Standards of Care Guidelinesfor Thalassemia

2012

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TABLE OF CONTENTS

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1 1 Introduction 1.1 Commondefinitionsusedinthalassemia

1 2 DNATestingPriortoTreatment

1 3 DiagnosisofThalassemia

2 4 BloodTransfusions 4.1 Assessingtheneedforroutinetransfusions 4.2 Baselinelaboratorytestspriortoregulartransfusions 4.3 Transfusionadministrationandmonitoring 4.3.1 Transfusionfacility 4.3.2 Typeofbloodproduct 4.3.3 Targethemoglobinandfrequencyoftransfusions 4.4 Adversereactionstotransfusions 4.5 Splenectomy 4.6 ThromboembolicDisease

4 5 IronOverloadandChelationTherapy 5.1 Initiationofchelation 5.2 Treatmentwithironchelators 5.2.1Treatmentwithdeferoxamine(Desferal) 5.2.2Treatmentwithdeferasirox(Exjade) 5.2.3Treatmentwithdeferiprone(L1/Ferriprox) 5.3 Patientswithsignificantironoverload 5.3.1High-dose,continuousdeferoxamine 5.3.2Combinationtherapy:deferoxamineanddeferasirox 5.3.3Combinationtherapy:deferoxamineanddeferiprone

9 6 TheUseofImagingtoMonitorIronOverloadandChelationTherapy 6.1 Monitoringtheefficacyofchelationtherapyinthepresenceofironcardiomyopathy

10 7 AssessmentofChelatorSideEffectsandToxicity 7.1 Audiology 7.2 Ophthalmology 7.3 Nephrology 7.4 Neutropenia 7.5 Growth 7.6 Localandallergicreactions 7.7 Over-chelation

11 8 LiverandGallBladderDiseases 8.1 Screeningforhepaticdysfunction 8.2 Monitoringpatientswithdocumentedhepatitisorhepaticdysfunction 8.3 EvaluationandtreatmentforhepatitisC 8.4 EvaluationandtreatmentforhepatitisB 8.5 Gallbladderdisease

12 9 EndocrineDysfunction 9.1 Routineendocrinescreening 9.2 Specificendocrinopathies:testingandevaluation 9.2.1 Diabetesmellitus 9.2.2 Lowbonemass(osteoporosis) 9.2.3 Growthhormonedeficiency 9.2.4 Hypogonadism 9.2.5 Hypothyroidism 9.2.6 Hypoparathyroidism 9.2.7 Adrenalinsufficiency

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13 10 CardiacDysfunction 10.1Cardiacevaluation 10.2Echocardiographystandards 10.3Treatmentofestablishedheartfailure 10.4Pulmonaryhypertension 10.5Treatmentofpulmonaryhypertension

15 11 PulmonaryCare

15 12 PainSyndromeinThalassemia

13 HematopoieticCellTransplantation 13.1IronoverloadafterHCT 13.2ExperimentalHCT 13.3Experimentaldrugtherapytoincreasefetalhemoglobin

16 14 AcuteInfection

16 15 DentalEvaluation

17 16 Nutrition

18 17 Vaccinations

18 18 FertilityandPregnancyinThalassemia 18.1Pregnancy

18 19 ThalassemiaIntermedia 19.1Nontransfusedthalassemiaintermedia 19.1.1 Growthanddevelopment 19.1.2 Extramedullaryerythropoiesis 19.1.3 Endocrinopathies 19.1.4 Cardiopulmonaryassessment 19.1.5 Considerationsfortransfusions 19.1.6 Considerationsforsplenectomy 19.1.7 Assessmentofironoverload

19 20 HemoglobinHDiseaseandItsVariants 20.1Diagnosis 20.2HemoglobinHdeletion 20.3Recommendationsforcare

20 21 ThalassemiaResearch

21 22 PsychosocialSupport 22.1Childlifeservices 22.2Psychologicalservices 22.3Socialservices 22.4Geneticcounseling

22 23 GeneticTesting

23 24 GeneralTimetableforClinicalandLaboratoryEvaluation

24 25 Authors

24 26 Support

24 27 References

TABLE OF CONTENTS

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1

1IntroductionThalassemiaisacomplexgroupofdiseasesthatarerelativelyrareintheUnitedStatesbutcommoninMediterraneanregionsandSouthandSoutheastAsia.Worldwide,thereare350,000birthsperyearwithserioushemoglobinopathies.IntheUnitedStates,asaconsequenceofimmigrationpatterns,occurrenceofthalassemiadisordersisincreasing.

Treatmentforthalassemiahasdramaticallyimproved.Patientsshouldlivefullliveswithcareersandchildrenoftheirown.Unfortunately,manypatientsdieprematurelyordevelopmorbidpreventablecomplications.Outcomesarefarbetterforpatientswhosecareiscoordinatedbythalassemiacenters(Modell,B.,Khan,M.,andDarlison,M.SurvivalinbetathalassaemiamajorintheUK:DatafromtheUKThalassaemiaRegister.Lancet355[2000]:2051–2052.Porter,J.B.,andDavis,B.A.Monitoringchelationtherapytoachieveoptimaloutcomeinthetreatmentofthalassaemia.Best Practice & Research: Clinical Haematology 15[2002]:329–368).Themajorityofpatientsaremanagedinsmallprogramswhichmaynothaveaccesstorecommendedmonitoringandtreatments.Therefore,anestablishednetworkofcarebetweenthalassemiacenters,localproviders,andpatientsisrequiredforoptimaltreatmentofthalassemiapatientsinNorthAmerica.EachcomponentofthisnetworkshouldfollowtheStandards of Care Guidelinesandcommunicatefrequently.

Allpatientsshouldundergoatleastanannualcomprehensiveassessmentatathalassemiacenter.Duringsuchanassessment,recommendationsaresummarizedafterconsultationwithmultiplespecialistsandcommunicateddirectlytotheprimaryproviderandfamily.Verbalandwrittencommunicationbetweenthecenterandtheprimaryprovidershouldoccuratleasteverysixmonthsfollowingtheformalannualvisitandwhentherearechangesinthepatient’sclinicalandtreatmentplan.

Aspecialtycentermanagestheregularcareofatleast20patients.Aspecialtyprogramincludesateamofthalassemiaexpertsworkingcloselytogether.Thisteamincludesahematologist,anursespecialist,ahepatologist,acardiologist,anendocrinologist,apsychologist,ageneticscounselor,asocialworker,andadietitian.Acenterincludeslinkagetoathalassemia-orientedbonemarrowtransplantandfertilityservice.Withinthecenter,specialtylaboratorysupportincludesdiagnosticimaging,ahemoglobinopathyreferencelaboratory,andaclinicalresearchcenter.

Theextentofservicesprovidedbyaprimaryorregionalprogramvaries.Servicesmayincludesupervisingofregulartransfusionsandprovidingnecessarymedicationsaccordingtothestandardsofcare.Primarycare,includingmonitoringofgrowthandgeneralhealthand—forpediatricpatients—liaisonwiththeschool,iscentralizedinthelocalprogram.Earlyrecognitionandstabilizationofacutecomplications—i.e.,sepsis,transfusionreactions,drugreactions,orcholecystitis—requireclosecommunicationbetweentheprimaryproviderandthefamily.Twenty-fourhourbackupconsultationshouldbeavailablethroughthepatient’sdesignatedthalassemiacenter.

InJune2000,agroupofprovidersdevelopedandfinalizedthefirstStandards of Care Guidelines for Thalassemia,withthegoalofstandardizingthemanagementofcareforthalassemiapatients

throughoutthestateofCalifornia.Sincethen,significantchangesintechnologyandtreatmenthavedevelopedthatrequiredtheoriginalguidelinestobeupdatedhere.

1.1 CommonDefinitionsUsedinThalassemiaBetathalassemiadisordersresultfromdecreasedproductionofbetaglobinchains,resultinginrelativeexcessofalphaglobinchains.Thedegreeofexcessnonfunctionalalphachainsisthemajorpredictorofdiseaseseverity.Beta0thalassemiareferstotheabsenceofproductionofbetaglobin.Whenpatientsarehomozygousforabeta0thalassemiagene,theycannotmakeanynormalbetachains(hemoglobinA).Beta+thalassemiaindicatesamutationthatpresentsdecreasedbutnotabsentproductionofbetaglobin.Thalassemiapatientsinwhichoneorbothoftheirbetathalassemiamutationsarebeta+mutationsmakesomehemoglobinA,andthedisordermaybelesssevere.Betathalassemiamajorisaclinicaldiagnosisreferringtoapatientwhohasasevereformofthediseaseandrequireschronictransfusionsearlyinlife.Betathalassemiaintermediaisaclinicaldiagnosisofapatientcharacterizedbyalessseverechronicanemiaandamorevariableclinicalphenotype.Alphathalassemiareferstoagroupofdisorderscharacterizedbyinactivationofalphaglobingenes.Thisresultsinarelativeincreaseinnonfunctionalbetaglobinorgammaglobintetramersandsubsequentcelldamage.Normally,therearefouralphagenes.Absenceornon-functionofthreealphagenesresultsinhemoglobinHdisease,andthelossofallfouralphagenesusuallyresultsinintrauterinedeath.

2DNATestingPriortoTreatmentBecauseoftheenormousdiversityinclinicalseverityofthalassemiapatients,completeDNAtestingpriortocommencementoftreatmentisrequiredtodetermineprognosis,appropriatetherapy,andfamilycounseling.Definitivediagnosisandfamilycounselingshouldbedoneinconjunctionwithathalassemiacenter.

3DiagnosisofThalassemiaPriortoconsiderationoftransfusiontherapy,itiscriticaltoconfirmthepatient’sdiagnosis.Inadditiontocompletebloodcount(CBC),hemoglobinelectrophoresisisthefirstdiagnostictest.FractionsofhemoglobinA,A

2,F,H,E,andothervariants

aremeasured.Hemoglobinanalysisbyhemoglobinelectrophoresisorhighperformanceliquidchromatographyisused.Mutationsmayoverlaponthescreeningtest,resultinginincorrectdiagnosisorafalsenegative.Therefore,geneticanalysisforbothbeta-thalassemiaandalpha-thalassemiamutationsarenecessary.Inaddition,parentsandsiblingsshouldbescreened.Occasionally(upto20percentofthetime),onlyasinglemutationwillbefoundthatisindicativeofthalassemiatrait.SomesuchcasesresultfromanautosomaldominantformofthalassemiaandothersfrominheritingamutationthatisnotdetectedbytheprobesutilizedintheDNAtesting.Alpha-genetriplicationisacommonco-factorthatmayconvertathalassemiatraittoadiseaseorworsenabenignmutation.Testingforco-mutationsneedstoberequestedfromtheDNAlaboratory—otherwise,itwillnotbeperformed.

Patientswiththalassemiaintermediamayhaveexaggeratedanemiaduetotemporarynutritionaldeficienciesorinfectiouscomplications.Itisimportanttocompleteadetailedmedicalhistoryconcerningfactorsthatmaytemporarilylowerhemoglobin,includingviralillness,marrow-suppressing

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 2

medication,orexposuretoenvironmentalfactorssuchaslead.Nutritionaldeficienciesinfolicacidorironmayexaggerateanemia.Correctingthesedeficienciesmayraisethehemoglobinlevelenoughtoobviatetheneedfortransfusion.*Therefore,laboratoryscreeningofpatientsisnecessarytoruleoutothercausesofanemia.

*MeasurementsshouldbetakenoftheG6PDlevel,serumferritin,totaliron-bindingcapacity,serumiron,andredcellfolate.Abrieftherapeutictrialofiron(6mg/kg/dayforfourtoeightweeks)andfolicacid(1mg/day)areindicatedifsignificantlaboratorydeficienciesarefound.

4BloodTransfusionsBloodtransfusionisthemainstayofcareforindividualswiththalassemiamajorandmanywithintermedia.Thepurposeoftransfusionistwofold:toimprovetheanemiaandtosuppresstheineffectiveerythropoiesis.Chronictransfusionspreventmostoftheseriousgrowth,skeletal,andneurologicalcomplicationsofthalassemiamajor.However,oncestarted,thetransfusion-relatedcomplicationsbecomeamajorsourceofmorbidity.Standardsmustbedevelopedandmaintainedtoensureasafeandrationalapproachtotheuseofbloodtransfusionsinthemanagementoftheseraredisorders.

Patientswithß+/ß+thalassemia;hemoglobinE-ßthalassemia;hemoglobinHdisease;andhemoglobinH–ConstantSpringoftenhaveathalassemiaintermediaphenotypeanddonotnecessarilyrequirechronictransfusion.However,theDNAmutationsdonotreliablypredicttheclinicalphenotype.ß0/ß+andevenß0/ß0mayoccasionallyhaveathalassemiaintermediaclinicalphenotype.Theclinicalphenotypeofthalassemiaintermediapatientsmaychangeastheyageandmayrequiretransfusiontherapy.Ongoingassessmentoftransfusionrequirementsarenecessaryforboththalassemiamajorandintermedia.

Thedecisiontostarttransfusionsisbasedoninabilitytocompensateforthelowhemoglobin(signsofincreasedcardiaceffort,tachycardia,sweating,poorfeeding,andpoorgrowth),orlesscommonly,onincreasingsymptomsofineffectiveerythropoiesis(bonechanges,massivesplenomegaly).Thedecisiontoinstitutechronictransfusionshouldnotbebasedexclusivelyonthepresenceofanemia.

Thedecisiontoinitiatechronictransfusiontherapyrequiressignificantinputfromthepatient,family,andmedicalteam.Anemiaaloneisnotanindicationoftheneedforchronictransfusion.Anemiashouldbelinkedwithasignificantimpairmentinqualityoflifeorassociatedmorbidities.Factorstoconsiderinclude:poorgrowth;inabilitytomaintaindailyroutinesandactivitiessuchasgoingtoschoolandwork;evidenceoforgandysfunction;evidenceofcardiacdisease;pulmonaryhypertension;anddysmorphicbonechanges.

Itmaybenecessarytoinitiateasix-monthtrialofbloodtransfusionsinpatientsoffamilieswhosedecisiontotransfuseisuncertain.Aftersixmonths,transfusionscanbestoppedandthepatientobservedforabriefperiodoftimetogivethefamilyandmedicalteaminformationastotheclinicalbenefitsandpsychologicalimpactofthetransfusions.

4.1AssessingtheneedforroutinetransfusionsThedecisiontostartregulartransfusionsisclearwhentheinitialhemoglobinleveliswellbelow6g/dL.Toassessachild’sneedforroutinetransfusionsduetothalassemia,anemiacausedbysepsisorviralinfectionmustberuledout.Assessmentmaybeaccomplishedbywithholdingtransfusionsandmonitoringweeklyhemoglobinlevel.Ifthehemoglobindropsunder7g/dLontwooccasions,twoweeksapart,thenregulartransfusionsshouldbecommenced.

Patientswithahemoglobinlevellessthan7g/dLmaysometimesrequireregulartransfusionsinthepresenceofgrowthimpairment,markedskeletalchanges,orextramedullaryhematopoiesis.

4.2BaselinelaboratorytestspriortoregulartransfusionsAnextendedredcellphenotypemustbeobtainedtoreducethefutureprobabilityofdevelopingalloantibodies.Ifachildhasalreadystartedtransfusions,theredcellantigengenotypecanbedeterminedbyDNAtesting,andattheminimum,shouldincludetheC,E,andKellalleles.

Althoughthehemoglobinlevelcandefineapatient’sdiseasetype,seldomdoesitalonedeterminetheneedfortransfusion.AntibodiestohepatitisB,hepatitisC,andHIVshouldalsobedetermined.PatientsshoulddemonstrateimmunitytohepatitisB.Thebilirubin,transaminase,andserumferritinlevelsshouldbechecked.

4.3TransfusionadministrationandmonitoringTheaimoftransfusiontherapyistopermitnormalgrowthandactivitylevelandtopreventskeletalchangesassociatedwithmarrowhyperplasia.Adequatetransfusiontherapywillalsoreducesplenomegalyandhypersplenismanddecreaseabsorptionofdietaryiron.

4.3.1 Transfusion facilityTransfusionsshouldbeadministeredinadesignatedoutpatientclinicalareabystaffexperiencedwithtransfusionpolicies.Writtentransfusionpolicies—includingmaximumrate,volumeoftransfusion,andprotocolfortransfusionreactions—arerequired.Theavailabilityofaccesstooutpatienttransfusionservicesonweekdays,weekends,andeveningsisimportantforschool-agedchildrenandworkingadults.

4.3.2 Type of blood productTheproductofchoiceispackedredbloodcellsdepletedofleucocytesandmatchedwiththepatient’sredantigenphenotypeforatleastD,C,c,E,e,andKell.

Wholebloodorbloodwithoutleukodepletionisunsuitableforregulartransfusions,sincenon-hemolytictransfusionreactionsarecommon.Whenpossible,largeunitslessthantwoweeksofagearerecommended.

Patientsshouldbeassessedforhemolyticreactionsifanyadverseeventisnotedduringatransfusion.Febrileandallergicreactionsmayrespondtoacetaminophenanddiphenhydraminebeforefuturetransfusions.

Patientswhodevelopallergicreactionsshouldbegivenwashedpackedredbloodcellunits.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 3

Thedevelopmentofalloantibodiescancomplicatetransfusiontherapyandmayrequiretheuseoffrozenpackedredbloodcellunitsofrarebloodtypes.Somepatientsaretransfusedwithirradiatedredcells.Thisprocessisusedtopreventgraft-versus-hostdisease.Itislargelyunnecessaryunlessthepatientisundergoingabonemarrowtransplantorhasanunderlyingimmunodeficiency.Cytomegalovirus(CMV)infectionistransmittedviatransfusion.Leukocytedepletionofaredcellunitpreventsitstransmission.CMVnegativeunitsareusuallyunnecessaryoncetheunitisleukocyte-depleted.

4.3.3 Target hemoglobin and frequency of transfusionsThegoaloftransfusionistoshutofferythropoiesisasmuchaspossible.Transfusionsshouldgenerallybegivenatanintervalofthreetofourweeks.(Withagingpatients,atransfusioneverytwoweeksmaybenecessary.)Transfusionsshouldbescheduledinadvanceandmaintainedatafixedschedule.Thisenablespatientsandfamiliestoestablishroutinesandwillimprovequalityoflife.

Theamountofbloodreceivedontransfusiondayisdeterminedbypre-transfusionhemoglobinlevels.Thetargetistomaintainthepre-transfusionhemoglobinlevelbetween9and10g/dL.Attemptstomaintainpre-transfusionhemoglobinatabove10g/dLincreasetransfusionrequirementsandtherateofironloading.Transfusionsshouldbegiveninanoutpatientsettingwithanexperiencedtransfusionteamthatusespropersafetyprecautions(patient/bloodidentificationbracelets).Bloodshouldbetransfusedat5mL/kgperhour,andthepost-transfusionhemoglobinshouldnotexceed14g/dL.

Inpatientswithsevereanemia(hemoglobinlessthan5g/dL)orcardiaccompromise,therateoftransfusionshouldbereducedto2mL/kgperhourtoavoidfluidoverload.Diureticssuchasfurosemide(1to2mg/kg)maybenecessaryforsomepatients.

Ifcardiacinsufficiencyispresent,higherpre-transfusionhemoglobinlevels(10to12g/dL)shouldbemaintainedwithsmallervolumetransfusionsgiveneveryonetotwoweeks.

Thepatient’sweightandpre-transfusionhemoglobinandthevolumeoftransfusionshouldberecordedateachvisit.Thesevaluesshouldbeperiodicallyreviewedtoassessthevolumeofbloodrequiredtomaintainthedesiredpre-transfusionhemoglobinlevel.Annualbloodtransfusionrequirementinpatientswithouthypersplenismisusuallybelow200mLpackedredbloodcells/kgperyear.

4.4AdversereactionstotransfusionsTheverybestpracticesforbloodtransfusionmustbeemployed,sincetheneedforlifelongtransfusionsleadstoacumulativeincreaseintheriskofadversereactions.

Alloimmunizationisafrequentproblemthatcanbepreventedbytransfusingbloodmatchedforthepatient’sextendedredbloodcellphenotype(notjusttheABOandRhDantigens).Analloantibodyscreenshouldbeperformedpriortoeachtransfusion.Analloantibodyisanantibodymadebythepatientagainstanantigenpresentonthetransfusedredcell.Oncealloimmunized,patientsmaybeatriskfordevelopinganantibodyagainsttheirownredcells(anautoantibody).Upto10percentofpatientswhodevelopalloantibodieswilldevelopanautoantibody.Thepresenceofan

autoantibodydoesnotalwaysresultindecreasedredcellsurvival,butitmay.Anautoantibodywilldelaythepatient’scrossmatchandtransfusionprogram.Autoantibodiescanbestbeavoidedbypreventingalloantibodies.

Ifanautoantibodyand/oralloantibodyisdetected,thespecificantibodiescausingthetransfusionreactionshouldbedeterminedbythebloodbankorbyareferencelaboratory.

Themanagementofpatientswhodevelopantibodiesrequiresuseofbloodmatchedbyextendedredcellantigenphenotype.

Theriskoftransfusion-transmittedinfections,whilelow,isstillaconcernforknownandemergingpathogens,andannualmonitoringforhepatitisB,hepatitisC,andHIVisnecessary.

Theriskofbacterialinfectionissmall,butthetransmissionofparasiticinfections(particularlymalaria)isasignificantthreatincertaingeographicalareas.

Theothercomplicationsofbloodtransfusionincludetheriskofmismatchedtransfusion,allergicreactions,andfebrile,non-hemolyticreactions.

4.5SplenectomyTheuseofsplenectomyinthalassemiahasdeclinedinrecentyears.Thisispartlyduetoadecreasedprevalenceofhypersplenisminadequatelytransfusedpatients.Thereisalsoanincreasedappreciationoftheadverseeffectsofsplenectomyonbloodcoagulation.Ingeneral,splenectomyshouldbeavoidedunlessabsolutelyindicated.

Splenectomyisindicatedinthetransfusion-dependentpatientwhenhypersplenismincreasesbloodtransfusionrequirementandpreventsadequatecontrolofbodyironwithchelationtherapy.Anenlargedspleen—withoutanassociatedincreaseintransfusionrequirement—isnotnecessarilyanindicationforsurgery.Patientswithhypersplenismmayhavemoderatetoenormoussplenomegaly,andsomedegreeofneutropeniaorthrombocytopeniamaybepresent.

Annualtransfusionvolumeexceeding225to250mL/kgperyearwithpackedredbloodcells(hematocrit75percent)mayindicatethepresenceofhypersplenism.Thevolumecalculationshouldbecorrectediftheaveragehematocritislessthan75percent.Thepossibledevelopmentofalloantibodyshouldalsoberuledout.Splenectomyshouldbeavoidedunlessthereisaninabilitytomaintainironbalancewithoptimalchelation,orifthereareclinicallysignificantcomplicationssuchaspancytopeniaandmarkedenlargement.Often,hypersplenismdevelopsbecauseofalowpre-transfusionhemoglobin.Increasingthepre-transfusionhemoglobintobetween9.5and10mayreversehypersplenism.

Ifadecisiontoperformsurgeryismade,partialorfullsplenectomyistheoption.Partialsplenectomyisacomplicatedsurgeryutilizedtopreservesomesplenicfunction.Itshouldbereservedforinfantsrequiringsplenectomy.Fullsplenectomycanusuallybeperformedbylaparoscopictechnique.However,openprocedureisnecessaryincasesofmarkedsplenomegaly.TheindicationsforsplenectomyinhemoglobinH–ConstantSpringpatientsaredifferentthaninbeta-thalassemiadisorders.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 4

Transfusion-dependentinfantswithhemoglobinH–ConstantSpringrespondrapidlytosplenectomybutrequireprophylacticanticoagulationbecauseofahighincidenceofseriousthrombosis.

PatientsmustreceiveadequateimmunizationagainstStreptococcus pneumoniae,Haemophilus influenzaetypeB,andNeisseria meningitidespriortosurgery.Splenectomyshouldbeavoidedinchildrenyoungerthanfiveyearsbecauseofagreaterriskoffulminantpost-splenectomysepsis.

Aftersplenectomy,patientsshouldreceiveoralpenicillinprophylaxis(250mgtwicedaily)andbeinstructedtoseekurgentmedicalattentionforafeverover101ºFahrenheit.

Post-splenectomythrombocytosisiscommon,andlow-doseaspirinshouldbegivenduringthistime.Anothercomplicationfollowingsplenectomyisthedevelopmentofathrombophilicstate.Venousthromboembolism,morecommoninthalassemiaintermediaandhemoglobinH–ConstantSpring,candevelopfollowingsplenectomy.

Patientsshouldhaveannualechocardiographicmeasurementofthepulmonaryarterypressuretomonitorfordevelopmentofpulmonaryhypertension.

4.6ThromboembolicdiseasePeoplewiththalassemiaareatincreasedriskofthrombosis.Thromboticeventsincludepulmonaryembolism,arterialocclusion,portalthrombosis,anddeepveinthrombosis.Approximately1to2percentofthalassemiamajorpatientsand5percentofthalassemiaintermediapatientsexperienceaseriousthrombosis.Oneofthemostcommonandseriouscomplicationsisstroke.RecentbrainMRIstudiessuggestthatthalassemiapatients(particularlythosewiththalassemiaintermedia)areathighriskforsubclinicalinfarctionorsilentstroke.Splenectomysignificantlyincreasestheprevalenceofthromboticevents.Inadequatetransfusionmayincreasetheriskofthrombosissecondarytoincreasedreleaseofprocoagulantredcellparticles.Manypeoplerecommendthatallpost-splenectomypatientsshouldreceiveanti-plateletoranti-thrombosistherapywithaspirinorlowdosewarfarin.

5IronOverloadandChelationTherapyIronoverloadisthemajorcauseofmorbidityforthalassemiapatients.Evennontransfusedpatientsdevelopironoverloadsecondarytoincreasedintestinalabsorptionofdietaryiron.Ironoverloadisaleadingcauseofmortalityandorganinjury.

Ironoverloadoccursveryrapidlyinpatientswhoareonchronictransfusionprograms.Sincehumanshavenomechanismotherthansloughingofthemucosaoftheirgastrointestinaltractsormenstruationtoexcreteexcessiron,patientswhoarebeingtransfusedeverythreeorfourweeksgain0.5mg/kgperdayofironinexcessofnaturallosses.Patientswhoarenotonatransfusionregimenarealsopronetoironoverloadduetosignificantlyincreasedintestinalabsorptionofironsecondarytoineffectiveerythropoiesis.

Theonlytreatmentoptionsforremovingexcessironarephlebotomyandchelation.Whilephlebotomyisaveryeffectivewayofremovingiron,itisnotappropriateforpatientswith

thalassemiaexceptafterbonemarrowtransplantation.Thalassemiapatientswhoarenottransfusiondependentcannotmaintainanadequatehemoglobinlevelandbecomesymptomaticafterphlebotomy.Outpatientexchangetransfusioncanbeusedinselectedcasestodecreaseironintake,butitisnoteffectivebyitselfinrapidlyreducingheavyironloadsandwouldnotbeappropriatebyitselfinthefaceofcardiacironloading.Theprimarytreatmentforironoverloadinthalassemiaischelation,whichisdescribedbelow.

Ironisverytoxictotissue.Undernormalcircumstances,inhumans,ironistransportedboundtoacarrierproteincalledtransferrin.Transferrintransportsironintocertaintissues.Becausetheironisboundtothisprotein,othertissuesareprotectedfromthetoxiceffectsoffreeiron.Patientsonchronictransfusionrapidlyacquiremuchmoreironthancanbeboundbytransferrin,andfreeironlevelsincreaseintheblood.Thisfreeiron,orsocallednon-transferrinboundiron,isdirectlytoxictotheheartandothertissues.

Therearetwogoalsofironchelationtherapy:thebindingoftoxicnon-transferrinboundironintheplasmaandtheremovalofironfromthebody.Detoxificationofexcessironisprobablythemostimportantfunctionofchelationtherapy.Itisclearthatcertainsymptomsofironoverload,suchascardiacarrhythmiaandheartfailure,canbeimprovedwellbeforelocaltissuelevelsofironhavedecreasedbythecontinualpresenceofachelatorintheplasma.

Itisusefultothinkaboutthetoxicityofironaccordingtothefollowingrelation:

Toxicity=[tissueiron]x[patient-andtissue-specificfactors]x[time]

Generally,timeismeasuredinyears.Thus,ittakesthreetotenyearsofchronicexposuretohighlevelsofironbeforemeasurableorgandysfunctionoccurs.Fortunately,thismeansthatthereistimetoimplementtreatmentstrategiestoreduceironloading.However,dependingupontheorgan,itcantakealongtimetosignificantlyreduceiron,sothebeststrategyisactingearlyand,infact,tryingtopreventsignificantironloadingfromthestart.

Newequipment—suchasthequantitativeMRIforironandtheferritometer(SQUID)—hasenabledproviderstomeasuretheamountofironintheorgansandalsolookattherelationshipbetweenexcessiron,time,andpatient-andtissue-specificfactors.Suchfactorsincludetransfusionregimen;weeklychelation;differencesoftransportofironintovariousorgans;geneticdifferencesinantioxidantdefensemechanisms;anddisease-specificdifferencesininflammationandmetabolism.Itisnowclearthatthereisatremendousrangeofvariabilityinendorgantoxicityamongpatientswhoseeminglyhavethesameamountoftissueiron.Fromaclinicalstandpoint,thismeansthatendorganfunction,aswellastissueironconcentration,mustbeseriallymonitoredduringthemanagementofchronicironoverload.

Ingeneral,significantironloadingofthelivercanbedetectedafteraboutsixmonthsofmonthlytransfusions,whilecardiacloadingtakesabouteighttotenyears.Theliverloadslinearlywithtime,whereastheheartremainsdevoidofironforyears.However,onceitstarts,ironloadingoftheheartisveryrapid.Evidenceofliver

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 5

damagecanoccurafteraboutfouryearsoftransfusions.Theonsetofcardiacdysfunctionismorecomplexandlesswellunderstood.Quantitativecardiaciron,determinedbyMRI,isreportedbyT2*.Thelowerthenumber,themoretheiron.AcardiacT2*greaterthan20msisnotassociatedwithiron-inducedcardiacdysfunction.AcardiacT2*between10and20msindicatesexcessironintheheartandrepresentsawarningforpotentialcardiacdysfunction.IftheT2*islessthan10ms,theriskofcardiacdysfunctionishigh,andtreatmentshouldbeconsideredemergent.

Underfullchelationwithdeferoxamine,about50percentofliverironcanberemovedinfourtosixmonths.Ittakesabout17monthstoremovehalfoftheheartiron.

5.1InitiationofchelationIngeneral,chelationshouldbestartedassoonasthepatientbecomessignificantlyironloaded.Sinceremovalofironfromnormaltissuescanresultintoxicityfromover-chelation,itisimportanttodelaythestartofchelationuntilthepatientissignificantlyironloaded.Sinceironloadingoccursmuchfasterthantoxicitydevelops,thisdelaywillnotputthepatientindanger.

GeneralrecommendationsfortreatmentwithironchelationarepresentedinTable5.1.Thedecisionpointsarebasedontotalamountofbloodtransfused,ferritinlevels,anddegreeofironloadingbasedonliverironconcentration(LIC).Liverironismeasuredbybiopsy,MRI,orSQUID.

Chelationtherapyshouldbestartedafteraboutoneyearofchronictransfusions.Thiscorrelateswithaserumferritinofapproximately1,000ng/mL.LICisthebestmeasureoftotalironloading.LICshouldbeatleast3,000µg/gdryweightbeforestartingchelation.Thegeneralguidelinesforironchelationaregraduallychanging.Manyexpertsareincreasingthetherapyinordertomaintainalowersteady-statebodyironstore.Whilelong-termprospectivedataislimitedontheseaggressiveprotocols,itisfeltthatmoreaggressivetherapymaybemoreeffectiveinpreventingiron-inducedorganinjury.Thisneedstobebalancedwiththedrugtoxicity.Whilethestandardrecommendationshavebeentomaintainaferritinbetween1,000and2,500ng/mL,severalprogramsareaimingtomaintainserumferritinat500ng/mLinadultpatients.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 6

Notes:

Ferritinmaybeamisleadingmeasurement;liverironisthemuchmoreaccurateone.Youngchildrenmayhavemoretoxicitywithchelatorsandmayneeddoseadjustment.

Therapeuticindex(TI)isoftenusedindeterminingthedeferoxaminedosewhenferritinisanalyzed.Thetherapeuticindexisequaltothemeandailydose(mg/kg)/serumferritin(mg/l).ThetargetistomaintainthevalueofTIatunder0.025.Themeandailydoseofdeferoxamineiscalculatedbymultiplyingthedoseadministeredineachtreatmentbythetotalnumberofdosesadministeredperweek,thendividingbyseven—thenumberofdaysinaweek.FerritinmeasurementsshouldbeaccompaniedbyperiodicLICmeasurements.

Consultationwiththalassemiaspecialistsshouldbeconsideredindoseadjustments.

Nontransfusedorintermittentlytransfusedpatientsshouldreceivechelationtherapyandhavetheirironstorescloselymonitored.Theirdosingshouldbemodifiedonanindividualbasiswithconsultation.

LICreferstodryweight,whichisthestandardmethodforreportingliverironbyliverbiopsyandMRI.Thewetweightconversion,whichisadirectmeasurementdeterminedbySQUID,isachievedusingadivisorof5to6.

Liver iron concentration (LIC)

Ferritin Recommended chelation

Monitoring Comments

<3,000µg/g <1,000ng/mL Lowerthedoseat<1,000ng/mLandholdmedicationat<500ng/mL

Monitorferritinmonthly;startreduced-dosechelationwhenferritingoesupto500ng/mLandfulldoseat1,000ng/mL,dependingonageandriskfactors

3,000to7,000µg/g 1,000to2,500ng/mL Maintainexistingtherapy Monitorferritinevery3months

Notechangesintrends.Moreaggressivetherapymaybeindicated,dependingonorgandysfunction.

>7,000µg/g >2,500ng/mL Intensivechelation Monitorferritinevery2to3months,andcheckLICwithin6months

Notechangesintrends.Moreaggressivetherapymaybeindicated,dependingonorgandysfunction.

Excesscardiacironwithoutcardiacdysfunction;T2*<20ms

Intensivechelation Monitorferritinevery2to3months,andcheckLICwithin6months

Intensivechelationconsistsofatleast12hoursofdeferoxamineperday,7daysperweek,ormaximumtolerateddeferasirox,aswellasconsiderationofcombinationtherapy.

Iron-inducedcardiomyopathy,T2*<20ms;orT2*<10mswithoutcardiomyopathy

Maximumchelation:24-hourdeferoxaminetherapyincombinationwithdeferiprone(alterna-tively,incombinationwithdeferasirox—limitedcom-binationdataavailable)

Monitorferritinevery2to3months,andcheckLICwithin6months;monitorcardiacfunctionwithin6months

Intensivechelationconsistsofatleast12hoursofdeferoxamineperday,7daysperweek.Combinationtherapywithdeferiproneormaximumtolerateddeferasiroxisrecommended.

Iron-inducedcardiomyopa-thy,T2*<20ms;orT2*<10mswithoutcardiomy-opathy

Maximumchelation:24-hourdeferoxaminetherapyincombinationwithdeferiprone(alter-natively,incombinationwithdeferasirox—limitedcombinationdataavailable)

Monitorintensivelywithcardiologyconsultationandironchelationspecial-ist

Table5.1:GuidelinesforIronChelationTherapyandMonitoring

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 7

Ininfants,chelationtherapymaybedelayedbeyondthefirstyearbecauseofknowntoxicityofchelatorsinyoungchildren.

Startingadailyregimenofchelationtherapy,whetheroralorparenteral,representsasignificantcommitmentanddisruptionoflifestyle.Beforecommencementofchelation,thepatientandfamilyshouldbetaughtaboutthereasonsforthetreatment,aswellashowtoprepareandtakethemedication.Acontinuededucationandsupportprograminvolvingthenursepractitioner,achildlifespecialist,andsocialworkerscanenhanceacceptanceandcompliancewiththiskindofchronictherapy.

Theadequateassessmentofironstoresbeforetheinitiationoftherapyisimportant;itallowsdeterminationofefficacyandappropriatedosing.PriortotheavailabilityofMRIandSQUID,quantitativeliverironmeasurementsweredeterminedbyliver

biopsy.ThismethodremainsacceptablewhenMRIorSQUIDisnotaccessible.However,noninvasive,quantitativeliverironassessmentsbyMRIorSQUIDperformedatanexperiencedcenterareasaccurateandlesspronetomeasurementerrorandshouldbeusedinplaceofbiopsywheneverpossible.WhilemostMRImachinesarecapableofmakingthesemeasurements,theyrequirespecialsoftwaremodificationandcalibrationtoproduceaccurateandreliableresults.

5.2TreatmentwithironchelatorsThebestironchelationregimenistheonethepatientiscompliantwith.Compliancewithchelationtherapyisthecriticalfactorintreatingironoverload.IntheUnitedStates,therearethreeFDA-approvedironchelators:deferoxamine(Desferal),deferasirox(Exjade),anddeferiprone(L1)

Table5.2:IronChelatorProperties

Agent Route Half-life of drug (hours)

Schedule Clearance Side effects and toxicity

Deferoxamine(Desferal)

Slowinfusion:intravenousorsubcutaneous

0.5 Eightto24hoursperday,5to7daysperweek

Renal,hepatic Dermatological,ocular,auditory

Deferasirox(Exjade) Oral 12to16 Oncedaily Hepatobiliary Gastrointestinal,renal,hepatic

Deferiprone(L1) Oral 2to3 Threetimesperday Renal,cardiac Hematological(neutropenia,agranulocytosis),arthropathic

5.2.1 Treatment with deferoxamine (Desferal)Deferoxamine(Desferal,DFO)isthemoststudiedironchelator.Ithasanexcellentsafetyandefficacyprofileandhasshownadramaticeffectonincreasingsurvivalratesanddecreasingmorbidity.

Deferoxaminehasapoororalbioavailability.Itisadministeredsubcutaneously,intravenously,oroccasionallyintramuscularly.Ithasashorthalf-life,necessitatingadministrationatleasteighttotwelvehoursdaily,fivetosevendaysperweek.Generally,ironisremovedmuchmoreefficientlywhendeferoxamineisinfusedoveralongerperiodoftime.Italsocanbegivenintravenously24hoursperdaywhenindicated.Theprimary—ifnottheonly—reasondeferoxamineisineffectiveinsomepatientsispoorcompliance.

Deferoxamineiseffectiveinchelatingnon-transferrinboundironandcanreversecardiacarrhythmiasandleft-ventriculardysfunction,although,combinationchelationtherapyisusuallyrecommendedforpatientswithcardiacdysfunction.

Thedosingofdeferoxaminedependsupontheweightofthepatient,thedegreeofironoverload,andthepresenceofiron-relatedcardiotoxicity.Sideeffectsofdeferoxamineandchelatorsingeneralaregreaterinpatientswithlimitedironstoresandinchildrenundertwotothreeyearsofage.Forthisreason,deferoxaminetreatmentisusuallywithhelduntilaftertwoyearsofage.

Ascorbicacid(vitaminC)increasestheexcretionofironinthepresenceofdeferoxamine.Itisstartedaftertheinitialmonthofdeferoxaminetherapy.Itisgivenorallyinthedoseof2to4mg/kgperday(100to250mg)andtakensoonafterthedeferoxamineinfusionhasbeeninitiated.Patientsshouldbecautionedagainstexcessiveascorbateintakewhendeferoxamineisnotbeinginfused.Ascorbatereleasesironandhasbeenassociatedwithincreasedcardiacdamagewhentakenintheabsenceofanironchelator.

Subcutaneousdeferoxamineshouldbeadministeredat30to60mg/kgforeighttofifteenhours,fivetosevendaysornightsperweek.Deferoxamineshouldrunoveraminimumofsixhours(orlonger)atamaximumof15mg/kgperhour.

Highdosesofdeferoxamine—morethan4to6mgover24hours—shouldnotbegiven.Increasingthedosebeyondthispointcancausedeferoxaminetoxicity.Overallsurvivalisrelatedtothenumberofhoursperweekthatdeferoxamineisinfused.Deferoxamineismoreeffectivewhenalowerdoseiscirculatedthroughthebodyoveralongerperiodoftimethanwhenahigherdoseiscirculatedoverashortperiodoftime.Therefore,timeofexposureismoreimportantthantotaldoseoncedosesof60mg/kgperdayarebeingutilized.

Startingatalowernumberofdaysperweekandadvancingtofivetosevenmayhelpthefamilyadapttoandacceptthenewtherapy.Treatmentsevendaysaweekshouldbethegoal.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 8

Asmall-gaugeneedleinthethighorabdomenisusuallyused.Itisimportantthattheneedlebelongenoughtogothroughthedermis.Intradermalinfusionispainfulandresultsinblisters,swelling,andreactions.Thesitesshouldberotatedtopreventreactionandfatnecrosis.(AlsoseeSection7.6,regardingtreatmentsuggestionsforlocalreactions.)

Additionalintravenousdeferoxaminecanbegivenduringeachtransfusion.However,itsefficacyislimited,andtoxicityissignificantwhengivenoverashortperiodoftime.Byitself,thismodeofadministrationisinadequateforcontrolofironoverload,andadditionaldailydosingasdescribedaboveisalwaysnecessary.

Deferoxamineat60mg/kgperday,24hoursperday,7daysperweek,maybeindicatedwithpatientswithseverehemosiderosisandvitalorgandysfunction.PatientswithaT2*lessthan10msoraliverirongreaterthan30mg/gdryweightarecandidatesforthistherapy.Ifthepatienthascardiacarrhythmiaorleft-ventriculardysfunction,thistherapyismandatoryandmustbeemergentlystarted.Deferoxaminecanbeadministeredintravenouslyusingacentralline.Theintravenoustherapeuticdoseis60mg/kgperday.Insuchhighriskpatients,combinationtherapywithdeferiprone—oralternatively,deferasirox—shouldbeutilized.Ifthepatienthassymptomaticcardiacdiseaseduetoiron,acardiologistwithspecialexpertiseincardiacironoverloadshouldbeconsulted.Certainstandardcardiactreatmentsrecommendedbycardiologistsunfamiliarwithironoverloadcanbedeleterioustoapatientinheartfailureduetoironoverload.

5.2.2 Treatment with deferasirox (Exjade)Theoralironchelatordeferasirox(Exjade)istakenasadispersibletabletonceaday.ItwasapprovedinNorthAmericainNovember2005forthetreatmentoftransfusionalironoverload.Theclinicalexperienceisnotasgreataswithdeferoxamine.However,thedrughasbeenusedinthousandsofpatientsandhasbeenshowntobeaneffectiveironchelatorandtohaveanacceptablesafetyprofile.IthasbecomethemostcommonironchelatorusedinNorthAmericaandmanypartsoftheworldbecauseofitsonce-per-dayoraldosage.

Deferasiroxhasgoodoralbioavailabilityandalonghalf-lifesuitableforonce-dailydosing.Ingeneral,deferasiroxappearssimilartodeferoxamineinloweringliverironandserumferritinlevelsinadose-dependentmanner.Thestartingdoseis20mg/kgperday.Thedoseisoftenincreasedto30mg/kgperday,andincertaincases,to40mg/kgperday.Afterstartingtherapy,increasethedoseby5to10mg/kgeverythreetosixmonthsbasedonironstores.Adoseof20mg/kgperdayiseffectiveinestablishingnegativeironbalanceinsomepatients.However,ahigherdoseof30to35mg/kgperdayisusuallyrequiredtoestablishnegativeironbalance.Recentdataindicatesthatdeferasiroxindosesofatleast30mg/kgperdaysignificantlyimprovescardiaciron.Toxicitieslikeskinrash,nausea,anddiarrheaaredose-related,sostartingat20mg/kgperdayandworkingupwardcanhelpdeveloptolerancetothemedication,eventhoughthepatientwilllikelyrequireahigherdoseatsomelaterpoint.Ferritinisusuallythemostfrequentparameterusedtomonitorefficacy.Itisimportanttocheckferritinwitheachtransfusionandusetheaveragechangefromthreetofivemeasurementstojudgeefficacy.(AlsoseeSection6,onmonitoringironoverload.)

Thesafetyprofileofdeferasiroxissimilarinpediatricandadultpatients.Instudiesofdeferasiroxinchildrenlessthantwoyearsold,themedicationappearstobesafe,butthestudiesarelimited.Themostcommonsideeffectsincludegastrointestinalsymptomssuchasnauseaandvomiting,diarrhea,andabdominalpain;mildskinrashisthesecond-mostcommonsideeffect.Thesesideeffectsoftenresolvewithtimeandaredose-related.Ifgastrointestinalsymptomsaresignificant,thedosecanbeloweredorstoppedandthengraduallyincreased.Dividingthesamedoseintotwice-dailyadministrationmaydecreasethesesideeffects.

Themostserioussideeffectwithdeferasiroxispotentialkidneydamage;amildnonprogressiveriseinserumcreatinineisseeninaboutone-thirdofpatients.Thedoseshouldbeloweredifthereisanincreaseinserumcreatininethatexceeds33percentofthebaselineorgreaterthantheupperlimitofnormalontwoconsecutivetests.Creatininelevelsshouldbemonitoredmonthlyandrepeatedmorefrequentlyifrisesarenoted.Renaltubularproblems,includingsevererenaltubularacidosis,havebeenseen.

Deferasiroxisadispersibletabletthatcanbesuspendedinwater,applejuice,ororangejuice.Itshouldbetakenonanemptystomach30minutesbeforeoraftereating.Recentdatasuggeststhattakingdeferasiroxwithfoodisacceptableinpatientswhohavedifficultywithdeferasiroxonanemptystomach.

Aswithdeferoxamine,deferasiroxdoesn’tworkifthepatientdoesnottakeit.Whilethereisimprovedqualityoflifewiththeoralchelator,complianceremainsaproblem.Ifapatientseemstonotberesponding,complianceshouldbethefirstissueaddressed.Eventhoughitisaonce-dailydose,thepreparationoftheliquidtakestimeandplanning.Thedrugissuspendedintheliquidandhasachalkytexture.Somepatientsletitsettlebeforedrinking,discardingthescum(theactualdrug)atthebottom.Othersdescribeforgettingtoputthetabletinliquidinthemorningbeforetheirshowersowhentheyarereadyforschoolorwork,thedrugisnotready,andtheyskipit.Itmaytakesomecreativityonthepartoftheteamtohelpthepatientgetpastsomeofthesebarriers.Aswithdeferoxamine,somepatientshaveaseriouspsychologicalaversiontotakingthemedicineandmayneedprofessionalcounseling.Addressingcomplianceissuesisprobablyoneofthemostimportantadvantagesofhavingacomprehensiveteamtohelpthepatientwithachronicdisease.

5.2.3 Treatment with deferiprone (L1/Ferriprox)Deferiprone(L1,Ferriprox)hasbeenapprovedforuseinseveralcountriesformanyyearsandrecentlyreceivedFDAapprovalforpatientswhoarenoteffectivelychelatedwithstandardtherapy.Deferipronereducesormaintainstotalbodyironstoresinthemajorityofpatients.Studiessuggestthatdeferipronemaybemoreeffectivethandeferoxamineinreducingcardiaciron.Deferiproneincombinationwithdeferoxaminemaydecreasetheriskofcardiacdiseaseandimprovecardiacfunction.StudiesinEuropesuggestthatdeferiprone,particularlyincombinationwithdeferoxamine,isbeneficialinpatientswithironcardiomyopathyandcardiacdysfunction.Thestandardtherapeuticdailydoseis75mg/kggiventhreetimesdailyandmaybeincreasedto100mg/kgthreetimesadayinhigh-riskpatients.

Themajorsideeffectsofdeferiproneincludegastrointestinalsymptoms,jointpain,andneutropenia.Duetotheriskof

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 9

agranulocytosisandassociatedraredeaths,weeklywhitebloodcellcountsarerequiredforallpatientsreceivingthisdrug.Zincdeficiencymayoccurparticularlywithdeferiproneandrequiresupplementation.

5.3PatientswithsignificantironoverloadSomepatientshaveparticularlyhighironloads,ahighpresenceofcardiaciron,orotherorgantoxicitythatmayrequiremoreaggressivetreatment.Therearemanywaystoapproachthesepatients,andtreatmentsneedtobetailoredtoachievereductionofironinawaythatisacceptabletoeachpatient.Withtheavailablyofseveralchelators,anumberofnewapproacheshavebeensuggested.Thereisnoextensiveexperiencewithanyofthem.Somearepresentedbelow.

5.3.1 High-dose, continuous deferoxamineAnaggressivechelationregimenisrecommendedwhenliverironisgreaterthan20mg/gdryweight,orcardiacT2*islessthan20.Ahigher—butnotatoxic—doseofdeferoxamineisrecommended.Intensificationoftreatmentcanbeaccomplishedbyadministeringcontinuousintravenousdeferoxamine(viaacentralintravenousline,ifpossible)inthehospitalorinanoutpatient/dayunit.Aminimumof72hourscontinuous,onetotwotimesamonth,in addition toregularuseofsubcutaneousdeferoxaminehasbeenrecommendedtoincreaseironremoval.Thecontinuousregimenalonemaycontrolliverironconcentrationbutwillallowdevelopmentofcardiaciron.Intravenoustreatmentisgivenat50to100mg/kgperday(withamaximumdoseof6gperday).Thisregimenshouldbecontinueduntiltheferritinlevelislessthan2,000ng/mLontwoconsecutiveoccasions.Alternativeregimensincludedailyintravenousadministrationofdeferoxamine,orcontinuousdeferoxamineviapercutaneouslineoranindwellingvenousaccessdevice.Inallsuchtreatment,high-dose,continuoustreatmentsrequirecarefulmonitoringforsignsoftoxicity.

5.3.2 Combination therapy: deferoxamine and deferasiroxCombinationtherapyofdeferoxamineanddeferasiroxispresentlybeingstudiedinNorthAmerica.Inover30patientsfollowedforoveroneyear,combinationtherapyappearedsafeandeffectiveinloweringbodyandcardiaciron.Largermulticentertrialsarenowunderway.

5.3.3 Combination therapy: deferoxamine and deferiproneCombinationtherapywithdeferoxamineanddeferiproneisincreasinglybeingusedworldwide.Treatmentprotocolsincludebothsequentialandsimultaneousadministrationofbothdrugs.Pilotstudiesshowthatsequentialtherapy(forexample,threedaysofdeferoxamineandfourdaysofdeferiprone)appearstoimprovecomplianceandmaintainironlevels.Simultaneoustherapy(bothdrugsdaily)improvescardiacfunctionbetterthaneitherdrugalone.Carefulmonitoringforincreasedsideeffectsisimperative.

6TheUseofImagingtoMonitorIronOverloadandChelationTherapy

LICisonewaytodeterminetotalbodyironcontent.WhileliverbiopsydeterminationofLIChasbeenrecommendedforyears,recentprogresswithMRIimagingprovidesanexpedientandnoninvasivewaytodirectlymeasureLIC,aswellasironconcentrationinmultipleorgans.AFerriScanisacommerciallyavailableandvalidatedsystemforquantitativeMRImeasurementsofiron.TheSQUIDisalsoaneffectivewaytononinvasively

monitorLIC.TheLICisreportedinwetweightanddryweight.TheLICinpatientswiththalassemiashouldalwaysbemaintainedbelow7,000µg/gdryweightand1,100µg/gwetweightinordertoavoidiron-inducedorgandamage.

Serumferritinisaconvenientwaytomonitorironoverload.Themagnitudeanddirectionofchangeinferritinisareasonablepredictorofthemagnitudeanddirectionofchangeintotalbodyiron.Whilethereisabouta70percentcorrelationofferritinwithLICinpopulationstudies,thereistremendousscatterintherelation,soferritinisapoormarkerofabsoluteironcontentinanindividualpatient.

TheintermittentmeasurementofLICbybiopsy,MRI,orSQUID,inadditiontomeasurementofferritinwitheachtransfusion,istherecommendedwaytofollowchangeinironburdeninchronicallytransfusedpatients.Itisimportanttousetheaveragechangeof3to5ferritinmeasurementstodeterminethedirectionofchangeiniron.Becauseofthesensitivityofferritinlevelstoinflammation,vitaminC,andiron,changesbetweentwoconsecutivemeasurescanbeverymisleading.Ifthereseemstobelittlechangeinferritin,inspiteofgoodcompliancewithchelation,changeinironstatusshouldbeverifiedbyliverironmeasurementbeforemakingdrasticchangesinchelationtherapy.

Theavailabilityofnoninvasivewaystodirectlymeasureironinseveralorganshasledtoabetterunderstandingofhowironisstoredinthebodyanddifferencesinironstorageamongindividualpatients.Itwasoncethoughtthatliverironcorrelatedwithheartiron,butduetofurtherresearch,itisnowclearlyunderstoodthatirontransportintoandremovalfromvariousorgansoccursatdifferentrates.Wealsoknowthatferritinlevelscanbemisleadingandthatperiodicdirectmeasurementofliverironcanbeofgreatbenefitinmonitoringpatients.Newironmeasurementtechniqueshavehadadirectimpactonmanagementofironoverload.Forexample,itisnowknownthatapatientcanalmostcompletelyemptytheliverofironandreduceferritintoverylowlevelseventhoughsignificantamountsofironmayremainintheheart.Thismeansthatpatientswithsuchironlevelsmustcautiouslyproceedwithchelationtoemptytheheart,whentheymightotherwisehaveconsideredstoppingorreducingchelationtreatment.

RecommendationsforLICgoalsarechanging.TherecommendationsinTable5.1arebasedonpreviouslypublishedresultsandmayneedmodificationasnewdataispublished.Someleadingexpertssuggestthattheserecommendationsshouldbemodifiedandlowerliverandferritinlevelsshouldbeusedtoincreasedosing.Infact,thereisemergingdatathatsomecomplicationssuchasendocrinedysfunctionmayrespondtoloweringironlevelstonearnormal.Sincerecommendationsareevolving,wehaveincludedthestandardacceptedguidelines.LowerLICandferritinlevels,asindicatorsfordoseadjustment,shouldonlybeattemptedbyproviderswhoareveryfamiliarwiththetoxicitiesofover-chelationandcanseriallymonitorlivertissueiron.Suchlevelsshouldnotbeattemptedusingferritinmonitoringalone.

6.1MonitoringtheefficacyofchelationtherapyinthepresenceofironcardiomyopathyCardiomyopathyisthemostlife-threateningoftheiron-related

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 10

complications.Theheartoftenremainsiron-freeformanyyears.Oncecardiacironloadingstarts,itprogressesveryrapidly,sincethepresenceofironintheheartincreasestherateofinfluxofiron.Removalofironfromtheheartprogressesveryslowlywithahalf-lifeofapproximately17months.EventhoughthereisnolinearcorrelationbetweenLICandcardiaciron,theheartoftendoesnotreallybegantounloaduntiltheLICdropstoverylowlevels.Thecornerstoneofeffectivetreatmentofironcardiomyopathyiscontinualexposuretochelation.Thiscanreducecardiacarrhythmiasanddysfunctionevenbeforetheheartbeginstounloadiron.TheactualdoseofchelatordependsprimarilyontheLICandmustbereducedastheLICapproachesnormalinordertoavoidsymptomsofover-chelation.(AlsoseeSection7.7,onover-chelation.)However,inthepresenceofcardiaciron,andespeciallyifthereiscardiacdysfunction,chelationcannotbestopped.

Inthepresenceofcardiacsymptoms(arrhythmiaordecreasedleftventricularejectionfraction)thepatientmustbeexposedtochelator24hoursperday,7daysperweek.Thistreatmentisconsideredtobeemergent.Multipledrugtherapy—inparticular,therapyinvolvingdeferiprone—shouldbeconsideredinthiscircumstance.Othercardiacmedicationsmayberecommendedbythecardiologist.PatientswhosecardiacT2*islessthan10msandwhodonothavecardiomyopathyshouldreceivemaximumtherapy(seeTable5.1).ConsultationwithanironchelationspecialistisstronglyrecommendedinthemanagementofallpatientswithanabnormalcardiacT2*.Sinceseveralpatientsmayhavelowbodyironandhighcardiaciron,ironchelationtherapydecisionsmaybecomplex.LiverironmeasurementsshouldalsobecloselymonitoredwitheachcardiacT2*.Itisveryimportanttonotethatotherthings,suchasmyocarditis,vitaminB

1deficiency,

andvitaminDdeficiencycanalsoaffectcardiacfunctionandneedtobeexplored,particularlyifthereisnocardiacironandfunctionremainsabnormal.

7AssessmentofChelatorSideEffectsandToxicity

Theprimarysignsofchelatortoxicityarehearingloss,temporarylossofsight,cataracts,renaldysfunction,growthfailure,andsymptomsrelatedtoirondeficiency.Sideeffectsfromdeferoxaminetoxicityincludeauditoryandvisualchanges,andmayoccurwhentotalbodyironislowbuthighdosesofdeferoxaminearestillbeingused.Thetablebelowindicatestoxicity-monitoringparameters.Thefollowingshouldberoutinelymonitored.

7.1AudiologyAbaselineformalaudiologyexamshouldbegivenpriortostartingachelator.Anyhistoryofhearingdifficultyortinnitusshouldpromptaphysicalexamofthetympanicmembranesandformalaudiologytesting.

Inquireabouthearingproblemsateachmonthlyvisit.Ascreeningaudiogramshouldbeperformedincliniceverysixmonths.Referpatientsforformalaudiogramassessmentevery12months,ormoreoftenifapatientisunabletoundergoascreeningtestinclinic.

Ifthereisnewonsetofhearinglossortinnitus,thechelatorshouldbestoppedandtheaudiogramrepeated.Thetestingshouldbe

confirmedwithinamonth.Thechelatorcanberestartedifthehearingchangeshaveimproved.Reevaluationofironstatusmaybenecessary.

7.2OphthalmologyInquireaboutdecreasedvisualacuityateachvisit—especiallychangesincolorperception.Changesincolorvisionareoftenthefirstsymptomsofover-chelationAnannualevaluationbyanophthalmologistshouldbeperformedtoruleoutcataracts,decreasedacuity,nightblindness,anddecreasedvisualfields.Anyvisionchangeshouldbeexaminedwithcausesunrelatedtoironinmind,aswell.Areevaluationofthechelationregimenshouldbedoneifanyophthalmologicabnormalitiesarefound.

7.3NephrologyCreatinineandBUNwiththeserumchemistry,urineprotein/creatinine,andmicroalbuminshouldbemonitoredmonthlyforpatientsondeferasiroxandeverythreemonthsforpatientsondeferoxamine.

7.4NeutropeniaNeutropenia,orlowneutrophilcount,mustbemonitoredweeklywithaCBCforpatientsondeferiprone.

7.5GrowthEvaluatepatientsforevidenceofgrowthdelay.Routinelyrecordheightandweightmonthlyandcalculateannuallygrowthvelocity.Measuresittingheighteverysixmonthstoassesstruncalshortening.Tibialandspinalradiographsshouldbeevaluatedforevidenceofmetaphysealcartilaginousdysplasiainyoungerpatientswithevidenceofgrowthdelay.

7.6LocalandallergicreactionsLocalreactionsatthedeferoxamineinjectionsitethatareurticarialinnaturewillusuallyrespondtoincreaseddilutionofthedeferoxamineby25to30percent.Hydrocortisoneshouldbeusedonlyinseverecasesandunderthedirectionoftheconsultinghematologist.Insomecases,treatmentwithantihistaminesmaybehelpful.

Severe,life-threateningallergicreactionsmayoccur.Patientswhoreportsystemicallergicsymptomsshouldbeobservedandpossiblychallengedinclinic.Desensitizationprotocolshavebeenusedsuccessfullyonsomepatients.Whendesensitizationhasbeenaccomplished,itiscriticalthatthepatientdoesnotstopthemedication,asitmaynecessitatereinstitutionoftheentiredesensitizationprocess.Withtheavailabilityofalternativechelationdrugs,changingchelatorsmaybeabetteroptionthandesensitization.

7.7Over-chelationPersistentlowserumferritinlevels(below500ng/mL)inthefaceofregularchelationarenotoptimalduetotheincreasedtoxicityofdeferoxamine,particularlyinchildren,andpresumablydeferasirox,atlowlevelsoftotalbodyiron.ThechelationprogramshouldbemodifiedandtheLICevaluated.Inselecthigh-riskpatients,verylowironlevelsaremaintainedbutconsultationwithexpertsinironchelationisrequiredduetotoxicity.Lowlevelsofzinc,copper,selenium,andionizedcalciumcanalsobeindicatorsofdeferoxaminetoxicity.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 11

Table7.7:ChelatorToxicityMonitoring

8LiverandGallBladderDiseasesLivertoxicitycanoccurasadirectconsequenceofirontoxicity,fromtransfusion-acquiredhepatitis,and/orfromothercausesofliverdiseasesuchasmedications,livertoxins,autoimmunereactions,ormetabolicdisease(Wilson’sdisease,alpha-1antitrypsin).Liverfunctionandhepatitisserologyshouldberoutinelyscreenedinthalassemiapatientsonchronictransfusionasdescribedbelow.

8.1ScreeningforhepaticdysfunctionAhepatitisBsurfaceantibodyshouldbedocumentedattheinitialscreeningofthepatient.PatientsshouldhaveapositivehepatitisBantibody.Thiswillusuallyoccurfollowingavaccinationoraninfection.Ifitisnegative,thenasurfaceantigenandcoreantibodyshouldbemonitoredannuallyuntilpatientsdemonstratesurfaceantibody,eitherfromresolvedinfectionorvaccination.

AnnualhepatitisCantibodyshouldalsobechecked.IfthehepatitisCantibodyscreenbecomespositive,PCRforhepatitisCshouldbemeasured.

Everythreemonths,bilirubin,AST(SGOT),ALT(SGPT),andalkalinephosphataseshouldbemeasuredviaabloodtest.IftheALTiselevated,itshouldberepeatedintwoweeks.IftheALTremainselevatedattwoweeksorifitisintermittentlyelevatedoveraperiodofthreemonths,acompleteevaluationforcausesofhepatitisshouldbeperformed.Suggestedevaluationmightincludethefollowing.

1. PT,PTT,albumin,albumin/globulinratio2. HepatitisAIgM(ifnotpreviouslypositiveorknownto

beimmune)3. HepatitisBDNAquantification4. HepatitisCantibody(iftheantibodyscreenispositive,

viralRNAshouldbedocumentedbyqualitativeTMAassayandloadshouldbemeasuredbyquantitativePCR)

5. CMVtiters(IgG,IgM),CMVPCRand/orurinecultureforCMV

6. EBVtiters(PCRforreactivation)7. BaselineliverbiopsyifPCRispositiveforhepatitisC,to

evaluateseverityofdiseaseandneedfortherapy8. Autoimmunehepatitis,biliaryobstruction,metabolic

disease,andtoxichepatitis

8.2MonitoringpatientswithdocumentedhepatitisorhepaticdysfunctionOncehepaticdysfunctionhasbeendocumented,hepatologyconsultationisimportant.Thecombinationofhepatitisandironoverloadincreasestheriskofliverdamage.Rapidremovalofironandtreatmentofviralhepatitisshouldbeconsidered.

Allpatientswithhepatitisshouldbeevaluatedwithaliverbiopsy.PatientswhohavehepatitisBorCshouldbemonitoredforhepatocellularcarcinomawithalfa-fetoproteinandhavehepaticultrasoundevaluationsbiannually.Thisisparticularlyimportantifthereisevidenceofcirrhosisonthebiopsy.EarlytreatmentisrecommendedfornewlyacquiredinfectionwithhepatitisC.

Deferoxamine Deferasirox Deferiprone

Complete blood count (CBC);absolute neutrophil count (ANC)

Weekly

Liver function tests (LFTS) Every3to4weeks Every3months

Creatinine Every3months Every3to4weeks Every3months

Urine protein/creatinine Every3months Every3to4weeks

Urine microalbumin/Creatinine Every3months Every3to4weeks

Urine glucose Every3to4weeks

Zinc, copper, calcium, and magnesium Annually Annually Annually

Electrolytes Every3to4weeks

Eye exam Annually Annually Annually

Audiogram Annually Annually Annually

Sitting height Biannually Biannually Biannually

Height/weight Every3to4weeks Every3to4weeks Every3to4weeks

Clinical symptoms (nausea, diarrhea, color-vision change) Every3to4weeks Every3to4weeks Every3to4weeks

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 12

Liverbiopsyresultsshowingmoderateand/orprogressingfibrosisareanindicationfortreatment.

8.3EvaluationandtreatmentforhepatitisCAdecisiononwhethertorecommendtreatmentofestablishedhepatitisCdependsonclinicalstatus,severity,orprogressionoffibrosis.Treatmentconsistsofpegylatedinterferonalfagivenasasubcutaneousinjectiononceaweekandoralribavirintwicedailyforpatients18yearsandolder.(Aninterferonalfaandribavirincombinationisapprovedforchildren.)Recentdatasuggeststheadditionofproteaseinhibitors(suchasboceprevirandtelaprevir)mayfurtherimprovecurerates.

Treatmentwithpegylatedinterferonalfarequiresmonitoringduetosignificantsideeffects,including• neutropeniaandthrombocytopenia• evidenceforhypothyroidism(antithyroidperoxidaseantibody

titerpredictscomplicationsofhypothyroidism)• visionandhearingchanges• cardiacarrhythmiaorfailure• depression

LiverenzymesandhepatitisCquantitativeandqualitative(TMA)PCRshouldbemonitoredforresponsetotreatmentatone,two,three,six,twelve,andeighteenmonths.Ribavirinrequiresclosemonitoringofthehemoglobinbecauseofincreasedriskofhemolysis.Patientsonribavirinrequireincreasedtransfusionstoavoidcomplicationsrelatedtorapidlyworseninganemia—particularlycardiacevents.Anincreaseinchelationisfrequentlynecessarywithanincreaseinbloodrequirement.

8.4EvaluationandtreatmentforhepatitisBAdecisiononwhethertorecommendtreatmentofestablishedhepatitisBdependsonclinicalstatus.Aliverbiopsyshouldbeobtainedbeforeinitiatingtreatment.Patientswithindicesofactiveviralreplication(HBVDNA),e-antigenstatus,liverinjury(elevatedtransaminasesand/oractivehepatitisonbiopsy),orfamilyhistoryofhepatocellularcarcinomaarecandidatesfortherapy.

Severaldrugs(interferonalfa,pegylatedinterferonalfa,lamivudine,adefovir,entecavir)areFDA-approvedforuseinadults.(Someareapprovedforchildren.)Consultwithyourhepatologistregardingtreatmentoptions.

8.5GallbladderdiseaseChronichemolyticanemiasresultinthedevelopmentofbilirubingallstones.Uptotwo-thirdsofthalassemiapatientsdevelopgallstones.Thalassemiaintermediapatientsmaybeatgreaterrisk.Mostpatientsremainasymptomaticanddonothavecholecystitisorcholangitis.Surgicalremovalofgallstonesshouldbereservedforthesymptomaticpatient.

9EndocrineDysfunctionEndocrinedysfunctionduetoirondepositionandtoxicitytotheendocrinetissueisacommoncomplicationofironoverload,causingsignificantmorbidity.Gonadalfailure,sterility,andgrowthfailurearecommon,aswellasosteopeniaandosteoporosis.Diabetesmellitusmayalsodevelopinpatientswithironoverload.

9.1RoutineendocrinescreeningHeightandweightshouldbemeasuredaccuratelyateachvisit.EvaluategrowthonCDCorWHOcharts.Ethnic-specificchartsareunnecessary.Sittingheightshouldbemeasuredsemiannually.

Annualendocrinologyconsultationandscreeningshouldbestartedatfiveyearsofage,afterthreeyearsoftransfusions,orasotherwiseclinicallyindicated.Thefollowingtestsarerecommendedannuallyorsemiannually.

1. TSHandfreeT42. Cosyntropinstimulationtest(semiannually)3. PTH4. Serumcalcium,ionizedcalcium,andvitaminD5. Fastingglucose(semiannually)6. Oralglucosetolerancetestingasindicatedbyfastingglucose

(seethefollowingsection)7. IGF-1andIGFBP-3toscreenforgrowthhormone

deficiency8. Bonedensity(DXAandCT)9. Traceelements:zinc,copper,andselenium10.VitaminsB

1,B

6,B

12,C,E,andA;alsopyridoxine,carnitine,

methylmalonicacid,andhomocysteine.

9.2Specificendocrinopathies:testingandevaluation

9.2.1 Diabetes mellitusAtwo-houroralglucosetolerancetestshouldbeperformedat10,12,14,and16yearsofage.Theoralglucosetolerancetestshouldbeperformedannuallythereafter.Iffastingserumglucoseisgreaterthan110mg/dL,anoralglucosetolerancetestisindicated.

• Afastingglucosegreaterthan126mg/dLisdiagnosticofdiabetesmellitus.

• Aserumglucoseattwohoursover200mg/dLisdiagnosticofdiabetesmellitus.

• Aserumglucoseattwohoursbetween140and200mg/dLindicatesglucoseintolerance.

• Acasualbloodglucosegreaterthan200mg/dLwithassociatedsymptomssuchaspolyuria,polydipsia,orunexplainedweightlossisdiagnosticofdiabetesmellitus.

Thepatientshouldbereferredtoendocrinologyformanagementofdiabetesmellitusorglucoseintolerance.Patientsdiagnosedwithglucoseintoleranceshouldhavetheirchelationtherapyreviewedandintensified.

9.2.2 Low bone mass (osteoporosis)Initialbone-densityassessmentbydual-energyX-rayabsorptiometry(DXA)orquantitativecomputerizedtomography(QCT)shouldbeperformedateightyearsofageandannuallythereafter,asnecessary.Aslowbonemasshasbeenobservedinallthalassemiasyndromes,itissuggestedthatallpatientswiththalassemiahaveaninitialbonemineraldensityassessment.Thesamemethodofbone-densitymeasurementshouldbeusedforeachevaluation.Thereissignificantinter-methodvariabilityinbone-densitymeasures.Therefore,differentmanufacturersofinstruments(e.g.,HologicversusLunar)ormethodsofassay(DXAversusQCT)arenotacceptableformonitoringofasinglepatientovertime.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 13

Bone-densitymeasurementsareinfluencedbythetrabecularbonedensityandthecorticalthicknessofthebone.Patientswiththalassemiahavebeennotedtohavethinnerbonecortex.Therefore,integraldensitymeasures(DXA)mayprovidedifferentresultsthanatruevolumetricdensitytest(QCT).

Thecurrentaccepteddefinitionoflowbonemassforallpatientsunder50yearsisabonemineraldensityZ-scorebyDXAgreaterthan–2.0.Lowbonemassforchronologicalagemaybeobservedinthespine,thehip,orwholebodyregions.(Thehipregionshouldnotbeusedfordiagnosisinpatientslessthantenyearsold.)

Patientsshouldhaveanannualevaluationofcalciummetabolismandparathyroidfunction:nutritionalhistory,25-hydroxyvitaminD,PTH,andserumcalciumshouldbemeasured.Ifthepatienthasachievedpubertyorispubertal,FSH,LH,andtestosteroneorestrogenshouldbeexamined.

Follownutritionalstatusandkeepupadequatevitaminlevels.Supplementwithupto1,300mgcalciumperdaystartingatnineyearsofage.Patientswithlowlevels(25-hydroxyvitaminDlessthan30ng/mL)orthoseathighrisktodevelopvitaminDdeficiencyshouldbesupplementedwithvitaminD(1,000unitsperday).Nutritionreferralisrecommended.(AlsoseeSection14,onnutrition.)

Endocrinereferralisrecommendedforolderpatientswithestablishedosteoporosis(DXAT-scoreofgreaterthan–2.5)priortotreatmentwithbisphosphonates.Seriousthoughtshouldbegiventothesafetyofbisphosphonateuseinwomenwithchildbearingpotential.

9.2.3 Growth hormone deficiencyEndocrineevaluationisrequiredifthereisa5percentormorefalloffonthegrowthcurveorpoorgrowthvelocityfortheage.Theevaluationshouldincludethefollowing.

1.Adietaryassessmentbyaregistereddietitian2.Laboratorytests:serumcalcium,PO4,albumin,urinalysis,

urinecultureT4,TSH,IGF-1,andIGFBP-33.Aboneageassessment

LowIGF-1orIGFBP-3shouldpromptreferraltoanendocrinologistfordeterminationandtreatmentofgrowthhormonedeficiency.Earlydiagnosis,forsuccessfultreatmentbeforecompletionofpuberty,isrecommended.

9.2.4 HypogonadismTannerstagingshouldbedeterminedeverysixmonths.Girlswithoutevidenceofanadvancingpubertalstageby12yearsandboysby14yearsrequirescreeningwithLH-ICMA,FSH,andestradiollevels.Boneagefilmsshouldbeobtained.

ElevatedLH-ICMAandFSHsuggestprimaryhypogonadism.IfLH-ICMAandFSHlevelsarelowforthepatient’sage,suspectsecondaryortertiaryhypogonadism.

IfLH-ICMAand/orFSHareabnormal,performGnRHstimulation.Considerperformingthistreatmentatage12ingirlsandage14inboys,thenannuallyasclinicallyindicated.(This

shouldtobedonepriortoabloodtransfusiononadifferentdaythantheoralglucosetolerancetest.)

Testosteronelevelshouldbecheckedannuallyinboys,startingintheearlyadolescentyears(atapproximately12yearsold).Ifapatient’stestosteronelevelislow,obtainanendocrineconsultationandstartmonthlytestosteronetreatment.Thestartingdoseisusually50to100mg,givenmonthlyasanintramuscularshot.Thedosewillneedtobeadjustedperiodicallyforthepatient’sageandpubertalstatus,aswellasforasexuallyactiveman.

Estrogenreplacementisrecommendedforamenorrheicadolescentgirlsandadultwomen:Premarinatalowdose(0.0375µgperdayforsixmonths).Thedoseshouldbeadvancedaftersixmonthsforanadditionalsixtotwelvemonths.Afterward,anoralcontraceptivepillmayreplacePremarin.Agynecologicalconsultationandfertilityevaluationisrecommendedforwomenonestrogentherapy.

9.2.5 HypothyroidismTSHandfreeT4shouldbemeasuredatfiveyearsofageorafterthreeyearsoftransfusion.ElevatedTSHanddepressedT4suggestprimaryhypothyroidism.DepressedTSHanddepressedT4suggestsecondaryortertiaryhypothyroidism.Thepatientshouldbereferredforanendocrinologyconsultationandstartreplacementtherapyasindicated.

9.2.6 HypoparathyroidismParathyroidstatusshouldbeevaluatedannuallywithserumcalcium.PTH,and25-hydroxyvitaminDscreening.AnormalPTHwithdecreasedcalcium,oradecreasedPTHwithnormalcalcium,isdiagnosticofhypoparathyroidism.ThepatientshouldbereferredforanendocrinologyconsultationandstarttherapywithvitaminD(useanactivated1,25OHvitaminDproduct)andcalcium.

9.2.7 Adrenal insufficiencyAdrenalstatusshouldbecheckedbiannuallybeginningatagefive,usinganACTHstimulationtest.Thepatientisgiven1µgofcosyntropinintravenously,andcortisollevelsarethenmeasured30and60minutesafterdosing.Acortisolresponseoflessthan17mg/dLisdiagnosticofadrenalinsufficiency.Thepatientshouldbereferredforanendocrinologyconsultationforfurtherevaluationandreplacementtherapy.Ifapatientisacutelyilloratrisk,thecortisollevelismeasuredandastressdosereplacementisgiven.

10CardiacDysfunctionCardiacdiseaseisthemajorcauseofdeathinpatientswithironoverload.Theliverandhearthavedifferentratesandmechanismsofironuptakeandelimination.Asaresult,measurementsofferritinandliverirondonotcompletelypredictcardiacrisk;highvaluesareassociatedwithfuturecardiacironaccumulation,butlowvaluesmaynotnecessarilybereassuring.Recently,doctorsandscientistsusingcardiacMRIT2*havedevelopedameanstorecognizepreclinicalcardiacironaccumulation.Althoughcurrentlyavailableonlyatalimitednumberofthalassemiacenters,cardiacT2*measurementshavetransformedchelationandcardiacmanagementinthalassemia.

Improveddiagnosisofcardiacironhasledtoimprovedchelationstrategies.Deferoxaminedoesremovecardiacironbutis

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 14

significantlymoreeffectivewhengivensixtosevendaysaweekorcontinuously.

Theoralchelatordeferiprone,incombinationwithdeferoxamine,hasdemonstratedexcellentcardiacironremoval,aswellasimprovementsinleftventricularfunction.ItrequiresweeklyANCassessmenttomonitorforneutropeniaandagranulocytosis.

Thereislesscardiacdatafortheoralchelatordeferasirox,butavailablestudiesarepromisingandindicatethatdeferasiroxdoeslowercardiaciron.Severalclinicaltrialsareongoing.Itissignificantthatpatientsnowhavemanymoreoptionsfortherapytocontrolcardiaciron.

10.1CardiacevaluationPriortoinitiationoftransfusions,abaselineevaluationshouldbemade.Thisshouldincludeanechocardiogram,toevaluatepulmonaryarterypressures,systolicfunction,anddiastolicfunction,andabaselineelectrocardiogramtomonitorforventricularhypertrophyandrhythmabnormalities.

Monthlyevaluationsshouldincludeacardiachistory(palpitations,irregularheartrate,chestpain,dyspnea,exerciseintolerance,nocturnalcough,orthopnea,dependentedema,orunexplainedfevers)andexam(systemicorpulmonaryvenouscongestion,gallop,andedema).Anypositivehistoryofcardiacdysfunctionrequiresevaluationbyacardiologist.Serumferritinshouldalsobecheckedmonthly.

Forpatientsovereightyearsofage,anannualevaluationshouldincludeanechocardiogramassessmentofsystolicanddiastolicfunction,aswellaspulmonaryarterypressure(PIandTRjetvelocity).Patientsalsoshouldhaveanelectrocardiogram—cardiacironisassociatedwithnonspecificST-Twavechanges,T-waveinversions,leftventricularhypertrophy,bradycardia,andPRprolongation.ReadingsfromaHoltermonitorneedonlybeobtainedifthereisclinicalsuspicionofarrhythmias.PatientsshouldhavetheircardiacT2*andleftventricularejectionfractionevaluatedwithacardiacMRI,ifavailable.

10.2EchocardiographystandardsThefollowingparametersshouldbeincludedinanechocardiographicevaluation.

1. M-mode:Leftventricularenddiastolicandsystolicdimensions,wallthickness,leftventricularmassandwallstress,shortingfraction,andcorrectedmeanvelocityofcircumferentialshorting

2. PulseDoppler:mitralinflowpeakvelocities(EandA)andmitraldecelerationtime

3. TissueDoppler:measurementsofE,A,andSfromtheatrioventricularringattherightventricularfreewall,leftventricularfreewall,andinterventricularseptum

4. ColorandcontinuouswaveDoppler:severityandvelocityoftricuspidandpulmonicregurgitantjets(estimationofrightventricularandpulmonaryarterypressures)

10.3TreatmentofestablishedheartfailureHeartfailureisdefinedasalowejectionfractionwithevidenceofcardiomyopathy.Allpatientswithheartfailureshouldbeassumed

tohavehighlevelsofcardiaciron,regardlessoftheirliverironorferritin,untilprovenotherwisebycardiacT2*assessment.AcardiacMRIshouldbeperformed,ifpossible,toevaluatetherelativecardiacandliverironloading.Allpatientswithheartfailureshouldbeplacedoncontinuousdeferoxaminetherapy(24hoursperday,7daysperweek)at50to100mg/kgover24hours,administeredeitherintravenouslyorsubcutaneously,dependingonthepatient’saccessandtolerance.Patientswithlowferritinand/orlowliverironshouldstillbemanagedwithcontinuousdeferoxaminetodepleteintracardiacfreeiron,butthedailydosewillhavetobeloweredtoavoidover-chelation.

Combinationtherapywithdeferiproneandcontinuousdeferoxamineisrecommendedforpatientsinheartfailure.Thereislessexperiencewithcombinationtherapywithdeferasirox,butthisisanalternativeoption.Theintroductionofanydualagentshouldoccuraftertheinitiationofcontinuousdeferoxamine.

PatientsinheartfailureshouldbescreenedforthiamineandvitaminDdeficiency,hypoparathyroidism,hypothyroidism,diabetes,andadrenalinsufficiency.EmpiricL-carnitinetherapyat50mg/kgmaybebeneficialforcardiacfunctioninsomepatients.Stressdosesteroidsshouldbeadministeredempiricallyforpatientsintheintensivecareunit.

PatientsshouldbereferredtoacardiologistwhowillgenerallymanagetheircarewithACEinhibition,betablockers,digoxin,anddiuretics.Cardiacarrhythmiasshouldbetreatedwithamiodarone.Ablationisineffective.Arrhythmiasoftenreversewithironchelationtherapy.

Theplacementofautomaticintracardiacdefibrillatorsshouldbestronglydiscouragedbecausethecardiomyopathyisgenerallyreversible.Hearttransplantationshouldalsobestronglydiscouragedunlesstheheartfailurepersistsaftercardiacirondepletion(verifiedbyMRI),orthepatientwillnotsurvivelongenoughforeffectivechelation.

Patientsinheartfailurerequiremorefrequenttransfusions(attwo-weekintervals)tomaintainapre-transfusionhemoglobinofaround12.0gm/dL.Diuretictherapymayberequiredduringtransfusions.Frequentevaluationofserumelectrolytes,calcium,andmagnesiumwhileondiuretictherapyisrequired.

10.4PulmonaryhypertensionPulmonaryhypertensionisaprogressiveincreaseintheresistanceofbloodflowtothelungs.Itiscausedbythedisruptionofnitricoxidemetabolismsecondarytotheintravascularreleaseofhemoglobinfromredbloodcells,directirontoxicityofthevascularendothelium,andback-pressurefromtheheartasitstiffensfromironandfromaging.

Patientswiththalassemiaalsohavevasoactivefragmentsofplateletsandredbloodcellsthatappeartoconstrictpulmonaryvessels.Thiscirculatingcellulardebrisisgenerallyremovedbythespleen—thus,patientswhohaveundergonesplenectomyappeartobeathigherrisk.

Unsplenectomizedthalassemiamajorpatientswhoareregularlytransfusedtomaintaintheirpre-transfusionhemoglobinabove9to10g/dLdonothavemuchcirculatingfreehemoglobinor

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 15

cellularfragments.Pulmonaryhypertensionisrelativelyrareinthesepatients(lessthan10percent)andisusuallyresponsivetoimprovedironchelationstrategies.Incontrast,patientswhohavethalassemiaintermediaorwhoallowtheirhemoglobintofalltolowerlevelsbetweentransfusionsareatmuchhigherriskofpulmonaryhypertension—nearly50to60percentinsomestudies.

10.5TreatmentofpulmonaryhypertensionLiverironandferritinvaluesdonotreallyhelpdiscriminatethemechanismsofpulmonaryhypertension.Physiciansmustdecidewhetherthepulmonaryhypertensionisprimaryorsecondarytoiron-mediatedcardiomyopathy.Theformerconditionwillhaveelevatedcirculatingfreehemoglobin,lowhaptoglobin,lowarginine,elevatedplatelets,andplateletadhesionmarkers.Treatmentconsistsofinitiatingtransfusiontherapyifthepatientisnotalreadyonregulartransfusionsandmaintainingpre-transfusionhemoglobinabove9.5g/dL.Thelatterconditionwillexhibitleftventricularsystolicanddiastolicdysfunction,abnormalcardiacT2*,andcardiacarrhythmias.Treatmentofthelatterconditionconsistsoftreatingironcardiomyopathy.

Forpatientswithpulmonaryhypertension,optimizetheirtransfusionprogramtomaximizesuppressionofallmarrowactivity.Allpatientswithseverepulmonaryhypertension(TRjetgreaterthan3mpersecond)shouldundergodiagnosticcatheterizationtoassesspulmonaryvascularresistanceanditsresponsivenesstonitricoxideandoxygen.Patientsshouldbeevaluatedforoxygendesaturation,particularlyatnight.Supplementaloxygenshouldbeadministered,asneeded,tomaintainsaturationsgreaterthan95percent.Acompletecoagulopathyworkupshouldbeperformed.

Warfarinshouldbeinitiatedforpatientshavingpersistentpulmonaryhypertension.TheINRtargetis1.5to2.0.Patientsfailingtorespondtohematologicmanagementshouldbestartedonsildenafilasthefirstlineoftherapy.

11PulmonaryCarePulmonarydiseaseisanuncommonphenomenoninthalassemia,althoughabodyofdataexistsregardingpulmonarydiseaseinthalassemiapatients.Inaddition,thepulmonarydiseasewhichhasbeendescribedisgenerallyasymptomatic.

Themostcommondisorderisarestrictivepulmonaryconditionwhichappearstobeassociatedwithironoverload.Therestrictivepulmonaryconditionisseenin30to60percentofpatients.However,mostoftheserestrictivefindingsareasymptomatic,andthereislittletherapyforthiscondition.Thisemphasizestheneedforaggressivechelationandmonitoringoftransfusion-relatedhemosiderosis.Hypoxiaisrarelyencountered.

Themosteasilytreatableconditionthatmayaffectthelungsispulmonaryembolism.Patientswiththalassemiaareknowntobehypercoaguable,whichleadstoahigherriskfordevelopingthromboembolicevents.Splenectomymaybeanadditionalthrombophilicriskfactor.Thethrombophiliaofthalassemiapatientsmaycontributetothepathophysiologyofpulmonaryhypertension,andasthisphenomenonmaypresentwiththerespiratorysymptomsofdyspneaorexerciseintolerance,attentiontothepulmonarysystemisimportant.(AlsoseeSections10.4and10.5,onpulmonaryhypertension.)

Recommendationsforpulmonarycareincludethefollowing:1. Anannualreviewofrespiratorysymptomsandalungexam2. Anannualpulse-oximetry3. Aggressiveironchelationiftransfusion-relatedhemosiderosis

ispresent4. Anechocardiogramtoevaluateforpulmonaryhypertension,

ifsymptomatic5. Apulmonaryfunctiontestorhigh-resolutionCT,if

symptomatic6. Areferraltopulmonologyinthecaseofrestrictivedisease7. Ananticoagulationtreatmentifthromboembolismispresent;

ASAmaybeconsideredifthepatientissplenectomized

12PainSyndromeinThalassemiaChronicpainhasnotbeennotedasamajorcomponentofthesymptomsofthalassemia.However,inthelastdecade,asprognosishasimproved,cumulativetissueinjuryappearstoberesultinginchronicpainsyndrome.ArecentstudyutilizingtheBriefPainInventory(BPI)assessedpainin250thalassemiapatientsinNorthAmerica.Two-thirdsofthepatientsreportedrepeatedpainepisodeseachmonth,and20percentreporteddailypain.Theprevalenceandseverityofpaincorrelatedwithageofthepatient.Aspatientsage,painbecomesamoreprominentproblemintheirlives.Mostpatientshavebackpain.Three-quartersofthepatientsweretakingnon-steroidalanalgesicsforpainrelief.Inaddition,24percentwerereceivingshort-actingnarcoticanalgesics,andanother11percentwerereceivinglong-actingnarcoticanalgesics.

Painassessmentonaregularbasisisrecommendedforallpatients.Whiletransfusiontherapymaydecreasethepaininthalassemiaintermedia,thishasnotbeenprospectivelyevaluated.Allpatientsshouldundergoassessmentforcausesofpain,includingextramedullarymasses,osteoporosis,andspinalfractures,aswellasotherlesscommonproblems,suchassecondarygoutandthrombosis.

13HematopoieticCellTransplantationHematopoieticcelltransplantation(HCT)istheonlytreatmentthatoffersapotentialcureforthalassemiaatthistime.HCTreliesonhigh-dosechemotherapytoeliminatethalassemia-producingcellsinthemarrowandreplacesthemwithhealthydonorcellsfrombonemarroworumbilicalcordblood,usuallytakenfromahuman-leukocyteantigen(HLA)match:anidenticalsibling.Thistherapyshouldbeconsideredforallpatientswhohaveasuitabledonor.Earlyreferraltoatransplantcenterisrecommended,asHCThasabetteroutcomeinyoungerpatients.

PatientsareclassifiedbeforeHCTasClass1,2or3patientsonthebasisofriskfactorsthatinfluenceoutcomeafterHCT.Theseriskfactorsinclude:• ageofthepatient• adequacyofchelation• thepresenceorabsenceofliverfibrosis• thepresenceorabsenceofhepatomegaly

Theoverallthalassemia-freesurvivaloflow-risk,HLA-matchedsiblingstemcelltransplantationpatientsis85to90percent,witha95percentoverallsurvival.Whilenotaseffective,newapproachestoClass2and3patientshavesignificantlyimprovedtheiroverallsurvival.Theproblemsofrejectionandengraftmentinthesepatientsareimprovingwiththeuseofmoreintensifiedimmunosuppressivetherapy.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 16

IfHCTisconsidered,patientsshouldbereferredtothenearesttransplantcenterwithexperienceinHCTforgeneticdiseases.Theliver,lungs,heart,andskeletonareparticulartargetsofcomplicationsofthalassemiaandchronictransfusion.ThefollowingstudiesmustbedonebeforeHCT:1. Astagingofliverfibrosisandinflammatorylesionsbyliver

biopsy,aspertheKnodellnumericalscoringsystem(Knodell,R.G.,etal.Hepatology1[1981]:431.),withmeasurementofLIC

2. Ameasurementofhepatic,cardiac,endocrine,renal,andpulmonaryfunction

3. Adentalevaluationandrestoration

13.1IronoverloadafterHCTAfterasuccessfulHCT,continuoustreatmentofpreexistingironoverloadisindicated.

AfteranHCT,aphlebotomyof5cc/kgpermonthshouldbeperformeduntilliverironislessthan7.5mg/gdryweight.Forpatientsonwhomphlebotomycannotbeperformed,ironchelationtherapyusingdeferoxamineisalsoeffective,butmorecumbersomeandexpensivethanphlebotomy.

Ifthepre-transplantationliverbiopsywasperformedmorethantwoyearsbeforestartingphlebotomy,considerrepeatingameasurementoftheLICbynoninvasivemethodsorbyliverbiopsytoconfirmthebaselineliverironlevel.MeasurementofLICbynoninvasivemethodsorbyliverbiopsyshouldbecontinuedevery12to24monthstomonitortheresponsetothephlebotomy.Apost-HCTphlebotomyshouldbeperformedifhepaticironbeforetheHCTexceeds7mg/gdryweight,orifferritinisgreaterthan2,000ng/mL.

13.2ExperimentalHCTSinceHLA-matchedsiblingtransplantationinhealthythalassemiapatientsoffersaveryhighcurerate,stemcelloptionsforfamilieswithoutmatchedsiblingsarebeingstudied.MostpatientsdonothaveanHLA-matchedsibling.Experimentaltrialswithunrelated,matchedumbilicalcordbloodorstemcelltransplantationarebeingconducted.Alternativeimmunosuppressivepreparationsandtherapyarebeingstudiedtodecreasegraft-versus-hostdiseaseandimprovegraftsurvival.PregnantmothersofaffectedchildrenaremorefrequentlyundergoingprenataldiagnosisforthalassemiaanddeterminingafetalHLAtypingontheprenatalsample.Ifthereisamatchwiththesibling,theumbilicalcordbloodcellscanbestoredfortransplantation.Anexperimentalprocedurecalledpre-implantationgeneticdiagnosisisanoptionavailableforpreselectedHLA-compatibledonorsofaffectedsiblings.

13.3ExperimentaldrugtherapytoincreasefetalhemoglobinTheamountoffetalhemoglobinwithineachredcellplaysamajorroleindeterminingtheseverityofthalassemia.Theincreaseingammaglobinchainsynthesisdecreasesthealphachainimbalanceandimprovestheanemia.MultipledrugshavebeenstudiedtoincreasehemoglobinF.Histonedeacetylase(HDAC)inhibitorssuchasbutyrateandshort-chainfattyacidshavehadbenefitinselectpatients,butmostresponseshavebeenmodestandunpredictable.NewHDACdrugsareunderstudy.Thefirstsuccessfuldrugtherapyforfetalhemoglobininthalassemiawas5-azacytidine.Thiswasabandonedbecauseoftoxicity.Recentpilotstudiesevaluatingasaferanalog(decitabine)

areongoing;however,thelong-termbenefitandtoxicityareunknown.Erythropoietinhasincreasedfetalhemoglobinandtotalhemoglobin,particularlyinpatientswithrelativelylowlevelsoferythropoietin.However,thelong-termbenefitisunknown,andtheriskofmarrowexpansionisacauseforconcern.

Themostsuccessfulfetalhemoglobinagenttodateisoralhydroxyurea.Hydroxyureaisacytotoxicdrugthatisshort-actingandrelativelyeasytomonitor.ItisFDA-approvedforthetreatmentofseveresicklecelldisease.However,itislesseffectiveandpredictableinthalassemiaandmorelikelytobebeneficialinthalassemiaintermedia.Approximately40percentofpatientswillhaveamodestincreaseinhemoglobinandadecreaseinmeasurementofhemolysis.BaselinehemoglobinFisthestrongestpredictorofresponse.Splenectomyandbaselineerythropoietinlevelsmayalsoinfluenceitsbenefit.Thedosageofhydroxyureaislowerinthalassemiathaninsicklecelldisease.Often,thedrugisstartedat5to10mg/kgperdayandslowlyescalatedastoleratedto20mg/kgperday.Whilemodestresponsescanbeobserved,hydroxyureaisnotusuallysuccessfulinpreventingeventualtransfusiontherapy.

14AcuteInfectionAcuteinfectionremainsamajorcauseofdeathinthalassemiapatients.Avigilantapproachtorecognizingandtreatingseriousinfectionswillpreventunnecessarymortality.Patientsshouldbeeducatedonmanagementoffeverandacutesymptoms,withadvancedunderstandingofwhotocallandwheretoseekcare.Easyaccesstomedicalrecordscanassistintherapidassessmentandtreatmentofpatients.Thiscanbefacilitatedbypatientscarryinghealthrecordslistingdiagnosis,complications,andtreatments.

Prophylacticantibioticsforsplenectomizedpatientsdolowertheriskofpneumococcalinfections.However,gram-negativeorganismsarethemajorcauseofbacteriainthalassemiapatients.Prompttreatmentwithbroadspectrumantibioticsshouldstartbeforetheresultsofbloodculturesareindicated.Patientswithcentralvenouscathetersmayhavestaphylococcusepidermidisandrequirevancomycintherapy.ThalassemiapatientshaveanincreasedriskofYersinia enterocolitica.Thisiron-avidorganismmaypresentclinicallywithfever,abdominalpain,anddiarrhea.Antibioticsshouldbestartedbeforestoolandbloodcultureresultsareavailable.Ingeneral,allchelationtherapyshouldbestoppeduntilthefebrileillnessisadequatelytreated.

15DentalEvaluationTheteethcanbesignificantlyaffectedinpatientswiththalassemia,butpropertransfusiontherapycanpreventmanyofthechanges.However,closedentalandorthodonticmonitoringiscrucial.Inadditiontoregularannualdentalcare,thalassemiapatientsshouldbeevaluatedbyadentisttodetermineifbonychangesrequiringorthodontictreatmentshavedeveloped.Iforthodonticsarerecommended,theywillbecoveredbyinsurance,sincetheirnecessityisdisease-related.

Furthermore,splenectomycancomplicatedentalcareduetoincreasedriskofinfection.Priortodentalwork,whichislikelytocausebleedingofthegums,splenectomizedpatientsshouldreceivedentalprophylaxis.Recommendedtreatmentis50mg/kgofamoxicillin(toamaximumdoseof2g)onehourpriortodentalwork.Ifthepatientisallergictopenicillin,20mg/

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 17

kgofclindamycin(toamaximumdoseof600mg)shouldbeadministeredonehourpriortoprocedure.

16NutritionNutritionaldeficienciesarecommoninthalassemia,duetohemolyticanemia,increasednutritionalrequirements,andmorbiditiessuchasironoverload,diabetes,andchelatoruse.

Patientsshouldbeevaluatedannuallybyaregistereddietitianregardingadequatedietaryintakeofcalcium,vitaminD,folate,traceminerals(copper,zinc,andselenium)andantioxidantvitamins(EandC).Annualnutritionallaboratorytestingshouldincludealbumin,25-hydroxyvitaminD,fastingglucose,fastingplasmazinc,serumcopper,ceruloplasmin,serumselenium,alphaandgammatocopherol,plasmaascorbate,andserumfolate.(Seenutritiontablebelow.)

Recommendationsfordietarysupplementationshouldbemadeasindicatedbynutritionalhistory,complicationsofthedisease,and,inchildren,growthstatus.Typicallymultivitaminsupplementationwithoutironissuggested(e.g.,CentrumSilverintabletorchewableformisnowavailable).

Fornontransfusedthalassemiapatients,folatesupplementation(1mgdaily)isrecommended,andconsumingamoderatelylow-

irondietisencouraged—thatis,avoidingiron-fortifiedcerealsandotherproductsandexcessiveconsumptionofredmeat.Drinkingblackteawithmealsisrecommendedtoreduceironabsorptionfromfood.

Fortransfusedpatientsonchelationtherapy,alow-irondietisunnecessaryandmaydecreasethequalityoflifeforsomepatients.Theamountofironobtainedfromjustoneunitofpackedredcells(200mg)faroutweighstheamountofironobtainedfroma3-ouncesteak(5mg).

VitaminDsupplementation(50,000IUonceaweekuntillevelsnormalize)isrecommendedforpatientswitha25-hydroxyvitaminDlessthan20ng/dL.Calciumsupplementationshouldbeencouragedifdietaryintakeisinsufficient.

Counselingshouldbeofferedforpatientswithspecialdietaryneeds.Theseincludepatientswithdiabetesorlactoseintolerance,thosewhopracticevegetarianism,thosewhoarepregnant,orthoseonoralchelatorsorbisphosphonatemedications.

Alcoholconsumptionandcigarettesmokingaretobediscouraged.AlcoholpotentiatestheoxidativedamageofironandaggravatestheeffectofhepatitisBandConlivertissue.Cigarettesmokingaffectsboneremodelingandisassociatedwithosteoporosis.

Table16:NutritionTableRecommendedforPatients

Nutrient Diagnosis of adequacy U.S. dietary recommended intake

Tolerable upper limit

Calcium Serumcalciumnotinformativeasitisbuffered.

19to50years—1,000mg/day9to18years—1,300mg/day4to8years—800mg/day

2,500mg/day

VitaminD Serum25-hydroxyvitaminD>30ng/mL

400IUperday 10,000IU/dayforadults;unknownforchildren

Folate Serumorplasmafolate>3ng/mL 1mgperdayfornontransfusedpatients

Unknownforthalassemiapatients;forgeneralpopulation,suggestedupperlimitis1mg/day

Zinc Fastingmorningplasmazinc>70µg/dL

Women/girls:8mg/daymen/boys:11mg/day4to8years:5mg/day

Over19years—40mg/day14to18years—34mg/day9to13years—23mg/day

Copper Serumcopper>70µg/dL 19to50years—900µg/day14to18years—890µg/day9to13years—700µg/day4to8years—440µg/day

Over19years—10mg/day14to18years—8mg/day9to13years—5mg/day

Ceruloplasmin Ceruloplasmin>17mg/dL N/A N/A

Selenium Serumselenium>45µg/L 19to50years—55µg/day9to18years—40µg/day4to8years—30µg/day

400µg/day

VitaminC Plasmaorserumascorbate>0.4mg/dL(avoidhemolysis)

75to90mg/dayIfonchelation,100to250mg/dayrecommended

Unknownforthalassemiapatients;forgeneralpopulation,suggestedupperlimitis2,000mg/day

VitaminE Serumorplasmafastingalphaandgammatocopherol(seelocallabfornormalforageandgender)

Adults:100IU/day Unknownforthalassemiapatients;forgeneralpopulation,suggestedupperlimitis1,000mg/day

Notes: Alltraceelements(zinc,copper,selenium)needtobecollectedintotraceelement–freevacutainers.

Normativevaluesmaybesomewhatdifferentdependinguponthereferencelab.TheupperlimitforvitaminDis10,000IUwhentakendaily;muchhigherdoses(e.g.,200,000IU)havebeenusedinvitaminD–deficientpatientswhentakenweeklyormonthly.

1mgvitaminE=0.45to0.67IUvitaminD,dependingupontheformofvitaminE.

STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 18

17VaccinationsOptimalimmunizationiscriticalforallpatientswiththalassemia,especiallytransfusedpatientsandindividualswhohavebeensplenectomized.PriortosplenectomypatientsshouldreceivethemeningococcalconjugatevaccineandshouldbeuptodateforHibandpneumococcalvaccines.

Routinepediatricimmunizationsshouldbecurrentandvaccinationrecordsshouldbecheckedannually.Beginningattwomonthsofage,patientsshouldbegiven7-valentconjugatepneumococcalvaccineasrecommended.Aboosterwith23-valentvaccineshouldbeadministeredat24months.Pnuemovaxboostersshouldbeconsideredeveryfivetotenyears.Checkthepneumococcaltitersfollowingimmunization.Severelocalreactionscanindicatehightiter.

PatientsneedtobeimmunizedagainsthepatitisAandB,especiallypatientsonchronictransfusions.Annualmonitoringoftitersandboosterimmunizations,whenindicated,willensurepatientsarewellprotected.IndividualswhoareHIVpositiveorundergoingtreatmentforhepatitisCshouldnotreceivelivevirusvaccines.AnannualinfluenzavaccinationandannualPPDshouldalsobeadministered.ParticularattentionshouldbegiventotheH1N1virus,asthispathogenmaycausemoreseveresymptomsinpatientswiththalassemia.

18FertilityandPregnancyinThalassemiaDelayedpubertyandprimaryorsecondaryamenorrheaduetoironoverloadarecommoncomplicationsintransfusedthalassemicfemales.Ironcancausedamagetothehypothalamic-pituitaryaxisandpossiblytotheovariesandtestes.Aswithpreventionofotherendocrinopathies,itisimportanttoensureadequatechelationstartinginearlychildhoodandthroughadolescence.(AlsoseeSection9.2.4,regardingevaluationofadolescentfemalesandmaleswithdelayedpubertyduetoendocrinopathy.)

AdultfertilitystatusinbothgendersmaybeassessedbytestingLH,FSH,andestradiolinfemales(canbetestedatanytimeiffemalesaremenstruating)andLH,FSH,andtestosteroneinmales.ObtainfreeT4,TSH,ACTH,andcortisolstimulationteststoassesscentralhypothalamic-pituitaryaxisfunction.Infemaleswithamenorrhea,obtainprolactinlevels.

Ifgonadotropins(LH,FSH)areelevated,therehasbeenprimarytesticularorovarianfailure.IfLH,FSH,andestradiolortestosteronearelow,thereislikelyahypothalamic-pituitaryaxisfailureorsecondaryfailure.However,inthissituation,thepresenceofovarianortesticularfailurecannotberuledoutinadditiontothepituitaryfailure.Ifpregnancyissought,additionalevaluationandtreatmentrequirereferraltoareproductivecenter.

18.1PregnancyInthepast,pregnancywasuncommonandoftendiscouragedbecauseofrisk.Now,withimprovedtreatmentincludingtransfusionandchelation,pregnanciesarerelativelycommon.Bothspontaneouspregnanciesandinvitrofertilizationhavebeensuccessful.Pregnancyeveninpatientswhodevelopamenorrheaisbeingobserved.Pregnancyinapatientwiththalassemiaishigh-riskandrequiresmultidisciplinarymanagement.Deathsduetocardiacfailureoccur.Patientswithcardiacdiseaseandsignificantcardiacironareatparticularrisk.Optimaltransfusiontherapyandironcontrolshouldbeestablishedbeforepregnancy.

Thereislimiteddataonironchelatorsadministereddur