Acquired Aplastic Anemia in Children and Adolescents

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OfficialreprintfromUpToDate www.uptodate.com2015UpToDate

AuthorsStanleyLSchrier,MDAlisonABertuch,MD,PhD

SectionEditorDonaldHMahoney,Jr,MD

DeputyEditorJenniferSTirnauer,MD

Acquiredaplasticanemiainchildrenandadolescents

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.Literaturereviewcurrentthrough:Jan2015.|Thistopiclastupdated:Nov19,2013.

INTRODUCTIONAplasticanemia(AA)isararedisordercharacterizedbypancytopeniaandahypocellularbonemarrow[1,2].Injurytoorlossofpluripotenthematopoieticstemcells,intheabsenceofinfiltrativediseaseofthebonemarrow,isthemajorpathophysiologiccharacteristicofthedisease[3].Incontrast,bonemarrowfailureisamoreencompassingtermthatdescribespancytopeniafromavarietyofdifferentmechanisms,includingbonemarrowreplacementbytumororfibrosis,disorderedcellularmaturation(eg,vitaminB12deficiency),andmyelodysplasia,inwhichthestemcellsaremalignantandmaybepresentinincreasednumbersbutdonotmature(table1)[4].Ineithercondition,theassociatedneutropeniaandthrombocytopeniacanleadtopotentiallylifethreateninginfectionsandbleeding,respectively.

AcquiredAA,characterizedbypancytopeniaandhypocellularbonemarrowintheabsenceofabnormalinfiltratesandwithoutincreasedreticulin,accountsformostcasesofAAinchildrenandyoungadults(table2).AcquiredAAinchildrenandyoungadultswillbereviewedhere[5,6].Aplasticanemiainadultsisreviewedseparately.(See"Aplasticanemia:Pathogenesisclinicalmanifestationsanddiagnosis"and"Aplasticanemia:Prognosisandtreatment".)

ThemajorconstitutionalorinheritedcausesofpancytopeniaandAAinchildrenincludeFanconianemia,dyskeratosiscongenita,ShwachmanDiamondsyndrome,andcongenitalamegakaryocyticthrombocytopenia.Diagnosisandtreatmentofthesedisordersarediscussedseparately.(See"ShwachmanDiamondsyndrome"and"Inheritedaplasticanemiainchildrenandadolescents"and"HematopoieticcelltransplantationforidiopathicsevereaplasticanemiaandFanconianemiainchildrenandadolescents".)

ETIOLOGYANDINCIDENCENoclearcausecanbedeterminedinmorethan70percentofchildrenwithacquiredaplasticanemia(AA).Themajoridentifiableetiologiesareexposuretoawidevarietyofdrugsandchemicals,ionizingradiation,andsomeviruses(table2).AAmayalsorarelycomplicateorthotopiclivertransplantationAAinthissettinghasaverypooroutcomeexceptinthosepatientswhodevelopthedisorderinthecontextoffulminanthepaticfailure[7].(See'Hepatitis'below.)AAalsohasoccurredinpatientswithotherimmunedisorderssuchassystemiclupuserythematosusand,occasionally,inpregnancy[8,9].

Inonestudyof213children

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marrowdamage(table3).

Withtheexceptionofnuclearreactoraccidents,thereappearstobelittleroleforoccupationalradiationorbackgroundenvironmentalexposureasariskfactorforAA[17,18].(See"Clinicalfeaturesofradiationexposureinchildren"and"Biologyandclinicalfeaturesofradiationinjuryinadults".)

DrugsNumerousdrugs,suchascertainnonsteroidalantiinflammatorydrugs(particularlyphenylbutazone,whichisnowrarelyused),chloramphenicol,gold,sulfonamides,certainoftheantiepilepticagents,nifedipine,andcytotoxicdrugscanbeassociatedwithAA[15,1923].Aplasiacausedbyphenylbutazoneusuallyoccursafterprolongedtreatment[19].Similarly,goldinducedaplasiatypicallyoccursinpatientswhohavereceivedatotaldoseof200to450mgitisusuallysevereandoftenirreversible[20].Felbamate,anantiepilepticmedication,hasbeenassociatedwithnumerouscasesofAA[21].

Cytotoxicdrugsusedinthetreatmentofmalignancycankillstemcellsdirectly,resultinginaplasia.TheproposedmechanismsfordruginducedAAarediscussedelsewhereintheprogram.(See"Aplasticanemia:Pathogenesisclinicalmanifestationsanddiagnosis".)

OtherchemicalagentsOtherchemicalagentsthatdirectlyinjurestemcellsinclude:

AreducedabilitytodetoxifyenvironmentaltoxinsmayplayaroleinthegenesisofAA.TwostudieshaveshownthattheincidenceofgenedeletionsforglutathioneStransferase,anenzymeinvolvedindetoxifyingpotentiallymutagenicelectrophiliccompounds,wassignificantlyhigherinpatientswithacquiredAAandmyelodysplasticsyndromesthaninhealthycontrols[28,29].(See"Disordersofthehexosemonophosphateshuntandglutathionemetabolismotherthanglucose6phosphatedehydrogenasedeficiency",sectionon'GlutathioneStransferasedeficiency'.)

InfectiousagentsPatientswithbacterialorviraldiseasesmayexperiencepancytopenia.Thisconditionisusuallytransientandmayrelatetomultiplefactors,includingtheuseofantibioticsandothermedications[11].

Certainvirusescandirectlydamagestemcellsandcauseaplasia[30].ThebestdocumentedvirusisparvovirusB19.Thisagentmorecommonlyattacksproerythroblastsandcausestransientredcellaplasia,asseeninpatientswithchronichemolyticanemia.(See"Acquiredpureredcellaplasiaintheadult".)However,pancytopeniacanoccur,particularlyinimmunocompromisedpatients.(See"ClinicalmanifestationsanddiagnosisofhumanparvovirusB19infection".)

HepatitisHepatitisassociateddiseasemostoftenaffectsboysandyoungmen,withaplasiadevelopingwithinsevenmonths(manywithinonemonth)afteranepisodeofacutehepatitis[3133].Hepatitismayaccountfor2to5percentofcasesofAAinwesterncountries[31,34].TheresponsiblevirushasnotbeenidentifiedhepatitisA,B,C,andGdonotappeartobeinvolved[3133].Notably,upto15percentofpatientswithseronegativeacuteliverfailurewilldevelopAA[32].ThemechanismmayinvolveTcellactivationwithreleaseofcytokines.(See'Immunesystem'below.)

AstudyfromJapancollected61casesofhepatitisassociatedAA(HAA)outofatotalof525childrenwithacquiredAA(12percent)[35].Of49patientswithviralstudies,hepatitisA,hepatitisC,EpsteinBarrvirus,andcytomegalovirus(CMV)weredetectedinonecaseeachnopatienthadhepatitisB.Seventeenof20patientswithHAAunderwentsuccessfulhematopoieticcelltransplantation,andwerealiveatamedianfollowupof66months,while28of41werealivefollowingtreatmentwithimmunosuppressiveagents,withanactuarialsurvivalrateof61percentatsevenyears.

Fiveof30patientswithsevereAAduetohepatitistreatedwithimmunosuppressivetherapydevelopedeithermyelodysplasia(MDS)oracutemyeloidleukemia(AML),similartothe15percentincidenceofMDS/AMLintheirpatientswithsevereidiopathicAA.Actuarialsurvivalsat10yearsforthepatientswithsevereHAAandsevereidiopathicAAweresimilarat60and56percent,respectively.

SomeindustrialchemicalshavebeenidentifiedascausingAA,althoughtheunderlyingmechanismisunknown[2426].Prolongedexposuretobenzeneisparticularlynotoriousinthisregardinthepast,thisconditionoccurredprimarilyinpoorlyventilatedrubberfactoriesandshoeshops[24].

Theinsecticidebenzenehexachloride(lindane)[27].

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Anotherstudyof44childrenwithhepatitisassociatedAAtreatedwithimmunosuppressivetherapyreportedasimilaroverallresponserateof70percent,withoverallsurvivalat10yearsat88percent[36].Theresultsfromthesetwostudiesshowtheefficacyofimmunosuppressivetherapyinthesettingofhepatitisassociateddisease.

PregnancyAAassociatedwithpregnancyfrequentlyisselflimited,endingwithdelivery[9].Whetherpregnancyiscausallyrelatedtothedevelopmentofaplasiaremainsuncertain[37].

IdiopathicAsmentionedabove,thecauseremainsobscureinmostchildrenandyoungadultswithacquiredAA.Asdescribedbelow,immunesystemabnormalitiesandgeneticpredispositionmayplaycausativeroles.(See"Aplasticanemia:Pathogenesisclinicalmanifestationsanddiagnosis",sectionon'Causesandmechanismsofstemcellfailure'.)

ImmunesystemTwomajorobservationsareconsistentwiththeimmunesystemplayingamajorroleinthedestructionofstemcellsinAA:

Inonereport,IFNgammageneexpressionwaspresentinthebonemarrowof14of17patientswithsevereAA,fourofsevenwithmoderateaplasia,andnoneof39withotherhematologicdisorders,includingchemotherapyinducedpancytopeniaormarrowfailurecausedbyotherdisorderssuchasthemyelodysplasticsyndrome[39].AnotherstudysuggestedthatoverexpressionofTNFaffectedstemcellsbypromotingdifferentiationratherthanselfrenewal[40].

TheseobservationshaveledtoaunifyinghypothesisforAAthatdamageinducedbychemicals,drugs,viruses,orantigensleadstolymphocyteactivation,whichproducesahematopoieticinhibitoryresponse,perhapsmediatedbyIFNgammaorbythecytokinecascadereleasedbyIFNgamma[38,41].IFNgamma,inturn,mayleadtoincreasedexpressionoftheFasreceptor.ThisreceptorisinvolvedininductionofapoptosisandinTcellmediatedkillingitisfoundinincreasedconcentrationinCD34+bonemarrowcellsinpatientswithAA[41].

GeneticroleSeveralfindingssuggestthatgeneticmechanismshavearoleintheevolutionofAA.Theseinclude:

CLINICALPRESENTATIONANDDIAGNOSISTheclinicalpresentationofaplasticanemia(AA)isvariableandincludessymptomsandsignsrelatedtocytopeniaineachofthethreecelllineages[46]:

Manyofthesepatientsrespondtoimmunosuppressivetherapy(see'Immunosuppressivetherapy'below).

AutoreactiveTlymphocytesfromthebonemarrowofpatientswithAAcaninhibithematopoiesiswhencoculturedwithpatientornormalmarrow[11,38].Thisinhibitionmaybemediatedbythereleaseofmarrowsuppressingcytokines,suchasinterferongamma(IFNgamma),tumornecrosisfactor(TNF),andinterleukin2.IFNgammageneexpressionisspecificallyprevalentinthebonemarrowofpatientswithacquiredAA,anddisappearswithresponsetoimmunosuppression.

Progressivetelomereshortening,acommonfindingwithsomaticcellaging,ispresenttoasignificantdegreeinAA.Followinghematologicalrecovery,therateoftelomericlossstabilizes.Incontrast,patientswithouthematologicalrecoveryhavefurthertelomericshorteningandanincreasedriskforevolutiontothemyelodysplasticsyndrome[42].

Approximately8percentofpatientswithpresumedacquiredAAhavemutationsofthehumantelomeraseRNA(TERC)orreversetranscriptase(TERT)genesthesemutationsmaylimitmarrowstemcellselfrenewalandpredisposesomepatientstomarrowfailure[43,44].

Genearraytechnologieshaveidentifiedlargenumbersofupregulatedgenesimportantinapoptosis,stressresponse,immunedefense/response,andcelldeath[45].Theseobservationsmayleadtonewtargetsfortherapeuticintervention.

Hemorrhagicmanifestationssecondarytothrombocytopenia(see"Clinicalmanifestationsandevaluationofthrombocytopeniainchildren",sectionon'History')

Fatigue,pallor,andcardiovascularcomplaintscausedbyprogressiveanemia(see"Approachtothechild

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DiagnosisAdiagnosisofAAissuggestedbythepresenceofpancytopeniawithabsolutereticulocytopenia(frequently100).Theperipheralbloodsmearshowsthattheremainingelements,whilereduced,aremorphologicallynormal.

ThediagnosisofAAisestablishedbybonemarrowaspirationandbiopsy.Thecharacteristicfindingsinclude:

Oncethediagnosisisconfirmed,thepatientshouldundergoadetailedevaluationforpossibleprecipitatingfactors(table4).

DefinitionsofseverityTheclinicaloutcomeofacquiredAAisdependentinpartupontheseverityofthepancytopenia.

ModerateaplasticanemiaModerateAA(MAA)isdefinedbyfulfillingallthreeofthefollowingfindings:

TheoutcomeforpatientswithMAAisunclearspontaneousrecoverymayoccur.Inoneseries,16of24childrenwithMAAprogressedtoSAAatamedianfollowupof66months[47].

SevereaplasticanemiaThecriteriaforsevereaplasticanemia(SAA)are[4850]:

VerysevereaplasticanemiaThepatientisconsideredtohaveverysevereaplasticanemia(vSAA)iftheANCis

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and"Inheritedaplasticanemiainchildrenandadolescents"and"HematopoieticcelltransplantationforidiopathicsevereaplasticanemiaandFanconianemiainchildrenandadolescents".)

PatientswithAAwhodonotfulfillcriteriaforaknowninheritedbonemarrowfailuresyndromemaybeconsideredtohaveanunclassifiableinheritedAAifthereisafamilyhistoryofbonemarrowfailure,theypresentedbeforeoneyearofage,ortheyhaveanomaliesinvolvingmultiplesystems[36].PatientswithAAnotmeetingsuchcriteriashouldbeconsideredtohaveacquireddisease.

ThetestssuggestedfordeterminingthecauseofAAaslistedinthetablewillhelptoruleoutthepresenceofapreviouslyunrecognizedinheritedcause(eg,dyskeratosiscongenita,Fanconianemia)(table4),whileahistoryofseverethrombocytopeniaduringtheneonatalperiodmaysuggestthediagnosisofcongenitalamegakaryocyticthrombocytopenia,whichmaydevelopintoSAAanumberofyearslater.AreportfromtheEuropeanGroupforBloodandMarrowtransplantationindicatestheimportanceofsuchadditionaltesting.Intheirstudyof295childrenandadultsinitiallydiagnosedashavingsevere"acquired"aplasticanemiaandwhohadfailedimmunosuppressivetherapy,suchadditionaltestingrevealedthat22(7percent)wereinfactduetooneofthesethreeinheritedcauses(Fanconianemia:15dyskeratosiscongenita:5congenitalamegakaryocyticthrombocytopenia:2)[51].(See"Inheritedaplasticanemiainchildrenandadolescents",sectionon'Amegakaryocyticthrombocytopenia'.)

TREATMENTSevereaplasticanemia(SAA)islifethreatening,requiringurgentevaluationandcarebycompetenthematologicspecialists[5].Treatmentincludeswithdrawalofoffendingagents(ifany),supportivecare[52],andsomeformofdefinitivetherapyagainsttheaplasia.Bloodandplatelettransfusionsshouldbeusedselectivelyincandidatesforhematopoieticcelltransplantationinordertoavoidsensitization.Anybloodproductsshouldbeirradiated,leukocytereduced,andcytomegalovirus(CMV)safe,andshouldnotbefromfamilymembers.(See"Redbloodcelltransfusionininfantsandchildren:Selectionofbloodproducts".)

Patientswithsevereneutropeniaareatriskforseriousbacterialinfections(table5).Thus,affectedchildrenwithfeverrequireimmediateevaluation,bloodculture,andtreatmentwithbroadspectrumantibiotics.Prophylacticantibioticshavenorole[4].(See"Evaluationandmanagementoffeverinchildrenwithnonchemotherapyinducedneutropenia",sectionon'Guidelinesfortreatmentoffeverandneutropenia'.)

SevereaplasticanemiaTwomajormodalitiesfortreatmentofsevereacquiredaplasticanemia(AA)arehematopoieticcelltransplantation(HCT)andimmunosuppressivetherapy(IST)[4,53].

HematopoieticcelltransplantationTheissueofHCTinAAisdiscussedindetailelsewhere.(See"Hematopoieticcelltransplantationinaplasticanemia".)

ForchildrenwithSAAorverysevereAA(vSAA),includingthosewithhepatitisassociatedAA[35],theproblemsassociatedwithadvantagesofHCT(eg,stableengraftmentandhematopoiesis,lowriskforclonaldisorderssuchasmyelodysplasticsyndrome[MDS]oracutemyeloidleukemia[AML])outweightheproblemsassociatedwiththeprocedure(eg,lowfrequencyofmatchedsiblingdonors,graftfailure,graftversushostdisease).Therefore,HCTfromamatchedsiblingdonoristhetreatmentofchoice,withlongtermdiseasefreesurvivalratesapproaching90percent[4,5356].

Thefollowingobservationsillustratethedatasupportingthisconclusion:

Inaseriesof48consecutivelytreatedchildrencaredforatasingletertiarycenter,10yearsurvivalwithHCTandISTwereequivalent(76and74percent)[55].However,HCTwaspreferredfortworeasons.First,theoutcomewithHCTimprovedovertime.Second,theHCTpatientswerepresumedtobestablebecausenosurvivorhadchronicgraftversushostdisease.

PatientstreatedwithISTremainatriskforrelapseorthedevelopmentofclonaldisease.Thiswasillustratedinaseriesof860pediatricandadultpatients,inwhichthe10yearincidenceofmalignancyafterHCTwas3percent(mostlysolidtumors)comparedwith19percentafterIST(mostlyMDSandAML)[57].Otherstudieshavereportedahigherrateformalignancyof10.9percent15yearsafterHCTwhenthepreparativeregimenincludedthoracoabdominalirradiation[58].

AstudyfromJapanof525childrenwithAAidentified61casesofhepatitisassociatedAA(HAA)[35].Thesurvivalrateof20patientswithHAAwhounderwentsuccessfulHCTcomparedwiththosewho

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ThelongtermoutcomeaftersuccessfulHCTwasevaluatedinareportfromtheLateEffectsWorkingCommitteeoftheInternationalBoneMarrowTransplantRegistrythereportincluded1029patientswithAAtreatedwithallogeneicHCTbetween1980and1993andwhowerealiveandfreeofAAforatleasttwoyearsaftertransplantation[59].Atamedianfollowupof11years,60ofthesepatientshaddied(5.8percent).(See"Hematopoieticcelltransplantationinaplasticanemia".)Thecausesofdeathwere:

ImmunosuppressivetherapyOnly20to25percentofchildrenwithAAhaveanHLAmatchedsibling.Fortheremainingchildren,intensiveimmunosuppressivetherapy(IST)isthepreferredoption.Initialregimensoftenconsistedofantithymocyteglobulin(ATG)alone,orcyclosporinealone,withresponseratesofabout50percent[49,60,61].Currently,higherresponseratesof75to80percentareachievedbytheuseofmoreintensivecombinationregimensconsistingofATG,cyclosporine,corticosteroids,withorwithouthematopoieticgrowthfactors[4,55,6264].Anumberofcaseseriessuggestthattheresponseratesandsurvivalmaybesuperiorinpediatricpatientscomparedwithadultpatients[6569],althoughthisfindinghasnotbeenuniversal[64].

Thebenefitsandrisksoftheadditionofhematopoieticgrowthfactors(ie,GCSForgranulocyte/macrophagecolonystimulatingfactor[GMCSF])toISTforSAAremainuncertainandarediscussedingreaterdetailseparately.Inaddition,theuseofcyclophosphamide,withorwithoutcyclosporine,hasnotbeenshowntoprovideadditionalbenefitandisassociatedwithanincreaseinmortalityandmorbidity.(See"Aplasticanemia:Prognosisandtreatment",sectionon'AdditionofGCSF'and"Aplasticanemia:Prognosisandtreatment",sectionon'Highdosecyclophosphamide'.)

OurapproachWecurrentlyusethefollowingregimen:

receivedimmunosuppressivetherapywas85percentat5.5yearsversus61percentatsevenyears.PatientstreatedwithISTwerealsoatriskfordevelopingMDSorAML(12percent).

GVHD38patientsInfectionwithoutGVHDsevenpatientsOrganfailure(liver,cardiac,pulmonary,renal)fivepatientsOther(hemorrhage,interstitialpneumonia,drugreaction,miscellaneous)sevenpatients

Onestudy,whichincludedbothadultsandchildren,evaluated100patients(medianage16years)treatedwithacombinedregimenofATG,cyclosporine,prednisolone,andgranulocytecolonystimulatedfactor(GCSF)[64].Trilineagerecoveryatamedianofthreemonthsoccurredin77patients(48complete)afteroneormorecoursesoftherapy.Amongthe23nonresponders,11diedatamedianintervalofthreemonthssixwereconsideredtreatmentfailuresandunderwenttransplantation.Theactuarialsurvivalwas87percentatfiveyears(98versus76percentinthosewithneutrophilcountsgreaterthanorlessthan200/microLatpresentation,respectively).Childrendidnotfarebetterthanadults(88versus87percent).

Inaretrospectiveanalysisof77childrenwhocompletedacourseofATGandcyclosporineforSAAbetween1989and2006,acomparableresponserateof74percentatsixmonthswasobserved[69].The10yearsurvivalwas89percentforthosepatientswhorespondedtoIST.Althoughsurvivalandinitialresponserateswerehigh,onethirdofpatientsrelapsed(mediantimetorelapse558days),definedasreinstitutionofISTduringthe10yearperiod.TheseresultsunderscoredtheneedforlongtermfollowupofchildrenwithSAAtreatedwithIST.Ofthe13deathsinthestudy,fouroccurredinpatientswhohadrelapsed.

Antithymocyteglobulin(ATG)40mg/kgperdayforfourdays.

CyclosporineA(CSA)12mg/kgtotaldoseperday(administeredindivideddosesevery12hours)begunondayfivetomaintainabloodtroughof250to350ng/mL.Atthreetosixmonths,weassesstheresponse.Ifthereisevidenceoftrilineagerecovery,weattemptaslowwean(ie,taperingofthedailydoseatarateof

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Theresponsetotherapymaybeslow,withgranulocyterecoveryoccurringfirst,followedbystabilizationofhemoglobinandadeclineintransfusionrequirements.Plateletrecoverymaytakemonthstoyears.Longtermsurvivorsmayshowpersistentthrombocytopenia,redbloodcellmacrocytosis,andelevatedhemoglobinFconcentrations[70].

PredictorsofresponseSubsetsofpatientsmayvaryintheirresponsetodifferentcomponentsoftherapy:

ComplicationsAvarietyofacuteordelayedcomplicationsmaybeobservedfollowingimmunosuppressivetherapyinchildrenwithAA:

fortwoweeksfollowedbyaslowtapertopreventandcontrolpotentialcomplicationsofserumsickness.Theaimistodiscontinuecorticosteroidtherapyby30days.

RecombinanthumanGCSF5mcg/kgperdaySQbegunondayfiveasneededtomaintainanabsoluteneutrophilcountgreaterthan1000/microL.Asnotedabove,thebenefitsofaddedgrowthfactorsarenotclear.

Inonestudy,patientsexpressingIFNgammaonCD8cellshadahigherresponseratetoATG/CSAcomparedwiththosewhodidnotexpressIFNgamma(96versus32percent)[71].

SurvivalmightbeexpectedtobepoorerinpatientswithlowerANCs[72].InanItalianstudy,patientswithverysevereAA(ie,anANC

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TreatmentfailuresOtheroptionsforchildrenwhenISTfailsinclude:

ModerateAAForpatientswithmoderateaplasticanemia(MAA),treatmentrecommendationsareunclear.Withprogressivecytopenias,particularlysevereneutropeniaand/ortransfusiondependence,treatmentwithHCTorimmunosuppressionshouldbeconsidered.Inoneseries,childrenwithMAA,treatedwithATG/CSA,hadan87percentresponserate[47].Inasmallstudy,treatmentwithdaclizumab,amonoclonalantibodydirectedagainstIL2R,resultedina50percentresponseratewithminimalsideeffects.FurtherstudiesareneededforthisvariantofAA.

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"BeyondtheBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5 to6gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10 to12 gradereadinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingon"patientinfo"andthekeyword(s)ofinterest.)

SUMMARYANDRECOMMENDATIONS

ofMDSwere5.4(95%CI1.915)fornoresponseatsixmonths,and4.4(95%CI1.315)for120daysoftreatmentwithGCSF.Theseobservationshavenotyetbeenconfirmedbyothers.Inadditiontofindinganincreasedriskofrelapse,theNIHstudyfoundonmultivariateanalysisthatshortertelomerelengthwasassociatedwithahigherprobabilityofclonalevolution[24.5percentforpatientsinthefirstquartile(95%CI8.737.5)and8.4percentforpatientsinquartiles2through4(95%CI3.213.3)][75].

Fifteento33percentofpatientswithAAtreatedwithimmunotherapyrecover,withclonalevidenceofparoxysmalnocturnalhemoglobinuria(PNH)andclinicalmanifestationsthatmaybemild,transient,orprogresstofullblowndisease[77,78].Whythisphenomenonoccursisnotwellunderstood.PeriodicassessmentsforaPNHcloneshouldbeperformed.(See"Clinicalmanifestationsanddiagnosisofparoxysmalnocturnalhemoglobinuria",sectionon'Pancytopenia'.)

MatchedunrelatedHCTdonors.MatchedunrelateddonorHCTisrecommendedifthereisnoresponseatfourmonthsafterATG.Highresolution,molecularHLAmatchingbetweendonorandrecipient,andimprovementsinconditioningregimenshaveresultedinbetteroutcomesinpatientsreceivingalternativedonorHCT.Thissubjectisdiscussedseparately.(See"HematopoieticcelltransplantationforidiopathicsevereaplasticanemiaandFanconianemiainchildrenandadolescents",sectionon'HCTfrommatchedunrelateddonors'.)

ChangeinthesourceofATG(eg,substitutionofrabbitATGforhorseATG).Inanuncontrolledseries,transfusionindependencewasachievedin23of30suchpatients(77percent)afteramedianof95days,withninepatientsachievingcompleteremission[79].Theoverallsurvivalratewas93percentatamedianfollowupof2.5years.Aloweroverallresponserate(30percent)wasobservedinaretrospectiveanalysisof22patients(includingtwochildren)refractorytohorseATG/CSAwhowereretreatedwithrabbitATG[80].

Substitutionoftacrolimusforcyclosporine.Thismaybetried[81],butthereisnoproofofbenefit.

Highdosecyclophosphamide.Responsestohighdosecyclophosphamide(45mg/kgperdayforfourdays)wereobservedintwooffivetreatedchildrenwithrefractorySAA[82].

th th

th th

Basicstopics(see"Patientinformation:Aplasticanemia(TheBasics)")

Acquiredaplasticanemiaaccountsformostcasesofaplasticanemia(AA).Inmorethan70percentofchildrenwithacquiredAA,noclearcausecanbedetermined.Identifiableetiologiesincluderadiationexposure,drugsandchemicals,andinfectiousagents,usuallyviruses(table2).AcquiredAAcanbe

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Topic5923Version18.0

seenfollowingviralhepatitisandduringpregnancy.(See'Etiologyandincidence'above.)

TheclinicalpresentationofAAisvariableandisrelatedtothedegreeofcytopeniapresent.Thisincludesbleedingsecondarytothrombocytopenia,fatigueandpallorduetoanemia,andfeverandbacterialinfectionsresultingfromneutropenia.

ThediagnosisofAAissuggestedbyacompletebloodcountrevealingpancytopeniaandisconfirmedbybonemarrowaspirationandbiopsydemonstratinghypocellularityofallthreecelllines.(See'Diagnosis'above.)

TheclinicaloutcomeofpatientswithacquiredAAisdependentupontheseverityofthepancytopenia.Patientswithsevereandveryseverediseasehavea70percentmortalityratewithinoneyearifnotsuccessfullytreated.(See'Definitionsofseverity'above.)

ForpatientswithsevereandverysevereacquiredAA,hematopoieticcelltransplantation(HCT)fromanHLAmatchedsiblingdonoristhetreatmentofchoice.(See'Treatment'aboveand"Hematopoieticcelltransplantationinaplasticanemia".)

IfanHLAmatchedsiblingdonorisnotavailableforpatientswithsevereandverysevereacquiredAA,werecommendintensiveimmunosuppressivetherapyovertheuseofmatchedunrelated,mismatchedrelated,ormismatchedunrelatedHCT.Thecurrentregimenthatwerecommendincludesantithymocyteglobulin,cyclosporine,prednisoneandshorttermuseofrecombinanthumangranulocytecolonystimulatingfactor.(See'Immunosuppressivetherapy'aboveand"Aplasticanemia:Prognosisandtreatment".)

WhenintensiveimmunosuppressivetherapyfailsinchildrenwithsevereAA,optionsincludeachangeinimmunosuppressivetherapyoruseofanalternativedonorHCT.(See'Treatmentfailures'aboveand"Hematopoieticcelltransplantationinaplasticanemia",sectionon'MatchedunrelateddonorHCT'.)

TreatmentrecommendationsforpatientswithmildtomoderateacquiredAAareunclear.(See'ModerateAA'above.)

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GRAPHICS

Majorcausesofpancytopeniasecondarytobonemarrowfailure

Congenitalaplasticanemia

Fanconianemia

Dyskeratosiscongenita

ShwachmanDiamondsyndrome

Amegakaryocyticthrombocytopenia

Reticulardysgenesis

Other

Acquiredaplasticanemia

Drugs/chemicals

Radiation

Viralinfections

Immunedisorders

Idiopathic

Paroxysmalnocturnalhemoglobinuria

Hypoplasticmyelodysplasticsyndromes

Largegranularlymphocyticleukemia

Graphic52354Version4.0

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Majorcausesofacquiredaplasticanemia

Idiopathic

Cytotoxicdrugsandradiation

Cancertreatment(anticipatedeffect)

Drugreaction

Anticonvulsants:carbamazepine,hydantoins,phenacemide

Antibiotics:sulfonamides,chloramphenicol

Nonsteroidalantiinflammatorydrugs(NSAIDs):phenylbutazone,indomethacin

Antithyroidmedications:methimazole,propylthiouracil

Gold

Arsenicals

Toxicchemicals

Benzene

Solvents

Gluevapors

Viralinfections

EpsteinBarrvirus

Seronegative(nonAthroughG)hepatitis

Humanimmunodeficiencyvirus(HIV)

Otherherpesviruses

Immunedisorders

Eosinophilicfasciitis

Systemiclupuserythematosus

Graftversushostdisease

Miscellaneous

Paroxysmalnocturnalhemoglobinuria

Thymoma

Pregnancy

Anorexianervosa

Graphic70072Version5.0

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Phasesofradiationinjury

Dose(Gy)

SymptomsPrognosis

Prodrome Hematologic GI Cerebrovascular

0.5to1.0 + + 0 0 Survivalalmostcertain

1.0to2.0 +/++ + 0 0 Survival>90percent

2.0to3.5 ++ ++ 0 0 Probablesurvival

3.5to5.5 +++ +++ + 0 Deathin50percentat3.5to6weeks

5.5to7.5 +++ +++ ++ 0 Deathprobablein2to3weeks

7.5to10 +++ +++ +++ 0* Deathprobablein1to2.5weeks

10to20 +++ +++ +++ +++ Deathcertainin5to12days

>20 +++ +++ +++ +++ Deathcertainin2to5days

Gy:doseinGreyGI:gastrointestinalsideeffects0:noeffects+:mild++:moderate+++:severeormarked.*Hypotension.Alsocardiovascularcollapse,fever,shock.

Modifiedfrom:WaselenkoJK,MacVittieTJ,BlakelyWF,etal.Medicalmanagementoftheacuteradiationsyndrome:Recommendationsofthestrategicnationalstockpileradiationworkinggroup.AnnInternMed2004140:1037.

Graphic53570Version4.0

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Bonemarrowbiopsyinaplasticanemia

Bonemarrowbiopsyinaplasticanemia.Therearevirtuallynohematopoieticcells,andthemarrowspaceconsistsoffatandstroma.

CourtesyofStanleyLSchrier,MD.

Graphic63867Version2.0

Normalbonemarrowbiopsyatlowpower

Lowpowerviewofanormalbonemarrowbiopsy.Theoverallcellularityisbetween30and70percent,withtheremainderofthespacebeingoccupiedbyfatandstroma.

CourtesyofStanleyLSchrier,MD.

Graphic68384Version2.0

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Assessmentofchildrenpresentingwithpancytopenia

Carefulphysicalexaminationfordysmorphicfeatures

Laboratorytesting

Completebloodcount

Serumaminotransferases

Viralserologies

HIV

Cytomegalovirus

EpsteinBarrvirus

Hepatitis

Herpessimplexvirus

SerumfolateandvitaminB12concentrations

HemoglobinFlevels

Cytogeneticstudiesonbonemarrow*

DiepoxybutanescreenforFanconianemia

Telomerelengthanalysisofleukocytesubsetsfordyskeratosiscongenita

CD55/59screenforparoxysmalnocturnalhemoglobinuria

Redbloodcellphenotyping

HLAtissuetyping

*FISHanalysisisalsoperformedbysomeproviders,andisspecificallyrecommendedifconventionalcytogeneticstudiesarelimitedbecauseofinadequatemetaphasesinthebonemarrowsample.Themostfrequentanomaliesincludetrisomy8,trisomy6,5q,andanomaliesofchromosome7(monosomy)and13 .

Reference:1. RovoA,TichelliA,DufourC.Diagnosisofacquiredaplasticanemia.BoneMarrow

Transplantation201348:162.

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[1]

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Infectionassociatedhemophagocyticsyndrome

Bonemarrowfromachildwithhemophagocyticsyndrome,secondarytoEpsteinBarrvirusinfection.Reactivehistiocytesshowphagocytosisofnucleatedredbloodcells(redarrows)andplatelets(blackarrows).WrightGiemsastain.

From:BrunningRD,McKennaRW.Tumorsofthebonemarrow.Atlasoftumorpathology(electronicfascicle),Thirdseries,fascicle9,1994,Washington,DC.ArmedForcesInstituteofPathology.

Graphic81067Version3.0

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Relationofabsoluteneutrophilcounttoriskofinfection

Absoluteneutrophilcount

Riskmanagement

>1500/microL(>1.5x10 /liter)

None

1000to1500/microL Nosignificantriskofinfectionfevercanbemanagedonanoutpatientbasis

500to1000/microL Someriskofinfectionfevercanoccasionallybemanagedonanoutpatientbasis

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