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anemia aplastica uptodate
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25.02.2015 Acquiredaplasticanemiainchildrenandadolescents
http://www.uptodate.com/contents/acquiredaplasticanemiainchildrenandadolescents?topicKey=HEME%2F5923&elapsedTimeMs=0&source=searc 1/17
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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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
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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
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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.
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Bonemarrowbiopsyinaplasticanemia
Bonemarrowbiopsyinaplasticanemia.Therearevirtuallynohematopoieticcells,andthemarrowspaceconsistsoffatandstroma.
CourtesyofStanleyLSchrier,MD.
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Normalbonemarrowbiopsyatlowpower
Lowpowerviewofanormalbonemarrowbiopsy.Theoverallcellularityisbetween30and70percent,withtheremainderofthespacebeingoccupiedbyfatandstroma.
CourtesyofStanleyLSchrier,MD.
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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.
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Relationofabsoluteneutrophilcounttoriskofinfection
Absoluteneutrophilcount
Riskmanagement
>1500/microL(>1.5x10 /liter)
None
1000to1500/microL Nosignificantriskofinfectionfevercanbemanagedonanoutpatientbasis
500to1000/microL Someriskofinfectionfevercanoccasionallybemanagedonanoutpatientbasis
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