rev bras hematol hemoter. 2017;39(3):283–284
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Letter
to
the
Editor
FMS-related
tyrosine
kinase
3
internal
tandem
duplication
(FLT3-ITD):
a
villain
among
others
Acute myeloid leukemia (AML) is the most frequentacute leukemiaofadultpatientswithanestimated10,070newcases inBrazil in2016. Most ofthe casesare de novo, without a definedetiology,andaroundtwothirdsofthepatientswilldie ofthedisease,accordingtotheInstitutoNacionaldeCâncer (INCA).1Geneticaberrationsmayhelptodifferentiatepatients
whohaveagoodfromthosewithadismalprognosis. Infact,chromosomalabnormalitiesdetectedbyG-banding karyotype and generearrangements revealed bymolecular testsare importanttoolstostratify patientsinto favorable, intermediate or unfavorable prognoses. The World Health Organization(WHO) classificationofhematopoietic tumors listsrecurrentgeneticabnormalities.2
FMS-related tyrosine kinase 3 (FLT3), a tyrosine kinase receptorusuallyexpressed inhematopoieticprogenitors,is the most common genetic lesion in AML with mutations detectedinfrom25%to40%ofthecases.3Thesemutations
mayoccur inany subtypeofAML(including acute promy-elocyticleukemia –APL),andarefrequentwiththenormal karyotypeort(6;9).
Therearetwomaintypesofmutations:internaltandem duplication(ITD),whichisthemostcommon(∼25%ofcases), andapointmutation(D835)(∼5%).4
Except for APL, AML patients with FLT3-ITD present increasedchanceofrelapse, shortdisease-freesurvivaland reduced overall survival, despite an unchanged complete remissionrate.5 ThedetectionofFLT3-ITDisimportantfor
prognosisparticularlyinthosewithanormalkaryotype. However, there remains some controversy about the impactofthesizeofFLT3-ITDfragmentontheprognosis.One study showedthat 48–60base-pairduplicationsare associ-atedwithaworseoutcome6andotherauthorsreportedthat
itisnotpossibletoconfirmthisrelationshipbythelengthof FLT3-ITDalone.Thereisalargevariationintheclinical char-acteristicsofpatients,makingitdifficulttocorrelatedataand setstandards.7,8
AimingtoevaluatethelengthofduplicationinBrazilian patients, we evaluated AML casesdiagnosed from January 2013untilJuly2015attheFleuryMedicinaDiagnóstica labora-toryaccordingtotheWHOclassificationusingbonemarrow morphology and flow cytometry immunophenotyping. We identified26(29%)outof89AMLcaseswithFLT3–ITD.The meanageofthepatientswas54yearsold(range:13–79years)
andthemaletofemaleratiowas1:0.7.Thesizeofthe duplica-tionvariedfrom21to87basepairs(mean:57basepairs)and onlytwocaseshadtwopeaks,showingaveryheterogeneous pattern. From these cases, ten (38%) had follow-ups with nodifferencesbeingfound(unpairedt-test:p-value=0.44)in respecttothesizeoftheduplicationandsurvival,probably duetothelownumberofcasesstudied.Indeed,manyfactors contributetothelackofsuccessanddeathsduringinduction remainsasignificantprobleminAMLindependentlyofthe mutation.Infact,age,whitebloodcellcountandprimaryor secondaryleukemiaaddtotheprognosticdifficulties.7
Moreover,theimpactofFLT3-ITDonprognosismaydepend onthepresenceofbiallelicmutations.Studieshaveshowna significantlyworseprognosisinpatientswithhighermutant towild-typeallelicratios(>0.4).8
As FLT3-ITD is a common mutation, tyrosine kinase inhibitors have been recognized as potential therapeutic agents,andmanydrugsareinclinicaldevelopment includ-ingsorafenib,sunitinib,midostaurin,quizartinib,lestaurtinib, crenolanibandgilteritinib,inthehopeofreducingthis thera-peuticfailure.9Nevertheless,takingintoaccountthemultiple
hitsthatarethoughtnecessaryinleukemogenesis,FLT3plays asmallrole.Itactivatesproliferationpathways(classI muta-tions,suchasoftheK/NRAS, TP53andc-KITgenes),while other mutations impair differentiation (class II: NPM1 and
CEBPagenes),epigeneticregulation(classIII:DNMT3A,TET2
andIDH1/2genes),thep53pathway,withevenmorealso play-ingarole.10Inthisscenario,theFLT3mutationisnottheonly
villain.
In conclusion, further studies are needed to confirm whetherthesizeoftheFLT3-ITDmutationiscorrelatedtoa worseprognosis.7,8,11
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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VanessaY.N.deArrudaa,∗,LisaN.Matsuzakia, MariadeLourdesChauffaillea,b
aGrupoFleury,SãoPaulo,SP,Brazil
bUniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,
SP,Brazil
∗Corresponding author at: Grupo Fleury, Avenida General ValdomirodeLima,508,04344-903SãoPaulo,SP,Brazil, Tel.:+551150147328;fax:+551150147223.
E-mailaddress:vanessa.arruda@grupofleury.com.br
(V.Y.N.Arruda).
Received23November2016 Accepted7March2017 Availableonline3April2017 1516-8484/
©2017Associac¸ ˜aoBrasileiradeHematologia,Hemoterapiae TerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).