• Nenhum resultado encontrado

Rev. Bras. Hematol. Hemoter. vol.39 número3

N/A
N/A
Protected

Academic year: 2018

Share "Rev. Bras. Hematol. Hemoter. vol.39 número3"

Copied!
2
0
0

Texto

(1)

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.

r

e

f

e

r

e

n

c

e

s

(2)

284

revbrashematolhemoter.2017;39(3):283–284

connect/tiposdecancer/site/home/leucemia/definicao[cited 30.4.16].

2. ArberDA,OraziA,HasserjianR,ThieleJ,BorowitzMJ,LeBeau MM,etal.The2016revisiontotheWorldHealthOrganization classificationofmyeloidneoplasmsandacuteleukemia. Blood.2016;127:2391–405.

3. Lucena-AraujoAR,SouzaDL,MoratodeOliveiraF,Benicio MT,Figueiredo-PontesLL,Santana-LemosBA,etal.Resultsof FLT3mutationscreeningandcorrelationswith

immunophenotypingin169Brazilianpatientswithacute myeloidleukemia.AnnHematol.2010;89(2):225–8.

4. YaghmaieM,AlimoghaddamK,MozdaraniH,Ghavamzadeh A,HajhashemiM,AznabM,etal.CytogeneticandFMS-like tyrosinekinase3mutationanalysesinacutepromyelocytic leukemiapatients.IranBiomedJ.2012;16(1):10–7.

5. EsteyEH.Acutemyeloidleukemia:2012updateondiagnosis, riskstratification,andmanagement.AmJHematol.

2012;87(1):89–99.

6. KoszarskaM,MeggyesiN,BorsA,BataiA,CsacsovszkiO, LehoczkyE,etal.Medium-sizedFLT3internaltandem duplicationsconferworseprognosisthanshortandlong duplicationsinanon-elderlyacutemyeloidleukemiacohort. LeukLymphoma.2014;55(7):1510–7.

7. KusecR,JaksicO,OstojicS,Kardum-SlelinI,VrhovacR, JakisicB.MoreonprognosticsignificanceofFLT3/ITDsizein acutemyeloidleukemia(AML).Blood.2006;108(1):405–6.

8. GaleRE,GreenC,AllenC,MeadAJ,BurnettAK,HillsRK,etal., MedicalResearchCouncilAdultLeukemiaWorkingParty.The impactofFLT3internaltandemduplicationmutantlevel, number,size,andinteractionwithNPM1mutationsinalarge cohortofyoungadultpatientswithacutemyeloidleukemia. Blood.2008;111(5):2776–84.

9. SteinEM,TallmanMS.EmergingtherapeuticdrugsforAML. Blood.2016;127(1):71–8.

10.DombretH.GenemutationandAMLpathogenesis.Blood. 2011;118(20):5366–7.

11.PonzianiV,GianfaldoniG,MannelliF,LeoniF,CiolliS, GuglielmelliP,etal.Thesizeofduplicationdoesnotaddto theprognosticsignificanceofFLT3internaltandem duplicationinacutemyeloidleucemiapatients.Leukemia. 2006;20(11):2074–6.

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/).

Referências

Documentos relacionados

The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem

The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem

Rev Bras

Mutations with loss of heterozygosity of p53 are common in therapy-related myelodysplasia and acute myeloid leukemia after exposure to alkylating agents and significantly

Evaluation of red cell and reticulocyte parameters as indicative of iron deficiency in patients with anemia of chronic disease. Rev Bras

adult patients diagnosed with myeloid leukemia from 1994 to 2011 in the Vale do Paraíba,.. State of

Splicing factor SF3B1 mutations and ring sideroblasts in myelodysplastic syndromes: a Brazilian cohort screening study. Rev Bras

Internal tandem duplication of the FLT3 gene confers poor overall survival in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and