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revbrashematolhemoter.2015;37(2):142–143

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

the

BCR-ABL/GUSB

transcript

level

at

diagnosis

an

early

predictive

marker

for

chronic

myeloid

leukemia

patients

treated

with

imatinib?

DearEditor,

Thedevelopmentofthefirst target-specifictyrosinekinase inhibitor(TKI)anditsintroductionintheclinicalpractice rad-ically changed chronic myeloid leukemia (CML) treatment. MonitoringtherapeuticresponsetoTKIsisacriticalstepin themanagementofCML.1

Recently,severalfollow-upstudiesuponwhichthe Euro-peanLeukemiaNet2013(ELN)recommendationswerebased, pointedtotheimportanceofearlyclearanceofleukemiccells as demonstrated by molecular methods. Attaining a BCR-ABLIStranscriptlevel≤10%threemonthsafterinitialimatinib mesylate (IM) treatment was found to be associated with afavorableoutcome,includinglongerprogression-free(PFS) andoverallsurvival(OS),andhigherprobabilityofachieving completecytogeneticresponse(CCyR)and majormolecular response(MMR).1

Quantification of the BCR-ABL transcript level reflects leukemicburden,andiscarriedoutbyquantitativereal-time polymerase chainreaction(RQ-PCR). Molecular response is basedon theratio ofBCR-ABL transcriptlevelsand a con-trolgene.Resultsareexpressedaccordingtoaninternational scale(IS)assignedtoeverypatientatdiagnosis,whichisequal to 100%of BCR-ABL/controlgene transcripts, regardless of theabsoluteamountofBCR-ABLtranscripts.Thus,theactual leukemicburden ofpatientsatdiagnosis is nottaken into account.2

Anidealcontrolgenewouldbeexpectedtobeuniformly expressedindifferentcelltypesregardlessofitsproliferative statusaswellasbeunaffectedbytherapeuticregimens, con-stantbetweenindividualsandexpressedatalevelsimilarto BCR-ABL.Infact,this controlgenedoesnotexist, andBCR andABLarethemostwidelyusedcontrolgenesfor quanti-fyingBCR-ABLtranscripts,mainlyduetohistoricalreasons. However,bothBCRandABLcontrolgenesdonotshow linear-itywithBCR-ABLtranscriptlevelsabove10%contrarytothe GUSBgenethatisnotaffectedbyhigh-leveldistortionswhich allowforbetterestimationsoftheBCR-ABLtranscriptlevelat diagnosis.3

In this study, the BCR-ABL transcript levels of 31 CML patients under IM treatment were analyzed by RQ-PCR in

respecttotheABLandGUSBcontrolgenesatdiagnosisand afterthreemonthsoftherapy.Thesepatientswerefollowed up foratleast 24 months.Themedian BCR-ABL1/ABL and BCR-ABL1/GUSB transcript levels at diagnosis were 87.84% (range:16.24–184.4)and29.8%(range:5.76–216.9),respectively. Atthree months,the medianBCR-ABL/ABLtranscriptlevel was7.14(range:0.053–307)whereasthemedianBCR-ABL/GUS transcript levelwas 21.94(range: 0.19–85.16). Patients were classified asoptimal responders ornon-responders (failure ofresponse)accordingtoaBCR-ABL1IStranscriptlevel≤0.1%

and >0.1% at 12 months. In responders, the median BCR-ABL/ABLandBCR-ABL/GUStranscriptlevelsatdiagnosiswere 68.13%(range:26.8–99.29)and23.77(range:8.2–62.97), respec-tivelywhileinnon-responderstheselevelswere86.10(range: 30.87–96.11)and40.92(range:17.21–96.85).

The median BCR-ABL/ABL of responders and non-responders at diagnosis was not significantly different (p-value=0.89) while the median BCR-ABL/GUS between responders and non-responders at diagnosis was signifi-cantlydifferent(p-value<0.001)indicatingthat,unlikeABL, GUS levels are capable of discriminating responders from non-responders(Figure1).Themediantranscriptlevelof BCR-ABL/GUSofrespondersatdiagnosiswas28.38%whichmight beconsideredathresholdforearlydiscriminationaspatients withlevelsunder28.38%werelesslikelytoachieveMMRat12 months(p-value<0.05).

Comparisonsoftranscriptlevelsthreemonthsafter ini-tiating IM treatment were also carried out considering a BCR-ABL/controlgeneIS thresholdof≤10%asdiscriminative

ofrespondersvs.non-responders.Inpatientsconsideredtobe optimalresponders,themedianofthetranscriptsestimated withanycontrolgenewasbelow10%,asexpectedaccordingto previousreports.Wedidnotobserveastatisticallysignificant differencebetweenABLandGUScontrolgenes(p-value=0.19) ineitherrespondersor non-responders(p=0.41),indicating thatatthethreemonthtimepoint,bothgenescanbeequally usedaspredictivebiomarkers,showingsignificantdifferences betweenrespondersandnon-responders(p-value=0.003for GUSandp-value=0.01forABL;Figure1).

(2)

revbrashematolhemoter.2015;37(2):142–143

143

ns

ns

100

50

BCR-ABL

0

At diagnosis 3 months

BCR-AB

L1/GUS(%) - Resp

BCR-A BL1/ABL1(%) - R

esp

BCR -ABL1/GUS(%) -

Res p

BCR-ABL1/ ABL1(%) -

Resp

BCR-ABL1

/GUS(%) - No Resp

BCR-ABL1/AB L1(%) -

No Resp

BCR-ABL1/G US(%) -

No Resp

BCR-ABL1/ABL1 (%) -

No Res p

ns

Figure1–Themedianlevelsofthetranscriptsconsidering bothcontrolgenes(GUSandABL)atdiagnosisandafter threemonthsonimatinib(IM)asfirstlinetherapy.Patients arediscriminatedasrespondersornon-responders accordingtotheirresponseat12monthsaccordingtothe ELNguidelines.Themediansofthetranscriptswere comparedbyMann–Whitneyunpairedtwo-tailedtest.At diagnosis:*p-value<0.001.At3months:*p-value=0.01; **p-value=0.003.Resp=responders;No

Resp=non-responders;ns=non-significant.

futureresponse. Inthis study,we usedparameters recom-mendedforidentifyingoptimalresponse(withBCR-ABLIS≤10

atthreemonthsand≤0.1at12monthsafterinitiating treat-ment).However,BCR-ABL/ABLtranscriptlevelscannotbeused aspredictiveestimatesduetothelackoflinearityoftheABL geneinassessingleukemicburdenatlevelsabove10%and actuallevelsofBCR-ABLtranscriptsatdiagnosiscanbe accu-ratelyestimatedwithGUSasthecontrolgene.Wefoundthat highlevelsofBCR-ABL/GUSatdiagnosiswereassociatedwith a lower probability ofachieving optimalresponse (p-value <0.001)andlowratesofCyCRafter12monthsofIMtherapy (p-value<0.001).ThesefindingscoincidedwithVignerietal.4who

showedthathighratesofBCR-ABL/GUSwereassociatedwitha lowprobabilityofevent-freesurvival(p-value<0.001)andPFS

(p-value=0.01).Asexpected,thelossofABLlinearity result-ingintranscriptquantificationwithhighlevelsofleukemic burdenindicatedthatABL,ifusedasthecontrolgeneat diag-nosis,wouldnotprovidepredictiveestimates.Conversely,the useofGUSasthecontrolgeneallowsforareliableprediction oftherapeuticresponsebasedonBCR-ABLtranscriptlevelsat diagnosis.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

r

e

f

e

r

e

n

c

e

s

1.BaccaraniM,DeiningerMW,RostiG,HochhausA,SoveriniS,

ApperleyJF,etal.EuropeanLeukemiaNetrecommendations

forthemanagementofchronicmyeloidleukemia:2013.Blood.

2013;122(6):872–84.

2.GabertJ,BeillardE,vanderVeldenVH,BiW,GrimwadeD,

PallisgaardN,etal.Standardizationandqualitycontrolstudies

ofreal-timequantitativereversetranscriptasepolymerase

chainreactionoffusiongenetranscriptsforresidualdisease

detectioninleukemia–aEuropeAgainstCancerprogram.

Leukemia.2003;17(12):2318–57.

3.CrossNC.Standardisationofmolecularmonitoringforchronic

myeloidleukaemia.BestPractResClinHaematol.

2009;22(3):355–65.

4.VigneriPG,StagnoF,StellaS,CupriA,ForteS,MassiminoM,

etal.HighBCR-ABL/GUSEILevelsatdiagnosisareassociated

withunfavorableresponsestoimatinib.Blood.2013;122(21),

abstract#1495.

SimoneBoneckera,MarinaMagnagob,JaspalKaedac,

CristianaSolzab, IlanaZalcbergRenaulta,∗

aInstitutoNacionaldoCâncer(INCA),RiodeJaneiro,RJ,Brazil bUniversidadedoEstadodoRiodeJaneiro(UERJ),RiodeJaneiro,RJ,

Brazil

cUniversitätsmedizinBerlin,Berlin,Germany

∗Correspondingauthorat:Prac¸aCruzVermelha,23,6◦ andar,

LaboratóriosCEMO,Centro,20230-130RiodeJaneiro,RJ,Brazil. E-mailaddress:zalcberg@inca.gov.br(I.ZalcbergRenault).

Received14July2014 Accepted27August2014 Availableonline31January2015

http://dx.doi.org/10.1016/j.bjhh.2014.08.003

Imagem

Figure 1 – The median levels of the transcripts considering both control genes (GUS and ABL) at diagnosis and after three months on imatinib (IM) as first line therapy

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