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Therapyforchroniccoldagglutinindisease:perspectiveforfurtherimprovements

BloodTransfus.2013Apr11(2):167168.

PMCID:PMC3626464

doi:10.2450/2013.027312

Therapyforchroniccoldagglutinindisease:perspectiveforfurtherimprovements
SigbjrnBerentsen
DepartmentofMedicine,HaugesundHospital,HelseFonnaHF,Haugesund,Norway
Correspondence:SigbjrnBerentsen,DepartmentofMedicine,HaugesundHospital,P.O.Box2170,5504Haugesund,Norway,email:
sigbjorn.berentsen@haugnett.no
Received2012Nov27Accepted2012Dec19.
CopyrightSIMTIServiziSrl

Autoimmunehaemolyticanaemia(AIHA)isacollectivetermforseveraldisorderscharacterizedbyautoantibody
mediateddestructionoferythrocytes1.AIHAareclassifiedintowarmantibodyandcoldantibodytypes,depending
ontheoptimaltemperatureofactionoftheautoantibody.Primarychroniccoldagglutinindisease(CAD)hasbeen
consideredmoredifficulttotreatthanwarmantibodyAIHA2.Thisisbecauseofthelackofefficacyoftherapy
withcorticosteroidsorothernonspecificimmunosuppressiveagents2,3.
UnlikepatientswithwarmAIHA,whooftenhavegeneralimmunesystemdysregulation4,5,patientswithCAD
probablyhavecompetentregulationoftheimmunesystem,whichexplainsthelackofassociationbetweenCAD
andotherautoimmunedisorders6.AnincreasingbulkofdatahasshownthatprimaryCADisaclonal,
lymphoproliferativebonemarrowdisorder,whichismostoftennonprogressiveandclinicallynonmalignant3,7.It
isnotsurprising,therefore,thatnonspecificimmunosuppressionormildcytotoxictherapyusuallyfailstoinduce
remission,whilemorespecificandpotenttherapydirectedatthepathogenicBcellcloneismorelikelytosucceed3.
InthisissueofBloodTransfusion,Gueliandcolleaguesdescribeacompleteremissionofmorethan3years
durationfollowingtreatmentwithrituximabandbendamustineincombinationinaheavilypretreatedpatientwith
CADnotrespondingtopreviouschemotherapies8.Thecombinationwaswelltolerated.Ifrepresentative,thisfirst
publishedcaseobservationmayprovideacluetonewtreatmentoptionsinthischallengingdisease.
Primaryorsecondary:diseaseorsyndrome?

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ThepatientdescribedbyGuelietal.hadacoldagglutininmediatedhaemolyticanaemiaassociatedwithaBcell
lymphoproliferativebonemarrowdisorderwhichwasdifficulttoclassifyaccordingtotheWHOlymphoma
classification9.Inapopulationbasedstudyof86patientswithCAD,aclonalbonemarrowlymphoproliferation,
frequentlydescribedaslymphoplasmacyticlymphoma,marginalzonelymphomaorunclassifiedclonalBcell
proliferation,wasdemonstratedbybonemarrowbiopsyin75%ofthepatientsandbyflowcytometryin90%7.
Undoubtedly,thesepatientsrepresentthesamemajoritythathastraditionallybeenclassifiedashavingprimary
CAD3,7,10.ThepatientdescribedbyGuelisgroupdid,therefore,havetypicalprimaryCAD8.
Electrophoresisofthepatientsserumshowednomonoclonalprotein8,whichisthecaseinlessthan10%of
patientswithprimaryCAD7.Thisisprobablyamatterofsensitivityoftheelectrophoresis.Intheremaining
majority,amonoclonalimmunoglobulin(Ig)canbefoundbyserumelectrophoresisand/orimmunofixation
providedthebloodspecimeniskeptat3738Cfromthetimeofbeingcollectedtoremovalofserumfromthe
clot.ThemonoclonalIgisusuallyanIgM,whileIgG,IgAorphenotypeisfoundinafewpercentofpatients7.
ColdagglutininswithantiIspecificityaretypicallypresentathightitresintheserumofuntreatedpatients,andthe
directantiglobulintest(DAT)isinvariablystronglypositiveforcomplementproteinC3d6,7,11.
ThetermsCADandcoldagglutininsyndrome(CAS)havebeenusedintheliteratureinaratherconfusingmanner.
ThewelldefinedclinicopathologicalentityexemplifiedbyGuelietal.8andcomprehensivelydescribedbyothers
shouldbecalledadisease,notsyndrome3.CASshouldbeusedasacollectivetermforthefarmoreuncommon,
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Therapyforchroniccoldagglutinindisease:perspectiveforfurtherimprovements

truesecondarycaseswithmuchmorediverseaetiologyandpathogenesis3.
Therapeuticoptionsandperspectives

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NotallpatientswithCADrequiredrugtherapy.Forthosewithmilddisease,withveryslighthaemolyticanaemia
andnoornegligiblecoldinducedcirculatorysymptoms,thenonpharmacologicalmanagementdescribedindetail
elsewhereshouldstillbeappropriate12.Apopulationbasedstudyshowed,however,thatinmostpatientsCADis
notanindolentdiseaseintermsofmajorclinicalsymptomsandqualityoflife7.Thepatientdescribedinthecase
reportinthisissueofthejournalsufferedfromsevereanaemia8,whichisthecaseinonethirdofpatientswith
CADwhendefinedashaemoglobin<8.0g/dL7.About90%ofthepatientshavecoldinducedischaemic
symptoms,varyingfrommildtodisablingandcomplementinducedexacerbationduringfebrilediseaseshasbeen
observedintwothirds6,7,13.Activetherapyshould,therefore,probablybeconsideredindicatedmoreoftenthan
traditionallyrecommendedintheliterature3,12.Theresultsofsuchtherapyhaveimproveddramaticallyduringthe
lastdecade1,3,12.
Typically,giventhepersistingbutundeservedpopularityofcorticosteroidsinthetreatmentofthisspecifictypeof
AIHA,thepatientdescribedbyGuelisgrouphadreceivedsteroidtherapywithoutanyimprovementbeforebeing
referredtotheirdepartment8.Corticosteroidsresultinsomedegreeofpartialremissioninlessthan15%ofpatients
withCADandthefewpatientswhodorespond,usuallyrequireunacceptablyhighdosesinordertomaintainthe
response7.Corticosteroidsshouldnot,therefore,beusedtotreatCAD2,3,12.
Rituximabmonotherapyhasbeenshowntoinducepartialremissionsinabout50%ofpatients14,15.Thosewho
experiencerelapseafterhavingbeenpreviouslytreatedwithrituximabmayrespondtoasecondorevenathird
seriesofmonotherapywithmonoclonalantibodyandthetreatmentiswelltolerated.Despiteasomewhat
disappointingmedianresponsedurationofabout1year,singleagenttherapywiththisrituximabshouldstillbe
consideredfirstlinetreatmentinsomepatients.
Combinationtherapywithfludarabineandrituximabisveryefficient,resultinginremissionsinapproximately75%
ofthepatients,completeresponsesin20%,andamedianresponsedurationofmorethan66months16.However,
becauseofthetoxicityprofile,thistreatmentisnotsuitableforallpatientswithCADrequiringtherapy16.Short
termtoxicityincludinggrade34neutropeniainapproximately40%ofpatientsshouldleadtocautioninthevery
oldandcomorbidpatientsandthepossiblelongtermleukemogenicpotentialmaybeaconcernintheoccasional
youngpatients1618.Nevertheless,thefludarabineandrituximabcombinationremainsawelldocumentedand
oftensuccessfulchoiceinreasonablyfit,elderlyindividualsaswellasthosepatientsinwhomrituximab
monotherapyhasfailedtoinduceremission.
ItistobehopedthatfuturetherapiesdirectedatthepathogenicBcellclonemightbeasefficientastherituximab
fludarabineregimenbutlesstoxic.SuchnewdrugcombinationswouldallowmoreCADpatientstoachievelong
lastingimprovement,possiblyincreasingthefrequencyofcompleteremissionsandprovidingopportunitiesfor
thoseinwhomtreatmentwithrituximabfludarabinefails.Althoughthepossibilityofsuccessfullycombining
rituximabandbendamustineinCADisfarfrombeingdocumentedbythissinglecasereport,theobservationby
Gueliandcolleagues8ispromisingandshouldpromptsystematicstudies.PatientswithCADrequiringtherapy
shouldbeincludedinprospectivetrialswheneveravailable.
Footnotes

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TheAuthordeclaresnoconflictsofinterest.

References

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