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Treatmentofautoimmunehemolyticanemias|Haematologica

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TreatmentOfAutoimmuneHemolyticAnemias
AlbertoZanellaandWilmaBarcellini
U.O.Ematologia,FondazioneIRCCSCGrandaOspedaleMaggiorePoliclinico,Milan,Italy
Correspondence:zanella@policlinico.mi.itorwbarcel@policlinico.mi.it
Abstract
Autoimmunehemolyticanemia(AIHA)isarelativelyuncommondisordercausedbyautoantibodiesdirectedagainstselfredbloodcells.
Itcanbeidiopathicorsecondary,andclassifiedaswarm,cold(coldhemagglutinindisease(CAD)andparoxysmalcoldhemoglobinuria)
ormixed,accordingtothethermalrangeoftheautoantibody.AIHAmaydevelopgradually,orhaveafulminantonsetwithlife
threateninganemia.ThetreatmentofAIHAisstillnotevidencebased.ThefirstlinetherapyforwarmAIHAarecorticosteroids,which
areeffectivein7085%ofpatientsandshouldbeslowlytaperedoveratimeperiodof612months.Forrefractory/relapsedcases,the
currentsequenceofsecondlinetherapyissplenectomy(effectiveapprox.in2outof3casesbutwithapresumedcurerateofupto
20%),rituximab(effectiveinapprox.8090%ofcases),andthereafteranyoftheimmunosuppressivedrugs(azathioprine,
cyclophosphamide,cyclosporin,mycophenolatemofetil).Additionaltherapiesareintravenousimmunoglobulins,danazol,plasma
exchange,andalemtuzumabandhighdosecyclophosphamideaslastresortoption.Astheexperiencewithrituximabevolves,itis
likelythatthisdrugwillbelocatedatanearlierpointintherapyofwarmAIHA,beforemoretoxicimmunosuppressants,andinplaceof
splenectomyinsomecases.InCAD,rituximabisnowrecommendedasfirstlinetreatment.

Introduction
Autoimmunehemolyticanemia(AIHA)isarelativelyuncommondisordercausedbyautoantibodiesdirectedagainstselfredbloodcells,
withanestimatedincidenceinadultsof0.83per105/year,aprevalenceof17:100,000andamortalityrateof11%.1,2Itcanbe
idiopathic(50%)orsecondarytolymphoproliferativesyndromes(20%),autoimmunediseases(20%),infectionsandtumors.3AIHAis
veryrareininfancyandchildhood(0.2per105/year),4whereitisprimaryin37%andassociatedwithimmunedisordersin53%of
cases.Mortalityislowerinchildren(4%),butrisesto10%ifthehemolyticanemiaisassociatedwithimmunethrombocytopenia
(Evanssyndrome).5AIHAisclassifiedaswarm,cold(whichincludescoldhemagglutinindisease(CAD)andparoxysmalcold
hemoglobinuria)ormixed,accordingtothethermalrangeoftheautoantibody.Thediagnosisisusuallysimple,basedonthepresence
ofhemolyticanemiaandserologicalevidenceofantierythrocyteantibodies,detectablebythedirectantiglobulintest(DAT).Inwarm
AIHA,DATistypicallypositivewithantiIgGantisera(andantiC3dinsomecases).ColdformsareusuallyduetoIgM,andtheDATis

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positiveforC3d,sinceIgMantibodiesareoftenlostoronlypresentinsmallamountsontheredbloodcellsat37C.Itisimportantto
rememberthatDATmayyieldfalsenegativeresultsduetoIgAautoantibodies(thatarenotdetectablebymostroutinereagents),low
affinityIgG,orRBCboundIgGbelowthethresholdofthetest.Fortheformertwoconditions,theuseofmonospecificantiseraagainst
IgAandlowionicstrengthsolutionsorcoldwashingscanovercometheDATnegativity.SmallamountsofRBCboundIgGcanbe
detectedemployingtechniquesthataremoresensitivethanthetraditionalDATtube,suchasmicrocolumn,solidphase,enzyme
linked,andflowcytometry.Finally,therearerarecasesofwarmAIHAcausedbyIgMwarmautoantibodiesthatmayrequirespecial
tests(dualDAT)fordiagnosis,andarecharacterizedbymoreseverehemolysisandmorefatalitiesthanothertypesofAIHA.Despite
thenumeroustestsavailable,approximately10%ofAIHAremainDATnegative,andthediagnosisismadeafterexclusionofother
causesofhemolysisandonthebasisoftheclinicalresponsetotherapy.Theseatypicalcases,whichareidentifiedwithincreasing
frequency,mayrepresentacriticaldiagnosticproblemandcausedelaysintherapy.1,6,7
AIHAmaydevelopgradually,withconcomitantphysiologicalcompensation,ormayhaveafulminantonsetwithprofound,life
threateninganemia.Clinicalfeaturesaredeterminedbythepresence/absenceofunderlyingdiseasesandcomorbidities,andbythe
rateandtypeofhemolysisthatmainlydependsonthecharacteristicsoftheautoantibody.Inparticular,IgMwarmAIHAoftenhave
moreseverehemolysisandmorefatalities(upto22%)thanpatientswithothertypesofAIHA.6Itisworthrememberingthatthe
degreeofanemiaalsodependsontheefficacyoftheerythroblasticresponse.Infact,patientswithreticulocytopenia,reportedtooccur
insome20%ofadults8and39%ofchildren,5mayneedverystrongtransfusionsupportandrepresentaclinicalemergency.9The
treatmentofAIHAisstillnotevidencebasedasthereisonlyonerandomizedstudy10andfewprospectivephaseIItrials.1115Wewill
brieflyconsiderthemaintherapeutictoolsforthisdisease,withafocusonpatientswithidiopathicAIHArefractorytothetraditional
therapy.

TreatmentofwarmAIHA
ThetraditionaltreatmentofAIHAincludescorticosteroids,splenectomyandconventionalimmunosuppressivedrugs.Overrecentyears,
somenewtherapieshavebecomeavailableandtherehasbeensomeevidenceofsuccess.Thesetherapiesareprimarilyusedin
patientswhoarenotcandidatesfororfailtorespondtosplenectomy,thosewhorelapseaftersplenectomy,andthosewhocannot
maintainstablehemoglobinlevelswithoutunacceptablyhighdosesofcorticosteroids.

Firstlinetherapy
Corticosteroids
ThereisgeneralagreementthatcorticosteroidsrepresentthefirstlinetreatmentforpatientswithwarmantibodytypeAIHA,albeit
theiruseisbasedonexperienceratherthanhardevidence.Infact,thereislittlepublishedinformationontheireffectiveness,1,16,17
andthisisnotsupportedbyclinicaltrials.Corticosteroids,usuallyprednisone,aregivenattheinitialdoseof1.01.5mg/kg/dayfor1
3weeksuntilhemoglobinlevelsgreaterthan10g/dLarereached.Responseoccursmainlyduringthesecondweek,andifnoneor
minimalimprovementisobservedinthethirdweek,thistherapyisassumedtobeineffective.Afterstabilizationofhemoglobin,
prednisoneshouldbegraduallyandslowlytaperedoffat1015mgweeklytoadailydoseof2030mg,thenby5mgevery12weeks
untiladoseof15mg,andsubsequentlyby2.5mgeverytwoweekswiththeaimofwithdrawingthedrug.Althoughonemightbe
temptedtodiscontinuesteroidsmorerapidly,AIHApatientsshouldbetreatedforaminimumofthreeorfourmonthswithlowdoses
ofprednisone(10mg/day).1Infact,patientsreceivinglowdosesofcorticosteroidsformorethansixmonthshavealowerincidenceof
relapseandlongerdurationofremissionthanthosediscontinuingthemedicationwithinsixmonths.18Moreover,anearlieronsetof
steroidtherapycorrelateswithalowerprobabilityofrelapse.16ItisworthrememberingthatAIHApatientsonprolongedsteroid
therapyshouldbegivenbisphosphonates,vitaminD,calcium,andfolicacidsupplementation.2Patientswithparticularlyrapid
hemolysisandverysevereanemia,orcomplexcasessuchasEvanssyndrome,mayrequireintravenousmethylprednisoloneat100200
mg/dayfor1014daysor2501000mg/dayfor13days,althoughhighdosecorticosteroidtherapyforAIHAhasbeendescribed
essentiallyascasereports.19,20Firstlinetherapywithcorticosteroidsisexpectedtoprovidearesponsein7085%ofpatients
however,only1in3casesremaininlongtermremissiononcethedrugisdiscontinued,afurther50%requiremaintenancedoses,and
approximately2030%needadditionalsecondlinetherapies.Itisnotknownhowmanyadultpatientsarecuredbysteroidsalone,but
itisestimatedthatthisoccursinlessthan20%ofpatients.2Patientsunresponsivetofirstlinetherapyshouldundergoadiagnosticre
evaluationforapossibleunderlyingdisease,sinceAIHAassociatedwithmalignanttumors,ulcerativecolitis,benignovarianteratomas,
orwithIgMwarmautoantibodiesareoftensteroidrefractory.2

Secondlinetherapy

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Oncethedecisionforasecondlinetreatmenthasbeentaken,thereareseveraloptions,althoughsplenectomyandrituximabarethe
onlysecondlinetreatmentswithaprovenshorttermefficacy.2

Splenectomy
SplenectomyiscommonlythoughttobethemosteffectiveconventionalsecondlinetreatmentofwarmAIHAtobeproposedto
patientsunresponsiveorintoleranttocorticosteroids,inthosethatrequireadailymaintenancedoseofprednisonegreaterthan10mg,
andinthosewithmultiplerelapses.2However,itsefficacyhasneverbeencomparedtothatofothersecondlineapproaches,andno
convincingdataonremissiondurationaftersurgeryareavailable.1Factorsinfavorofsplenectomyasthebestsecondlinetherapy
includeitsshorttermefficacyandthegoodinitialresponserate:apartialorcompleteremissionisobtainedinapproximately2in3
patients(3882%dependingonthepercentageofsecondarycaseswhichseemtobelessresponsivethanidiopathicforms21).
Moreover,asubstantialnumberofthemremaininremissionforyearswithoutmedication,withapresumedcurerateofupto
20%.2,22,23Itisworthmentioningthatpatientswithpersistentorrecurrenthemolysisaftersplenectomyoftenrequirelowerdosesof
corticosteroidsthanbeforesurgery.2Adrawbackofsplenectomyisthelackofreliablepredictorsoftheoutcome,sinceitseffectiveness
isnotrelatedtodiseaseduration,responsetosteroidsnortheextentofsplenicsequestration.24Moreover,splenectomymaybe
associatedwithsurgicalcomplications(pulmonaryembolism,intraabdominalbleeding,abdominalabscess,abdominalwallhematoma),
althoughlaparoscopicinterventionhasloweredthesurgicalriskcomparedtoconventionalsurgery(0.51.6%vs.6%).25Themost
fearedcomplicationaftersplenectomyisoverwhelmingsepsisduetoencapsulatedbacteria,withariskof3.35%andamortalityrate
ofupto50%,26,27evenaftertheintroductionofpreoperativevaccinationagainstpneumococci,meningococci,andhemophilus.The
roleandefficacyofantibioticprophylaxisinthissettingremainsunclear,andnotallinvestigatorsrecommendthisapproach.1,28Finally,
small,butnotinsignificantadditionalrisksincludethromboembolismandpulmonaryhypertension.29,30Therateofsplenectomyin
adultsisnotknown2whileinalargepediatricseriesof256AIHA(99ofwhomwithEvanssyndrome)splenectomywasperformedin
13.9%ofcases.5Itshouldberememberedthatinspiteofthefactthattheincidenceofinfectioninchildrenandadultsisreportedto
besimilar,thedeathratesamongchildrenarehigherthanadults(1.7%vs.1.3%).26
Rituximab
Rituximab,amonoclonalantibodydirectedagainsttheCD20antigenexpressedonBcells,hasbeenshowntobeeffectiveinAIHA,
althoughthecomparisonofresponseratesinvariousstudiesisdifficultintheabsenceofcommonresponsecriteria.Recentreviews31,32
reportedthatrituximab(375mg/m2weeklyforamedianof4weeks)iseffectiveintreatingbothwarmAIHAandCAD,withamedian
responseratehigherinthewarmforms(overallresponse(OR)8387%,completeresponse(CR)5460%vs.OR58%,CR4.5%)
diseasefreesurvivalhasbeenreportedtobe72%atoneand56%attwoyears.33Rituximabhasbeenshowntobeeffectivebothin
idiopathicandsecondaryAIHA,includingthoseassociatedwithautoimmuneandlymphoproliferativedisorders,andbonemarrow
transplant.31,32,3437Responsestotreatmentwereobservedinmonotherapyorincombinationwithcorticosteroids,
immunosuppressantsandinterferon,35,36andregardlessofpriortherapy.34,35Thetimetoresponsevariesconsiderably,withsome
patientsrespondingveryquicklyandotherstakingweeksorevenmonthstoachievetheirmaximumresponse.35,38Inarecent
multicenterretrospectivestudy,thetimetoresponsewasonemonthpostinitiationofrituximabin87.5%andthreemonthsin12.5%
ofpatients.39Itisworthrememberingthatrituximabretreatmentmaybeeffective35,39,40andsomepatientsrespondedtore
treatmentmorethanonce.34,35RituximabhasalsobeenfoundtobeeffectiveinEvanssyndromewithareportedoverallresponseof
83%(66%complete).41Theresponseisevengreater(upto94%)consideringthemorerecentandnumerousseries.32Thetreatment
iseffectivealsoinchildren42andinEvanssyndromesecondarytolymphoproliferativeorotherautoimmunediseases.43,44Rituximab
treatmentiswelltoleratedandnoadverseeventsarereportedformostpatients,excludinginfusionrelatedsideeffects.35,40,45The
drughasawellestablishedsafetyprofile(infectiouseventsinapprox.7%),althoughrarecasesofprogressivemultifocal
encephalopathy,mostlyinoncohematologicconditions,hepatitisBreactivationandotherviralinfectionshavebeenreported.31,32To
preventhepatitisBreactivationbothafterrituximabandprolongedsteroidtherapy,antiviralprophylaxisisnowrecommended.46
Inanattempttominimizesideeffectsandreducecosts,lowdoserituximab(100mgfixeddose/weeklyfor4weeks)wasreportedto
beeffectiveinpatientswithAIHAwhofailedtorespondtoconventionaltreatment,asmonotherapy47orincombinationwith
alemtuzumab.13Moreover,lowdoserituximabasfirstorsecondlinetherapywasabletoinduceanoverallresponserateof89%
(completeresponse67%),14and68%relapsefreesurvivalat36months,15suggestingthatthisdrugshouldbeusedearlyinthe
treatmentscenarioofAIHA.Finally,arecentphaseIIIrandomizedtrialshowedthatapproximately70%ofpatientstreatedwith
glucocorticoidsandrituximabwerestillinremissionat36months,comparedwithapproximately45%ofthosetreatedwithsteroids
alone.10
Immunosuppressivedrugs
BeforetheintroductionofrituximabinthetherapyofAIHA,azathioprine(100150mg/day)andcyclophosphamide(100mg/day)were

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oftenusedassecondlinetreatmentbecausegoodresponses(4060%ofcases)hadbeenreportedintheearlyliterature(althougha
subsequentcriticalanalysisdemonstratedthataresponsehadbeenobtainedinlessthanonethirdofpatients).1,2CyclosporinAhas
beenusedsuccessfullyinalimitednumberofrefractoryAIHApatients.1,22Inparticular,longtermtherapywithcyclosporinewas
reportedtoinducecompleteremissionin3in4ofwarmAIHApatientswithlifethreateninghemolysisunresponsivetoprevious
treatments.48Inassociationwithprednisoneanddanazol,cyclosporinwasshowntoimprovethecompleteresponseratein18warm
AIHApatientscomparedwith26patientstreatedwithonlyprednisoneanddanazol(89%vs.58%),andtoreducetheincidenceof
relapse.49,50OnlylimiteddataontheuseofmycophenolatemofetilinpatientswithrefractorywarmAIHAareavailable.Complete
remissionandgoodpartialresponseshavebeenreportedinalltreatedadultpatients(9idiopathicand2secondarytosystemiclupus
erythematosus).5154Thedrughasbeenproventobeeffectiveinrefractoryimmunecytopenias(9AIHA)inchildrenwiththe
autoimmunelymphoproliferativesyndrome,ofwhom12of13patientsrespondedwithreductionindosesorcessationofother
immunosuppressivedrugs55thetreatmentwaswelltoleratedinallpatients.Ithasbeensuggestedthatthisdrugcouldbeincludedin
thetreatmentarsenalofrefractoryimmunecytopenias,asasteroidsparingoption.23Recently,mycophenolatemofetilhasalsobeen
successfullyusedinassociationwithrituximabinacaseofposthematopoieticstemcelltransplant,refractoryAIHA.56
Otheroptions
Danazol,asyntheticanabolicsteroidwithmildandrogenicproperties,hasbeensuccessfullyusedin28AIHApatientsconcurrentwith
oraftersteroids,butitseffectivenesswaslimitedinrefractoryorrelapsedcases,ofwhomonly43%achievedacompleteremission.57
Inanotherseriesof17patientstreatedwithdanazolplusprednisone,anexcellentresponsewasobtainedasfirstlinetherapy(8of10
patients),whereastreatmentwaslesseffective(3of7)inrelapsedorrefractorypatients.58Incontrast,amorerecentretrospective
studydidnotobserveanysubstantialmodificationintheresponseratenorinthedurationofprednisonetherapyinpatientstreated
withdanazol.59Noarticlesupportingitsusehasbeenpublishedinthelastdecade.
Intravenousimmunoglobulins(IVIG)arefrequentlyusedinAIHA,aloneorincombinationwithprednisone,60andmostlyinchildren,
probablybecauseoftheirproveneffectivenessinprimaryimmunethrombocytopenia,andtherelativelylowincidenceofadverseeffects
comparedwithothertreatmentoptions.However,theiruseiscontroversial,primarilybecauseonlysmallcaseserieshavebeen
reported.1,22Agoodresponsewasobtainedin5patientswithrecurrentwarmAIHAassociatedwithCLL,61therecoveryofthe
hemoglobinlevelsbeingfasterwhenprednisoneandhighdoseIVIGwerecombined.Inaretrospectivestudyof73patients,62a
responsewasobservedin40%ofcases,only15%achievinghemoglobinlevelsof10g/dLorgreaterchildrenweremorelikelyto
respond(54%).Inarecentguideline,highdoseimmunoglobulinwasnotrecommendedforuseinAIHA,exceptundercertainlife
threateningcircumstances.63
PlasmaexchangehasbeenperformedinarelativelysmallnumberofseverelyaffectedwarmAIHApatients,bothchildrenandadults,
inwhomtheanemiacouldnotbestabilizedwithsteroidsandtransfusiontherapyalone,asatemporizingmeasure.1Theresultswere
inconsistent,andfavorableeffectsgenerallyshortlived.Moreover,concomitanttherapywithsteroidsandimmunosuppressivedrugs
oftenmadeitdifficulttodefinethecontributionofthisproceduretotheoutcome.McLeodetal.64reviewed17casesofwarmAIHA
treatedwithplasmaexchangeshowingthatitseemedtostabilizethediseaseandincreasetheefficiencyofbloodtransfusionsincases
withfulminanthemolysis,whereasotheracutelyillpatientsshowednoimprovement.Aretrospectivesinglecentercasecontrolstudy
failedtodemonstratethatplasmaexchangeincreasesredbloodcelltransfusionefficiencyinsevereautoimmunehemolyticanemia.65
InasummaryofcurrentindicationcategoriesendorsedbytheAmericanAssociationofBloodBanks(AABB)andtheAmericanSociety
forApheresis,plasmaexchangeforAIHAisconsideredasacategoryIIIindication,i.e.anapplicationrepresentingheroicorlastditch
effortsonbehalfofapatient.66
Lastoptiontreatments
Highdosecyclophosphamide(50mg/kg/dayfor4days)followedbygranulocytecolonystimulatingfactorwaseffectiveinachieving
completeremissionin5of8patientswithhighlyrefractorywarmAIHA.67
Alemtuzumab,ahumanizedantiCD52monoclonalantibody,hasbeenshowntobeeffectiveinsmallseriesofpatientswithidiopathic
refractoryAIHA,withanoverallcompleteremissionratein13of16,including3pediatriccases.23,68,69However,becauseofthehigh
toxicity,itisconsideredalastresortoptioninsevereidiopathicAIHAunresponsivetoallprevioustreatments.2Alemtuzumabinduced
anoverallresponsein11of12caseswithCLLassociatedAIHA,refractorytocorticosteroid,splenectomyandrituximab,suggesting
thatitshouldbeconsideredevenbeforerituximabinwarmAIHAaccompaniedbyprogressiveCLL.22,7072Ofatumumab,amonoclonal
antibodytargetingauniqueepitopeonCD20thatdiffersfromthattargetedbyrituximab,hasrecentlybeensuccessfullyusedinacase
ofCLLassociatedwarmAIHArefractorytorituximab.73
Hematopoieticstemcelltransplantation
Informationontheuseofhematopoieticstemcelltransplantation(HSCT)inwarmAIHAislimitedtosinglecasesorsmallseries,
1,74,75

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mostlyEvanssyndromes,1,74,75withanoverallcompleteremissionrateofapproximately60%inallogeneicand50%inautologous
HSCT.Theanalysisofdataof36patientswithrefractorycytopenias(n=7AIHA,n=7Evanssyndrome)includedintheRegistryofthe
EuropeanGroupofBloodandMarrowTransplantationshowedacontinuousremissionin1of7autologousHSCTand3of7allogeneic
HSCT,withatransplantrelatedmortality(TRM)ofapproximately15%.75,76
Supportivetherapy
PatientswithAIHAmayoftenrequireredbloodcell(RBC)transfusiontomaintainclinicallyacceptablehemoglobinvalues,atleastuntil
specifictreatmentsbecomeeffective.Thedecisiontotransfuseshoulddependnotonlyonthehemoglobinlevel,butratheronthe
patientsclinicalstatusandcomorbidities(particularlyischemicheartorseverepulmonarydisease),theacutenessofdiseaseatonset,
therapidityofprogressionoftheanemia,andthepresenceofhemoglobinuriaorhemoglobinemiaandothermanifestationsofsevere
hemolysis.1Thebloodtransfusionshouldneverbedeniedtopatientsinacriticalclinicalsituation,evenincasesinwhichnotruly
compatibleunitscanbefound,sincewarmautoantibodiesarefrequentlypanreactive.ABOandRhDmatchedredcellconcentratescan
inanycasebesafelyadministeredinurgentcasesifalloantibodies(knowntooccurin1240%ofAIHApatients1)arereasonably
excludedonthebasisoftheprevioustransfusionand/orpregnancyhistory.Inlessurgentcases,anextendedphenotypingisadvisable
andcompatibleredcellunitsmaybeselectedfortransfusion.77Insomepatients,morecomplexprocedures,suchaswarm
autoadsorptionorallogeneicadsorption,maybeneededforthedetectionofalloantibodies.1Undetectedalloantibodiescouldbethe
causeofincreasedhemolysisfollowingtransfusion,whichmightfalselybeattributabletoanincreaseintheseverityofAIHA.1Incase
theautoantibodyspecificityiswelldefined(mostfrequentlywithintheRhsystem),itisstilldebatedwhetheritispreferabletoignore
ortorespectitintheselectionofbloodtobetransfused,thelatterapproachimplyingtheadministrationofRBCscontainingRh
antigensthatthepatientslackswiththeriskofalloimmunization.Someauthorsrecommendignoringthespecificityofthe
autoantibodybecauseitisnotextensivelyproventhatantigennegativeRBCtransfusionsresultinanincreasederythrocytesurvival.78
Moreover,somedatasuggestthatpatientswithAIHAhaveanincreasedpropensitytodevelopRBCalloantibodiesaftertransfusion.1
Ignoringtheautoantibodyspecificityhasbeendemonstratedtobesafeandeffectiveinagreatnumberoftransfusions.79,80To
minimizerisksoffebrilenonhemolyticreactionsduetoantileukocyteantibodies,nowadaysleukodepletedredcellsareusedinAIHA
patients.Asregardsthevolumetobetransfused,itisworthrememberingthatovertransfusionshouldbeavoidedbothfor
hemodynamicreasons(particularlyinelderlypatients),andfortheoccurrenceofhemoglobinemiaandhemoglobinuria,whichmight
notbeduetoalloantibodyinducedhemolysis,asgenerallythought,butrathertotheincreaseofthetotalmassofRBCsavailablefor
destruction.Finally,notonlyshouldtheamountofbloodtransfusedbelimited,butRBCsshouldalsobeadministeredslowly,when
possible,notexceeding1mL/kg/h.1
ItisworthmentioningthatC1esteraseinhibitormighthavepotentialasasafetherapytocontrolcomplementinducedRBC
destructioninAIHApatients.81Moreover,theadministrationoferythropoietinwassuccessfullyusedinpatientswiththerapyrefractory
AIHA,particularlyinthepresenceofreticulocytopenia.82

TherapyofcoldAIHA
ThedecisiontotreatCADshouldbereservedforpatientswithsymptomaticanemia,transfusiondependence,and/ordisabling
circulatorysymptoms.Infact,nonsevereasymptomaticformsofCADmayrequireonlyprotectionagainstexposuretocold
temperaturesandoccasionaltransfusionsupportinwinter.1,83,84ErythrocytetransfusionscansafelybegiveninCAD,provided
appropriateprecautionsaretaken.Inparticular,thepatientandtheextremitychosenforinfusionshouldbekeptwarm,andtheuseof
aninlinebloodwarmerisrecommended.Moreover,infusionofcoldliquidsandbloodproductswithahighplasmacontentshouldbe
avoided.1,84,85Inarecentretrospectiveanalysisof89patients,40%receivedtransfusionsduringtheirdiseasecourseand82%
receiveddrugtherapy.84
Asregardsfirstlinetherapy,responsetosteroidshasneverbeensupportedbysystematicstudiesandisstillcontroversial,being
effectiveinasmallfractionofcases(1435%)andusuallyrequiringunacceptablyhighdosesinordertomaintainthe
remission.1,83,84,86,87Therefore,thistreatment,althoughstillwidelyusedintheclinicalpractice,isnowdiscouraged.
Concerningconventionalcytotoxicimmunosuppressivedrugs,monotherapywithchlorambucilorcyclophosphamidehasshownsome
beneficialeffectinsmallseries(16%ofcases),1,87,88whereasnoconvincingresponseswereobservedinthefewpatientstreatedwith
azathioprine87,89andinterferonorlowdosecladribine.90Splenectomyisusuallyineffective1,84duetothefactthatclearanceofC3b
opsonizederythrocytesprimarilyoccursintheliver,althoughithasoccasionallybeenreportedtobeeffectiveinrarecasesofIgG
mediatedCAD.Finally,erythropoietin,widelyusedintheUSAbutnotsoofteninWesternandNorthernEurope,hasnoevidencebased
proofofefficacy.84
Theavailabilityofrituximabinthelast1015yearshassubstantiallychangedthetherapyofCAD,sincethisdrugisdirectedagainst

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thepathogenicBcellclone,whichisdetectedinthemajorityofpatientsbyflowcytometryand/orimmunohistochemistry.84,87,91The
standarddosagewasreportedeffectiveinapproximately60%ofcases,witharesponsedurationofoneyear,bothinseveralcase
reportsandinlarger,prospective,butuncontrolledpublishedtrials.11,12,31,32Themediantimetoresponsewas12monthsand
responseswereobservedfollowingasecond,andevenathirdcourse,inrelapsedcases.Rituximabisnowrecommendedasthefirst
linetreatmentofCAD,84althoughcompleteandsustainedremissionsareuncommon.91Furthermore,combinedtreatmentwith
rituximabandfludarabineadministeredorally(40mg/m2onDays15)resultedinhigherresponserates(76%ofcases)andsustained
remissions(estimatedmedianresponseduration6.5years).92Sincehematologictoxicitiesandinfectivecomplicationswerecommon,
thisregimenissuggestedforcasesrefractoryto12coursesofrituximab.84Inamorerecentretrospectiveanalysisof89patients,
rituximabwasassociatedwithresponseratesofapproximately80%(bothassingleagentandincombinationtherapy),alonger
responseduration(median2years),andalowerproportionofpatientsneedingfurthertreatment(55%).91Finally,plasmapheresis
maybeusefulinacutehemolyticcrisisandbeforesurgeryrequiringhypothermia,93,94althoughitseffectistransient.
Asregardsnewexperimentalapproaches,improvementofanemiahasbeenobservedin2patientsfollowingmonotherapywith
bortezomib,aninhibitorof26Sproteasome,95andin2casesafteradministrationofeculizumab,themonoclonalantiC5antibody
licensedforparoxysmalnocturnalhemoglobinuria.96,97However,theseobservationsneedtobeconfirmedinprospectivetrials.
ThereisnoevidencebasedtherapyforCADsecondarytomalignantorinfectiousdiseases.Generally,treatmentoftheunderlying
diseaseisaccompaniedbyresolutionofthehemolysis,particularlyinlymphoproliferativediseasesandMycoplasmapneumonia.1,85The
associationofcorticosteroidtherapyisasubjectofdebate,particularlyinCADsecondarytoinfection.1,13,85Itsuseissuggestedin
severeformsorincasesinwhichthereisnospontaneousimprovementwithinafewdays.
Paroxysmalcoldhemoglobinuria(PCH)ischaracterizedbyacuteintravascularhemolysismediatedbytheDonathLandsteinerbiphasic
hemolysin,whichbindstoerythrocytesatlowtemperaturesandcausescomplementmediatedhemolysisat37C.Mostantibodiesare
IgGanddirectedagainstthePbloodgroupsystem.Inthepast,PCHwasmainlyassociatedwithsyphilis,andnowusuallyfollowsviral
andbacterialinfections,includingMycoplasmapneumonia.1PCHisusuallyaselfresolvingdisease,althoughdeathshavebeen
reported.98Thefewseverecasesmayrequiretransfusionsandsteroidtreatment,whoseeffectivenessisdifficulttoevaluatebecauseof
thetransientnatureofthehemolysis.1EculizumabwasreportedineffectiveinacaseofsteroidrefractoryPCHwithassociated
myeloma.99
Approximately78%ofautoimmunehemolyticanemiashaveserologicalfindingscharacteristicofwarmAIHAandCAD,andare,
therefore,classifiedasmixedforms.1,100Cautionhadbeenexpressedaboutthisdiagnosis,assometimesitismadeonthebasisof
inadequateserologicalstudies.101Petzetal.1reportedthat35%ofpatientswithWAIHAhavecoldagglutininsreactiveat20C,which
were,however,clinicallyinsignificantinalmostallcases(only5%reactedat37C).Someauthorssuggestthatpatientswithmixed
AIHAhaveamoresevereonsetandmorechroniccoursethanpatientswithothercategoriesofAIHA,althoughacomprehensive
comparisonoftheclinicalcourseinthedifferentformshasnotbeenmade.Weretrospectivelystudied157AIHApatientsfollowedup
atourinstitutionandfoundthatthemostseverecases(hemoglobinlowerthan6g/dLatonset)weremainlymixedandatypicalforms
(DATnegative,warmIgMpositive).Thesecasesfrequentlyshowedreticulocytopenia,whichmaycontributetotheclinicalpicture.
Moreover,caseswithsevereonsetweremoreoftenrefractorytofirstlinetherapyandrequired3ormorelinesoftherapy.

Conclusions
ThetherapeuticarsenalnowavailableforsteroidrefractorywarmAIHAiscertainlybroaderthaninthepast.However,nocontrolled
clinicaltrialshaveyetbeenperformedthatcanguidethechoiceoftreatment.24Itiscurrentopinionthatthesequenceofsecondline
therapyinprimarywarmAIHAshouldbesplenectomy,rituximab,andthereafteranyoftheimmunosuppressivedrugs.Nevertheless,
thechoiceofsecondlinetherapiesdependsonthephysicianspersonalexperience,thepatientsageandcomorbidity,andpatient
preference.2,24However,inclinicalpractice,rituximabisusedwithincreasingfrequencybeforesplenectomy,particularlyinthemost
severecasesandchildrenagedunder56years(www.AIEOP.org,RecommendationsfortheManagementofAIHAinchildren).The
therapeuticalgorithmforwarmAIHAadoptedinourinstitutionisshowninFigure1.Asexperiencewithrituximabevolves,itislikely
thatthisdrugwillbeusedearlierintherapy,beforemoretoxicimmunosuppressants,andinsomecasesinplaceofsplenectomy.As
regardsCAD,rituximabisnowrecommendedasfirstlinetreatment.
Figure1.

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TreatmentalgorithmforwarmAIHAinadults.SR:sustainedresponsedefinedasmaintenanceofHbvalues>10g/dLovertimeNR:noresponsed:day
w:weekAZA:azathioprineCyA:cyclosporineACTX:cyclophosphamideMMF:mycophenolatemofetilPEX:plasmaexchangeIVIG:intravenous
immunoglobulin.

Footnotes
Thisreviewarticlewasoriginallypublishedintheeducationbookofthe19thcongressofEHA(June2014).
AuthorshipandDisclosures
Informationonauthorship,contributions,andfinancial&otherdisclosureswasprovidedbytheauthorsandisavailablewiththe
onlineversionofthisarticleatwww.haematologica.org.
ReceivedJuly23,2014.
AcceptedAugust26,2014.
CopyrightFerrataStortiFoundation

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