Symposium Update - Iron Metabolism & Related Disorders · • Formulate treatment strategies that...

Table of Contents

Iron Overload Diagnosis, Treatment, and Management Goals ..............2

Applying Advances in Iron Chelation: Review of Current Treatments for Clinical Practice ....................4

Case 1: Advances in Managing Transfusional-Related Iron Overload: MDS Case Study ........................6

Case 2: New Approaches for Chelation Therapy: Beta-thalassaemia Intermedia Case Study ................9

Conclusion: Choosing the Right Therapy for the Right Patients ..........................11

Poll Results ..............................11

References .............................12

Target Audience

This activity is designed for haematologists, medical oncologists, haematology-oncology specialists, and other healthcare professionals involved in the care of adults and children with myelodysplastic syndromes and thalassaemia.

Activity Goal

The goal of this newsletter is to provide clinicians with information about recent advances in assessing, monitoring, and treating iron burden in their patients and to describe treatment strategies for iron overload in patients with myelodysplastic syndromes and occasionally transfused patients with thalassaemia intermedia.

Symposium UpdateTreatment Strategies from Turning the Science of Iron Overload into Iron Chelation Practice Symposium at the 12th Congress of the European Hematology Association, Vienna

DearColleague,

Maintainingahealthyironbalanceisofcriticalconcerninthemanagementoftransfusional-dependentanaemiasandotherdisorders.Bloodtransfusionsareoftennecessaryforthepatient’ssurvivalandwell-being.However,unlessexcessironisremoved,thetreatmentitselfbecomesasignificantcauseofmorbidity.Althougheffectivechelationhasbeenavailableforseveraldecades,complianceandavailabilityhavefrequentlylimitedaccesstothistherapy.Recentadvanceshaveprovidedadditionaltherapeuticoptions,includingaonce-dailyoralchelatorwith24-hourchelationcoverage.

Thisnewsletterpresentsbackgroundinformationandtwocasestudiesincludedinasymposiumatthe12thCongressoftheEuropeanHematologyAssociation(EHA),calledTurning the Science of Iron Overload into Iron Chelation Practice.Ipresentanoverviewoftheclinicalsciencesupportingcurrenttrendsindiagnosing,treating,andmanagingironoverload.Prof.MariaCappelliniprovidesdetailedcomparisonsoftheefficacyandsafetyofthethreecurrentlyavailableironchelators:desferrioxamine,deferiprone,anddeferasirox.

Thetwocasestudieseachhighlightmanagementconsiderationsthatariseinthetreatmentofironoverloadindifferentclinicalsituations.Dr.AristotelesGiagounidisdescribesthefactorstobeconsideredwhendecidingwhethertochelateahigh-riskpatientwithmyelodysplasticsyndromewhoisacandidateforstemcelltransplantation.Hispatientshowedimprovementswithpretransplantationdeferasiroxtherapy.ThecasepresentedbyDr.AliTaherinvolvesapatientwiththalassaemiaintermediawhohasreceivedinfrequenttransfusions,illustratingtheclinicalimportanceofchelationinpatientswhoarenotregularlytransfused.WeinviteyoutoconsidertheclinicaldecisionpointsraisedinthesecasestudiesandtocompareyouranswerstothoseoftheEHAsymposiumattendees.

Ihopethisnewsletterwillprovidevaluableinformationregardingcurrentchelationoptionsandfurtheryourinsightsintowhetheraparticularpatientwouldbenefitfromchelationtherapy.

Sincerely,

JohnB.Porter,MA,MD,FRCP,FRCPath

Iron Overload UpdateManaging Iron Overload in Clinical Practice

Maria D. Cappellini, MD ProfessorInternalMedicineUniversityofMilanMilan,Italy

John B. Porter, MA, MD, FRCP, FRCPath

ProfessorDepartmentofHaematologyUniversityCollegeLondonLondon,UnitedKingdom

Chair Faculty Contributor

Aristoteles A.N. Giagounidis, MD St.JohannesHospitalMedizinischeKlinikIIDuisburg,Germany

Ali T. Taher, MD

ProfessorDepartmentofInternalMedicineAmericanUniversityofBeirutMedicalCenterBeirut,Lebanon

Faculty ContributorFaculty ContributorSponsored by

The materials presented in this newsletter reflect the opinions of the faculty, and off-label usage or speculation is not endorsed by Novartis.

12TH CONGRESS

JUNE 7 - 10, 2007

Vienna, Austria

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12TH CONGRESS

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Vienna, Austria Symposium Update

Transfusional Iron Overload Intransfusion-dependentdisorders,thebodytakesinanadditional200mgofironwitheachtransfusionalunit,withnomechanismforeliminatingtheexcessiron.1Eventually,theamountofironexceedstheamountthatcanbeboundbytransferrin.Thisnon–transferrin-boundiron(NTBI)isabsorbedintosomeorgantissueswhilstsparingothers,andthedistributionofthisuptakeaccountsprimarilyforthetoxiceffectsofironoverload.Excessirondepositionhasbeenfoundinthepituitarygland,thyroid,parathyroid,heart,liver,pancreas,andgonads.Thehighestconcentrationofironisfoundintheliver,whichcanleadtolivercarcinomaandcirrhosis.2Ironaccumulationintheheartisofcriticalclinicalimportanceaswell;heartdiseaseisthegreatestcauseofdeathintransfusion-dependentpatientswiththalassaemiamajor(TM).3

TheratesoftransfusionalironloadinganditsdeleteriouseffectshavebeenstudiedmostextensivelyinpatientswithTMwheretransfusionalratesofironloadingvarywidely,withanaverageof0.36mg/kg/day.4Levelsofironburdenoversustainedperiodsoftimeimpactonclinicaloutcomes,andbothserumferritin(SF)levelsandliverironcontent(LIC)provideaccurateestimatesofironburden.5Theratesofironloadingforothertransfusionaldisordersvary,dependingonthetransfusionalrequirements.PatientswithDiamond-BlackfananaemiahaveahigherironintakethanpatientswithTM,averaging0.40mg/kg/day.6Patientswithmyelodysplasticsyndromes(MDS)andsicklecellanaemia(HbSS)onaveragehavelowertransfusionalrates.6,7Unlikepatientswiththalassaemia,ironoverloadingresultssolelyfromtransfusions,withnogutabsorption.TransfusionalrequirementsvarygreatlyamongHbSSpatients;someHbSSpatientsreceiveonlysporadictransfusions,forintermittentcomplications,whileothersreceiveregulartransfusionsforpreventionofstroke.Furthermore,ironloadingisgreaterwithtop-uptransfusionsthanwithexchangetransfusions.Interestingly,thereisemergingevidencethatHbSSpatientshaveloweraccumulationsofironinheartandendocrineorgansthandoTMpatients,evenwhenliverironaccumulationiscomparable.8,9Furtherresearchisneededtoexplorethedifferentdistributionoftissueironinthedifferentdiseasestates.

Diagnosing Iron Overload and Monitoring Iron LevelsIronburdencanbeestimatedthroughavarietyofdifferentmeasurements.Currently,LICisconsideredthegoldstandardformeasuringironoverload,accuratelyreflectingbodyironstores.2NewdevelopmentsinMRImakeitpossibletomeasureLICnoninvasively.10

Serumferritinisthemostfrequentlyusedmeasureofironoverload.Overthelongterm,SFcorrelateswithclinicaloutcomesandmorbidity.3,5,11-13WhilsttherearebroadcorrelationsbetweenSFandLIC,ferritinlevelsinindividualpatientsmaynotaccuratelypredicttheLIC,especiallyinpatientswithHbSSandthalassaemiaintermedia(TI).ThisispartlybecauseSFlevelsmayfluctuateindependentlyofironloading,forexample,risingwithinflammationandfallingwithascorbatedeficiency.

Iron Overload Diagnosis, Treatment, and Management Goals John B. Porter, MA, MD, FRCP, FRCPath

Learning Objectives

• Increase awareness of patients at risk for iron overload and the impact of transfusion therapy on the development of iron overload and its sequelae in patients with myelodysplastic syndromes and thalassaemia in order to institute interventions that improve patients’ outcomes.

• Implement monitoring of iron levels of at-risk patients with myelodysplastic syndromes and thalassaemia receiving routine/intermittent blood transfusions, utilizing a knowledge of reliable invasive/noninvasive methods.

• Assess the consequences of iron overload on organ function and organ failure and therefore the importance of intervention, based on an understanding of its pathophysiology.

• Formulate treatment strategies that include the use of iron chelators in patients with transfusion-related iron overload, assessing the efficacy and safety of iron chelator treatment options.

Disclosure Information

Maria D. Cappellini, MD, is a consultant for and has received speaker honoraria from Novartis Pharmaceuticals Corporation. Prof. Cappellini has disclosed that she will not reference any unlabeled/unapproved uses of drugs or devices.

Aristoteles A.N. Giagounidis, MD, is a consultant and is on advisory boards for Novartis Pharmaceuticals Corporation, Celgene Corporation, and Pharmion Corporation; and is a stock shareholder in Hoffmann-La Roche Inc. Dr. Giagounidis has disclosed that he will not reference any unlabeled/unapproved uses of drugs or devices.

John B. Porter, MA, MD, FRCP, FRCPath, is a consultant and has received grant/research support and speaker honoraria from Novartis Pharmaceuticals Corporation. He is also a consultant for Genzyme Corporation and Resonance Health Ltd. Prof. Porter has disclosed that he will reference the unlabeled/unapproved uses of deferiprone combined with desferrioxamine, and deferasirox.

Ali T. Taher, MD, has received speaker honoraria from and is on the advisory board for Novartis Pharmaceuticals Corporation. Dr. Taher has disclosed that he will not reference any unlabeled/unapproved uses of drugs or devices.

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Managing Iron Overload in Clinical Practice

AnotherclinicallyvaluabletoolforestimatingironburdenismeasuringmyocardialT2:patientswithincreasedmyocardialiron(asshownbyshorteningoftheT2*)areatincreasedriskofdecreasedleftventricularfunction.14

Goal of Chelation Therapy—24-Hour CoverageIronchelatorsactbyremovingtransientlyavailable(labile)ironpools,eitherinplasmaorwithincells,becausecellularstorageiron(presentasferritinandhaemosiderin)arenotdirectlyaccessibleforchelation.Chelatableironisderivedfromtwomainsources:(a)ironreleasedfrommacrophagesafterthecatabolismofredcells,and(b)ironreleasedwithincellsafterthecatabolismofcellularferritinandhaemosiderin.Bothoftheseprocessesarecontinuous:ironfrom(a)willberapidlyfoundinplasmaasNTBIifitisnotimmediatelychelated,andironfrom(b)willberapidlyreincorporatedintocellularferritinifnotinterceptedwhilestillinthelabilestate.Forexample,labileplasmaNTBIpoolsre-formwithinminutesofremovalofthechelatingagentfromplasma.15,16 Ironchelationmustthereforeprovidecontinuous24-hourcovertomaximizechelationefficiency.

Eachofthethreeironchelatorscurrentlyavailable—desferrioxamine,deferiprone,anddeferasirox—haveadistinctefficacy,safety,andtolerabilityprofile,andthesearediscussedmorefullyinthefollowingsectionbyProf.Cappellini.AllthreecurrentlyavailablechelatorscandecreaseplasmalevelsofsomeNTBIspecies,butthedurationofprotectionvariesdependingonhowtheyareused.Theclinicalbenefitofdesferrioxamineinironchelationhasbeenwell-establishedduringseveraldecadesofclinicaltrialsandclinicalpractice.Itsmajorshortcomings,however,aretherigoroustreatmentregimenrequiredanditsshortplasmahalf-life.Furthermore,becausethehalf-

lifeissoshort,intheorderofminutes,17plasmaconcentrationdropsandNTBIbeginstore-formalmostimmediatelyafteraninfusionstops.15ThefractionofplasmaNTBImeasuredaslabileplasmairon(LPI)alsoreappearsrapidlyaftercessationofdesferrioxamineinfusion(Fig 1A).16Thus,thestandard8-to10-hourdesferrioxamineinfusionisinsufficienttoprovide24-hourprotectionandthiscanonlybeachievedwithcontinuousinfusionseithersubcutaneouslyorintravenously.Theoralchelatordeferipronehasahalf-lifeof2to3hours18,andinmostpatients,whentakenthreetimesaday,LPIrisesbeforethenextdoseisgiven(Fig 1B)andnoprotectionisavailableatnight.BycombiningtherapywithdeferiproneTIDduringthedayanddesferrioxamineinfusioneverynight,24-hourironchelationis,inprinciple,achievable(Fig 1C).Thisprocedure,however,isdemandingforthepatient,resultinginvariablecompliance.Asimplerregimentoprovide24-hourchelationistheonce-dailyoralchelatordeferasirox.Deferasirox

hasaplasmahalf-lifeof8to16hours19andprovideseffective24-hourironchelationwithasingledailydose(Fig 2, see next page).20ThishasbeenshowntoproduceprogressiveandsustainedreductionsinLPI.21The24-houravailabilityofchelationwithdeferasiroxalsocontributestoitshighchelationefficiency(thehighproportionofdrugthatisexcretedintheiron-boundstate)comparedwithotherchelators.

Figure 1. Effects of Monotherapy and Alternating Combined Therapy on LPI

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LPI = labile plasma iron.Reprinted from Cabantchik ZI et al. Best Pract Res Clin Hematol. 2005;18:277-287, with permission from Elsevier.

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Forpatientswithtransfusionalironoverload,chelationtherapyreducestheriskofadverseeffectsonliver,heart,endocrinesys-tem,andotherorganswithhighironburden.Inordertoachievetheseclinicalgoals,theclinicianmustconsiderspecificity,efficacy,safety,tolerability,andconveniencewhenselectinganappropriatechelationregimen.

SpecificityTheidealchelatorshowsspecificityforiron,withoutremov-ingzinc,copper,orothermetalsfromthebody.Inpractice,allthreecurrentlyavailableironchelatorshavehighaffinityforiron.However,theyalsobindtoothermetalstosomedegree,includ-ingcopperandzinc.22-24Theaffinityforcopperhaslittleclinicalsignificance,sincecopperistightlyboundtoproteinsinvivo.22Significantincreasesinurinaryzincexcretionhavebeenobservedinpatientsreceivingdesferrioxamineanddeferiprone,andwashigherinpatientswithdiabetes.23Clinicallysignificantzincdefi-cienciesoccurredinafewpatients,althoughtheywererapidlycorrectedwithzincsupplements.23

EfficacyThegoalofironchelationtherapyistopreventironaccumula-tioninnewlytransfusedpatients,bymatchingironintakewithironexcretion,ortoreducetheironburdeniniron-overloadedpatients.Allthreeironchelatorshavedemonstratedclinicaleffica-cyinmeetingthisgoal.ForpatientswithTM,survivalrateshavecontinuallyimprovedsincetheintroductionofdesferrioxaminetherapyinthe1970s.3DesferrioxamineiseffectiveinreducingLPIandNTBI,themosttoxicformsofserumiron.15,16However,theselabilepoolstendtore-formwhenthepatientisnotbeinginfused.Inironoverloadedpatients,desferrioxaminereducesbothliverandheartironburden,althoughimprovementsinliverironburdenoccurmorerapidlythanintheheart.25Themainlimitationfortheeffectivenessispoorcom-pliance,duetothedifficultadministration.26,27

DeferipronewasapprovedintheEUasasecond-linetreatmentforironoverloadinpatientsforwhomdesfer-rioxamineisnotappropriate.18Theefficacyofdeferi-proneinreducingSFhasbeenstudiedwhendeferiproneisadministeredeitherasmonotherapyorincombinationwithdesferrioxamine.Whendeferipronewasadminis-teredasmonotherapy,itloweredSFlevelsinsometrialsbutnotinothers.StudiesofdeferiproneincombinationwithdesferrioxaminearemoreconsistentinshowingasignificantreductioninSFinresponsetodeferiprone.28

Therearefewpublishedprospective,randomizedtrials

studyingtheeffectsofdeferiproneonLIC.Theresultsofthesetri-alshavebeeninconsistent.OnetrialfoundadecreaseinLICdur-ingdeferipronemonotherapy,relativetobaseline.However,deferi-pronewasassociatedwithanincreaseinLICrelativetobaselineinaseparatetrial.28Also,LICissignificantlyhigherfollowingtreat-mentwithdeferipronethanwithdesferrioxamine.29Morerecently,itwasclaimedthatdeferiproneremovesironfromtheheartmoreeffectivelythandesferrioxamineandpreventsheartfailureinTMpatients.30Thiseffectisevenmoremarkedwhendeferiproneisusedincombinationwithdesferrioxamine.31

Theefficacyofdeferasiroxinpreventingorreversingironoverloadhasbeenestablishedinlong-term,large-scaleclinicaltrials.7,20,32Additionally,initialreportsfromtheonce-dailyadministrationofdeferasirox20mg/kgintheESCALATORtrialshowedasignifi-cantreductioninLPIovera24-hourperiod.Thisindicatesthatonce-dailyadministrationofdeferasiroxpotentiallyprotectstheheartandliverfromcellularandtissuedamageensuingfromironoverload.33AsillustratedintheprevioussectionbyProf.Porter,deferasirox-inducedreductionoflabileironpoolsismaintainedovera24-hourdosinginterval(Fig 2).20,33Inalarge-scalephaseIIItrial,deferasirox20mg/kg/daywaseffectiveinmaintainingironbalance(ironintake=ironexcretion)and30mg/kg/dayresultedinanetlossofiron.32Patientsreceiving30mg/kg/dayhadasig-nificantreductioninLICandSF,andanegativeironbalance.32Onemustconsiderthegoalsofchelationtherapywhenselectingthestartingdose;20mg/kgisrecommendedforpreventingironoverloadinregularlytransfusedpatients,and30mg/kgisrecom-mendedforreversingironoverloadthathasalreadyoccurred.Ironoverloadcausesdamagetoorgans,includingthecardiactissue.Therefore,byreducingtheironoverload,ironchelatorscanpro-duceacardioprotectiveeffect.

Figure 2. 2�-Hour Chelation Coverage After Repeated Daily Dosing

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Piga A, et al. Haematologica. 2006;91:873. Reprinted with permission.

Steady-state levels with daily deferasirox

Applying Advances in Iron Chelation: Review of Current Treatments for Clinical Practice Maria D. Cappellini, MD

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SafetyEachofthethreechelationregimenshasitsownsafetyandtoler-abilityprofile.Foreachpatient,theclinicianmustweightherisksofthedrugagainsttheriskofmorbidityduetoironoverload.Manysideeffectscanbeminimizedbyreducingthedosageortemporarilydisruptingtreatment,ratherthandiscontinuingchelationtherapy.

Desferrioxamineisnotassociatedwithanysevereadverseeffects(AEs).17,34ThemostfrequentlyreportedAEsarelocalreactionsattheinjectionsite.These,however,canbesevereenoughtoimpactpatientcompliance.AdditionalAEsthatneedtobemonitoredforaregrowthdelaysandhearingandvisualimpairments.35,36TheriskofhearinglossisgreatestwithhigherdesferrioxaminedosesandinpatientswithlowerlevelsofSF.Porteretal(1989)havecalculatedatherapeuticindexof0.025(desferrioxaminedosagemg/kgdivid-edbySFµg/L)tobeusedasaguidelineforsafedosage.37

ThemostfrequentlyreportedAEswithdeferipronearegastrointes-tinalsymptomsandarthralgia.18ThemostseriousAEisagranulo-cytosis(neutrophils<0.5x109/L),whichoccurswithanincidenceof1.2%.Less-severeneutropaenia(neutrophils<1.5x109/L)occurswithanincidenceof6.5%.18Neutropaeniaandagranulo-cytosisresolveaftertherapyisdiscontinued.Weeklymonitoringofwhitebloodcellsisrequiredduringdeferipronetherapy.18

ThemostcommonAEsreportedduringdeferasiroxtherapyweregastrointestinalsymptoms,rash,andelevatedlevelsofcreatinine.19Occurrencesoflensopacityandhearinglosswereuncommonandcomparabletothatobservedwithdesferrioxamine.19SixpercentofpatientsexperiencedanincreaseinALTduringdeferasiroxtreat-ment,with2%consideredtreatment-relatedandtwocasesofdrug-inducedhepatitis.Interpretingtheeffectofachelatoronliverfunc-tionisconfoundedbythefactthatironlevelsmayincreaseduringthecourseoftreatment,especiallyinpatientsreceivinginsufficientdosage.Althoughdefera-siroxisgenerallysafeandwell-toleratedinbothadultandpaediatricpatients,clinicalmanage-mentrequiresregularpatientmonitoringtoidentifypotentiallyseriousAEs(Table 1).

Forsevererashorrashesthatdon’tresolvespontaneously,therecommendationistotemporarilydiscontinuetreatmentuntiltherashresolves,andthenreintroducedeferasiroxatalowerdose,graduallytitratingup.Ashortperiodoforalsteroidsmaybewarrantedforsevererash.19

Inclinicaltrials,36%ofpatientshadelevatedserumcreatininelevels(33%abovebaselinefortwoconsecutivevisits).32Inadditiontotheyear-longclinicaltrial,patientswerefollowedina1½-yearextension.Overthecourseof2½years,creatinineincreasesremainedmildandnonprogressive.AsofDecember2006,

morethan13,000patientshadbeenexposedtodeferasirox.Therehavebeencasesofacuterenalfailurereported,however,mostofthesecasesinvolvedconfoundingmedicalfactors.Aninitialdosereductionof10mg/kg/dayisrecommendedforadultswithcreati-ninelevels≥33%abovebaselinefortwoconsecutivevisits.Asimi-lardosereductionisrecommendedforpaediatricpatientsmeetingthesamecriteria,providedtheserumcreatininelevelisabovetheage-appropriateupperlimitofnormal.19

Nocasesofdrug-relatedcytopaeniaswereobservedduringdeferasiroxclinicaltrials.Cytopaeniashavebeenreportedpostmarketing;mostofthepatientshadpreexistinghaematologicdisordersthatarefrequentlyassociatedwithbonemarrowfailure.

Tolerability and ConvenienceAccordingtoarecentstudy,significantlymorepatientstakingdeferasirox(85.1%)reportbeingverysatisfiedorsatisfiedthandothosetakingdesferrioxamine(38.7%;P <.0001).38Deferasiroxwaspreferredby96.9%ofpatientswhohadpreviouslybeentreatedwithdesferrioxamine.38Theprimaryreasonsgivenforpreferringdeferasiroxwere:moreconvenienttotake(37.4%),lesssoreness(25.3%),andlessdisruptivetotheirday(22.8%),theirsleep(6.2%),andtotheirfamily(4.2%).Inthepast,compliancehasbeenamajorfactorlimitingthesuccessofironchelationtherapy.Theresultsofthisstudyonpatientattitudessuggestthatcompliancemayimprovewiththeavailabilityofaonce-dailyoralchelator.

Insummary,eachofthethreeironchelatorshasauniqueefficacy,safety,andtolerabilityprofile.Whenchoosingachelator,theclinicianmustconsiderthetherapeuticneeds,complianceissues,andco-morbiditiesoftheindividualpatient.Often,dosemustbeadjustedtoeitherimproveefficacyormanagesideeffects.

Table 1. Optimizing Deferasirox Therapy: Summary of Monitoring Recommendations

Deferasirox should not be combined with other iron chelation therapiesDeferasirox should not be combined with other iron chelation therapies

In duplicate before initiating deferasiroxIn duplicate before initiating deferasiroxtherapytherapy

Monthly during therapyMonthly during therapy

Renal function testsRenal function tests

Before the start of deferasirox therapyBefore the start of deferasirox therapy

Annually during therapyAnnually during therapy

Auditory and ophthalmicAuditory and ophthalmictestingtesting

Monthly during therapyMonthly during therapyLiver function testsLiver function tests

Monthly with dose adjustment based onMonthly with dose adjustment based on3-6 month trends3-6 month trends

Serum ferritinSerum ferritin

OngoingOngoingBlood intakeBlood intake

FrequencyFrequencyItem to monitorItem to monitor

Deferasirox core data sheet. Novartis data on file.

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Myelodysplasticsyndromes(MDS)areclinicallyheterogeneous.Consequently,evenwiththedevelopmentofclinicalguidelines39thedecisiontoinitiateironchelationtherapymustbemadeonacase-by-casebasis.Amajorfactorthatwillinfluencethedecisiontochelateistheoverallprognosisofthepatient.Clearly,iftheanticipatedsurvivaltimeisshort,chelationwillhavelimitedtherapeuticvalue.ThefollowingcasestudydescribesthemanagementofSFlevelsinahigh-riskMDSpatientwhowasconsideredtobeagoodcandidateforironchelation.

Patient Description • 64-year-oldfemalewithtransfusion-dependentMDS,

RCMD-RSsubtype

• Karyotype:46,XX,del(5q),-7,add(17)(p),der(21),+mar[12]/46,XX[13]

• Neutrophils1300/µL

• Haemoglobin7.2g/dL

• Platelets73,000/µL

• Bonemarrowblasts<5%

• Ferritin3600ng/mLintheabsenceofinflammation

Basedontheseclinicalvalues,thepatient’sInternationalPrognosticScoringSystem(IPSS)scorewasthatofIntermediateRiskII(Int-2).

Clinical Decision Point 1: Determining Prognosis in Newly Diagnosed MDS Patients

Question 1. Factors influencing overall survival in MDS patients include:

a) Age

b) Bone marrow blast count

c) Karyotype

d) Number of cytopaenias

e) Transfusion dependence

f ) All of the above

Discussion(f )AllofthefactorslistedaboveareassociatedwithsurvivalinpatientswithMDS.40,41TheInternationalPrognostic

Figure �. Pretransplantational Ferritin and Allotransplantation Outcome in MDS

Armand P, et al. Blood. 2007;109:4586-4588,with permission.

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Case 1. Advances in Managing Transfusional-Related Iron Overload: MDS Case Study Aristoteles A. N. Giagounidis, MD

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ScoringSystem(IPSS)isameansofpredictingsurvivalandriskofevolutiontoAMLbasedonbonemarrowblastcount,karyotype,andnumberofcytopaenias.40Patientsareassignedtooneoffourriskgroups:Low,Int-1,Int-2,andHigh.40Inclinicalpractice,thoseinIPSScategoriesLowandInt-1aregenerallyconsideredaslow-risk,whileInt-2andHighpatientsarecollectivelyconsideredashigh-risk.InadditiontothefactorsincludedintheIPSSscore,ageandtransfusion-dependencearealsoinverselyrelatedtosurvivalinMDSpatients.40,41

Case ContinuesOurpatienthadanIPSSclassificationofInt-2,placingherathighrisk.Thefirststepwastoaddresstheimpactofthecomplexkaryotypeonthepatient’sclinicaloutcome.Patientswith5q-syndrome,orakaryotypeinwhicha5qdeletionistheonlyabnormality,havearelativelygoodprognosis,withamediansurvivalofapproximately9years.42Incontrast,patientswithadditionalcytogeneticabnormalities,aswellastherefractorycytopaeniawithmultilineagedysplasiaandringedsideroblasts(RCMD-RS)identifiedinthispatient,haveamuchpoorerprognosis.ThemediansurvivalforpatientswithRCMD-RSisapproximately3years.42Prognosisinthispatientdependsontheabilitytosuppressthehigh-riskkaryotypes.

Thepatientreceivedtheimmunomodulatorydruglenalidomide,andwasmonitoredwithshort-termbonemarrowfollow-ups.Shortlyaftertheinitiationoflenalidomidetreatment, thepatientbecametransfusionindependent,withanormalizationofthekaryotype.However,theabnormalkaryotypereappearedafter9months,followedbyadropinhaemoglobinafter11months.Thepatient’sbrotherwashumanleukocyteantigen-compatible.Therefore,thenextstepwastoproceedwithallotransplantation.

Clinical Decision Point 2: Is the Patient a Candidate for Iron Chelation Therapy?

Question 2. In MDS, I am using iron chelation:

a) In all transfusion-dependent patients with an elevated ferritin level

b) Very rarely, as the expected overall survival of this patient group is low

c) Very rarely, as I fear interactions between iron chelators and other drugs in this patient group with co-morbidities

d) Only in low-risk MDS patients with elevated ferritin levels

e) In both low- and high-risk MDS patients on an individual basis as long as the expected overall survival is reasonable

Discussion(e)Thisoptionmostcloselyconformstoclinicalguidelines.39Inpatientswithelevatedironlevels,ironchelationisanimportanttherapeutictool,providedthepatientshaveareasonableexpectedoverallsurvival.Onesmallstudyhasfoundthatironchelationincreasesplateletandneutrophilcountsanddecreasestransfusionrequirements,suggestingthatironchelationhastherapeuticeffectsonbonemarrowfunction.43Ironchelationisalsorecommendedpriortoallogeneicstemcelltransplantation,sincelowerSFlevelsareassociatedwithimproveddisease-freesurvivalandreducedtreatment-relatedmortality(Fig 3, see previous page).44In2005,aninternationalconferencemeetinginNagasakidevelopedaconsensusstatementfortheuseofironchelationinthemanagementofMDS.AccordingtotheNagasakiconsensus,ironchelationshouldbeconsideredforpatientsmeetingthefollowingcriteria39:

• Transfusion-dependentpatients

• Low-riskMDS:IPSSLoworInt-1

• WHO-typeRAandRARSand5q-

• Candidatesforallografting

• MDSpatientswithdocumentedstabledisease

• Ferritinlevels>1000–2000ng/mLorotherevidenceofsignificanttissueironoverload

• Absenceofco-morbiditiesseverelylimitingprognosis

Chelationshouldcontinueforaslongastherisksofirontoxicityremainclinicallyrelevant.Forexample,ifthediseaseprogressestoacutemyeloidleukaemia,chelationtherapymaynolongerseemappropriate.39TheconsensusguidelinesformonitoringandtreatementofironoverloadinMDSpatientsaresummarizedinTable2(seenextpage).39

Case ContinuesOurpatientwasanappropriatecandidateforironchelation,meetingmostofthecriteriaestablishedattheNagasakimeeting.39Shewastransfusion-dependent,withSF>2000ng/mL,acandidateforallotransplantation,andhadnoco-morbiditiesseverelylimitingprognosis.Althoughbeinginahigh-riskIPSScategory,thefactthatthispatienthadadel(5q)cytogeneticabnormalityandanormalbonemarrowblastcountmadetreatmentwithlenalidomideapossibility.Indeed,shebecametransfusionindependentafter1monthoftreatment.Toreduceironoverload,treatmentwithdeferasirox20mg/kgwasinitiatedwithin2monthsoflenalidomidetreatmentandforatotalof12monthspriortotheallogeneictransplantation.While

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Thalassaemia intermedia has anextraordinarily wide clinical spectrum

Severe end:Presentation between age 2 and 6 years

Retarded growth and development

Mild end:Completely asymptomatic until adult life

Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

ondeferasirox,herSFlevelsfellfromaninitiallevelofapproximately3500ng/mLtoapproximately1800ng/mLatmonth12,whenweproceededwiththestemcelltransplantation(Fig 4).Duringthecourseofcoadministrationwithlenalidomideanddeferasirox,thepatient’shaemoglobinremainedover12g/dLforseveralmonths(Fig 4).Wedidnot,however,proceedwithvenisectionatthispoint.Shehadacomplexkaryotypeanditwasthereforeuncertainwhetherthehaemoglobinresponsewouldbemaintained.Ironchelation,however,mayhaveprovidedsometherapeuticadvantageinmaintainingimprovedbonemarrowfunction,asdiscussedearlier.43

Thepatienthasnowbeeninclinicalremissionfor7monthsfollowingtransplantation. Deferasiroxwasnotrestarted,topreventpotentialinteractionsandcumulativetoxicitywithposttransplantationmedications, includingimmunosuppressivedrugsandantiviralandantibioticprophylaxis.However,thedeferasiroxwaseffectiveinreducingherironburdenpriortransplantation,thusreducingtheriskoforgantoxicityandpotentiallyimprovingposttransplantationoutcomes.

Table 2. Consensus Guidelines for the Monitoring and Treatment of Iron Overload in MDS Patients

Monitoring Iron Overload

Treating Iron Overload

When should body iron stores beassessed in MDS patients?

Which tools should be used todiagnose and monitor ironoverload?

How frequently should ironoverload be monitored?

When should the initiation of chelationtherapy be considered in MDS patients?

How long should chelation therapycontinue?

At diagnosis of MDS and at regular intervalsthereafter, depending on the transfusion rate

Serum ferritinTransferrin saturationLiver MR imaging

When serum ferritin levels reach 1000 to 2000ng/mL, depending on the transfusion rate

As long as transfusion therapy continues andas long as iron overload remains clinicallyrelevant

At least every 3 months in patients receiving transfusions

•••

Figure �. Clinical Outcome on Deferasirox

HLA-identical bone marrow transplantation afterHLA-identical bone marrow transplantation after 1212 monthsmonths

0

2

4

6

8

10

12

14

1 2 3 4 5 6 7 8 9 10

Haemoglobin Ferritin

5000

4000

3000

2000

ng

/mL

g/d

L

Months

Courtesy of Dr. A. Giagounidis.

11 12

ReprintedfromHematol/Oncol Clin N Am,19(suppl1),GattermannN,etal,pp18-25.Copyright2005,withpermissionfromElsevier.

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Case 2. New Approaches for Chelation Therapy: Beta-thalassaemia Intermedia Case Study Ali T. Taher, MD

Thalassaemiaintermedia(TI)occupiestheclinicalspectrumbetweenthalassaemiaminorandthalassaemiamajor,withagreatdealofclinicalvariationamongindividualpatients(Fig 5).45Ingeneral,patientswithTIareanaemicbuttypicallydonotrequireregulartransfusions.TIpatientsaremostcommonlyhomozygousorcompoundheterozygousforbeta-globinmutations.Inbeta-thalassaemia,anexcessofalpha-globinchainsaccountsfortheineffectiveerythropoiesisthatcharacterizesthedisease.ThreegeneticfactorscommoninTI,whichreducetheclinicalseverityofthedisease,are45,46:

• Inheritanceofamildorsilentbeta-chainmutation,ratherthanacompleteabsenceofbeta-chainsynthesis

• Co-inheritanceofanXmnI-Gγpolymorphismthatresultsinproductionofexcessγchains,whichpairwiththealphachains

• Co-inheritanceofalphathalassaemia,reducingthealpha/betaratio.

ThephenotypeofTImayresultfromtheincreasedproductionofalpha-globinchainsbytriplicatedalphagenotypeassociatedtobeta-heterozygosityandalsofromtheinteractionofbetaanddeltabetathalassaemia.Thus,TIisdefinedbybothclinicalandgenotypicparameters.46

Patient DescriptionThispatientfirstpresentedasa3-year-oldLebanesegirlofMediterraneanorigin.Herchiefcomplaintswereanaemia,

pallor,slightlyyellowsclera,andenlargedspleen.Theresultsofhercompletebloodcountwere:

• Lowhaemoglobin—7g/dL

• Redcell(distribution)width—15(12–18)

• Meancorpuscularvolume—70(80–95fl)

• MCV/redbloodcountindex—<13

Clinical Decision Point 1: DiagnosisQuestion 1. What tests are needed to diagnose thalassaemia?

a) Genotypic studies

b) Haemoglobin electrophoresis

c) Ferritin and iron studies

d) Family studies

e) a, b, and d

Discussion(e)Genotypicstudies,haemoglobinelectrophoresis,andfamilystudiesarethenecessaryteststoruleoutotherpossiblecausesoftheobservedanaemia.Haemoglobinelectrophoresiswillidentifythepresenceofthalassaemia;genotypicandfamilystudiesarenecessarytodistinguishTIfromTM.ThispatienthadelevationsinhaemoglobinFandA2andwashomozygousfortheIVSI-6mutation,thusconfirmingtheTIdiagnosis.

Clinical Decision Point 2: Transfusions and TIQuestion 2. When is transfusion indicated in thalassaemia intermedia?

a) Growth delay

b) Right after diagnosis of thalassaemia intermedia

c) Definitely after the age of 1 year

d) Never indicated

e) None of the above

Discussion(a)AlthoughpatientswithTIarenotautomaticcandidatesforregulartransfusions,transfusionsareindicatedinpatientsexperiencingdelayedgrowth,poorpubertalgrowth,bonedeformities,increasinganaemia,thrombosis,pulmonary

Figure �. Clinical Spectrum

Thalassaemia intermedia has anextraordinarily wide clinical spectrum

Severe end:Presentation between age 2 and 6 years

Retarded growth and development

Mild end:Completely asymptomatic until adult life

Cappellini N, et al, eds. Thalassaemia International Federation; 2000.

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hypertension,progressivesplenicenlargement,andextramedullaryhaematopoiesis.

Case ContinuesAtage7,thepatientreturnedtotheclinicduetoinadequategrowth.Shereceivedtransfusionsevery2monthsforaperiodof1year.Shewastransfusionindependentforatime,thenstartedrequiringmoretransfusions.Atage10,aphysicalexamrevealeda12-cmspleen.

Clinical Decision Point 3: Splenectomy and TIQuestion 3. What are the indications for splenectomy in thalassaemia intermedia?

a) Symptomatic enlargement of the spleen

b) Growth retardation

c) Leukopaenia

d) Increased transfusion demand

e) All of the above

Discussion(e)ThemainindicationsforsplenectomyinTIpatientsaregrowthretardationorpoorhealth,leukopaenia,thrombocytopaenia,increasedtransfusiondemand,andsymptomaticsplenomegaly.Splenectomyalsocarriescertainrisks,includingsepsisandthrombosis.47,48Therefore,itisdonelessfrequentlythaninthepastandprimarilyinregularlytransfusedTMpatients.

Case ContinuesOurpatientunderwentasplenectomyduetoherenlargedspleenandincreasedtransfusionalrequirements.Atage18,

shereturnedtoourclinicwithpaininthelowerbackandrightlegandnumbnessoftherightleg.Shehadnotreceivedtransfusionssincehersplenectomyatage10.MRIofthespineconfirmedthediagnosisofextramedullaryhaematopoiesis,whichoccursmorecommonlyinpatientswithTIthanTM.Thepatientwastransfusedwith2unitsofredbloodcellseveryweekfor5weeks.Hersymptomswerecompletelyrelievedandnomasseswereobservedonthefollow-upMRI.Shewasstartedonhydroxyureaatadoseof500mg/day.

Atage26,thepatientreturnedtotheclinicwithpainandwarmthinherrightcalf.Shewasdiagnosedwithsuperficialvenousthrombophlebitis,basedonduplexultrasound.Shehadseveralrisksforthrombosis,includingsplenectomy,withnosubsequentaspirinintake,andtransfusionindependence,exceptforthetransfusionstoresolveherextramedullaryhaematopoiesis.49Smokingandfamilyhistory,additionalriskfactors,didnotapplytoourpatient.Herthrombosiswasmanagedwithlowmolecularweightheparin(LMWH)andbabyaspirinfor6months.ShewasalsoinstructedtoreceiveLMWHandtransfusionbeforehigh-riskprocedures.

Clinical Decision Point 4: Assessing Iron OverloadQuestion 4. Would you expect an occasionally transfused thalassaemia patient to be iron overloaded?

a) Yes

b) No

Discussion(a)AlthoughironoverloadhasbeenstudiedmostextensivelyinpatientswithTM,apopulationthatreceivesregulartransfusions,itcanoccurinnontransfusedandoccasionallytransfusedTIpatients,aswell.Elevatedconcentrationsofliverironhavebeenobserveddespite

slightincreaseinSFinTIpatients.50ThisdiscrepancybetweenliverironconcentrationandSFdelaysinitiationofpossibletherapy.51InTI,patientsabsorb1to3.5gironperyearthroughgutabsorption.52Wearecurrentlyconductingastudyinourclinictoestablishtheprevalenceofironoverloadintransfusion-naïvepatientswithTI.51Todate,wehaveanalyzeddatafrom37TIpatients;theanalysiswillgainmorepoweronceweenrollandanalyzedatafromatotalof80patients.PatientshadameanLICof7.76mgFe/gdryweightofliverandameanSFof957.35µg/L.IronchelationtherapyisrecommendedforTIpatientswithLIC≥7mgFe/gdryweight.53AninterestingobservationfromourstudyisthatalthoughSFiscorrelatedtoLICinbothTIandTMpatients,SFmoreaccuratelyreflectsironburdeninpatientswith

Figure �. Ferritin vs LIC in Thalassaemia Major and Thalassaemia Intermedia

Courtesy of Dr. A. Taher.

LIC by MRI vs Ferritin in TM and TI

0

Fer

riti

n n

g/m

L

Y = 86.216xR2 = 0.034

LIC mg Fe/g Dry Weight of Liver

5 10 15 20 25 30 35 40 45 50

1000

2000

3000

4000

5000

6000

7000

8000

9000

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Y = 183.76xR2 = 0.0091

TI

TM

TM

TI

11


Poll ResultsTheEHAsymposiumattendees’responsestoeachofthesixClinicalDecisionPointquestionsappearinginthisnewsletterarepresentedbelow.

Case 1 (Begins on page 6)

Question1 a.1% b.2% c.1% d.0% e.2% f.94%

Question2 a.28% b.8% c.1% d.13% e.51%

Case 2 (Begins on page 9)

Question1 a.2% b.26% c.3% d.3% e.67%

Question2 a.65% b.3% c.3% d.2% e.26%

Question3 a.4% b.0% c.2% d.5% e.90%

Question4 a.75% b.25%

Conclusion: Choosing the Right Therapy for the Right Patients John B. Porter, MA, MD, FRCP, FRCPath

TMthanTI(Fig 6, see previous page).FortypercentofTIpatientshadLIC>7mgFe/gdryweight,whileonly13.5%hadSF≥1500µg/L.AccordingtothegraphinFigure6,thethresholdforironchelation,LIC≥7mgFe/gdryweight,correlatesto500to600µg/LferritininpatientswithTI.Therefore,cliniciansmayfailtodiagnoseironoverloadinpatientswithTIbysolelyrelyingonSF,unlesstheylowertheirthresholdforclinicalsignificance.

Case Study ContinuesAthervisitatage26,wealsofoundthatthepatientwasironoverloaded.ShehadLIC7.9mgFe/gdryweightofliverandSF750ng/mL.Shewasstartedondesferrioxamine30mg/kg/daybutrefusedtostayontherapy.Currently,LICisbeingmonitoredbyR2MRI.WeneedtodecidethenextapproachtoreducingtheironburdeninthisoccasionallytransfusedpatientwithTI.

Excessiveironlevelsexerttheirtoxiceffectsoncetheyhavebeenabsorbedintothetissueofthevariousorgans.Chelatorscanpreventtissueabsorptionbyremovinglabilepoolsofironbeforetheyareabsorbed.Inpatientswhoarealreadyironoverloaded,continualchelationwilldepletetheLPIandcauseareductioninbodyironstores,aswell.Becausetheselabilepoolscanreformsorapidly,maximaltherapymustprovide24-hourexposuretothechelator.Asdiscussedinthisnewsletter,thatcancurrentlybeprovidedbycombinedtherapywithdesferrioxamine,orwithonce-dailyoraladministrationofdeferasirox.

Whichofyourpatientswouldbenefitfromironchelationtherapy?Appropriatepatientselectioniskey.Asdiscussed,ahigh-riskMDSpatientwhowasinstableconditionand

awaitingtransplantationappearedtobenefitfromdeferasiroxtherapy.Patientswhoreceiveintermittentbloodtransfusionsmayalsobecomeironoverloadedandinneedofchelationtherapy,asdemonstratedbytheTIpatientpreviouslydiscussed.FurtherresearchisnecessarytodocumenttheextentofironoverloadinTIandtoprovideclearsupportfortheuseofchelationinpatientswhoareinfrequentlytransfused.Hopefully,thisnewsletterhasprovidedinformationandinsightthatwillhelpyouselecttherighttherapyfortherightpatients.

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