rev bras hematol hemoter. 2017;39(3):281–282
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
Is
karyotyping
still
needed
in
the
diagnosis
and
monitoring
of
chronic
myeloid
leukemia?
DearEditor,
Weliveinadigitalerainwhichspeedandknowledgeturnover areveryhigh.Inthisscenario,patientsandphysiciansdesire fasterbutprecisediagnostictestsatalowcost.
Chronicmyeloid leukemia(CML) ischaracterizedbythe presence oft(9;22)(q34.1;q11.2), the Philadelphia (Ph) chro-mosome, or the breakpoint cluster region-Abelson murine leukemia1(BCR-ABL1)rearrangement.1Thediagnosiscanbe
madeusingfindingsfromperipheralblood(PB)exams com-binedwiththedetectionofthePhchromosomebykaryotyping usingabonemarrow(BM)sampleortestingfortheBCR-ABL1 byrealtimequantitativepolymerasechainreaction(RqPCR) inPBorBMsamples.
ComparingkaryotypingwithRqPCR,theformerisatime consumingprocessthattakesaround15dayswhileonegets theresultsofRqPCRinsevendays.Furthermore, karyotyp-ingismoreexpensiveandperformedaftermarrowaspiration whereasRqPCRmaybecarriedoutusingPB.Therefore,some patientsanddoctorsoptforthefasterandcheapertestwith easysamplecollectionanddiscardkaryotyping.
However,bothtestshavetheirpeculiaritiesandshouldbe performedatdiagnosis.Around90%ofCMLpatientshavethe classicalPhchromosomeatdiagnosis,but 5%may present varianttranslocations,involvingchromosomesotherthan9 and222 thatare usuallynotdetrimentaltotyrosinekinase
inhibitor(TKI)therapy.Yet,theremaining5%mayhave addi-tionalaberrations,alsoknownasclonalevolution(CE),and thesecases are associatedwithworse outcomes.3–5 RqPCR
doesnotdetecttheseadditionalaberrations.
CEcanbedividedintomajorandminorroutes.Themajor route(70%ofcases)involvesasecondPhchromosome(+Ph), +8,i(17q)or+19orcombinations.Theminorrouteoccursin 30% ofthe cases and includes: −7, −17, +17, +21,−Yand t(3;21)(q26;q22). Recently, Wang et al.5 showed that +8,
−Y and +Phhave relativelygood prognoses whereas the prog-nosis of patients with i(17)(q10), −7/del7q, and 3q26.2 are poor.Nevertheless,theEuropeanLeukemiaNetandtheWorld HealthOrganization(WHO)1guidelinesconsiderthepresence
ofthemajorrouteasacceleratedphasediseasewheneverthe
abnormalitywasnotpresentatdiagnosis.Hence,the karyo-typehelpstodefinethediseasephase.
Lessthan2%ofCMLpatientshavenormalkaryotypesat diagnosis.Inthesepatients,theBCR-ABL1fusiongenecanbe detectedbyfluorescenceinsituhybridization(FISH)orRqPCR provingthattheuseofkaryotypingwithoneofthesetestsis valuable.
RqPCR, on the other hand, detects the BCR-ABL1 rearrangement in >95% of CML cases. The most frequent transcript types are b2a2 (e13a2) and b3a2 (e14a2) with the b2a2 type being associated with longer response time and lower response rates. Fewpatients present bothtypes simultaneously.6ThefewBCR-ABL1negativecasesmayhave
differentbreakpoints,notdetectedbyregular primersused inthetest.Here,thebenefitofusingbothtestsisonceagain clear.ThosewithaPhchromosomepositivekaryotype,once sequencedhaveshowntheBCRjuxtaposedtoABL1inexon 3.7
Atdiagnosis,thedeterminationoftransformationriskhas animportantroletoestablishtheidealtherapywith appropri-atedosesandmanagement.Pre-existingcomorbiditiesmay guide TKI selection. Patients who achieve complete cyto-genetic remission may have life expectancy similar to the generalpopulation.Evenso,aminoritywillprogressto accel-eratedorblastphases.
According to the National Comprehensive Cancer Net-work (NCCN),8 karyotyping is suggested at three and six
monthsafterstartingTKItherapytomonitortherapy,ifthe RqPCRinternationalscale(IS)isnotavailable,at12months ifcompletecytogeneticremission(CCR)ormajormolecular response (MMR) is not achieved; or whenthere is onelog increase inBCR-ABL1transcriptlevels withoutMMR. Kary-otypingperformedinthe courseofthedisease may reveal diseaseprogressionmarkers(CE).Moreover,in5–10%ofcases, karyotypingmayshowclonalalterationsinPhnegativecells, which,intheabsenceofdysplasia,doesnotaffectthe out-comeexceptfor–7/7q–thatcanevolveintomyelodysplasia oracuteleukemiaandshouldbecloselyfollowed.9
282
revbrashematolhemoter.2017;39(3):281–282transcripts.Itisrecommendedtotesteverythreemonthsafter startingTKItherapyuntilcompletingtwoyearsofcomplete cytogeneticresponseandeverythreetosixmonthsthereafter. Inaddition,incasesthatlackidealmolecularresponse,the BCR-ABL1mutationshouldbeinvestigatedandkaryotyping performedinordertodetectpotentialCE.
Thatsaid,karyotypingstillhasarelevantroleinthe diag-nosisandmonitoringofCMLandshouldnotbereplacedby RqPCR,asthecheapalternativemayturnoutexpensiveinthe end.Thedesireforaprecisediagnosis,prognosisandchoice oftherapydoesincludekaryotypingandRqPCR.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
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1.ArberDA,OraziA,HasserjianR,ThieleJ,BorowitzMJ,BeauML, etal.The2016revisiontotheWorldHealthOrganization classificationofmyeloidneoplasmsandacuteleukemia. Blood.2016;127(20):2391–405.
2.ChauffailleML,BanderiaAC,SilvaAS.Diversityofbreakpoints ofvariantPhiladelphiachromosomesinchronicmyeloid leukemiainBrazilianpatients.RevBrasHematolHemoter. 2015;37(1):17–20.
3.FabariusA,LeitnerA,HochhausA,MüllerMC,HanfsteinB, HaferlachC,etal.Impactofadditionalcytogeneticaberrations atdiagnosisonprognosisofCML:long-termobservationof115 patientsfromtherandomizedCMLStudyIV.Blood.
2011;118(26):6760–8.
4.GuilhotF.CytogeneticsinCML:moreimportantthanyou think.Blood.2016;127(22):2661–2.
5.WangW,CortesJE,TangG,KhouryJD,WangS,Bueso-Ramos CE,etal.Riskstratificationofchromosomalabnormalitiesin
chronicmyelogenousleukemiaintheeraoftyrosinekinase inhibitortherapy.Blood.2016;127(22):2742–50.
6.JainP,KantarijianH,PatelKP,GonzalesGN,LuthraR, ShamannaRK,etal.ImpactofBCr-ABLtranscripttypeon outcomeinpatientswithchronicphaseCMLtreatedwith tyrosinekinaseinhibitors.Blood.2016;127(10):1269–75. 7.ChauffailleML,MiyashiroK,SacramentoR,KellerW,Cantagalli
D,SantosG,etal.AtypicalBCR-ABL1rearrangementsdetected byDNAsequencing.Haematologica.2012;97Suppl.1:283. 8.NationalComprehensiveCancerNetwork(NCCN);2016.
Availablefrom:https://www.nccn.org/professionals/ physiciangls/pdf/cml.pdf.
9.BaccaraniM,DeiningerMW,RostiG,HochhausA,SoveriniS, ApperleyJF,etal.EuropeanLeukemiaNetrecommendations forthemanagementofchronicmyeloidleukemia.Blood. 2013;122(6):872–84.
MariadeLourdesL.F.Chauffaillea,b,∗
aUniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,
Brazil
bFleuryMedicinaeSaúde,SãoPaulo,SP,Brazil
∗Corresponding authorat:Universidade Federalde SãoPaulo (UNIFESP),Hematologia.R.DiogodeFaria824,04023-011São Paulo,SP,Brazil.
E-mailaddress:[email protected]
Received8September2016 Accepted15December2016 1516-8484/
©2017Associac¸ ˜aoBrasileiradeHematologia,Hemoterapiae TerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan openaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).
