![Page 1: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/1.jpg)
Standards of Care Guidelinesfor Thalassemia
2012
Published by
![Page 2: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/2.jpg)
TABLE OF CONTENTS
PAGE
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
![Page 3: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/3.jpg)
PAGE
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
![Page 4: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/4.jpg)
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
![Page 5: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/5.jpg)
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.
![Page 6: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/6.jpg)
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.
![Page 7: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/7.jpg)
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
![Page 8: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/8.jpg)
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.
![Page 9: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/9.jpg)
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
![Page 10: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/10.jpg)
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.
![Page 11: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/11.jpg)
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
![Page 12: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/12.jpg)
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
![Page 13: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/13.jpg)
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.
![Page 14: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/14.jpg)
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
![Page 15: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/15.jpg)
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.
![Page 16: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/16.jpg)
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
![Page 17: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/17.jpg)
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
![Page 18: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/18.jpg)
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.
![Page 19: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/19.jpg)
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/
![Page 20: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/20.jpg)
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.
![Page 21: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/21.jpg)
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.
Thereislimiteddataonironchelatorsadministeredduringthefirsttrimester,andrisksdoexist.Whileironchelationduringpregnancyshouldgenerallybeavoided,normalbirthshaveoccurredinmothersonchelation.
19ThalassemiaIntermediaThalassemiaintermediaisaseveredisease,andspecialcareneedstobemadetoassurepropertreatmentandcare.Thalassemiaintermediaisdifficulttodiagnose,andtherearemanyvariantswhichneedtobeconsidered.
Thalassemiaintermediaisamoreseriousthalassemiasyndromethanpreviouslythoughtandfrequentlydoesnotreceivetheattentionitdeserves.Itisvitalthatpeoplewiththalassemiaintermediabemonitoredcloselythroughoutlife.Unlikethalassemiamajor,wherethelevelofanemiamakestransfusionmandatory,thalassemiaintermediapatientsmaynothavehemoglobinlevelslowenoughtowarrantmandatorybloodtransfusionandregularcare.However,progressionofboththeanemiaandineffectiveerythropoiesismayeventuallyresultinseriouscomplications.Thisimportantgroupofpatientssuffersimmeasurablyduetoanunpredictabledegreeofanemiaandcourseoftreatment;therefore,followingstandardsofcareisofutmostimportance.
Manyofthecomplicationsnotedinthalassemiamajoroccurinthalassemiaintermedia.Thesecomplicationsresultfromineffectiveerythropoiesis,anemia,dietaryironabsorption,andinadequatetransfusion.Patientswiththalassemiaintermediaexperiencebonechanges,endocrinopathies,osteoporosis,cardiacdisease,pulmonaryhypertension,andchronicboneandjointpain.Theextentofthesecomplicationsaffectsinterventionandinitiationoftreatment.Beyondsupportivetreatment,treatmentmodalitiesinvolvetransfusions,splenectomy,andmedicationsthatincreasehemoglobinFsynthesis.Occasionally,attentionshouldbegiventotreatmentofspecificcomplications,includingironoverload,pulmonaryhypertension,osteoporosis,andgallstones.
19.1NontransfusedthalassemiaintermediaAbaselineredbloodcellphenotypeshouldbeobtainedfrompatients,whoshouldthenbeseenatathalassemiacentereverythreetosixmonths,withattentiontooverallclinicalwell-being,anthropometricsasdescribedforthalassemiamajor,changesinexercisetolerance,complaintsofpainand/orshortnessofbreath,CBC,reticulocytecount,andferritinlevels.
Alow-irondietanddrinkingteawithmealstodecreaseabsorptionofironisrecommended.Ifzinclevelislow,patientsshouldbeputonsupplementation.Dailysupplementationof1mgfolicacidshouldalsobetaken.Patientsshouldreceiveimmunizationsasoutlinedforthalassemiamajorpatients.
19.1.1 Growth and developmentLookforchangesinfacialbonestructure.Forgrowingchildren,obtainbiannualskullX-raysandfacialphotographs:anterior/posteriorandlateral.Payattentiontogrowthvelocity,especiallyinyoungchildrenandinadolescents.Patientsshouldhaveannualdentalandorthodonticevaluationsandbeobservedfordelayedorarrestedpuberty.Somepatientshaveexcessivegrowthoftheirheadsevenwithonlymildanemia.Thisinitselfcouldbeanindicatorfortransfusiontherapy.Therefore,closemonitoringoftheheadcircumferenceisnecessary.
![Page 22: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/22.jpg)
STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 19
19.1.2 Extramedullary erythropoiesisTumormassesofextramedullaryerythropoietictissueareacommoncomplicationofthenontransfusedthalassemiapatient.Theseoftenoccurintheparaspinalareas,andareasymptomatic.However,somecasesleadtospinalcordcompressionandacuteneurologiccomplications.Transfusiontherapyoftendecreasestheirsizeandpreventsfurthergrowth.Rarely,emergencyinterventionisnecessary.
19.1.3 EndocrinopathiesOsteopeniaandosteoporosisshouldbeassessedannuallyoreverytwoyearsviaDXAscan.Bonepainandfracturesshouldbeanemphasis.
Fertilityshouldbeassessedonanindividualbasis.Transfusionsupportduringpregnancyshouldalsobeconsidered.
19.1.4 Cardiopulmonary assessmentAdultsshouldhaveanannualechocardiogramforearlydetectionofleftheartdecompression,andTRjet,whichdetectspulmonaryhypertension.Thosewithexistingpulmonaryhypertensionshouldhaveanannualpulmonaryfunctiontestandasix-minutewalktest.
19.1.5 Considerations for transfusionsThedecisiontostartregulartransfusionsdependsonclinicalandlaboratoryassessment.Thisdecisionisnotnecessarilyapermanentcommitmenttolifelongtransfusion.Suchdecisionsaredifficultandbestmadeatathalassemiacenter.
Indicationsthatmightbeconsideredbeforestartingchronictransfusionincludethefollowing:• Inchildhood,growthfailure,delayedpuberty,orpoorschool
performance• Symptomaticanemia• Skeletalmalformationorbonedisease• Pulmonaryhypertensionwithorwithoutleftheart
decompression
Transienttransfusionsmayalsobeconsideredduringpregnancyortimesofinfection.
19.1.6 Considerations for splenectomySplenectomyisreservedforcasesofmassivesplenomegalyorhypersplenism,orinstanceswherepatientsareunabletobetransfused.Thebenefitsandcomplicationsoftransfusionsandsplenectomyneedtobediscussedwiththefamily.
Thegeneralrecommendationsforendocrineandiron-statusmonitoringoutlinedforthalassemiamajorshouldbeappliedtopatientswiththalassemiaintermedia.Aftertheinitialevaluations,thefrequencyofmonitoringcanbemodifiedbasedonthedegreeofironloadingorgrowthfailure.
19.1.7 Assessment of iron overloadFerritinandironsaturationlevelsshouldbemonitoredannually.Iftheferritinlevelsarepersistentlygreaterthan1,000ng/mLortheironsaturationisgreaterthan60percent,obtainaquantitativeassessmentofliveriron.UsetheguidelinesinSection5fortheadministrationofdeferasiroxordeferoxamine.Whenathalassemiaintermediapatientdoesnotgettransfused,theironburdendevelopsfromincreasedgastrointestinalabsorptiononly,sodrug
dosingmayneedtobemodified.Consultationwithanironchelationspecialistisrecommended.
20HemoglobinHDiseaseandItsVariantsThegenefrequenciesofalpha-thalassemiaexceedthoseofbeta-thalassemia.Thelossofalpha-genefunctionmaybesecondarytoadeletionalornondeletionalmutation.Nondeletionalmutationsaremoresevere.Theinactivationofonealpha-globingeneisinsignificant.Theinactivationoftwoalpha-globingenescausesaverymildmicrocytic,hypochromicanemia.Thelossoffunctionofthreealpha-globingenesiscalledhemoglobinHdisease.PeoplewithhemoglobinHdiseasehaveavariablephenotypethatcanrangefrommildsymptomstothosesimilartothalassemiamajor.Duetophenotypicvariabilityorinuterointervention,morepatientswiththisdisorderarebeingreported.
HemoglobinHdiseaseisaserioushealthprobleminSoutheastAsiaandsouthernChina.ThousandsofaffectedpatientsliveintheMiddleEast,theMediterraneanregion,andNorthAmerica.Manypatientsrequireintermittenttransfusions.Theclinicalseverityisstronglyinfluencedbythetypeofmutation.Deletionsonchromosome16areresponsiblefor75percentofhemoglobinHmutations,andthesedeletionscauseamilderformofthedisorder.Theremaining25percentofpatientswithhemoglobinHdiseasehavetwodeletionsplusapointmutationorinsertioninthealpha-globingene.NondeletionalhemoglobinHisoftensevereandlikelytorequiretransfusions.Inbothgroups,however,thereismarkedphenotypicvariability.
20.1DiagnosisThediagnosisofhemoglobinHmaybedifficult.HemoglobinHandhemoglobinBartsarefast-movinghemoglobinsthatmayappearonelectrophoresis.However,theyareunstableandoftengoundetected.PatientswithhemoglobinHdiseasehavegreaterthan20percenthemoglobinBartsatbirth.HemoglobinBartsrapidlydisappearsonelectrophoresisafterbirth.SincehemoglobinHandhemoglobinBartsareunstable,electrophoresismayfailtodetecttheseabnormalities.
ThestateofCaliforniascreensnewbornsforhemoglobinHdiseaseutilizinghighperformanceliquidchromatographytomeasurehemoglobinBarts.Newbornswithgreaterthan20percenthemoglobinBartsundergoDNAtestingtodistinguishmoresevere,nondeletionalhemoglobinH,suchashemoglobinH–ConstantSpringfromdeletionalhemoglobinHdisease.Highperformanceliquidchromatographyorhemoglobinelectrophoresiscannotreliablydetectnondeletionalmutations.
20.2HemoglobinHdeletionAfterthenewbornperiod,thediagnosisofdeletionalhemoglobinHdiseaseisoftenmadeonlyafterthedetectionofcomplicationssuchascholelithiasis,exacerbationoftheanemiainducedbyinfection,orthefindingsofsplenomegalyandgrowthfailure.ThemeanhemoglobinindeletionalhemoglobinHisquitevariablebutaverages9.5g/dL.Twenty-nineto50percentofpatientswithdeletionalhemoglobinHrequireintermittenttransfusiontherapy,buttheneedforchronictransfusiontherapyisuncommon.Pregnancyisoftenassociatedwithanincreasedseverityofanemia,aswellaspre-eclampsia,andmaynecessitatetransfusion.Ironoverloadandiron-inducedheartfailureareincreasinglybeingnotedinadultpatientsnotreceivingintermittenttransfusions.
![Page 23: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/23.jpg)
STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 20
Serumferritinlevelsusuallyunderestimatethemagnitudeofironoverload.Irondepositsinnontransfusedpatientsareintheferrihydrideform,whichcausesmoredamagethanthegoethiteironthatresultsfromtransfusion.EarliertherapeuticinterventionforironoverloadinnontransfusedhemoglobinHdiseaseisindicated.
HemoglobinH–ConstantSpringisthemostcommonnondeletionalalpha-thalassemiamutationassociatedwithhemoglobinHdisease.HemoglobinH–ConstantSpringdiseasehassignificantlymoreineffectiveerythropoiesis.ThelaboratoryandclinicalcourseofhemoglobinH–ConstantSpringdiseaseismoreseverethanhemoglobinHdisease.Theaveragehemoglobinis2g/dLlessthanindeletionalhemoglobinHdisease.Themeancorpuscularvolumeisanear-normal72fL,comparedto59fLfordeletionalhemoglobinHdisease.Mostpatientshavemoderatelyseveresplenomegaly,andover50percentrequiresplenectomy.Splenectomyoftenresultsinimprovedhemoglobinlevelsbutisassociatedwithahighrateofportalveinthrombosis.NinetypercentofpatientswithhemoglobinH–ConstantSpringdiseasehavebeenintermittentlytransfused,andupto40percenthaverequiredrepeatedtransfusions,particularlyinearlyinfancyandinlateradulthood.Ironoverloadoccursin75percentofpatientsbyadulthood.Rarely,hemoglobinH–ConstantSpringdiseaseandothernondeletionalhemoglobinHdisordershavecausedfatalhydropsfetalissyndrome.
Homozygousalpha-thalassemia,causedbyadeletionofallfouralpha-globingenes,leadstotheformationofhighlevelsofhemoglobinBartsinutero.HemoglobinBartshasanextremelyhighoxygenaffinity,andthereforedeliverslittleoxygentofetaltissues.Theseverehypoxiaresultsincardiacfailure,massiveascites,andintrauterinedeath.Congenitalmalformationsassociatedwithhomozygousalpha-thalassemiaincludehypospadias,othergenitourinarydefects,andlimbmalformations.Infantssurvivingtodeliverywithoutprenatalinterventionareusuallyhydropicandcommonlyhaveneurologicalimpairment.Intrauterinetransfusionsfollowingearlydetectionofhomozygousalpha-thalassemiahaveresultedinthebirthofseveralnonhydropicinfants,somebutnotallofwhomhavenosignificantneurologicalabnormalitiesorcongenitalanomalies.Affectedinfantswhosurvivegestationandtheneonatalperiodsubsequentlyrequirechronictransfusiontherapyormaybeappropriatecandidatesforhematopoieticstemcelltransplantation.
Occasionally,infantswithhomozygousalpha-thalassemiaarebornwithouthydrops,evenintheabsenceofintrauterinetransfusions.Nondeletional,highlyunstablealpha-globingenemutationsmayresultinahemoglobinHgenotype,causinghydropsfetalis.Inpregnanciesknowntobeatrisk,chorionicvilloussamplingwithmolecularanalysisidentifieshomozygousalpha-thalassemiawithinthefirstmonths.
Theethicalissuesofmanagingafetusknowntohavehomozygousalpha-thalassemiaarecomplex.Obstetriccomplicationsandthenecessityforlong-termtransfusiontherapyareseriousconsiderations.Increasedriskofbothmaternalandfetalmorbidityshouldbeincludedincounselingfamiliesatriskforanaffectedfetus.Education,screening,andcounselingofthefamilyareessential.
20.3RecommendationsforcareOftenthepatientwithhemoglobinHisasymptomaticandisunpreparedfortheacutecomplicationsthatoccurduringinfection,pregnancy,anddrugexposure.Inparticular,theseincludehemolyticandaplasticanemicepisodes.Folicacidsupplementsandavoidanceofoxidativecompoundsandmedicationsarerecommended.Inmildcases,biannualvisitsareadequate.Inmoreseverecases,morefrequentvisitsareindicated.Atroutinevisits,growth,development,facialbonedeformity,dentalstatus,andhepatosplenomegalyshouldbemonitored.Routinemonitoringofhemoglobinlevelsisrequired.
PatientswithhemoglobinHdisordersdevelopneonatalanemia.Splenomegalyandhypersplenismarerelativelycommon.SplenectomyusuallyamelioratesthesevereanemianotedinnondeletionalhemoglobinHcases.Splenectomymayberequiredataveryyoungageintransfusion-dependentcases.Prophylacticantibioticsandinfectionprecautionsaresimilartoothersplenectomypatients.Thrombosispreventionisindicatedincasesrequiringsplenectomy.Low-doseaspirinorotheranticoagulantsmaybeused.
Ongoingmonitoringofironstoreswithquantitativeimagingoftheliverisindicatedbecauseoftheunreliabilityofserumferritintests.Innontransfusedpatients,imagingshouldbeinitiatedinearlyadolescence.Cardiacfunctionmonitoringisindicated.Thefrequencyisdeterminedbytheanemiaandtheiron-overloadstatus.GallstonesfrequentlyoccurinhemoglobinHdisease,andcholecystectomyisindicatedinsymptomaticpatients.Bone-densitymeasurementshouldbeinitiatedinearlyadolescence.Pregnancyrequiresmorefrequentmonitoringbecauseoftheriskofsevereanemiaandpre-eclampsia.
21ThalassemiaResearchResearchandclinicalteamsincomprehensivethalassemiacentersworktogethertoprovidethehighest-quality,integratedhealthcarepossible.Researchisanimportantcomponentofcomprehensivecareforpatientswiththalassemia.Researchallowsdoctorstoofferpatientsandfamiliesthemostup-to-dateandinnovativetherapies.Inrecentyears,researchhasledtomanyadvancesinthalassemiatreatment.
Aspartofthalassemiapatients’care,theyshouldbeinformedaboutstudiesthattheymightbeeligibletoparticipatein.Patientsareneverobligatedtojoinanystudy,andiftheychoosenottoparticipate,theyshouldbeassuredthattheywillstillreceivehigh-qualityhealthcare.
Thereareavarietyoflong-termprojects,fundedbydifferentsources—theNationalInstitutesofHealth(NIH),theCenterforDiseaseControl(CDC)—thatareavailableforpatients.TheThalassemiaClinicalResearchNetwork(TCRN)wasfundedin1998bytheNationalHeart,Lung,andBloodInstitute(NHLBI)toprovideanationalstructuretoconductclinicalstudiesinthalassemia.TheTCRNhasbeensuccessfullyfundedbytheNHLBIfortwofive-yearcycles,basedontheprevioussuccessfulstudiesthathavebeendone.
TheCDCalsofundsanationalstudytomonitorthesafetyofthenation’sbloodsupply.TheCDCiscollectingbloodsamplesfrompatientswiththalassemiatoscreenfordisease(HIV,hepatitisA,
![Page 24: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/24.jpg)
STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 21
B,andC).Thisstudyisalsocollectinganannualvisitformtoevaluatecareforpatientswiththalassemiaatvarioussitesaroundthecountry.
22PsychosocialSupportThalassemiaimposesasignificantintrusioninthelivesofpatientsandtheirfamilies.Theeffectsaremany,sweepingfromfinancialhardshipsandabsencefromschoolandworktosignificantproblemswithself-imageandself-esteem.Alloftheseissueshaveatremendousimpactoftheeffectivenessoftherapyandonthequalityoflifeofpatients.Thesechallengesarefurthercomplicatedbynormalstagesofdevelopmentincurredfrominfancytoadulthoodandbyvastculturaldifferences.Thislatterpointcannotbeemphasizedenough.Becauseoftheethnicpredilectionofthalassemia,thepatientscomefromdiverseculturalbackgroundswhichareusuallydifferentfromthoseoftheirhealth-careproviders.
Thus,allprofessionalswhoprovidecareandsupporttothesepatientsmustbeawareofthecultural,social,developmental,andbehavioralissuesthataffectthisdiversepopulation.Behavioralproblemshavegreatbearingoncompliancewiththerapy,andthuswithmedicaloutcome,aswellaswithqualityoflifeforpatientswithchronicdisease.Medicalandpsychosocialprofessionalsmustalsocollaboratecloselywitheachotherinordertoprovideoptimalcaretotheirpatients.Referraltooutsideproviderswhohavenoknowledgeorunderstandingofthemedicalproblemsisgenerallyineffective.
22.1ChildlifeservicesCulturallysensitivechildlifeservicesareanintegralpartofcomprehensivecare.Childlifeservicesassurethatcareisfamily-centeredanddevelopmentallyappropriateforthepatient.Itisimperativethatpatientswiththalassemiaunderstandtheirdiseaseandtreatmentinordertofollowtheirprescribedmedicalregiments.Childlifeprogramsinhealth-caresettingsminimizepsychologicaltraumaandpromoteoptimaldevelopmentofchildrenandtheirfamilies.
Throughobservationanddiscussion,assesstheresponseofthepatientandfamilytohealth-careexperiences,anddevelopaplantomeettheirneedsandfacilitatecoping.Provideopportunitiesforgainingasenseofmastery,forplay,forlearning,forself-expression,forfamilyinvolvement,andforpeerinteraction.Thiscanbeachievedinmanyways,includingmedicalplayandarttherapy.
Provideapositivegrowthexperienceforpatients.Minimizestressandanxietyforthepatient,parents,andsiblings.Providecontinualteachingtopatientstohelpthemunderstandallaspectsofthalassemia,includingbloodtypeandtransfusion,chelation,andgeneralhealthandwellness.
Preparechildrenandfamiliesforhealth-careexperiences.Forexample,conductamedicalpreparationpriortoapatient’sliverbiopsy/SQUIDandsplenectomy.Thisincreasesoverallunderstandingoftheprocedure,reducesanxiety,andenablespatientstogainmasteryovertheirhealth-careexperiences.
Duringhospitalizations,provideessentiallifeexperiencessuchasplay,school,peerinteraction,communityevents.Theseactivities
commonlytakeplaceinthehospitalplayroomorschoolroom.Alsocreateopportunitiesthatstrengthenself-esteemandindependence.
Childlifespecialistsareanintegralpartofthehealth-careteam.Theycanworktoempowerpatientsandfamilies,aswellasteachthemtobeproactivemembersintheirownhealthcare.Childlifecanalsoassistwithtransitionalissuesaspatientsgetolderandnewissuesandchallengesarise.
22.2PsychologicalservicesCulturallysensitivepsychologicalservicesmakeupacriticalpartofallcomprehensivecareplansforpatientswiththalassemia.Thalassemiarequirestime-intensive,lifelongmedicaltreatment.Therefore,ongoingtherapeuticservicesareneededtohelppatientscopewithissuesrelatedtochronicillnessandmortality.Psychologistsprovidingsupportshouldbeexperiencedandconsistent.Studentinternsarenotrecommendedtogivepsychologicalcounselingforpeoplewithchronicillnessduetoahighrateofturnoverandtheinabilitytoestablishlongrelationshipsneededtobuildtrust.
Patientsshouldhaveanevaluationofgeneralfunctioningandadaptationtochronicillnessandhospitalculture.Inaddition,assesspatients’abilitytocomplyandcopewithmedicalregimen.Assistanceandinterventionwithissuesofcomplianceandcopingstylesshouldbeconsideredforeverypatient.Evaluateandreferpatientstoapsychiatristforadministrationofpsychotropicmedication.Inaddition,therapeuticgroupsforadolescentsandadultsmustbeorganizedanddirected.
22.3SocialservicesSocialservicesthatmeettheneedsofthepatientsinaculturallysensitivewayarecriticalforpatientswithachronicdiseasethatrequiresaninordinateamountofresources.Socialservicesshould:• evaluatefunctioninginthecommunityandatschool/work• provideforadequatesocialandmedicalservices• assesstheneedforfinancialassistanceandmakereferralsto
communityservices/resources• makeitaprioritytoobtainhealthinsuranceforpatients
(childrenandadults)andfamilieswiththalassemia
22.4GeneticcounselingGeneticcounselingisthecommunicationprocessofprovidinginformationandsupporttoindividualsandfamilieswithadiagnosisand/orriskofoccurrenceofaninheriteddisorder.Culturallysensitivegeneticcounseling,withanemphasisonreproductiveissues,isanintegralandnecessarycomponentofcomprehensivecareforpatientsandparentsaffectedbyallformsofthalassemiadiseaseandtrait.ServicesshouldbeprovidedbyalicensedgeneticcounselorinstateswithlicensurelegislationandbyanABGCboard-certifiedorboard-eligiblegeneticcounselorinallotherstates.
Geneticcounselingisneeded:• atdiagnosis• duringadolescence• priortoandafteranygenetictesting• priortopregnancyand/orasearlyinpregnancyaspossible
Annualfollow-upsareneededtoreinforceteaching.
![Page 25: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/25.jpg)
STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 22
Criticalcomponentsofgeneticcounselinginclude:• obtainingathree-generationgeneticfamilyhistory(pedigree)• assessingriskforthalassemiainfamilymembers• identifyingriskfactorsimpactingmedicalmanagement
(e.g.,familyhistoryofotherhemoglobintraitsordiseases,hereditaryhemochromatosis,G6PDdeficiency,inheritedthrombophilia,cardiovasculardiseaseoritsriskfactors,cardiacconductiondefects,diabetes,renaldisease,ophthalmologicdisorders,hearingloss,allergies,ethnicity,consanguinity)
• incorporatingpsychosocialinformationimpactingthefamilysystemandrelationships(e.g.,locationofresidence,disclosure/nondisclosureofdiagnosis,reliablesourceofemotional/socialsupport)
• assistingpatientsinconveyinginformationaboutgeneticrisktootherfamilymembers
• providinginformedconsent,pre-,andpost-counselingforallgenetictesting
• alpha-globingenotyping:hemoglobinH–ConstantSpringandotherstructuralalpha-globinvariants,possiblemodifyingeffectsofalpha-globindeletions/triplicationsonbeta-thalassemia
• beta-globingenotyping:beta0/beta+,S,D,E,O,andotherstructuralvariants
Thelimitationsofdrawinggenotype/phenotypecorrelationsinclude:• developmentallyappropriateconsent/educationforminors• reproductivegenotypepost–stemcelltransplantorbone
marrowtransplant• thepossibilityofrevealingundisclosedadoptionoralternative
paternity• discussing/facilitatingappropriatescreeninganddiagnostic
testsforrelatives
23GeneticTestingIfHLAtypingisperformedwhenstemcelltransplantorbonemarrowtransplantisanoption,geneticcounselingandeducationisvitalduetoethicalimplications.Ageneticcounselorshouldprovideinitialandongoingteachingregardingnaturalhistoryandclinicalmanifestations;signsandsymptomsofdiseasethatwarrantimmediatemedicalattention;andavailableemotionalandsocialsupportservices.Geneticcounselorsshouldalsoprovideavailableresourcesincollaborationwithoutreachcoordinatorsandsocialworkers(e.g.,researchstudies,supportgroups,advocacyorganizations,andpatient-to-patientorparent-to-parentconnections).
![Page 26: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/26.jpg)
STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 23
Category Measurement Check after thisnumber of months
As clinically indicated
Initially Comments
1 3 6 12 24Growthanddevelopment
Height X
Sittingheight X
Weight
Growthvelocity X
TannerStage X
Headcircumference Thisshouldbecheckedeveryothermonth.
Hematology CBC,reticulocytes X
T+CCoombs(indirect) X
Coombs(direct) X
Serumtransferrinreceptor X
General HLAtyping X
DNAmapping(alphaandbeta) X
Redbloodcellphenotype X
Volumeofpackedredbloodcellstransfused X X
Ironandtoxicity Ferritin X
Liveriron X X Ifthereisevidenceofhepatitis,histologyisnecessary.
Audiologyevaluation X X
Visionscreen X X
Ophthalmologyevaluation X
Iron,TIBC X
Transferrinsaturation X
Liverfunctionanddisease
AST,ALT X
Bilirubin(total) X
Bilirubin(direct) X
HepatitisAserology X
HepatitisBserology X
HepatitisBPCR X X
Whenhepatitisisactive,dothistestannually.Withundiagnosedhepatitis,thismaybemonitored.
HepatitisCserology X
HepatitisCPCR X Evaluationofpositiveserologyorundiagnosedhepatitis.
PT,PTT XHavethisbeforealiverbiopsy.Patientswithactivehepatitisshouldhavethetestannually.
Albumin X
Periodic Chemistrypanel X
Urinalysis X
Dental X
24GeneralTimetableforClinicalandLaboratoryEvaluation
![Page 27: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/27.jpg)
STANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 24
24GeneralTimetableforClinicalandLaboratoryEvaluation(continued)
Category Measurement Check after thisnumber of months
As clinically indicated
Initially Comments
1 3 6 12 24
Endocrine T3,freeT4,TSH X Startat5years.
PTH X Startat5years.
Calcium,ionizedcalcium X Startat5years.
Fastingglucose X Startat5years.
Glucosetolerancetest X Performat10,12,14,and16years.
IGF-1,IGFBP-3 X Performatnotedgrowthdelay.
LH-ICMA XPerformatnoteddelayinpuberty:12yearsforgirlsand14yearsforboys.
FSH XPerformatnoteddelayinpuberty:12yearsforgirlsand14yearsforboys.
Estradiol XPerformatnoteddelayinpuberty:12yearsforgirlsand14yearsforboys.
25AuthorsElliottVichinsky,MD,andLauriceLevine,MA,CCLS
SuruchiBhatia,MDJenniferBojanowski,CGCThomasCoates,MDDruFoote,PNPEllenFung,PhD,RDPaulHarmatz,MDMichaelJeng,MDJeanMarieKnudsen,MSWAshLal,MDZahraPakbaz,MDConnieSchroepfer,RDSylviaTitiSinger,MDNancySweeters,PNPMarkWalters,MDJohnWood,MDMatthewLevine,editor
26SupportChildren’sHospital&ResearchCenterOaklandCentersforDiseaseControl(CDC)Cooley’sAnemiaFoundationHealthResourcesandServicesAdministration(HRSA)ItalianCatholicFederation(ICF)ThalassemiaSupportFoundation(TSF)PaulDiLorenzo,presidentofTSF(technicalsupport)
27ReferencesForget,B.,G.Cannelos,andN.Berlin,eds.PediatricClinicsofNorthAmerica.Thalassemia.Volume24,Number6.W.B.SaundersCompany,2010.
VichinskyE.P.,andE.J.Neufeld,eds.Cooley’sAnemiaNinthSymposium.Volume1202,Annals of the New York Academy of Sciences,2010.
.
![Page 28: Standards of Care Guidelines for · PDF fileSTANDARDS OF CARE GUIDELINES FOR THALASSEMIA • 1 ... , sepsis , transfusion ... of standardizing the management of care for thalassemia](https://reader034.vdocuments.mx/reader034/viewer/2022051719/5a738ed67f8b9aea3e8b6184/html5/thumbnails/28.jpg)
Children’s Hospital & Research Center OaklandHematology/Oncology Department
747 52nd StreetOakland, CA 94609
www.childrenshospitaloakland.orgwww.thalassemia.com