinuedtheDFXtreatmentdueto

gas-trointestinalAEs[30].IntheoneyearGIMEMAtrial,43%ofthe

patientscompletedthetrial.Themainreasonfordiscontinuation

wereadverseeventsin33%ofthepatientsandofthetreatment

relatedadverseevents45%weregastrointestinalinnature[34].

Althoughadverseeventsweremildtomoderateinthemajorityof

cases,theylimitedtheadherenceofthepatientstoaconsequent

andsufﬁcienttreatmentschedule.

Interestingly,subgroupanalysesoftheEPICcohortrevealedthat

GIdisturbancesweremorefrequentintheMDSpatientcohortas

comparedtopatientswithinheritedanemiassuchasthalassemia,

whichmightbeanindicationofahighersusceptibilityoftheelderly

patientstoDFXwithregardtoGIdisturbances.

Takentogether,toprovideasufﬁcientcoverageofiron

over-loadedMDSpatientswithDFX,effectivepreventionandtreatment

ofgastrointestinaladverseeventsiscrucial.

4. Managementofgastrointestinaladverseevents

OnJuly18th2014anexpertpanelhadanextensivediscussion

regardingoptimaldosingschedulesandprocedurestomanage

gas-trointestinaldisturbancesthatfrequentlyimpairthesuccessofiron

chelationinironoverloadedMDSpatientsusingDFX.Thepanel

agreedthatgastrointestinaldisturbancesinterferewiththedaily

routinesofthepatientsandaffecttheirqualityoflifeandshould

thereforebepreventedasfaraspossible.Ifadverseeventscannot

bepreventedtheyshouldbetreatedeffectively.Priortotreatment

initiationpatientsshouldbeinformedindetailaboutthe

neces-sityofthetreatmentandthepossibleadverseevents,particularly

gastrointestinaldisturbances.

Althoughnodatafromclinical trialsdo exist, that initiating

thetreatmentatlowDFXdosesandincreasingthedoseaccording

totolerabilityandefﬁcacymightpreventgastrointestinal

distur-bances, thepanel agreed that this might bea helpfulstrategy

tostart chelation with DFX. The drug should be initiated at a

ﬂatdose of 500mg once daily. If tolerability is good, thedose

shouldbeincreasedweeklyby500mgperdaytothetargetdose,

which should be calculated on the basis of the serum ferritin

levelandtransfusionfrequency.Forpatientswithaserumferritin

>1000ng/L,whoreceivemorethan2unitsPRBCper4weeksbut

lessthan2unitsper2weeks,thetargetdoseshouldbe30mg/kg

bodyweightperday.Forpatientswithahighertransfusion

fre-quencyand highserum ferritinlevelswhodo notrespondtoa

doseof30mg/kgbodyweight,eventargetdosesof40mg/kgbody

weightmightbenecessarytoreducebodyiron.Forironoverloaded

patientswithtransfusionfrequenciesoflessthan2unitsPRBC,DFX

Table1

Recommendationsforpreventionofgastrointestinaldisturbances. Timeofadministration

–Pre-prandialeveningDFXdosing(basedonexpertexperience) –DFXdosing(atleast30min)beforedinner

–Donotrecommendtotakewithfood Startingdoseandescalation

–InitiationofDFXdosingwithlowdose,e.g.500mg

–Doseescalationtotargetdosehastobedoneintimelyfashion –Targetdoseshouldbecalculatedbasedonserumferritinandtransfusion frequency

–B.i.d.dosingnotrecommended.Consideringthenegativeimpacton patientadherenceandthelackofPKandclinicaldataexpertsadviseagainst divideddosing

Useofprophylactics

–Donotuseprophylacticanti-acidicdrugs(PPI);treatonlysymptomatically ifneeded

–Patientswithlactoseintolerancearenotfrequent.Thereisnotenough evidencetorecommendexcludingforlactoseintolerancebeforetreatment withdeferasirox,ortorecommendtheprophylacticuseofLactobacillus preparations

–Potentialeffectofnewformulationsongastrointestinaldisturbanceshas tobeevaluated

dosesof20mg/kgbodyweightmightbeenoughtoreducebody

iron(seeFig.1).Ofnote,patientsshouldbecloselyfollowed-up

withregulardetermination ofbodyiron status,toavoid

under-treatment(butalsoover-treatment)byfailingtoachievesufﬁcient

andadequatedrugdosestoeliminateironfromthebodyeither

as“induction”therapyormaintenance.Forasummaryof

recom-mendationsforthepreventionofgastrointestinaldisturbancessee

Table1.Inadditiontotheserecommendations,itmightbe

ben-eﬁcialinsomepatientstotrydifferentsolventssuchaswateror

juicestoﬁndouttheoptimalcompositionforintakeofDFX.

More-over,toachieveathoroughdissolutionofDFXinthechosensolvent,

electronicdispersersmightbehelpful.

Pre-prandial evening dosing still might be a reasonable

approach.Evenifitdoesnotreducetheincidenceof

gastrointesti-naldisturbancesinallcases,itmightpreventinterferencewith

dailyroutinesofthepatientsbyvirtueoftheGIdisturbancesbeing

atnight.

ForthemanagementofdiarrheaduringDFXtreatmentthepanel

recommendsthealgorithmshowninFig.2,whichisaslightly

mod-iﬁedversionoftheinitialalgorithm,i.e.administrationoflowdoses

pre-prandialintheeveningshouldbethestartingscheduleand

isnotconsideredthealternativeprocedure,ifthetargetmorning

dosesarenottolerated.Forpractical reasonsasimpleguidance

usingthefrequencyofbowelmovementshasbeenappliedinthe

diarrheamanagementalgorithm.

Fig.1.Proposeddosingschedule.DFXshouldbeinitiatedatalowdoseinallpatients.Targetdoseshouldbeassessedaccordingtothetransfusionburden.Itisimportantto achievethetargetdoseinatimelymanner.

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Fig.2.Algorithmformanagementofdiarrhea.

The symptom“abdominal pain” requires an exact diagnosis

since management of upperand lower abdominal pain differs.

Switchingamorningdosetoaneveningpre-prandialdosingshould

beconsidered.Dosingbeforebedtimeisnotrecommendeddueto

theriskofoesophagealirritationandbleeding.Incasesofpersisting

mild-to-moderateabdominalpaindosereductionsshouldbe

con-sideredbeforetreatmentinterruptions.Reductionshouldbedone

instepsof5mg/kg/day.IfabdominalpainhasresolvedDFXdose

shouldbeincreasedin5mg/kg/daystepstothetargetdose.Use

ofantacidsforupperabdominalpainmightbeconsidered.

Spas-molyticdrugsmightbehelpfulforlowerabdominalpain.However,

analgesicdrugsandnon-steroidalanti-inﬂammatorydrugsarenot

recommendedduetothecommonGIsideeffectsofthesedrugs.

Temporaryinterruption of DFXtreatmentcanbe consideredin

caseofpersistingsevereabdominalpainuntilsymptomsresolve.

DFXshouldthenbereinitiatedandthedoseshouldbeescalated

in5mg/kg/daysteps.Ofcourse,seriousreasonsforsevere

abdom-inalpainshouldberuledout.Recommendationsaresummarized

inTable2.

Antiemetics such as metoclopramide can be used in case

of nausea and vomiting. Since vomiting is the only AE which

does not seem to improve with long-term use, pre-prandial

administration of DFX in the evening should be considered

especially if vomiting (and nausea) are related to the

morn-ingdose.In addition,administrationofthedrugintheevening

prevents, that gastrointestinal disturbances interfere with the

daily routines of the patients. Reduction of DFX in steps of

5mg/kg/dayshouldbedoneincasesofseverenausea/vomiting.

Re-initiationofDFXandincreaseontargetshouldbedonewhen

symptomshaveresolved.Recommendationsaresummarized in

Table3.

5. Alternativeironchelatorsandnewformulationsof Deferasirox

IncaseDFXisjudgedinadequateinapatient,otherchelators

canbeconsidered.Asmentionedabove,DFOhasshownefﬁcacyin

patientswithMDSandIOL.Nevertheless,treatmentadherenceto

Table2

RecommendationsformanagementofabdominalpainPatientswithconstipation havetobemanagedbyanotheralgorithm!

Diagnosisisimportant

–Managementofupperabdominalpaindiffersfromlowerabdominalpain (withconstipationand/ordiarrheaand/orbloating)

Timeofadministration

–Anecdotalreportsofbeneﬁt:patientisadvisedtorefrainfromsolidfoods for2hafterdeferasirox

–DonotrecommendDFXdosingbeforebedtime Useofmedication

–Forupperabdominalpain,useanti-acidicdrugs –Considerusingspasmolyticdrugs

–Donotusenarcoticpainmedicationsandnon-steroidalanti-inﬂammatory drugs

Dosing

–Mild-to-moderatecases,considerDFXdosereductionbeforetreatment interruptions

•ReduceDFXdoseinstepsof5mg/kg/day

•IncreaseDFXdosinginstepsof5mg/kg/dayontargetwhenabdominal painhasbeenresolved

–Severecases:temporarilyinterruptdeferasiroxuntilabdominalpainhas beenresolved.Restartatlowdoseandincreaseinstepsof5mg/kg/dayon target.

Table3

Recommendationsformanagementofnausea/vomiting. Vomitingconsideredasasevereexpressionofnausea

–Managementofbothsimilar Useanti-emetics(metoclopramide) Timeofadministration

–Strongnotionthatnausea(especiallyvomiting)mightberelated tothemorningdosing,especiallysincevomitingistheonlyAEthat doesnotshowatrendtowardreductionwithlong-termuse ReduceDFXdosinginstepsof5mg/kg/dayincaseofsevere nausea/vomiting

–Increasedosinginstepsof5mg/kg/dayontargetwhen nausea/vomitinghasbeenresolved

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DFOoftenishamperedbytheinconvenienceofitsadministration

i.e.continuoussubcutaneousapplicationfor 24ha dayfor

sev-eraldays.Deferiproneisanotheroralavailableironchelatorthat

isapprovedfortreatmentofIOL.Althoughithasshownitsefﬁcacy

inremovingexcessiron,Deferiproneisratherconsideredasathird

linedrug,duetoitssideeffectsparticularlyinductionof

neutrope-niaandagranulocytosis,respectively.However,Deferipronecanbe

consideredifDFXorDFOcannotbeappliedtoapatient,butclose

monitoringofdifferentialbloodcountsshouldbedone.Areview

ontheuseofthedifferentironchelatorsinthetreatmentofIOLin

MDSpatientshasbeenpublishedrecently[37].

Althoughtheexactmechanismsofgastrointestinalintolerance

arenotyetfullyunderstood,osmoticmechanismsmightplay a

roleinthedevelopmentofdiarrhea.Moreover,sinceDFXcontains

lactose,patientswithlactoseintolerancemightbemoresusceptible

toGIdisturbancessuchasdiarrhea.

Anew formulation ofDFXas a ﬁlm coatedtablet (FCT)has

beendeveloped and is currently under investigationin clinical

trials. The FCT contains the same active substance as the

dis-persibleformulationbut lackslactoseandsodiumsulphatethat

have been implicated in the induction of gastrointestinal

dis-turbances. Moreover, pharmacokinetic studies demonstrated a

superiorbioavailabilityoftheFCTascomparedtothedispersible

formwith360mgoftheFCTequatingto500mgofdispersibleDFX.

Interestingly,incontrasttoDFXinthedispersibleform,FCTseems

tolackafoodeffectwithregardtoitsbioavailability,whichmight

facilitateadministrationofthedrugandleadtoamorepredictable

drugexposure.

6. Briefsummaryandpracticaladvice

-DataregardingICinMDSpatientsarecontroversial,butmultiple

analysessuggestabeneﬁtincludingerythroidimprovementand

transfusionindependence.

-Patientsshouldbeinformedindetailaboutthenatureof

gastroin-testinaldisturbances.

-DFX dosing should be done pre-prandial in the evening for

patientswithGIsideeffects.

-DFXshouldbeinitiatedatlowdoselevels,e.g.500mgperday.

-EscalationofDFXdosetotargetdoseshouldbedoneinatimely

fashion.

-Targetdoseshouldbecalculated basedonserum ferritin and

transfusionfrequency.

-Newformulationsmightimprovetolerabilityandadherenceto

treatment.

Acknowledgement

We thank Christiane Schumann for critically reviewing the

manuscript.

References

[1]U.Germing,C.Strupp,A.Kundgen,etal.,Noincreaseinage-speciﬁcincidence ofmyelodysplasticsyndromes,Haematologica89(8)(2004)905–910.

[2]L.Malcovati,M.G.Porta,C.Pascutto,etal.,Prognosticfactorsandlife expectancyinmyelodysplasticsyndromesclassiﬁedaccordingtoWHO criteria:abasisforclinicaldecisionmaking,J.Clin.Oncol.23(30)(2005) 7594–7603.

[3]M.Takatoku,T.Uchiyama,S.Okamoto,etal.,Retrospectivenationwidesurvey ofJapanesepatientswithtransfusion-dependentMDSandaplasticanemia highlightsthenegativeimpactofironoverloadonmorbidity/mortality,Eur.J. Haematol.78(6)(2007)487–494.

[4]C.E.Chee,D.P.Steensma,W.Wu,C.A.Hanson,A.Tefferi,Neitherserum ferritinnorthenumberofredbloodcelltransfusionsaffectoverallsurvivalin refractoryanemiawithringedsideroblasts,Am.J.Hematol.83(8)(2008) 611–613.

[5]B.Modell,M.Khan,M.Darlison,Survivalinbeta-thalassaemiamajorinthe UK:datafromtheUKThalassaemiaRegister,Lancet355(9220)(2000) 2051–2052.

[6]C.Borgna-Pignatti,S.Rugolotto,P.DeStefano,etal.,Survivaland complicationsinpatientswiththalassemiamajortreatedwithtransfusion anddeferoxamine,Haematologica89(10)(2004)1187–1193.

[7]P.Brissot,M.Ropert,C.LeLan,O.Loreal,Non-transferrinboundiron:akey roleinironoverloadandirontoxicity,Biochim.Biophys.Acta1820(3)(2012) 403–410.

[8]L.Kautz,G.Jung,E.V.Valore,S.Rivella,E.Nemeth,T.Ganz,Identiﬁcationof erythroferroneasanerythroidregulatorofironmetabolism,Nat.Genet.46 (7)(2014)678–684.

[9]M.Mossner,A.Stöhr,F.Nolte,etal.,Geneexpressionoftheerythroid regulatorerythroferrone(ERFE)ishighlyderegulatedinCD71+ erythroprogenitorcellsofpatientswithmyelodysplasticsyndromesand demonstratesprognosticrelevance,Blood124(21)(2014)4620.

[10]N.Gattermann,E.A.Rachmilewitz,IronoverloadinMDS-pathophysiology, diagnosis,andcomplications,Ann.Hematol.90(1)(2011)1–10.

[11]P.D.Jensen,I.M.Jensen,J.Ellegaard,Desferrioxaminetreatmentreducesblood transfusionrequirementsinpatientswithmyelodysplasticsyndrome,Br.J. Haematol.80(1)(1992)121–124.

[12]P.D.Jensen,L.Heickendorff,B.Pedersen,etal.,Theeffectofironchelationon haemopoiesisinMDSpatientswithtransfusionalironoverload,Br.J. Haematol.94(2)(1996)288–299.

[13]R.Guariglia,M.C.Martorelli,O.Villani,etal.,Positiveeffectsonhematopoiesis inpatientswithmyelodysplasticsyndromereceivingdeferasiroxasoraliron chelationtherapy:abriefreview,Leuk.Res.35(5)(2011)566–570.

[14]P.L.Greenberg,C.A.Koller,Z.I.Cabantchik,etal.,Prospectiveassessmentof effectsoniron-overloadparametersofdeferasiroxtherapyinpatientswith myelodysplasticsyndromes,Leuk.Res.34(12)(2010)1560–1565.

[15]M.D.Cappellini,A.Cohen,A.Piga,etal.,Aphase3studyofdeferasirox (ICL670),aonce-dailyoralironchelator,inpatientswithbeta-thalassemia, Blood107(9)(2006)3455–3462.

[16]A.Piga,R.Galanello,G.L.Forni,etal.,RandomizedphaseIItrialofdeferasirox (Exjade,ICL670),aonce-daily,orally-administeredironchelator,in comparisontodeferoxamineinthalassemiapatientswithtransfusionaliron overload,Haematologica91(7)(2006)873–880.

[17]C.Rose,S.Brechignac,D.Vassilief,etal.,Doesironchelationtherapyimprove survivalinregularlytransfusedlowerriskMDSpatients?Amulticenterstudy bytheGFM(GroupeFrancophonedesMyelodysplasies),Leuk.Res.34(7) (2010)864–870.

[18]A.Raptis,M.S.Duh,S.T.Wang,etal.,Treatmentoftransfusionaliron overloadinpatientswithmyelodysplasticsyndromeorsevereanemia: datafrommulticenterclinicalpractices,Transfusion(Paris)50(1)(2010) 190–199.

[19]R.S.Komrokji,N.H.A.Ali,E.Padron,J.E.Lancet,A.F.List,Impactofiron chelationtherapyonoverallsurvivalandAMLtransformationinlowerrisk MDSpatientstreatedattheMofﬁttCancerCenter,Blood118(21)(2011) 2776.

[20]R.M.Lyons,B.J.Marek,C.Paley,etal.,Relationshipbetweenchelationand clinicaloutcomesin600lower-riskmdspatients:registryanalysisat36 months,Blood120(21)(2012)3800.

[21]J.Neukirchen,F.Fox,A.Kundgen,etal.,ImprovedsurvivalinMDSpatients receivingironchelationtherapy–amatchedpairanalysisof188patients fromtheDusseldorfMDSregistry,Leuk.Res.36(8)(2012)1067–1070.

[22]A.F.Remacha,B.Arrizabalaga,A.Villegas,etal.,Evolutionofironoverloadin patientswithlow-riskmyelodysplasticsyndrome:ironchelationtherapyand organcomplications,Ann.Hematol.94(5)(2015)779–787.

[23]M.Delforge,D.Selleslag,Y.Beguin,etal.,Adequateironchelationtherapyfor atleastsixmonthsimprovessurvivalintransfusion-dependentpatientswith lowerriskmyelodysplasticsyndromes,Leuk.Res.38(5)(2014)557–563.

[24]H.A.Leitch,C.S.Leger,T.A.Goodman,etal.,Improvedsurvivalinpatientswith myelodysplasticsyndromereceivingironchelationtherapy,Clin.Leuk.2(3) (2008)205–211.

[25]F.Nolte,E.Angelucci,P.Beris,etal.,Clinicalmanagementofgastrointestinal disturbancesinpatientswithmyelodysplasticsyndromesreceivingiron chelationtreatmentwithdeferasirox,Leuk.Res.35(9)(2011)1131–1135.

[26]A.F.List,Ironoverloadinmyelodysplasticsyndromes:diagnosisand management,CancerControl17(2010)2–8.

[27]D.P.Steensma,Myelodysplasiaparanoia:ironasthenewradon,Leuk.Res.33 (9)(2009)1158–1163.

[28]I.H.Kim,J.H.Moon,S.N.Lim,etal.,Efﬁcacyandsafetyofdeferasiroxestimated byserumferritinandlabileplasmaironlevelsinpatientswithaplastic anemia,myelodysplasticsyndrome,oracutemyeloidleukemiawith transfusionalironoverload,Transfusion55(July(7))(2015)1613–1620.

[29]G.Sanz,B.Nomdedeu,E.Such,etal.,Independentimpactofironoverloadand transfusiondependencyonsurvivalandleukemicevolutioninpatientswith myelodysplasticsyndrome,ASHAnnu.Meet.Abstr.112(11)(2008)640.

[30]N.Gattermann,C.Finelli,M.D.Porta,etal.,Deferasiroxiniron-overloaded patientswithtransfusion-dependentmyelodysplasticsyndromes:results fromthelarge1-yearEPICstudy,Leuk.Res.34(9)(2010)1143–1150.

[31]N.Gattermann,A.Jarisch,R.Schlag,etal.,Deferasiroxtreatmentof iron-overloadedchelation-naiveandprechelatedpatientswith myelodysplasticsyndromesinmedicalpractice:resultsfromthe observationalstudieseXtendandeXjange,Eur.J.Haematol.88(3)(2012) 260–268.

(6)

[32]A.F.List,M.R.Baer,D.P.Steensma,etal.,Deferasiroxreducesserumferritin andlabileplasmaironinRBCtransfusion-dependentpatientswith myelodysplasticsyndrome,J.Clin.Oncol.30(17)(2012) 2134–2139.

[33]F.Nolte,B.Hochsmann,A.Giagounidis,etal.,Resultsfroma1-year, open-label,singlearm,multi-centertrialevaluatingtheefﬁcacyandsafetyof oralDeferasiroxinpatientsdiagnosedwithlowandint-1risk

myelodysplasticsyndrome(MDS)andtransfusion-dependentironoverload, Ann.Hematol.92(2)(2013)191–198.

[34]E.Angelucci,V.Santini,A.A.DiTucci,etal.,Deferasiroxfor

transfusion-dependentpatientswithmyelodysplasticsyndromes:safety,

efﬁcacy,andbeyond(GIMEMAMDS0306Trial),Eur.J.Haematol.92(6) (2014)527–536.

[35]N.Gattermann,C.Finelli,M.DellaPorta,etal.,Hematologicresponsesto deferasiroxtherapyintransfusion-dependentpatientswithmyelodysplastic syndromes,Haematologica97(9)(2012)1364–1371.

[36]J.J.Meerpohl,L.K.Schell,G.Rucker,etal.,Deferasiroxformanagingiron overloadinpeoplewithmyelodysplasticsyndrome,CochraneDatabaseSyst. Rev.10(2014),CD007461.

[37]S.Temraz,V.Santini,K.Musallam,A.Taher,Ironoverloadandchelation therapyinmyelodysplasticsyndromes,Crit.Rev.Oncol.Hematol.91(1) (2014)64–73.