revbrashematolhemoter.2015;37(4):230–235
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Original
article
Experience
with
Evans
syndrome
in
an
academic
referral
center
José
Carlos
Jaime-Pérez
∗,
Liliana
Nataly
Guerra-Leal,
Olga
Nidia
López-Razo,
Nereida
Méndez-Ramírez,
David
Gómez-Almaguer
UniversidadAutónomadeNuevoLeón,Monterrey,Mexico
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received9December2014 Accepted14February2015 Availableonline28March2015
Keywords:
Autoimmunehemolyticanemia Thrombocytopenia
Neutropenia Evanssyndrome Rituximab
a
b
s
t
r
a
c
t
Objective:Todocumenttheexperienceofonereferralservicewithpatientsdiagnosedwith Evanssyndrome,thetreatmentandresponseandtobrieflyreviewcurrenttreatment strate-giesandresults.
Methods:Patientsenrolled inthisstudyfulfilledcriteria forEvanssyndrome. Datawere retrievedfromtheclinicalfilesandelectronicdatabasesoftheDepartmentofHematology, HospitalUniversitario“Dr.JoséEleuterioGonzález”.Treatmentmodalitiesandresponseand theuseofadditionaltherapieswereevaluated.Theliteraturewasreviewedinthecontext oftheclinicalcourseofthestudiedpatients.
Results:SixpatientswerediagnosedwithEvanssyndromeinthestudyperiod.Patient1was treatedwithsteroids,relapsedtwiceandwasagaintreatedwithsteroids.Patient2treated initiallywithsteroidsplusintravenousimmunoglobulinwassubsequentlylosttofollow-up. AgoodresponsewasachievedinPatients3and4,whoweretreatedwithsteroidsplus ritux-imab;patient4alsoreceiveddanazolasasecond-linetherapy.Howeverbothrelapsedand subsequentlyunderwentsplenectomyattenandninemonths,respectively.Onepatient, number5,treatedwithsteroids,danazolandrituximabdidnotrelapsewithinfouryears offollow-upandPatient6,whoreceivedsteroidsplusdanazoldidnotrelapsewithinthree yearsoffollow-up.
Conclusion:Evanssyndromeisanuncommonhematologicconditionrarelydiagnosedand notwidelystudied.Cliniciansmusthaveitinmindwhenevaluatingapatientwithapositive directantiglobulintest,anemiaandthrombocytopenia,sinceprognosisdependsonitsearly recognitionandopportunetherapy,buteventhisleadstovariableresults.
©2015Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.Allrightsreserved.
∗ Correspondingauthorat:HospitalUniversitarioDr.JoséE.González,EdificioDr.RodrigoBarragán,2◦Piso,Ave.MaderoyGonzalitosS/N,
ColoniaMitras,Centro,64460Monterrey,NL,Mexico. E-mailaddress:[email protected](J.C.Jaime-Pérez).
http://dx.doi.org/10.1016/j.bjhh.2015.03.002
Introduction
Evans syndrome is arare autoimmune disorder character-ized by simultaneous or sequential presenceof a positive anti-globulintest,autoimmunehemolyticanemia(AIHA)and immunethrombocytopenia(ITP).1Itischaracterizedby
fre-quentexacerbationsandremissionswithinachroniccourse. Evanssyndromewasfirstdescribedin19512anditis
recog-nizedasapoorprognosticfactorinautoimmunecytopenias.3
Itisararedisorderdiagnosedin0.8%to3.7%ofallAIHAorITP cases.1Itsetiologyandcauseareunknown,butalterationsin
immuneregulationmechanismsaredocumented.
Thissyndromecanbeclassifiedasprimaryoridiopathic whenthereisnoassociateddisease,andsecondarywhenitis associatedwithotherautoimmunediseases,suchassystemic lupus erythematosus (SLE), primary antiphospholipid syn-drome,Sjögrensyndrome,IgAdeficiency,Hodgkin’sdisease andchroniclymphocyticleukemia.4Thediagnosisismadeby
exclusionofotherpathologies,includinginfectiousprocesses and malignant and autoimmunediseases. Itpresents with bicytopenia,whichcancoincideoroccurseparatelyor sequen-tially.Aftertheappearanceofthefirstcytopenia,thesecond mayoccurmonthstoyearslater,whichcandelaydiagnosis.5,6
Management of Evans syndrome remains a challenge. Responsetotreatmentvariesevenwithinthesame individ-ual.Indicationsfortreatmenthavenotbeenestablishedby evidence-based studies,5 in part due tothe low frequency
andheterogeneousnatureofthedisease.Thefirst-line treat-mentforEvanssyndromeiscorticosteroidswithorwithout intravenousimmunoglobulin(IVIG).7Therangeofoptionsfor
second-linetreatmentincludesimmunosuppressiveagents, themonoclonalantibodyrituximab,chemotherapyora com-binationoftheseagents.However,onlyasmall percentage ofpatientsachievecompleteremissionandthesedrugshave numeroussideeffects.8Splenectomymayalsobeconsidered
asecond-linetreatment.Themajorityofpatientswillrespond tofirstorsecond-linetherapymodalities,sometimesfor sev-eralyears.However,forpatientswithsevererelapsingdisease despitesecond-line therapy, other options haveto be con-sidered.Themainthird-lineoptionsarecyclophosphamide, alemtuzumaborstemcelltransplantation.5
Thereisverylimitedinformationavailableintheliterature regardingthisinfrequentsyndrome;thereforewedecidedto presentanddiscusssixcasesdiagnosedinourhospitalover sixyearsinordertocalltheattentionofthephysiciantothe importanceofconsideringthisdiseasewhenconfrontedwith apatientexhibitingclinicalandlaboratoryfeatures compati-blewithEvanssyndrome.
Methods
Thisstudywasperformedinaccordancewiththeethical stan-dardsoftheHelsinkiDeclaration,includingtheprovisionsfor patientinformedconsent.TheReviewandEthicsCommittee oftheinstitutionapprovedthestudy.
Thesixpatients includedinthis report werediagnosed between 2007and 2012. All patients presentedwith AIHA and a positive direct antiglobulin test plus ITP. Clinical
presentationincluded theusual featuresofhemolytic ane-mia:pallor,lethargy,jaundice,thrombocytopenia,petechiae, bruisingandmucocutaneousbleeding.
There are no guidelines establishedfor managementof Evanssyndrome,thus,forthepurposeofthisreport,response was defined as resolution of all clinical symptoms and increase ornofurtherdecrease inboth,platelet countand hemoglobinconcentration. Relapsewasconsidered toexist when patients presentedwith the same or similar clinical symptoms and laboratory data, including a positive direct antiglobulintest.
Results
Patientcharacteristics
Data of six patients, four women (66.64%) and two men (33.32%),fulfillingthediagnosticcriteriaofEvansSyndrome wereretrievedfromtheclinicalfilesandelectronicdatabases
(Table1).Medianageatdiagnosiswas24years.Both
cytope-nias occurred simultaneously in all cases. No cases of autoimmuneneutropeniaatdiagnosisorduringtheclinical coursewereobserved.Evanssyndromewasconsidered idio-pathicinonepatient(16.6%)andwasassociatedwithoneor moreunderlying diseasesinthe other fivepatients (83.4%;
Table1).
Thecompletebloodcountatdiagnosisshowedremarkable alterations(Table2),includingplateletcountsrangingfrom 2.33to13.1×109/L(median:5.8×109/L);hemoglobin concen-trationatpresentationvariedfrom6.1to10.7g/dL(median: 6.9g/dL),theMeancorpuscularvolumewaswithinthe nor-malrange(76.2to101fL),buttheredcelldistributionwidth varied widely from 17.1 to 25.6% (median: 20%) reflecting the abundantpresenceofreticulocytes whichrangedfrom 6.8 to 23.1% (median: 9.8%). Accordingly, indirect bilirubin concentrationwas increasedinalmost everycase(median: 1.5mg/dL), and lactate dehydrogenase (LDH) values varied between 295and 554U/L (median:426.5U/L), reflecting the ongoing activehemolysis. Thepresenceofanemia at vari-abledegreeswithhemolyticcharacteristics,includingahigh levelofLDHand/orindirectbilirubin,witharepeatedly posi-tivedirectantiglobulintestandthrombocytopenialedtothe diagnosisofEvanssyndromeinallsixpatients.
Detailedinformationregardingclinicalpresentation, treat-mentandevolution,aswellasrelapsesandtheirtherapyis showninTable3.Patient1wastheonlycaseinwhichsteroids weresuccessfullyusedasbothfirst-linetreatmentandduring relapseswithoutadditionalmedications;inalltheremaining fivecasesacombinationoftherapieswasneededtoachieve response.Responsetimes,asdaysneededfortheincreasein hemoglobinconcentrationand plateletcounttotakeplace, areshowninTable3.Patientsweredischargedatamedianof ninedays(range:3–12days).
Follow-upandrelapses
232
revbrashematolhemoter.2015;37(4):230–235Table1–GeneralcharacteristicsofsixpatientsdiagnosedwithEvanssyndrome.
Patient Gender Age Dateofdiagnosis Medicalhistorybeforediagnosis
1 F 10 2007 ChronicITPsinceage4,treatedwithsteroids
2 F 14 2011 SLE,ITPsinceage10,treatedwithsteroids
3 F 42 2009 SLE,AIHA
4 F 19 2010 SLE
5 M 29 2011 None
6 M 29 2012 SLE,APLA,PTTprolongued
ITP:immunethrombocytopenia;SLE:systemiclupuserythematosus;AIHA:autoimmunehemolyticanemia;PTT:partialthromboplastintime; APLA:antiphospholipidantibody.
Table2–LaboratoryresultsatdiagnosisofsixpatientswithEvanssyndrome.
Patient 1 2 3 4 5 6
Plateletcount(×109/L) 8.26 3.47 13.1 9.37 2.33 3.12
Hemoglobin(g/dL) 10.7 7.18 6.37 6.58 6.09 10.5
Hematocrit(%) 33.6 22.3 18.4 19.0 18.4 31.9
MCV(fL) 76.2 81.7 101.0 88.9 86.9 78.7
RDW(%) 20.2 19.8 25.6 23.6 17.1 18.9
WBC(×109/L) 3.37 4.69 7.92 12.0 12.5 11.9
Neutrophilcount(×109/L) 2.79 3.73 4.98 9.01 11.5 9.06
Lymphocyte(×109/L) 0.489 0.76 2.06 2.16 0.74 1.85
Reticulocyte(%) 7.6 6.8 23.1 9.8 9.8 10.0
Totalbilirubin(mg/dL) 1.87 1.8 3.41 1.41 1.85 0.9
Directbilirubin(mg/dL) 0.25 0.32 0.61 0.23 0.33 0.2
Indirectbilirubin(mg/mL) 1.7 1.5 2.8 1.2 1.5 0.7
Lactatedehydrogenase(IU/L) 368 295 554 378 475 487
MCV:meancorpuscularvolume;RDW:redcelldistributionwidth;WBC:whitebloodcellcount.
autoimmunehemolytic anemiaand immune
thrombocyto-penia.Anappropriatefollow-upwasdocumentedinfiveof
thesixpatients.Threepatientsrelapsedwithinninemonths
tofiveyears.
One patient (Patient 2) responded satisfactorily to
ini-tialsteroidtherapyandwassubsequentlylost tofollow-up.
Two patients,5and 6,had notrelapsed45 and32 months
afterthe initialdiagnosis,respectively. Patients 1,3, and 4
relapsed.Patient1presentedtworelapses,thefirstone,five
years after diagnosis, was treated with steroids, obtaining
complete remission until a year later whenshe presented
moderatethrombocytopeniaandsevere AIHA.Thisepisode
wasagaintreatedasinherfirstrelapse,withsteroids,
obtain-ingathirdremissionlasting24monthstodate.Patient3had
arelapseattenmonthsafterdiagnosis;shewastreatedwith
dexamethasone,prednisoneandrituximab,withnoresponse;
splenectomy wasperformed atthis time.This patient has
notrelapsedtodate,57monthsaftersplenectomy.Patient4
relapsedatninemonths.Shewastreatedwithsplenectomy
andhasnotsufferedfurtherrelapse32monthsafterremoval
ofthespleen;clinicalcourseandtherapyforthesefivepatients
aresummarizedinTable3.
Discussion
Evans syndrome isa rare autoimmune regulation disorder whoseexactpathophysiologyisunknown.Clinically,the dis-ease consists of simultaneous or sequential autoimmune hemolyticanemia and immunethrombocytopenia, withor
without bleedingfrom mucousmembranes and petechiae, and/or immune neutropenia in the absence of any other cause.1
Thereisadecreaseinserumimmunoglobulins,especially IgG,IgMandIgA.9Savasanetal.4describedevidenceof
lym-phoidhyperplasiaandhyperactivitywithderegulationofthe APO-1antigen,whichisexpressedonactivatedTandBcells, and isin intimate relationship withthe immunepathway inducingapoptosis.Wangetal.9showedproportionsof
dimin-ishedT4andincreasedT8cellswithadecreasedT4:T8index. Decreases inthe productionofinterleukin-10 and gamma-interferonhavebeenreported,anditispostulatedthatthis causes the activation ofB cells producing auto-antibodies. ThesealterationsarenotexclusivetoEvanssyndromeasthey canbefoundinotherimmunediseases,thusitremainstobe establishediftheyareindeedacauseofthediseaseormerely associatedimmunephenomena.
The differential diagnoses for Evans syndrome include thrombotic thrombocytopenic purpura, chronic cold agglu-tinindisease,othercausesofacquiredorhereditaryhemolytic anemia,anddrug-inducedhemolyticanemiaand/or thrombo-cytopenia.Itsexactincidenceremainsunknown.Inareviewof adultpatientswithimmunocytopeniasincluding766patients with399casesofAIHAand367casesofthrombocytopenia, Evanssyndromewasdiagnosedinonlysix(0.78%)patients.10
Thelargest reported seriesofEvans syndrome inpediatric patientsincluded164casesofITPand15ofAIHA;onlyseven (4.1%)childrenwerediagnosedwiththesyndrome.11
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# Clinicalpresentation Treatment Responsetimeafter
first-linetreatment (days)
PLT(10/L) Hb(g/dL) Relapse C.P.ofrelapse Treatmentafter
relapse
1 Generalizedpetechiae, ecchymosis
1stDexamethasone 8 152 11.2 Twice5years Choluria,
jaundice,pallor
Steroids
2 Ecchymosis,gingivorrhagia, epistaxis,petechiae,pallor, jaundice
1st
Methylprednisolone+IVIG
10 71 10.5 No – –
3 Gingivalbleeding,epistaxis, fatigue,weakness,dyspnea
1st Dexametha-sone+Prednisone 2ndRituximab
10 34.5 8.9 10months Gingival
bleeding, epistaxis,fatigue, weakness, dyspnea
Splenectomy
4 Generalizedpetechiae, gingivorrhagia,pallor, fatigue,weakness, jaundice,andsyncope
1stDexamethasone 2ndRituximab+Danazol
7 59.7 8.51 9months Transvaginal
bleeding,anemic syndrome
Splenectomy
5 Petechiae,ecchymosis, epistaxis,gingivorrhagia, Anemicsyndrome
1stDexamethasone 2ndDanazol+Rituximab
8 11 8 No – –
6 Petechiae,ecchymosis, epistaxis
1stDexamethasone 2ndDanazol
10 57.3 11.3 No – –
234
revbrashematolhemoter.2015;37(4):230–235secondarywhenit isassociatedwithanotherautoimmune disease,suchasSLE,Sjögrensyndrome, Hodgkin’sdisease, orchroniclymphocyticleukemia,amongothers.4 Inadults,
anunderlyingcausecanbeexpectedin70%ofthecases.12
Inourstudyfiveofsixpatientshadanautoimmunedisease diagnosedbeforetheydevelopedEvanssyndrome.
Thediseaseischaracterizedbyfrequentexacerbationsand remissionswithinachroniccourseandresponsetotreatment variesevenwithinthesameindividual.5Mostpatientsrequire
treatmentalthoughoccasionalspontaneousremissionshave beenreported,aswasthecaseinoneof42patients.13
Indi-cations for treatment have not been established by other evidence-basedstudies.However,itisreasonableandusual to treat symptomatic patients with low blood counts; not all asymptomatic patients with low counts require treat-mentandthedecisiontotreatornotshouldbeconsidered accordingtoeachindividualcase.5Mostofthedataare
anec-dotalandinconclusivewithdifficultinterpretationbecauseof theconcomitantuseofcorticosteroidsandothertreatment modalities.13,14
Corticosteroidsremainthe mainstayoftherapyfor con-trolofthe acutesymptomaticcytopenias,withgood initial results,despitelackofcontrolledtrialsdemonstratingtheir efficacy.5Puietal.,ondescribingtheclinicalfeaturesand
long-termfollow-upofsevenchildrenwithEvanssyndrome,found thatinallsixchildrenrequiringtreatment,prednisoloneata dailydoseof1–2mg/kgresultedinremission;however,this responsewaslostupondosereductionand/orduringacute viralinfections.11 Inthecurrentstudy,all sixpatientswere
treatedwithatleast onecorticosteroid.Theinitialdose of methylprednisolone(1.0gIVdilutedin100mL,every24hfor fourdoses)wasusedonlyforPatient2.Thetreatmentstrategy forPatient3wasprednisoneadministeredatadoseof40mg p.o.every12huntilreachingaresponseorforfour weeks. Whenusingdexamethasone,aswasthecaseinfiveofthe sixpatientsinthisstudy,thedosewas40mgIVevery24h forfourdoses,withthisobtainingagoodclinicalresponsein allcases,withimprovementinplateletcountandhemoglobin concentrationbutwithoutreachingnormalization.
Ifsteroidsareineffectiveorunacceptablyhighdosesare required to maintain remission or if toxicity occurs, the mostcommonlyusedtreatmentisIVIG.Variousdoseshave beensuggested,mostcommonly0.4g/kg/dayforfourdoses withsomeotherauthorsrecommendinghigherdoses(upto 5.0g/kg)toimproveresponseinAIHA.15Inourpatients,only
onereceivedIVIGaspartofherinitialtreatment(Patient2)at asingledoseof1.0g/kgwithgoodresponse.
Second-line treatment includes immunosuppressive agents(cyclosporineandmycophenolatemofetil), chemother-apy (vincristine and cyclophosphamide), danazol and monoclonal antibodies (rituximab and alemtuzumab).5
Althoughsplenectomyhastraditionallybeenusedasinitial second-line therapy in patients with autoimmune cytope-nia(ITPor AIHA)whodidnotrespondtoor relapsedafter standardtherapywithsteroidswithorwithoutIVIG,therole ofsplenectomyinthe treatmentofEvanssyndrome isnot clearlyestablished.5Overall,theresponseratetosplenectomy
islower thanthe70–75%reportedinchronicITP.Thereare fewdataforEvans syndrome;thus accurateresponserates cannot be cited.16 Splenectomy often produces immediate
improvement or even complete normalization of blood counts.Thisresponseisoftentransientandrelapseoccursin mostcases1–2monthspost-splenectomyindependentlyof whether steroidsare continuedpostoperatively.11,13,14
How-ever,splenectomyoccasionallyresultsinsustainedremission (oneofeightpatientsremainedincompleteremissionatsix years post-splenectomyinonereport),15 and thereissome
evidence that splenectomy may be beneficial in reducing the frequency of relapses and lowering the maintenance doseofsteroids.11,13,14Onlytwopatientsinourgroupwere
splenectomized(Patients3and4)duetorelapse.
Danazolwasadministratedinthreeoutofsixpatientsin combinationwithsteroids.Thesethreeindividualshadgood initialresponses;however,tworelapsedand required addi-tionaltreatmentwithonebeingsuccessfullysplenectomized (Patient 4)afterthe firstrelapse. Onthe other hand, ritux-imabatadoseof375mg/m2wasusedinthreeofsixpatients,
withnoresponseintwopatients(Patients3and4),leadingto splenectomy.Onlyonepatient(Patient5)responded satisfac-torilytorituximab.
Themajorityofpatientswillrespondtofirstorsecond-line therapy, and thisresponsecan lastseveralyears.However, for patients withsevere, relapsing disease despite second-linetherapy,otheroptionshavetobeconsidered.Themain third-line options are cyclophosphamide, alemtuzumab or stemcelltransplantation.5Threeofthepatientsinthisstudy
relapsedwithinninemonthstofiveyears,howevernoneof them required athird-line treatment. Thiswide variability and unpredictabilityinrelapsing timeshavebeen reported previously.13,14
Thereareimportantissuestodefinewithrespectto treat-mentandresponsecriteriaforEvanssyndrome.Inthisregard itisnotclearwhetheritisimportantforsteroidstobe admin-istered atthe sametimeasIVIG, althoughthis iscommon practice.Themajorityofpatients,unfortunately,relapseas therapyistailedoffandsecond-linetherapywillberequired. Thechoiceofwhichsecond-lineagenttousedependsupon clinical criteria,particularly theageofthepatient, severity of the disease and its naturalhistory because all ofthese treatmentshavesignificantshort-andlong-termsideeffects.5
It is pertinent to underscore that there are no standard-izedresponsecriteriaforEvanssyndrome,incontrasttoITP where anincrease in the platelet countto ≥30.0×109/L is consideredasresponse(R)and≥100.0×109/Lonatleasttwo separateoccasions atleast sevendaysapartasa complete response.17
Oursixpatientspresentedwithsevereclinical manifesta-tionsandreceivedsteroidswithorwithoutIVIG,danazolor rituximabinordertopreventordelaycomplicationsthatcan endangerlife.18 Afterfailureofrituximab,splenectomywas
performed intwoofthreerelapsing patients,underscoring theimportanceofthisinterventioninthemanagementofthe disease,andsuggestingthat,atleastinthesettingof autoim-muneassociatedEvanssyndrome,theadditionofrituximab doesnotguaranteetherapeuticsuccess.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgments
TheauthorsgratefullyacknowledgeSergioLozano-Rodriguez, M.D.forhisreviewofthearticle.
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