ContentslistsavailableatScienceDirect
Leukemia
Research
j o ur n a l ho m e p age : w w w . e l s e v i e r . c o m / l o c a t e / l e u k r e s
Dasatinib
is
safe
and
effective
in
unselected
chronic
myeloid
leukaemia
elderly
patients
resistant/intolerant
to
imatinib
Roberto
Latagliata
a,∗,
Massimo
Breccia
a,
Fausto
Castagnetti
b,
Fabio
Stagno
c,
Luigiana
Luciano
d,
Antonella
Gozzini
e,
Stefano
Ulisciani
f,
Francesco
Cavazzini
g,
Mario
Annunziata
h,
Federica
Sorà
i,
Antonella
Russo
Rossi
j,
Patrizia
Pregno
k,
Enrico
Montefusco
l,
Elisabetta
Abruzzese
m,
Elena
Crisà
n,
Pellegrino
Musto
o,
Mario
Tiribelli
p,
Gianni
Binotto
q,
Ubaldo
Occhini
r,
Costanzo
Feo
s,
Paolo
Vigneri
c,
Valeria
Santini
e,
Carmen
Fava
f,
Giannantonio
Rosti
b,
Giuliana
Alimena
aaDipartimentodiBiotecnologieCellulariedEmatologia,Università“LaSapienza”,ViaBenevento6,00161,Rome,Italy bEmatologia,UniversitàdiBologna,Bologna,Italy
cEmatologia,OspedaleFerrarotto,Catania,Italy dEmatologia,Università“FedericoII”,Napoli,Italy eEmatologia,UniversitàdiFirenze,Firenza,Italy
fEmatologia,PoloUniversitarioASOSanLuigiGonzaga,Orbassano,Italy gEmatologia,UniversitàdiFerrara,Ferrara,Italy
hEmatologia,OspedaleCardarelli,Napoli,Italy
iEmatologia,UniversitàCattolicadelSacroCuore,Rome,Italy jEmatologiaconTrapianto,UniversitàdiBari,Bari,Italy kEmatologia,OspedaleSGiovanniBattista,Torino,Italy lEmatologia,OspedaleSant’Andrea,Rome,Italy mEmatologia,OspedaleSant’Eugenio,Rome,Italy nDivisionediEmatologia,UniversitàdiTorino,Torino,Italy
oDipartimentoOnco-Ematologico,IRCCS,CentrodiRiferimentoOncologicodellaBasilicata,RioneroinVulture,Vulture,Italy pEmatologia,UniversitàdiUdine,Udine,Italy
qEmatologia,UniversitàdiPadova,Padova,Italy rEmatologia,OspedaleSanDonato,Arezzo,Arezzo,Italy sDHEmatologico,AORummo,Benevento,Italy
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:Received3March2011
Receivedinrevisedform6May2011 Accepted10May2011
Available online 25 June 2011 Keywords:
ChronicMyeloidLeukaemia Dasatinib
Elderly Safety
a
b
s
t
r
a
c
t
To highlight dasatinib role in the elderly, 125 unselected patients with CP-CML aged >60 years
resistant/intoleranttoimatinibwereretrospectivelyevaluated.Grade3–4haematologicaland
extra-haematologicaltoxicitieswerereportedin39(31.2%)and34(27.2%)patients;grade3–4haematological
toxicitywashigherinpatientswith140mgstartingdose(50.0%vs19.6%,p=0.001).Grade3–4
pleuro-pericardialeffusionsoccurredin10patients(8.0%).Dosereductionsweremorecommoninpatients
with140mg(88.4%vs26.7%,p<0.001).Of122evaluablepatients,72(59.1%)hadcytogeneticresponse
[12(9.8%)partial,60(49.3%)complete].Overall,38/60patientsincompleteCyRalsoachieveda
molec-ularresponse.CumulativeOSat24and48monthswere93.1%(95%CI88.4–97.8)and84.2%(95%CI
74.6–93.7).Dasatinib,attherecommendeddoseof100mg/day,iseffectiveandsafealsoinunselected
elderlysubjects.
© 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Imatinib,theprototypetyrosinekinaseinhibitor(TKI)versus theBCR/ABLhybridgene,hasprofoundlychangedtheprognosis ofChronicMyeloidLeukaemia(CML)andisthecurrentstandard first-linetreatmentforpatientswithnewlydiagnosedCML[1–3].
∗ Correspondingauthor.Tel.:+3906857954537;fax:+390644241984. E-mailaddress:[email protected](R.Latagliata).
However,somepatientsdiscontinuethedrugduetotreatment fail-ureortoxicity[4,5].Asaconsequence,thereisincreasingeffort focusedonovercomingbothresistanceandintolerancetoimatinib. Dasatinibis a 2ndgenerationTKIwithgreaterpotencythan imatinibonBCR/ABL tyrosine-kinase[6,7]. Many phase IItrials withdasatinibinpatientsresistantorintoleranttoimatinibhave confirmeditsefficacywithanacceptablesafetyprofile[8–10]; fur-thermore,thedosageof100mg oncedailyemergedin a4-arm randomizedtrialasthebesttolerateddosageforstandard treat-mentinchronicphasepatients[11].
0145-2126/$–seefrontmatter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2011.05.015
Therearefewstudieswhichfocusedontheroleofimatinibin olderadultsand elderlypatients[12–14]. IntheMDACCreport
[12],comparableratesof completecytogeneticresponse(CCyR) wereobservedinolder(>60yrs)versusyoungerpatients;onthe contrary,lowerratesofresponse (hematologicandcytogenetic) inolder(>65yrs)versusyounger patientswereobservedinthe GIMEMAstudy[14].Howeverinbothstudiesthesurvivalratewas similar.
Nevertheless,verylimiteddataareavailableinolderadultsand elderlypatientsresistant/intoleranttoimatinibandtreatedwitha 2ndgenerationTKI.Inaddition,onlyselectedelderlypatientshave beenenrolledinphaseIIpublishedtrials,withamedianagelower thanexpectedaccordingtoepidemiologicalstudiesandarateof patientsaged>60yearsoften<35–40%[15].
Elderlypeopleinonco-haematologicalsettingsareextremely heterogenous.Ifwelookatcontrolledclinicaltrials,wecanget information ontreatmenttolerability and efficacyin fit elderly patientswho are compliant withtreatments, not in thewhole elderlypopulation;therefore,tohavea“real-life”evaluationwith usefulinformationsforcurrentclinicalpractice,weneedtogather datafromtheentiregroupofelderlypatients.
Theaimofourstudywastodescribethetolerabilityandthe effi-cacyofdasatinibinawideunselectedcohortofolderadultpatients withCMLresistantorintoleranttoimatinibcollectedbyseveral haematologicalCentersinItaly.
2. Patientandmethods
2.1. Inclusioncriteria
ParticipatingCenterswereasked to senddata onallCML patients resis-tant/intoleranttoImatinibreceivingdasatinibwhofulfilledatthestartofdasatinib treatmentthefollowinginclusioncriteria,irrespectivelyoftheirenrolmentornot incontrolledclinicaltrials;
-Age>60yrs
-Chronicphaseofdisease
Intolerancetoimatinibwasdefinedastheoccurrenceofsevere(grade3–4 WHO)ormoderate(grade2WHO)butpersistentorrecurrenthaematologicalor extra-haematologicaltoxicityduringimatinibtreatmentrequiringpermanentdrug discontinuation.Primaryresistancetoimatinibwasdefinedaccordingto Euro-peanLeukaemiaNetguidelinesforfailureat3months[nocompletehaematological response(CHR)],6months(nocytogeneticresponse),12months[lessthanpartial cytogeneticresponse(PCyR)]and18months(noCCyR)[16].Secondaryresistance toimatinibwasdefinedastheoccurrenceoflossofCCyRorlossofmajormolecular response(MMolR)atanytimeaftertheachievementofapreviousCCyRorMMolR. Anyclinicalillnessrequiringaspecificandprolongedtreatmentaswellas pre-viouscancerswasconsideredasconcomitantdisease.Thenumberofdrugsrequired byeachpatienttomanageconcomitantdiseaseswasalsorecorded.
Haematologicalandextra-haematologicaltoxicitiesweregradedaccordingto theWHOscale;forthepurposeofthepresentstudy,onlyseveretoxicities(grade 3–4)wereconsidered.
2.2. Cytogeneticandmolecularevaluation
Cytogeneticanalyseswereperformedonbonemarrow(BM)aspiratesby stan-dardGorQbandingtechniquesonatleast20cellmetaphasesfromdirectorshort term(24–48h)culturesatdiagnosis,after3,6,and12monthsoftherapywith dasa-tinibandevery6monthsthereafter.Fluorescence–insituhybridization(FISH)on bonemarrowinterphasecellswasrecommendediflessthan20metaphaseswere evaluableandwasperformedwithBCR-ABLextra-signal,dual-color,dual-fusion probes;CCgRwasdefinedbylessthan2of200(<1%)positivemarrowcellinterphase nuclei.
Real-timequantitativepolymerasechainreaction(RT-Q-PCR)toassessBCR-ABL transcriptlevelswasperformedaccordingtosuggestedproceduresand recommen-dationsandresultswereexpressedasBCR-ABL/ABLrationormalisedaccordingto internationalscale(IS)[17–19].
QualitativeRT-nestedPCRwascarriedoutaccordingtothestandardizedRT-PCR analysisoffusiongenetranscriptsaspreviouslydescribedintheBIOMED-16report.
Table1
ClinicalcharacteristicsatCMLdiagnosis.
No.ofpatients 125 Males,No.(%) 63(50.6%) Age(years):median(interquartilerange) 63.1(58.6–69.2) WBC(x109/l):median(interquartilerange) 63.1(30.1–117.0)
Hb(g/dl):median(interquartilerange) 12.2(10.5–13.3) PLTS(x109/l):median(interquartilerange) 396(277–608)
Sokalrisk:No.
Low 32
Intermediate 49
High 19
Notevaluable 25
2.3. Definitions
Cytogeneticandmolecularresponseswerecategorizedaccordingtostandard criteria:CCyRwasdefinedastheabsenceofPh+metaphases;iflessthan20 metaphaseswereevaluable,CCyRwasdefinedasBCR-ABLpositiveinterphasenuclei lessthan1%;partialcytogeneticresponse(PCyR)wasdefinedasthepresenceof1 to35%Ph+metaphases;MMolRwasdefinedasBCR-ABL/ABLratio<0.1and com-pletemolecularresponse(CMolR)astheundetectabilityofBCR/ABLbyqualitative RT-nestedPCR.
Primaryhaematologicalresistancetodasatinibwasdefinedasfailuretoachieve CHRafter3monthsoftreatment;primarycytogeneticresistancetodasatinibwas definedasfailuretoachieveatleastPCyRafter12monthsoftreatment.Secondary resistancetodasatinibwasdefinedasthelossofcytogeneticresponseatanytime aftertheachievementofapreviousPCyRorCCyR.
2.4. Statisticalanalysis
Datawereexpressedasmean±standarddeviation(SD)(normallydistributed data),medianandinterquartilerange(IR)(non-normallydistributeddata),oras percentagefrequencies,andwithin-patientcomparisonsweremadebypairedttest and2test,asappropriate,atsignificancelevelsofp<0.05.OverallSurvival(OS)
wascalculatedfromthedateofdasatinibstarttodeathduetoanycause. Event-FreeSurvival(EFS)wascalculatedfromthedatedasatinibwasstartedtoanyof thefollowingevents:primaryhaematologicalresistancetodasatinib,permanent dasatinibdiscontinuationduetotoxicityoranyotherunrelatedcause,secondary resistancetodasatinib,deathduetoanycause.TheCoxproportionalhazardmodel wasusedformultivariateanalysisofprognosticfactors.
Allcalculationsweremadeusingastandardstatisticalpackage(SPSSfor Win-dowsVersion15.0;Chicago,IL).
3. Results
3.1. Clinicalcharacteristics
Overall,125patientsresistant/intoleranttoimatinibandtreated
withdasatinibwhenaged>60 yearsweretreated by21 Italian
haematologicalCenters,ofwhich11wereuniversityhospitalsand
10community-basedhospitals.Theterritorialdistributionofthe
participatingCenters wasnationwide.Patientclinical
character-istics atCML diagnosisare shown inTable 1: asexpected in a
relatively aged population, intermediate and high Sokalscores werefrequent.Medianintervalfromdiagnosistostartofdasatinib treatmentwas75.8months(IR39.1–115.9)whilemedianageat dasatinibinitiationwas69.9years(IR65.4–74.4).Astoprevious treatments,57patients(45.6%)hadreceivedaninterferon-based therapybeforeimatinib.Accordingtotheinclusioncriteria,all125 patientshadreceivedimatinib,whichwasadministeredat stan-darddailydosageof400mgin116patientsandatareduceddaily dosageof<400mgin9patients;inaddition,58patients(46.4%) escalatedthedoseto600–800mg.Overall,themediandurationof imatinibtreatmentwas46.6months(IR21.8–61.8).Priortoswitch todasatinib,12patients(9.6%)receivedtreatmentwithnilotinib and16patients(12.8%)withotherdrugs.Inparticular,amongthe 12patientspreviouslytreatedwithnilotinib,8discontinued nilo-tinibforprimary resistance,3 forcytogeneticrelapse and 1for intolerance.
Atthestartofdasatinibtreatment,13patients(10.4%)resulted intolerant for extra-haematological toxicity to imatinib (skin
Table2
Concomitantdiseasesatstartofdasatinibtreatment.
Arterialhypertension 54(43.2%) Cardiovasculardiseases 22(17.6%) Previousorconcomitantneoplasia 11(8.8%) Gastro-intestinaldiseases 10(8.0%) Arrhytmias 9(7.2%) Thyroiddisfunctions 9(7.2%)
Diabetes 9(7.2%)
BPCO 7(5.6%)
Chronicrenalinsufficiency 4 (3.2%)
toxicityin5,gastro-intestinaltoxicityin3,astheniain2andliver
toxicity,pleural effusionand arterialstenosisin 1case,
respec-tively)and112(89.6%)resistanttoimatinib(primaryresistancein
60andsecondaryresistancein52patients,respectively).Onthe
whole,11patientswereinCCyRwhendasatinibwasstarted;of
them,6wereintoleranttoimatinib,4hadasecondaryresistance
due to lossof MMolR and 1 had a loss of MMolR withF359V
mutation.AccordingtoECOGscale,performancestatuswas0in67
patients(53.6%),1in48(38.4%)and≥2in10(8.0%),respectively.
Amajorpointindefiningourcohortofpatientswasthepresence
ofconcomitant diseases.Twenty-seven patients(21.6%) didnot
haveanyconcomitantdisease,48patients(38.4%)had1
concomi-tantdiseaseand50patients(40.0%)had2ormoreconcomitant
diseaseswhendasatinibwasstarted.Table2showsthe
concomi-tantdiseasesmostfrequentlyreported,possiblyinteractingwith TKIintake,metabolismandside-effects.
Strictlyrelatedtotheconcomitantdiseases,wealsoreportthe number of concomitantdrugs taken by patientsat thestart of dasatinibtreatment.Only29patients(23.2%)didnottakeany con-comitantdrug,57patients(45.6%)received1–3concomitantdrugs while39patients(31.2%)needed4ormoredifferentdrugs.
Starting daily dose of Dasatinib was 140mg in 52 patients, 100mgin56patientsandlessthan100mgintheremaining17 patients.Drug intakewasonce dailyin79 patients(63.2%) and twicedailyin46(36.8%),respectively.
3.2. Treatmenttoxicities
After a median period of treatment of 20.7 months (range 0.7–61.5; IR10.4–29.2)all patientswereevaluable for toxicity. Overall,39/125patients(31.2%)developedasevere haematologi-caltoxicity(grade3–4accordingtoWHO)afteramediantreatment periodof1.2months(IR0.7–2.4).
Regardingthestartingdosage,agrade3–4haematological toxi-citywasreportedin26/52patients(50.0%)treatedwithadailydose of140mgcomparedto11/56(19.6%)patientstreatedwith100mg (p=0.001).Differenceswerealsosignificantforthrombocytopenia andneutropenia,asshowninTable3.Furthermore,atunivariate analysisalsofemalegender(p=0.01),primaryresistance(p=0.018) and twicedailyadministration(p=0.002)had a badprognostic impactongrade3–4haematologicaltoxicity.Atmultivariate analy-sis,onlystartingdosageretainedstatisticalsignificance(p=0.014). Severeextra-haematologicaltoxicity(grade3–4accordingto WHO)was reported in 34/125 patients (27.2%) after a median treatmentperiodof 2.3months(IR0.9–6.9). Accordingto start-ingdosage,16/52(30.7%)patientstreatedwith140mgdeveloped asevereextra-haematologicaltoxicitycomparedto12/56(21.4%) Table3
Haematologicaltoxicitiesaccordingtostartingdose.
140mgNo.(%) 100mgNo.(%) p-Value Hb<8g/dl 9(17.3) 4(7.1) 0.10 PLTS<50×109/l 17(32.6) 3(5.3) <0.001 PMN<1.0× 109/l 15(28.8) 4(7.1) 0.003
Table4
Extra-haematologicaltoxicitiesaccordingtostartingdose.
Toxicity3–4WHO 140mgNo.(%) 100mgNo.(%) p-Value Pleuraleffusion 4(7.7) 5(8.9) NS Bonepain 2(3.8) 0 NS DVT 2(3.8) 0 NS Miocardialischemia 1(1.9) 0 NS Bronchopneumonia 1(1.9) 2(3.5) NS Cheratocongiuntivitis 1(1.9) 0 NS G.I.hemorrhage 1(1.9) 0 NS Skinrush 1(1.9) 0 NS Ascytis 1(1.9) 0 NS Sepsis 0 1(1.7) NS Diarrhea 0 1(1.7) NS Abdominalpain 0 1(1.7) NS Neurologicalsymptoms 0 1(1.7) NS Dysgeusia 0 1(1.7) NS Fluidretention 0 0 NS
patientstreatedwith100mg(p=0.26).Nootherfeatureatbaseline
showedaprognosticimpactonextra-haematologicaltoxicity.
Pleuro-pericardial effusions of any WHO grade occurred in
41/125 patients(32.8%) and weresevere(grade3–4) in10/125
patients (8.0%);with regard to initial dosage,pleural effusions
of anyWHO gradedeveloped in 25/52(48.0%) patientstreated
with 140mg compared to 13/56 (23.2%) patients treated with
100mg (p=0.01). The incidence of severe (grade 3–4 WHO)
pleuro-pericardialeffusionandotherextra-haematological
toxici-tiesrelatedtoinitialdoseofdasatinibissummarizedinTable4.
The numberof concomitant diseases aswellas thenumber of concomitant drugs didnot affect significantly theincidence of grade 3–4 haematological and extra-haematological toxicity (SupplementalTable1).Furthermore,itisworthofnotethatamong patientsstartingdasatinibduetoimatinibintolerance,nocaseof cross-intolerancewasreported.
Duringtreatment,58patients(46.4%)didnotrequireanydose adjustmentand67patients(53.6%)neededadosereductiondue totoxicity;19patients(15.2%)requiredpermanentdasatinib dis-continuationduetotoxicity,afteramedianperiodfromdasatinib startof4.0months(IR2.2–6.0).However,adifferentprofileofdose modificationwasobservedaccordingtotheinitialdoseofdasatinib, with46/52patients(88.4%)requiringdosereductioninthegroup receiving140mgcomparedwith15/56patients(26.7%)receiving 100mg(p<0.001).
3.3. Treatmentresponseandfollow-up
Withregardtoresponse,122patientswereconsidered evalu-able(≥3monthsoftreatment)and3wereconsideredastooearly. Intermsofbestresponse,thesewereasfollows:16patients(13.1%) didnot achieve anyresponse (including 12 patientswithearly dasatinibdiscontinuationfortoxicityand1patientwhodiedfrom unrelated2ndneoplasia);34patients(27.8%)hadaCHRonly,but acytogeneticresponselessthanpartial;72patients(59.1%)hada cytogeneticresponse(12PCyR,60CCyR).Among60patientswith CCyR,38(31.1%ofall122evaluablepatients)alsoachieved Molec-ularResponse(19MMolR,19CMolR).Resultsaccordingtostarting dosageareshowninTable5.
Atunivariateanalysis,baselinefeatureswithapoor prognos-ticimpactonCCyR achievementwereprimaryresistantdisease (p<0.001), twice daily drug administration (p=0.004) and bad PS (p=0.024): there was also a trend for 140mg initial dose as bad prognosticfactor (p=0.052).On thecontrary,the num-ber of concomitant diseases and the number of concomitant drugs(SupplementalTable2),gender,SokalriskandpreviousIFN treatmentdidnotaffectsignificantlycytogenetic andmolecular
Table5
Bestresponseaccordingtostartingdose.
Allpts 140mg 100mg Evaluablepatients 122 52 55 Nochr 16(13.1%) 7(13.4%) 3(5.5%) Chronly 34(27.8%) 18(34.6%) 13(23.6%) Cytogeneticresponse 72(59.1%) 27(52.0%) 39(70.9%) PCyR 12 5 7 CCyR 60(49.1%) 22(42.3%) 32(58.1%) Molecularresponse 38(31.1%) 14(26.9%) 20(36.3%) MMolR 19 6 11 CMolR 19 8 9
responserates.Atmultivariateanalysis,onlybaselinedisease
sta-tus(p<0.001)andPS(p=0.014)retainedstatisticalsignificance.
AfteramedianperiodfromstartofDasatinibtreatmentof24.4
months(IR17.3–32.9),11patientsdiedfromdiseaseprogression
(2)orothercauses(fromcardiacdisease3patients,frominfection
2patients,from2ndneoplasia2patients,fromacuterenalfailure1
patientandfromunknowncause1patient)and1patientwaslost
tofollow-up.Theremaining113patientsarestillalive.
ThecumulativeOSat24and 48monthswere93.1%(95%CI
88.4–97.8)and 84.2% (95% CI 74.6–93.7), respectively (Fig. 1a),
without differences according to starting dosage (Fig. 1b). The onlyfeatureaffectingOSatunivariateanalysiswasPSatbaseline (p=0.0001).
ThecumulativeEFSat24and48monthswere60.8%(95%CI 51.2–70.4)and49.5%(95%CI37.3–61.7),respectively;accordingto startingdosage,therewasnodifferencebetweenpatientsreceiving 140or 100mg, whileboth thesegroups hada betterEFS com-paredtopatientsreceiving<100mg(p=0.032)(Fig.2aandb).At univariateanalysis,otherbaselinefeatureswithapoorprognostic impactonEFSwereprimaryresistantdisease(p=0.0023),andbad PS(p=0.021):therewasalsoatrendfortwicedailyadministration asbadprognosticfactor(p=0.059).Onthecontrary,gender,Sokal riskandpreviousIFNtreatmentdidnotaffectsignificantlyEFS.
Atmultivariateanalysis,startingdosage(p<0.001)andbaseline diseasestatus(p=0.006)retainedstatisticalsignificance.
4. Discussion
Treatmentresultswith2ndgenerationTKIin patients resis-tant/intolerant toImatinib has already beenreported in many phaseII-IIItrialsoverthepast2years[8–11].However,data specif-icallyaddressingresultsandtoxicitiesinelderlypatientsarestill lackingand,therefore,theprimaryaimofthisstudywastogivenew insightsinthe2ndlinetreatmentofthesesubjectswithdasatinib. Wedescribedherea“real-life”cohortofpatients,insteadofa cohortfromaphaseII–IIIcontrolledtrial,invitingparticipant Cen-terstocollectdataonallelderlypatientstreatedateachinstitution withdasatinib,irrespectivelyoftheenrolmentornotinacontrolled trial.Patientsenrolledinsuchcontrolledtrialsareselected accord-ingtomanyinclusionandexclusioncriteria.Thisselectivebiasis evidentespeciallyamongolderpatients,asreportedbyRohrbacher
[15],andconfirmedbythemedianageinthesetrials,whichisoften <55years.Inourcohort,10patients(8.0%)hadabaselinepoor per-formancestatus,12patients(9.6%)werepreviouslytreatedwitha 2ndgenerationTKIinhibitor,22patients(17.6%)hadcardiological concomitantdiseasesand4patients(3.2%)hadchronicrenal insuf-ficiency;manyofthesepatientswouldhavebeenexcludedfrom aphase II–IIIcontrolledtrial.It isvirtuallyimpossibletoobtain acohortwithoutanyformofselection,assomepatients consid-eredtoofrailbyresponsiblephysiciansareprobablyexcludedfrom second-linetreatmentwithTKI;therefore,acollectionofclinical dataoutsidecontrolledtrialsmaybeconsidereda“real-life evalu-ation”andcouldbethebestmethodtoinvestigatethefeasibiltyof second-lineTKIinthissubsetofpatients.
Movingtothis“real-life”source,wecandiscussourresults try-ingtoanswerthreequestions;(1)isdasatinibsafeinelderlypeople incommonclinicalpractice?(2)whichisthebestdoseofdasatinib inthissetting?(3)arethetherapeuticresultssufficienttojustify dasatinibtreatmentalsointhissetting?
Fig.2.(a)Cumulativeevent-freesurvival(b)cumulativeoverallevent-freesurvivalaccordingtostartingdose.
Overall,bothhaematologicaland extra-haematologicalgrade 3–4toxicities aswellas therateofpermanent discontinuation duetotoxicity(15.2%)wereacceptable,consideringthehighrate ofpatientswithconcomitantdiseasesandreceivingconcomitant drugs.ItisworthofnotethatbothsafetyandefficacyofDasatinib werenotaffectedbythenumberofconcomitantdiseasesanddrugs ofthepatients.
Asexpected,theinitialdoseofdasatinibhadacrucialrolein determiningthetoxicityand compliancetotreatment[11].The majorityofpatientsstartingdasatinibat140mgneededtoreduce thedosagecompared topatientswho receivedlowerdoses; in addition,theinitialdosageof100mgwasassociatedwithalower incidenceofgrade3–4neutropeniaandthrombocytopeniawhen compared to140mg.On thecontrary,probablydue tothelow numberofpatients,grade3–4extra-haematologicaltoxicitieswere similaraccordingtotheinitialdoseofdasatinib.
Theoverallincidenceofpleuraleffusionswashigherinpatients receiving140mg,inlinewithdatafromthe034trial[11];however, thedifferencedisappearedwhenonlygrade3–4pleuraleffusions wereconsidered.
Responserateswerehigherthanexpectedconsideringthe uns-electedcohortandtheolderageofpatients.Overallresultswere similartodatapreviouslyreportedinphaseIItrials[8–11], show-ingaCCyRrateofabout50%andacumulativeOS>80%at4years but,unlikeinothertrials,inthepresentanalysissecondary resis-tancewasdefinedeitherascytogeneticandmolecularrelapse.Itis worthnotingthatresponseratesinpatientswhoreceived100mg asinitialdasatinibdosagewerehigher(althoughnotsignificantly different),withaCCyRrateofabout60%andacumulativeOS>95% at4years;alongerfollow-upandawidercohortofpatientsare neededtoaddressthepossiblefavourableimpactofthisdosageon treatmentresults.
Inconclusion,dasatinibseemstobeasafeandeffectiveoption forelderlypatientsresistant/intoleranttoimatinib,irrespectiveof
anyselectioncriteriaandespeciallyatthecurrentstandardinitial dosageof100mg.
Asamatteroffact,movingfromthis“real-life”approach,we outlinethatthereisnoreasontotreatelderlyCMLpatients resis-tant/intolerant to Imatinib with a conservative approach only, excludingthemfromasafeandeffectivedruglikedasatinib.Our “real-life”datainelderlyarealsopromisingifwepointatthefuture useof2ndgenerationTKIsinthe1stlineCMLtreatment.
Conflictofintereststatement
GRisa consultantwithNovartis andservesonthespeakers’ bureausofNovartisandBristol-MyersSquibbandallotherauthors havenodisclosuretodeclare.
Acknowledgements
Fundingsource.Therewasnofinancialsupporttodeclare. Contributions.RL,MBandGAdesignedthedatacollectionand wrotethepaper;FC,FS,LL,AG,SU,FC,MA,FS,ARR,PP,EM,EA, EC,PM,MT,GB,UO,CFcollecteddataandcontributedtothedata analysisandinterpretationandPV,VS,CF,GRanalyseddataand contributedtowritethepaper.
AppendixA. Supplementarydata
Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,atdoi:10.1016/j.leukres.2011.05.015.
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