Rev. Bras. Hematol. Hemoter. vol.37 número1

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Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

w w w . r b h h . o r g

Original

article

Acute

myeloid

leukemia:

survival

analysis

of

patients

at

a

university

hospital

of

Paraná

Sergio

Lunardon

Padilha,

Emannuely

Juliani

dos

Santos

Souza,

Marcela

Coriolano

Cruz

Matos

∗

_,

_Natália

_Ramos

_Domino

UniversidadeFederaldoParaná(UFPR),Curitiba,PR,Brazil

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Articlehistory:

Received20December2013 Accepted16June2014

Availableonline21November2014

Keywords:

Acutemyeloidleukemia Survivalanalysis Prognosis Adult Cytogenetics

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t

Objective:Theaimofthisstudywastoanalyzetheprognosticfactorscorrelatedwithsurvival ofpatientswithacutemyeloidleukemiaattheHospitaldeClínicas,UniversidadeFederal doParanábetween2003and2009,aswellastoinvestigatetheclinicalandepidemiological profile.

Methods:Theoverallsurvivalanddisease-freesurvivalwerestatisticallyevaluatedusing theKaplan–Meiermethod,thelog-ranktestandmultivariateevaluationbyCoxregression analysis.

Results:Thestudypopulationwaspredominantlyyoungerthan60yearsold(81,6%),had intermediatecytogeneticrisk(40.8%),infirstcompleteremissionafterinduction chemother-apy(46.9%),withawhitebloodcountatdiagnosisoflessthan30×109/L(57.1%)anddenovo

acutemyeloidleukemia(62.2%).Survivalcurvesshowedthatbetterprognosiswasrelated toagebelow60years(median:12,4months;p-value=0,2227;OddsRatio=0,6676),good pro-gnosticcytogeneticmarkers(median:97.7months;p-value=0.0037;OddsRatio=0.4239)and whitebloodcellcountatdiagnosisoflessthan30×109/L(mediansurvival:23.6months;p

-value=0.0001;OddsRatio=0.3651).RegardingtheFrench-American-Britishsubgroups,the medianoverallsurvivalwas23.5monthsforM0,M1andM2,97.7monthsforM3and7.4 monthsforM4,M5,M6,andM7(p-value=0.0288).

Conclusion: Prognosticfactorsstronglyinfluencedpatientsurvival,aswellasguided treat-ment.Moreover,thesefactorswereconsistentwiththeavailableliteratureadjustedforthe populationinquestion.

∗ _{Corresponding}_author_at_:_Hospital_de_Clínicas_da_Universidade_Federal_do_Paraná_(UFPR),_Rua_General_Carneiro,_181,_Alto_da_Glória, 80060-900Curitiba,PR,Brazil.

E-mailaddress:marcelacoriolano@hotmail.com(M.C.C.Matos). http://dx.doi.org/10.1016/j.bjhh.2014.11.008

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Introduction

Neoplasticdiseaseswerehistoricallyassociatedwith econom-icallydevelopedcountries.For approximatelyfour decades, however,thissituationhaschangedandalotoftheonusis observedindevelopingcountries.Infectiousdiseasesarenot themaincauseofdeathanymoreandcancerhasacquireda greaterdimension,becomingaglobalpublichealthproblem.1

Hematologicalmalignancies represent7%ofnewcancer caseseach year.2 _According _to_The_Brazilian_National

Can-cerInstitute,ithasbeenestimatedthattherewere4570new cases inmen and 3940in women in 2012. Acute myeloid leukemia(AML)isthemostcommonacuteleukemiainadults andaccountsforapproximately80%ofthecasesinthisgroup, withanannualincidenceof2.7casesper100,000population.3

AMLisarelativelyrarediseasewithhighheterogeneityin theaffectedpopulationintermsofmorphology, immunophe-notype, cytogenetics and molecular abnormalities. It is a clonalproliferationofmyeloidprecursors,theresultofgenetic and epigenetic alterations that disrupt self-renewal, prolif-eration and differentiation of cells, with accumulation of leukemicblastsorimmaturecellsinthebonemarrow.4_The

clinicaloutcomeisextremelyvariable,withsurvivalfrom a fewdaystoadefinitivecureofsomeclinicalandbiological aspects,whichisusefulinpredictingoutcomes.4–6

Several clinicalfeatures canpredict complete remission andtheevent-freesurvival(EFS)ofthesepatients.Themost importantprognosticfactorsregardingadverseclinical pre-sentations,includeage,cytogeneticabnormalities,secondary leukemia,whitebloodcell(WBC)countandcomplete remis-sionafterthefirstinduction.5,7

Thecasescanbemorphologicallysubclassifiedaccording tothe French-American-British(FAB) system. Thisform of organizationdoesnotprovideadditionalprognostic informa-tion,butit isimportanttosystematizeacutepromyelocytic leukemia, a biological and clinical variant of AML, classi-fied asAML M3 in the FAB system, currently calledacute promyelocyticleukemiawitht(15,17)(q24.1,q21.1),and PML-RARA,intheWorldHealthOrganization(WHO)classification system.8–10

Brazilhaspeculiaritiesregardingitsterritorialdimensions, withimportantregionaldifferencesintheoccurrenceofthe diseaseanddistributionofassociatedriskfactorsandsolocal informationisextremelyimportantforanalyticalexploration ofthismalignancy.

Prospectsforpatientshaveimprovedoverthelast30years, but despite significant progress, the treatment outcome is variableandfrequentlysuboptimal.Morethanhalfofyoung andadultpatients,andabout90%ofthedeathsofover 60-year-oldpatientsinthispopulationarediseaserelated.5,6,11,12

Thisstudy shows the indispensability ofregistries with standardized,up-to-dateandrepresentativeinformation,due theconsiderablevariationsbetweenpopulationsinrelationto survivalandepidemiologicalcharacteristicswhichcanpredict treatmentoutcome.

The aim of this study was to analyze the influence of prognosticfactorsdescribedintheliteraturecorrelatedwith survival of patients with acute myeloid leukemia treated between 2003 and 2009 at the Hematology and Oncology

ServiceoftheHospitaldeClínicas,UniversidadeFederaldo Paraná(HC-UFPR),Brazil,aswellastotracetheclinicaland epidemiologicalprofileofthepatients.

Methods

ThisretrospectiveanalyticalstudywasconductedatHC-UFPR afterbeingapprovedbytheEthicsCommitteeofthehospital. Thestudypopulationwasselectedusingrecordsfromthe ComputerInformationServiceandtheHospitalCancer Reg-istry ofHC-UFPRusing thefollowinginclusion criteria: the International Classification ofDiseases (ICD)ofAML, older than 15 yearsold anddiagnosis betweenJanuary2003and December2009.Theinitialpatientsetconsistedofpatients, predominantlytreatedwithcombinedinduction chemother-apyusingcytarabineanddaunorubicin(theso-called“7+3” regimen) fornon-M3 leukemias,and all-transretinoic acid (ATRA)aloneorcombinedwithananthracyclinefortheM3 subtype.

Patientswhowerenottreatedexclusivelyinthe Hemato-logyandOncologyService,HC-UFPRwereexcludedaswere thosewhohadbiphenotypicleukemia,Fanconianemiaeither associated with myelodysplastic syndrome or in isolation, thosewhowerediagnosedbefore2003andthosewhose med-icalrecordswerenotavailable.Theflowchartforselectionof thestudypopulationisdetailedinFigure1.

Datacollectionwasbasedonthereviewofmedicalrecords availablefromtheMedicalArchiveService(SAME),basedon theresultsofcytogeneticandimmunophenotyping examina-tionsprovidedbytherespectivelaboratories,aswellasrecords fromtheHospitalEpidemiologyServiceofHC-UFPR. Informa-tionofinterestwasinputonanExcelspreadsheettofacilitate furtheranalysisofthevariablesandtocompiletheresults.

Data forclinical andepidemiologicalcharacterizationof thestudypopulation,suchasgender,ageatdiagnosis,race, family history ofcancer, cytogenetics, the presenceof the t(15;17),completeremissionrateafterthefirstinduction,WBC count at diagnosis and type ofevolution (primary or sec-ondary) were arranged in a table of absolute and relative frequencies,withcalculationsperformedusingtheMicrosoft Excelprogram.

Regarding the analysis of overall survival (OS) and EFS of the patients, survival curves were constructed by the Kaplan–Meier method,using the statistical programPRISM (version 5.0). The definitions used for the calculation of survivalfollowedtherevisedrecommendationsofthe Interna-tionalWorkingGroupfortherapeuticstudiesinacutemyeloid leukemia.13_The_OS_was_defined_as_the_time_interval_between

thedateofdiagnosisanddateofdeathordateoflast follow-upvisit.TheEFSwastakenastheperiodbetweenthedateof diagnosisandthedateofrelapse,inductionfailureordateof deathfromanycause.

ThecurvesofOSand EFSwerealsocorrelatedwith cer-tainprognosticfactorsasreportedintheliterature,suchas ageatdiagnosis,FABclassification,cytogenetics,WBCcount at diagnosis and evolution (primary and secondary).11,12,14

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120 over 15-year-old patients with ICD of acute myeloid leukemia according to patients’ charts and

Cancer Hospital records between 2003 and 2009

31 patients were excluded for the following reasons

5 patients due to biphenotypic leukemia, associated Fanconi

anemia or isolated myelodysplastic syndrome

9 patients were previously treated at other centers

14 patients were diagnosed prior

to 2003

The medical records of 3 patients were inaccessible

98 patients were analyzed

Figure1–Flowchartusedtoselectthestudypopulation.

curvesalsoincludedtheOddsRatio(OR)withrespective95% confidenceintervals(95%CI).

Multivariateanalysesofprognosticfactorsinrelationtothe OS,includingcytogenetics,gender,age,WBCcountandtypeof evolutionwereperformedusingCoxregressionanalysiswith theSPSS20.0software.

Thepoorcytogeneticprognosiscategoryincludedcomplex karyotypes(twoormoreunrelatedabnormalities),monosomy of chromosome 5, monosomy of chromosome 7, translo-cations involving the 11q23 locus, and all deletions. The intermediateprognosiscategorywasdefinedasnormal kar-yotype and trisomies of chromosomes 4, 8 and 21. The translocationst(15;17),t(8;21)andinversions(16)/t(16;16)were considered the only entities capable of predictinga favor-ableprognosis. Other factors considered as poorprognosis inthecurrentstudywereagegreaterthan60,aWBCcount atdiagnosisover30×109/L,secondaryleukemiaandthelack

ofcompleteremissionatfirstinduction.Completeremission wasconsideredtobetheabsenceofsignsandsymptomsof diseaseassociatedwithnormalcompletebloodcountandless than5%blastsinbonemarrowaspirate.

The categorization used was based on the

French-American-British(FAB)groupclassification,whichcomprises eightsubtypesofAML(M0–M7)andisbasedon morpholog-icalandcytochemicalaspects.12_To_compare_survival_curves,

patientsweredividedintothreegroups:GroupI(FABM0–M2), GroupII(FABM3)andGroupIII(FABM4–M7).

Results

Thefinalstudypopulationwas98individuals.Patientswere predominantlyyoungerthan60yearsold(81.6%),inthe inter-mediatecytogenetic risk group(40.8%), withfirst complete remissionafterinductionchemotherapy(46.9%),whiteblood countlessthan30×109/L(57.1%)anddenovoleukemia(62.2%).

Themeanageatdiagnosiswas44.27years.Allclinicaland epidemiologicalfeaturesarelistedinTable1.

Therewasnostatisticallysignificantdifferencewhen com-paring the survival curves (Figure 2A) related to age for patientsaboveandbelowthecut-offdeterminedforthestudy population (median survival of 12.4 months for the group agedlessthanorequalto60yearsversus8.2monthsforthe groupolderthan60years;p-value=0.2227;OR=0.6676;95% CI=0.3488–1.278).ThemedianEFS(Figure2B)was10.7months fortheyoungergroupversus7.3monthsfortheover60-year olds(p-value=0.2448;OR=0.6812;95%CI=0.3567–1.301).The survivalcurvewasnotstatisticallysignificantforthe gender-relatedSGwithamediansurvivalof15.3monthsforfemales versus26.8monthsforthemen(p-value=0.2756;OR=0.7625; 95%CI=0.4684–1.241).

OScurvesforthetypeofevolutiondidnotshowany sta-tisticallysignificantdifferencebetweenthetwogroupswith a mediansurvivaltime forthe primary leukemia groupof 21.9monthsversus11.8monthsforthegroupwithsecondary leukemia(p-value=0.1706;OR=0.6824;95%CI=0.3951–1.179). ThisstudyfoundasignificantlyhigherOSinthegroupwith WBCcountlowerthan30×109/Latdiagnosis(Figure3A)with

amediansurvivaltimeof23.6monthsversus4.7monthsfor thegroupwithWBCcountofmorethan30×109/Lat

diag-nosis(p-value=0.0001;OR=0.3651;95%CI=0.1403–0.5160).As for EFS(Figure 3B), the groupwith leukocyte countslower than 30×109/L had asurvival time of19.3 months versus

3.0 months forthe group with aleukocyte count ofmore than30×109/Latdiagnosis(p-value=0.0003;OR=0.3042;95%

CI=0.1586–0.5834).

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100 80 60 40 20 0

0 12 24 36 48 60 72 84 96 108

Time (months)

0 12 24 36 48 60 72 84 96 108

Time (months)

Survival (%)

P=.222 P=.244

Younger than 60 years

Older than 60 years

A

100

80 60 40 20 0

Survival (%)

B

Figure2–Age-relatedsurvival.(A)Overallsurvivaland(B)event-freesurvival.

Sur

viv

al (%)

Sur

viv

al (%)

A

100

B

80

60

40

20

0

0 12 24 36 48 60 72 84 96 108

Time (months) P=.0001

100

80

60

40

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0

0 12 24 36 48 60 72 84 96 108

Time (months) P=.0003

Count lower than 30x109 Count over than 30x109

Figure3–Survivalinrespecttowhitebloodcellcount.(A)Overallsurvivaland(B)event-freesurvival.

100

80

60

40

20

0

0 12 24 36 48 60 72 84 96 108

Time (months)

0 12 24 36 48 60 72 84 96 108

Time (months)

Survival (%)

100

80

60

40

20

0

Survival (%)

P=.0037 P=.0005

Good prognosis

Poor and intermediate prognosis

A

B

Figure4–Survivalinrespecttocytogenetics.(A)Overallsurvivaland(B)event-freesurvival.

(97.7 versus 6.3 months; p-value=0.0005; OR=0.3591; 95% CI=0.2013–0.6407–Figure4B).

Someservicessentincompleteresultsfor immunopheno-typingandmyelogramanalysisandsoonly86%oftheresults oftheFABclassificationwereobtained.Accordingtothis clas-sification,5%ofthepatientswereintheM0subgroup,1%in M1,13%inM2,31%inM3,17%inM4,11%inM5,3%inM6and 1%ofthepatientsinM7.TheM3subgrouphadstatistically greatermedianOSandEFSasisshowninFigure5AandB (medianOSof23.5monthsforM0,M1,M2;97.7forM3and7.4 monthsforM4,M5,M6andM7;p-value=0.0288andmedian EFSof15.2monthsforM0,M1,M2;97.7forM3and6.1months forM4,M5,M6andM7;p-value=0.0047).

Multivariateanalysis wassignificant forcytogenetics(p -value=0.015).

Inthisanalysis,65.3%ofpatientsdied;25%ofthedeaths were dueto disease progression. Bleeding was the second mostcommoncauseofdeath,followedbyinfectionandthe consequencesoftreatment.

Discussion

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Survival (%)

A

Survival (%)

B

100

80

60

40

20

0

100

80

60

40

20

0 0 12 24 36 48 60 72 84 96 108

Time (months)

0 12 24 36 48 60 72 84 96 108

Time (months)

P=.0288 _P=.0047 M0-M2M3

M4-M7

Figure5–SurvivalinrespecttoFrench-American-Britishclassification.(A)Overallsurvivaland(B)event-freesurvival.

analyticalstudies,despitethelimitationsinherentto retro-spectivestudies.

The data shows a slight predominance of males than femalesandanabsolutemajorityofself-identifiedCaucasian patients.DataavailableforBrazilisscarce,butdataprovided

Table1–Globalclinicalandepidemiological characterization.

n %

Gender

Female 47 48

Male 51 52

Age

60yearsorless 80 81.6

Over60years 18 18.4

Race

Caucasian 91 92.9

Non-Caucasian 7 7.1

Familycancerhistory

Present 40 40.8

Absent 39 39.8

Insufficientinformation 19 19.4

Cytogenetics

Goodprognosis 21 21.4 Intermediaryprognosis 40 40.8 Poorprognosis 23 23.5 Insufficientinformation 14 14.3

Translocation(15;17)

Present 17 17.3

Absent 81 82.7

Completeremissionafterfirstinduction

Present 46 46.9

Absent 43 43.9

Whitebloodcellcount

Lowerthan30×109/L 56 57.1

Overthan30×109/L 26 26.6

Typeofleukemia

Primary 61 62.2

Secondary 36 36.7

bytheAmericanCancerSocietyshowthatAMLis1.7times

moreprevalentinmenandslightlyhigherinthenon-Hispanic whitepopulationthanotherraces.3_The_high_number_of

self-identifiedCaucasian patientsmayberelatedtotheequally highprevalenceofthisraceinthesouthernregionofthe coun-try, wherethe researchwas conducted, orthis is the kind ofinformationprovidedbypatientswho,forhistorical and culturalreasons,tendtoclassifythemselvesasWhite.

Themeanageatdiagnosiswaslowerthanthatfoundin theliterature.3,15_As_there_is_no_clear_definition_of_the_cut-off

agetodefinetheprognosisofAML,becauseofthestatistical significanceoftheresults,thisstudyestablishedthelimitof60 yearstostratifythepopulationintotwogroups.The disagree-mentwiththeliteratureregardingthestatisticalsignificance forthisfactormayberelatedtotheincorporationofAMLM3, prevalentinyoungerpatients,withothersubtypesofAML.3

TheM3subtypeisaverypeculiarformofleukemiaandmay beconsideredaparticulardisease,bothbytheclinical char-acteristicsandbythegoodprognosis.9_However,_due_to_the

limitednumber ofsubjects, thissubtypewasgroupedwith otherentities.

Olderindividualshadlowerratesofcomplete remission, OSandEFSwhencomparedwithyoungerpatients.AMLin elderlyisabiologicallyandclinicallydistinctentity.Basedon theanalysisofmolecularandcytogeneticdata,itisknown thattheleukemiccellsinolderpatientsareintrinsically resis-tanttoconventionalchemotherapy.Duetocomorbiditiesand the poor reserve of stem cells in the bone marrow, older adultsdonottoleratemyelosuppressivechemotherapywell andthereisahightreatment-relatedmortalityrateand evo-lutionofthedisease.3,15,16

Therewasnostatisticalsignificancerelatedtofamily his-toryofcancerandthetypeofevolution(primaryorsecondary) of the disease in the prognosis of these patients. Familial occurrenceisrareanditsroleinthedevelopmentofthe dis-ease isuncertain,sincetherole ofthetypeofevolutionis wellestablishedintheliterature.Historyofprior myelodys-plasiaormyeloproliferative diseasesiscommon(24–40%of cases) inelderlypatientswithacutemyeloidleukemia.17–19

Theabsenceofanyprognosticcorrelationmayberelatedto thehigherproportionofyoungpatientsinthestudy popula-tion.

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Thelimitof30×109/Lwasadoptedduetothehigher

statis-tical significancefoundforthis valueinthe current study, althoughtraditionallythedecisiveprognosticscoreiscloser to20×109/L.20

ThisstudyfoundacorrelationbetweenhigherWBCcounts andreduced OSand EFS.Onepossibleexplanationforthis findingisthatveryhighWBCcountsareassociatedwithan increasedriskoftumorlysissyndromeandleukostasis.Both theseare consideredoncologicemergenciesandareableto affecttheprognosisofpatients.21_In_a_multivariate_analysis,

thisfactor didnotshowthe samesignificance,despitethe borderlinevalue(p-value=0.063).

Cytogeneticsisakeypointinthediagnosis,treatmentand prognosisofAML.22,23_In_the_present_study,_the_survival_curves

ofpatientswithcytogeneticsrelatedtopoorprognosisand intermediateprognosisweregroupedtogetherwiththe prog-nosisbeingpoorduetooverlapping.

Cytogeneticswasstatisticallysignificantbothinunivariate analysisandinmultivariateanalysis,showingthat, irrespec-tiveofotherfactors,thisisanimportantprognosticfactor. Consistentwiththe literature,cytogeneticsrelated togood prognosisconferredabettersurvivalforpatients.22–24_There

wasasignificantdropinthesurvivalcurveofpatientswith cytogeneticsrelatedtopoorprognosis;survivalforthisgroup wascloseto20%withinthe firsttwoyears.TheOSrelated togoodprognosisbecamestableatbetween70%and80%in eightyearsoffollowup.Thisdatanotoriouslyrevealstherole ofcytogeneticsintheprognosisofpatients.

Currently,theclassificationrecommendedforAMLisone establishedbytheWHOin2008,whichassessesthe morpho-logical,immunophenotypicandgeneticcombinationsaswell asclinicalmanifestationsofthedisease.7,25_Since_this_is_a

ret-rospectivestudyandprevioustoWHOdefinitions,thisstudy was based exclusively on the FAB classification associated withcytogeneticstoestablishsubtypes.8

Acutepromyelocyticleukemia (knownasM3intheFAB classification) is characterized bythe translocationt(15;17) andisregardedasaparticulartypeofAML.9_In_the_present

study,similartootherpublications,thiskindofleukemia con-ferredbettersurvivalratesthanthoseobservedfortheother subtypes.26–28

Ahigherdeathratewasobservedrelatedtothe FABM3 classificationinthefirst daysfollowingdiagnosis,probably duetothehighfrequencyofcomplications,suchas dissemi-natedintravascularcoagulation(characteristicofthisclassof AML).Subsequentdeathsweremostlyrelatedtoaggressive treatment.Moreoverthesurvivalcurve showsthatpatients whosurvivedthefirststagesoftheillnessandtreatmenthad highersurvivalratesthanthoseofothersubgroups.Wemust stressthatinthisstudythepatientsweregroupedinrespect totheFABclassificationduetotheoverlapofthecurvesand thesizeofthepopulationstudied.

Conclusion

Prognostic factors significantly influenced the survival of patients,aswellasguidedtreatment.Moreover,theoutcomes wereconsistentwiththeliterature,adjustedforthe popula-tion inquestion. Clinicaland epidemiological dataprovide

important toolsfora possibledevelopment ofsurveillance systems forAML,so thatthe necessitiesofthe population consultedatHC-UFPRareprioritizedandeffectivelytreated bypublichealthpolicies.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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