Rev. Bras. Hematol. Hemoter. vol.37 número2

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

Revista

Brasileira

de

Hematologia

e

Hemoterapia

Brazilian

Journal

of

Hematology

and

Hemotherapy

Original

article

A

model

for

the

functional

assessment

of

elderly

with

myeloid

neoplasms

Ana

Lúcia

Ippolito

Carbonell

a,∗

,

Renata

Maceu

Salhab

a

,

Viviana

Giampaoli

b

,

Maysa

Seabra

Cendoroglo

a

_,

_Maria

_de

_Lourdes

_Chauffaille

a

a_Universidade_Federal_de_São_Paulo_(UNIFESP),_São_Paulo,_SP,_Brazil b_Universidade_de_São_Paulo_(USP),_São_Paulo,_SP,_Brazil

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received1November2014

Accepted26December2014

Availableonline17February2015

Keywords:

Performancetests

Karnofskyperformancestatus

Aged

Leukemia,myeloid

Myelodysplastic-myeloproliferative diseases

a

b

s

t

r

a

c

t

Objective:Myeloidneoplasmsare heterogeneousdiseases thataremoreincident inthe

elderly.Thegoalsofthisstudyweretoaggregateageriatricapproachtothepatient

assess-ment,toshowtheimpactofgender,age,hemoglobinconcentrationandcomorbiditieson

the functionalityofelderlywithmyeloid neoplasmsandtobetterunderstandhowthe

instrumentsoffunctionalassessmentworkaccordingtotheaggressivenessofthedisease.

Methods:Elderlypatients (≥60 years old)with myeloidneoplasms wereassessed using

the Karnofskyscale,Eastern CooperativeOncologic Groupscale,andbasic and

instru-mentalactivitiesofdailylivingscales.Thehematopoieticcelltransplantation-comorbidity

indexassessedthecomorbidities.Amixedlogisticalregressionmodelwasfittedto

esti-mate the impactof gender,age,hemoglobinconcentrationandthe hematopoieticcell

transplantation-comorbidityindexonpatients’functionality.

Results:Eighty-twopatientswithameanageof72.8years(range:60–92years)were

evalu-ated.EightypercenthadgoodKarnofskyandEasternCooperativeOncologicGroupscales

and39%wereindependentaccordingtothedailylivingactivityscales.Allofthepatients

withpoorKarnofskyandEasternCooperativeOncologicGroupscaleswereclassifiedas

dependentbythedailylivingactivityscales.Themixedlogisticregressionmodelsshowed

thatage,gender,hemoglobinconcentrationandthecomorbidityindeximpactedonthe

dailylivingactivityscales.KarnofskyandEasternCooperativeOncologicGroupscaleswere

affectedbyhemoglobinandthecomorbidityindex.Themodelhypothesizedthehemoglobin

concentrationatwhichtherewasahigherriskofpoorKarnofskyandEasternCooperative

OncologicGroupscales.Thishemoglobinconcentrationdependedoncomorbiditiesandon

theaggressivenessofthemyeloidneoplasm.

Conclusion: Thegeriatricapproachimprovedthesensitivityandspecificityofthepatients’

assessment.HemoglobinconcentrationassociatedtotheriskofpoorKarnofskyandEastern

CooperativeOncologicGroupscalesdependedonthecomorbidityscoreandonthedisease

aggressiveness.TheKarnofskyandEasternCooperativeOncologicGroupscaleshadhigher

sensitivityinpatientswithmoreaggressivediseases.

byElsevierEditoraLtda.Allrightsreserved.

∗

Correspondingauthorat:RuaDiogodeFaria,824,04037-000SãoPaulo,SP,Brazil.

E-mailaddress:acarbone@uol.com.br(A.L.I.Carbonell).

http://dx.doi.org/10.1016/j.bjhh.2015.02.003

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Introduction

Myeloidneoplasms(MN)are agroupofheterogeneous

dis-eases that include myeloproliferative neoplasms (MPN),

myelodysplastic syndromes (MDS) and acute myeloid

leukemia (AML). All these diagnosis are more incident

andprevalentinelderlyindividuals.

This group of diseases includes from indolent entities

suchaspolycythemiaveraandessential thrombocythemia,

toaggressive diseases,suchas AMLand MDS with excess

ofblasts.Chronicmyeloidleukemiaand myelofibrosishave

somerisktoevolveaggressively.1

ThemanagementofolderindividualswithMNtakesinto

account characteristics related to the patient and to the

disease.2–6_The_{chronological}_age,_the_performance_status_(PS)

andthecomorbidityscorearepatient-relatedvariablesthat

areconsideredduringtreatmentdecisionmakingofelderly

individuals.7–9

The PS assessment is carried out using the Karnofsky

PerformanceScale10_(KPS)_or_by_the_Eastern_Cooperative

Onco-logicGroup11_(ECOG)_scale._However,_over_the_last_thirty_years,

severalstudieshavedemonstratedthelowsensitivityofthese

instruments to evaluatefunction inolder individuals with

cancer.12–14_Thus,_it_has_been_recommended_to_aggregate

geri-atrictoolstothePSassessment.

The major clinical challenge in the management of all

myeloidneoplasmsisthetreatmentofAMLinolderpatients.

Depending on the clinical and functional reserve of the

patient,thetherapeuticapproachmaybeexcessivelytoxic.2

Thus,itisveryhelpfultodistinguishtheimpactoftheaging

processseparatedfromtheimpactofthedisease.15

Theobjectivesofthisstudyweretoassessthe

functional-ityofelderlypatientswithMNaggregatingthebasicactivity16

(ADL)andinstrumentalactivity17_(IADL)_of_daily_living_scales

totheKPSandECOGandtoevaluatetheimpactofgender,

age,hemoglobin(Hb)concentrationandcomorbidityscoreon

thefunctionalityofthesepatients.Athirdobjective wasto

designamodeltoshowhow functionalassessment

instru-mentsworkinrespecttotheaggressivenessofthedisease.

Methods

Elderlypatients(≥60yearsold)withMNfollowedatthe

Hema-tologicOutpatientClinicoftheUniversidadeFederaldeSão

Paulo,(UNIFESP)wereincludedinthisstudy.

Diagnoseswere basedontheWorld HealthOrganization

(WHO)Classification oftumors ofhematopoietic and

lym-phoid tissues18 _using _the _analysis _of_peripheral _blood _and

bonemarrowsmears,thehistologyofbonemarrowbiopsy,

andimmunophenotypic,cytogeneticandmolecularstudies.

The patient’s functional evaluation was performed by

a hematologist just before the clinical consultation and

included PS assessedemploying the KPS and ECOG scales

andfunctionalstatuswiththeADLandIADLscales.

Comor-biditieswere evaluatedaccording tothehematopoieticcell

transplantation-comorbidityindex(HCT-CI)developedby

Sor-rorin2005.19

The Hb concentration was measured by an automated

technique employing a multichannel hematology analyzer

(CELL-DYN Ruby, Abbott Diagnostic Division)using a blood

sampletakenbeforetheconsultation.

Patientswithtransfusionpositivestatusreceivedredblood

cells priortothedeterminationoftheHb concentrationin

the monthpreceding thefunctional assessment. The

deci-siontotransfusewasbasedonthedropinHbanditsrelated

symptoms.Demographicandclinicaldatawereobtainedfrom

medicalrecords.

ThestudywasapprovedbyResearchEthicsCommitteeof

UNIFESP(#0262/10) andtheprocedures undertakenwerein

accordancewiththeDeclarationofHelsinkiof1975,revised

in2008.20_All_patients_signed_informed_consent_forms.

Statisticalanalysis

Analyses ofmeans ofage and Hb concentrationwere

per-formed using Student’st test or ANOVA with Tukey’s test.

Thefrequenciesofcategoricalvariableswereevaluatedwith

Fisher’sexacttest.

Twomixedlogisticregressionmodelswerefittedtoassess

theimpactofgender,age,HCT-CIandHbconcentrationonPS,

dichotomizedasgood(KPS≥80%andECOG<2)orpoor,and

onfunctionalstatus,asindependentordependent(needhelp

inatleastonedailytask).

Generally,mixedmodelsconsidertheinformation

hierar-chicallystructuredattheunitandclusterlevels.Thesecluster

levelsresultfromagroupingprocessoutlinedby

character-istics shared bythe units. Moreover,in mixed models the

assumptionofindependenceisviolated,because thereisa

correlationbetweentheunitsthatbelongtothesamecluster.

Randomeffectsareincludedonconsideringthisfact.

Mixed models incorporate these random effects and

estimatethemforeachgroup.Therefore,thegroupsare

repre-sentedbyrandomeffectsandthevariabilityacrossthegroups

isdescribedbytheinterceptortheslopevariability.Themixed

modelbelongstogeneralizedlinearmixedmodels(MLGM),

whichisanextensionofgeneralizedlinearmodels(GLM).21,22

StatisticalanalysiswasperformedusingRstatistics(v2.15)

andtheStatisticalPackagefortheSocialSciences(SPSS–v18).

Results

Eighty-twopatients,40menand42women,withameanage

of72.8yearsold(range:60–92years),wereevaluated.Table1

showsthedescriptivestatisticsofthedemographicdata,

func-tionalityscoresandcomorbidityindices.

Ofthe fifteen patients withpolycythemiavera (PV) and

six with essential thrombocythemia (ET), 73% and 50%

wereJAKV617Fpositive,respectively.Ninetypercentofthese

patientsweretakinghydroxycarbamidetocontrolthedisease.

Alltheninepatientswhohadchronicmyeloidleukemia

(CML)wereinthechronicphase;sevenweretakingimatinib

mesylateandfourwereinmolecularremission.

Nine out of25 patientswith myelofibrosis (MF)were in

the sclerotic phase, two inblastic transformation and the

remaining14wereinthecellularphase.Elevenpatientswere

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Table1–Age,gender,functionalityscoresandcomorbidityindicesstratifiedbymyeloidneoplasm.

MN(n) Age(years)a _Gender_(n₌_male) _KPSb _ECOGb _ADLb _IADLb _HCT-CI_(n)

Index0 Index1–2 Index≥3

PV(15) 70.8(60–83;7.5) 10 100 (70–100)

0 (0–1)

6 (5–6)

27 (11–27)

6 5 4

ET(6) 72.3(63–83;8.2) 1 85 (60–100)

0.5 (0–2)

5.5 (5–6)

26.5 (18–27)

1 3 2

CML(9) 74.9(63–88;7.6) 3 90 (60–100)

0 (0–1)

6 (6–6)

26 (14–27)

6 3 0

MF(25) 72.7(61–92;8.5) 14 90 (40–100)

1 (0–2)

6 (4–6)

27 (11–27)

15 2 8

MDS(17) 74.4(64–90;8.2) 6 90 (40–100)

1 (0–3)

6 (3–6)

25 (12–27)

5 7 5

AML(10) 71.9(61–84;7.5) 6 70 (30–100)

2 (0–3)

5.5 (1–6)

16.5 (9–27)

5 4 1

TOTAL(82) 72.8(60–92;7.9) 40 90 (30–100)

0 (0–3)

6 (1–6)

26 (9–27)

38 24 20

MN:myeloidneoplasm; PV:polycythemiavera;ET:essentialthrombocythemia;CML:chronicmyeloidleukemia;MF:myelofibrosis;MDS: myelodysplasticsyndromes;AML:acutemyeloidleukemia;KPS:Karnofskyperformancescale;ECOG:EasternCooperativeOncologyGroup scale;ADL:basicactivitiesofdailylivingscale;IADL:instrumentalactivitiesofdailylivingscale;HCT-CI:hematopoieticcell transplantation-comorbidityindex.

a _Mean_(min-max;_standard_deviation).

b _Median.

Twooutof17patientswithMDShadrefractoryanemiawith

excessblasts(RAEB),onehadrefractoryanemia(RA),fourhad

refractoryanemia withringedsideroblasts (RARS),twohad

isolateddel(5q)andsixhadrefractorycytopeniawith

multi-lineagedysplasia(RCMD).TwoMDSpatientsweretreatedwith

hypomethylatingmorethansixmonthspriortothefunctional

evaluation. In addition, two patients were on the

thalido-mideprotocol23 _and _two_had_received_this _drug_more_than

sixmonthspriortothefunctionalassessment.Twopatients

withchronicmyelomonocyticleukemiawereincludedinthe

MDSgroup.

SixoutoftenpatientswithAMLhadreceived

chemother-apy,onaverage, 86daysbeforethe evaluationand were in

hematological remission at the moment of the functional

assessment.ThereweresevenAMLnototherwisespecified,

twowithmyelodysplasia-relatedchangesandonewith

recur-rentgeneticabnormalities[t(8;21)].

TheHbconcentration, the incidenceofanemiaand the

transfusionstatusweredifferentacrosstheMNtypes(Table2).

Inviewofthisevidence,patientsweredividedinto:GroupI(PV,

ETandCML),II(MF)andIII(MDSandAML).

TheHb concentration washigher inpatientswith good

PS(KPS/ECOG)thaninpatientswithpoorPS(p-value<0.01).

Likewise, the Hb concentrationwas higher inindependent

patients(ADL/IADL)thaninthosewithdependenceindaily

tasks(p-value<0.01).Patientswithsomedependenceindaily

activities were older than those with no dependence in

ADL/IADL(p-value<0.01).Therewasnosignificantdifference

inagebetweenpatientswithgoodandpoorPS.Womenhad

higherADL/IADLdependencescoresthanmen(p-value<0.01).

Eightypercent(n=65)ofthepatientshadgoodPS,however

50%ofthesepatients(n=33)hadsomedependenceindaily

activities.SeventeenpatientshadpoorPSandallofthemwere

dependentforsomedailyactivities(Table3).

TherewerepatientswithgoodPSandindependent;others

withgoodPSanddependentand,finally,therewerepatients

withpoorPS,allofwhohadsomedependencefordailytasks

(Table4).

Table 4 shows that whencompared to Groups Iand II,

Group III(MDSand AML) had ahighernumber ofpatients

withpoorPSandlowernumberofpatientswithgoodPSbut

dependent.

Table2–GroupingofpatientsbasedonmeanHbconcentrationandtransfusiondemand.

GroupI GroupII GroupIII p-value

PV(n=15) ET(n=6) CML(n=9) MF(n=25) MDS(n=17) AML(n=10)

Hb(g/dL) 14.8a

(12.1–16.8; 1.51)

13.55a (11.8–15.1; 1.31)

12.13 (11.0–13.2; 0.78)

11.33a (3.5–15.1; 2.90)

9.99a (6.3–12.9; 1.54)

9.66a (5.9–13.0; 2.36)

<0.01a

Tx Yes 0 0 0 7 7 8 <0.001

b

No 15 6 9 18 10 2

PV:polycythemiavera;ET:essentialthrombocythemia;CML:chronicmyeloidleukemia;MF:myelofibrosis;MDS:myelodysplasticsyndromes; AML:acutemyeloidleukemia;Hb:hemoglobinconcentration;TX:redcelltransfusionduring30daysbeforefunctionalassessment.

a _Identify_significant_differences_(ANOVA_with_Tukey’s_test).

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Table3–Distributionofpatientsbyperformanceand functionalstatus.

Functionalstatus Performancestatus Total

Good Poor

Independent 32(50%) 0 32

Dependent 33(50%) 17(100%) 50

Total 65 17 82

Goodperformancestatus:KPS≥80%andECOG<2;Independent:no

dependenceforADLandIADL.

Table4–Distributionofpatientsbygroupsand functionality.

Groups(n) Goodperformance

status

Poorperformance status

Independent Dependent Dependent

I–PV+ET+ CML(30)

13 14 3

II–MF(25) 13 11 1

III–MDS+ AML(27)

6 8 13

TOTAL(82) a_p₌_0.001

GoodperformanceStatus:KPS≥80%andECOG<2;Independent: nodependenceinADLandIADL.

PV: polycythemia vera; ET: essential thrombocythemia; CML: chronicmyeloidleukemia;MF:myelofibrosis;MDS:myelodysplastic syndrome;AML:acutemyeloidleukemia.

a _Fisher’s_exact_test.

Amixedlogisticregressionmodelwasappliedtoexplain

PS(byKPSandECOGscales)whichwasinfluencedbyHb

con-centration(p-value=0.019)andHCT-CI(p-value=0.07).Gender

(p-value=0.22)andage(p-value=0.77)didnotimpactonthe

PS.Thus,thefinallogisticmodelincludedonlytheHb

con-centrationandHCT-CI.Thevarianceoftherandomeffectof

groupingwas1.18.Therandomeffects(intercepts)inGroups

I,II,andIIIwere0.27,−1.15and1.06,respectively.

ThehypotheticalHb concentrationsatwhichtherewere

increasedrisksofhavingpoorPSarereportedinTable5.These

Hbconcentrationsdependedonthegroup(I,IIorIII)andonthe

HCT-CI(0,1,2or≥3).Thismodelhadanareaunderthereceiver

operatingcharacteristic(ROC)curveof0.85,withsensitivityof

76%andspecificityof75%.

Amixedlogisticregressionalsodemonstratedtheimpact

ofage(p-value=0.006),gender(p-value=0.002),comorbidities

(p-value=0.014)andHbconcentration(p-value=0.058)onthe

functionalstatus(byADLandIADL).Thevarianceofrandom

effectofgroupingwas0.09.Therandomeffects(intercepts)in

GroupsI,II,andIIIwere0.07,−0.23and0.16,respectively.

Consideringsimilar conditionsofcomorbidities, Hb and

age,femalepatientsweremorelikelytobedependentinsome

dailyactivitythanthemaleindividuals.Olderageandhigher

HCT-CIandlowerHbconcentrationincreasedthelikelihood

offunctionaldependence.Thismodelindicatedavalueof0.84

fortheareaundertheROCcurve,withsensitivityof74%and

specificityof72%,indicatinggoodpredictivepower.

Discussion

This study showed that the sensitivity of the functional

assessmentoftheseelderlypatientswithMNwasincreased

byaddingADLandIADLtotheKPS/ECOG.Thiswasproven

bythefactthat50%ofthepatientswithgoodPShadsome

dependenceindailyactivities(Table3).

Ontheotherhand,theheterogeneityofMNshowedthat

KPSandECOGhaddifferentsensitivityandspecificity

depend-ingontheclinicalcontexttheywereappliedin.Inthisstudy,

these instruments had higher sensitivityand specificity in

patients withAMLandMDS. AsillustratedbyTable4, this

grouphadalownumberofindividualswithgoodPSbutwith

dependenceinADL/IADL,andahighnumberofpatientswith

poorPSwithsomedependenceinADL/IADL.

Here,thecharacteristics relatedtoeachMNwere

repre-sentedbytheHb,transfusiondemandsandthediagnosisof

anemia.Alloftheotherdisease-relatedvariableswere

char-acterizedbythelogisticregressionmodelasrandomeffects.

Themodelfittedinthisstudyincorporatedthedifferences

betweentheMNasrandomeffects.Thesecharacteristicswere

relatedtothepathogenesisandtothetreatmentofeach

dis-ease. Thus, the analysis ofthe data ofGroups I, II and III

was significantto themixed logisticregression modelthat

detectedtheimpactofthesedifficult-to-controlvariables.

InthisgroupofpatientstheHbconcentrationandthe

HCT-CI,butnottheageorgender,impactedonthePSofelderly

patientswithMNasassessedbyKPSandECOG.Themixed

logisticregressionfittedamodelthathypothesizedanHb

con-centration that wascritical to poorPS (Table 5). Themost

importantclinicalvalueisthatthiscriticalHbconcentration

dependedontheaggressivenessoftheMNandontheHCT-CI.

ThisHbconcentrationshouldnotbeextrapolatedbut,as

farasweknow,thisisthefirstsurveythatfittedamodelwhich

Table5–Thehypotheticalhemoglobinconcentrationforpoorperformancestatusandhematopoieticcell transplantation-comorbidityindexofpatientswithmyeloidneoplasms.

Groups HCT-CI

0 1 2 ≥3

I–PV/ET/CML 9.53 10.52 11.51 12.50 Criticalhemoglobin

(g/dL)concentration forpoorperformance status

II–MF 5.61 6.61 7.60 8.59

III–MDS/AML 11.71 12.70 13.69 14.68

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couldcomprisefunctionalassessmentandcomorbidityscore,

linkedbyHbconcentration.Thus,itispossibletoconclude

thatanemiaandHCT-CIimpactonthefunctionalityofelderly

withMN,mainlythosewithAMLandMDS.

AsillustratedbyTable5,GroupIIIhasthehighestcriticalHb

forpoorperformance.Thisfactiscongruenttotheevidenceof

higherKPS/ECOGsensitivityinpatientswithAML/MDSthan

inotherMN.Thus,KPSandECOGaremoreeasilyaffectedby

dropsinHbinGroupIIIcomparedtoGroupsIandII.

Thisevidencemaybejustified,inpart,bythe factthat,

usually,anemia in patients ofGroups I and II occurs over

alonger periodoftime than inthose of GroupIII. Hence,

adaptivemechanismscanbetriggeredovertimetobetter

pre-servethe functional autonomyofpatientsinGroups Iand

II.

Another important aspect to be considered is that

HCT-CI is a score specifically validated in patients with

AML/MDS.Asfarasweknow,therearefewstudiesassessing

patientswithchronicmyeloproliferativedisordersusingthis

instrument.24,25

All theseaspects show the necessityfor aprocess that

validatesthehypotheticalHbvaluesthatarecriticaltopoor

performance(Table5).Thisprocesscanbedesignedby

com-paring the results of this model applied to patients with

chronic myeloproliferative disorders using HCT-CI and the

Charlsonscale,26_for_example.

Atthistime, theHb valuesshown inTable5should be

assumedlessasthe targets tobereachedinpatients with

MN and more as an alert that drops in Hb affect

func-tionality mainly of patients with AML/MDS and with high

HCT-CI.

FunctionalstatusassessedemployingADLandIADLwas

influencedbygender,age,Hbandcomorbidities.Therewas

anincreasing dependence in dailyactivities with drops in

Hbconcentration,increasesinHCT-CI,advancingageandfor

femalepatients.Thisevidencemay helphealthcare

profes-sionalsprovidesocialsupportbetteradjustedtothepatient’s

needs.

Asacross-sectionalsurvey,thisstudy wasnotdesigned

toanalyzeothermedicalprocedures.Itshouldbenotedthat

prognosticscoresforMFandMDStakeintoaccountHb

con-centrationand transfusion requirements. Thus, the model

fittedheresurelycanbebettercalibratedinalongitudinaltype

study.

Asanobservationalstudy,itwasveryhardtocontroleach

variableinparticularthosethatcomprisethelogistic

regres-sionmodel withmultivariate analysis. This study was not

designedtounderstandtheprognosticvalueofvariablesthat

wereincluded.Previousstudiespointedoutthatfunctionality

hasbeencorrelatednotonlytosurvivalbuttothequalityof

life,mainlyinelderlypatientswithMN.27

Thispaperisthepreliminaryresultofaresearchaimedat

improvingtheassessmentofelderlypatientswithMN.

Conclusions

The aggregation of ADL and IADL to the KPS and ECOG

scales improvedthe sensitivityand specificityofthe

func-tionalassessmentofelderlywithMN,mainlythosewithAML

and MDS.Age,gender,Hb andcomorbiditiesaffected

func-tionalstatus.However,onlycomorbiditiesandHbimpacted

on PS. The model fitted with KPS/ECOG identified

criti-cal Hb concentrations for poor PS which depends on the

aggressivenessoftheMNandonthe HCT-CI.Thusanemia

and HCT-CI impacted on thefunctionality ofthis groupof

patients, mainly those with AML and MDS. Patients with

AML and MDS were more sensitive in respectto KPS and

ECOG comparedtoother patients withless aggressive

dis-eases.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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1.ChauffailleML.Neoplasiasmieloproliferativas:revisãodos critériosdiagnósticosedosaspectosclínicos.RevBras HematolHemoter.2010;32(4):308–16.

2.PeyradeF,GastaudL,ReD,Pacquelet-CheliS,ThyssA. Treatmentdecisionsforelderlypatientswithhaematological malignancies:adilemma.LancetOncol.2012;13(8):

e344–52.

3.MalfusonJV,EtienneA,TurlureP,deRevelT,ThomasX, ContentinN,etal.Riskfactorsanddecisioncriteriafor intensivechemotherapyinolderpatientswithacutemyeloid leukemia.Haematologica.2008;93(12):1806–13.

4.KantarjianH,RavandiF,O’BrienS,CortesJ,FaderlS, Garcia-ManeroG,etal.Intensivechemotherapydoesnot benefitmostolderpatients(age70yearsorolder)withacute myeloidleukemia.Blood.2010;116(22):4422–9.

5.FerraraF.Treatmentofunfitpatientswithacutemyeloid leukemia:astillopenclinicalchallenge.ClinLymphoma MyelomaLeuk.2011;11(1):10–6.

6.EsteyEH.Treatmentofacutemyeloidleukemiaintheelderly. Haematologica.2011;96(6):795–8.

7.LowenbergB,DowningJR,BurnettA.Acutemyeloid leukemia.NEnglJMed.1999;341(14):1051–62.

8.DeschlerB,deWitteT,MertelsmannR,LubbertM.Treatment decision-makingforolderpatientswithhigh-risk

myelodysplasticsyndromeoracutemyeloidleukemia: problemsandapproaches.Haematologica.

2006;91(11):1513–22.

9.SandesAF,RibeiroJC,BarrosoRS,SilvaMR,ChauffailleML. Improvingtheoutcomesofelderlypatientswithacute myeloidleukemiainaBrazilianUniversityHospital.Clinics (SaoPaulo).2011;66(8):1335–40.

10.KarnofskyDAAWH,CraverLF,BurchenalJH.Theuseofthe nitrogenmustardsinthepalliativetreatmentofcarcinoma– withparticularreferencetoBronchogeniccarcinoma.Cancer. 1948;1(4):634–56.

11.ZubrodCG,SchneidermanM,FreiIiiE,BrindleyC,Lennard GoldG,ShniderB,etal.Appraisalofmethodsforthestudyof chemotherapyofcancerinman:comparativetherapeutic trialofnitrogenmustardandtriethylenethiophosphoramide. JChronicDis.1960;11(1):7–33.

(6)

13.BalducciL.Thegeriatriccancerpatient:equalbenefitfrom equaltreatment.CancerControl.2001;8(Suppl2):1–25,quiz 7–8.

14.ExtermannM,HurriaA.Comprehensivegeriatricassessment forolderpatientswithcancer.JClinOncol.

2007;25(14):1824–31.

15.DeschlerB,IhorstG,PlatzbeckerU,GermingU,MarzE,de FigueridoM,etal.Parametersdetectedbygeriatricand qualityoflifeassessmentin195olderpatientswith myelodysplasticsyndromesandacutemyeloidleukemiaare highlypredictiveforoutcome.Haematologica.

2013;98(February(2)):208–16.

16.KatzS,FordAB,MoskowitzRW,JacksonBA,JaffeMW.Studies ofillnessintheaged.TheindexofAdl:astandardized measureofbiologicalandpsychosocialfunction.JAmMed Assoc.1963;185(12):914–9.

17.LawtonMP,BrodyEM.Assessmentofolderpeople: self-maintainingandinstrumentalactivitiesofdailyliving. Gerontologist.1969;9(3):179–86.

18.SwerdlowSH.WHOclassificationoftumoursof haematopoieticandlymphoidtissues.WorldHealth Organization;2008.

19.SorrorML,MarisMB,StorbR,BaronF,SandmaierBM, MaloneyDG,etal.Hematopoieticcelltransplantation (HCT)-specificcomorbidityindex:anewtoolforrisk assessmentbeforeallogeneicHCT.Blood.2005;106(8):2912–9.

20.WilliamsJR.TheDeclarationofHelsinkiandpublichealth. BullWorldHealthOrgan.2008;86(8):650–2.

21.BauyoeL,LingsmaHF,SteyerbergEW,LesaffreE.Logistic

randomeffectsregressionmodels:acomparisonofstatistical

packagesforbinaryandordinaloutcomes.BMCMedRes

Methodol.2011;11:77.PubmedCentralPMCID:http://www.

biomedcentral.com/1471-2288/11/77

22.FreesEW,KimJS.Multilevelmodelprediction.Psychometrika. 2006;71(1):79–104.

23.RazaA,MeyerP,DuttD,ZoratF,LisakL,NascimbenF,etal. Thalidomideproducestransfusionindependencein long-standingrefractoryanemiasofpatientswith myelodysplasticsyndromes.Blood.2001;98(4):958–65.

24.PavluJ,KewAK,Taylor-RobertsB,AunerHW,MarinD, OlavarriaE,etal.Optimizingpatientselectionfor

myeloablativeallogeneichematopoieticcelltransplantation inchronicmyeloidleukemiainchronicphase.Blood. 2010;115(20):4018–20.

25.LekovicD,GoticM,Perunicic-JovanovicM,VidovicA, BogdanovicA,JankovicG,etal.Contributionofcomorbidities andgradeofbonemarrowfibrosistotheprognosisofsurvival inpatientswithprimarymyelofibrosis.MedOncol.

2014;31(3):869.

26.CharlsonME,PompeiP,AlesKL,MacKenzieCR.Anewmethod ofclassifyingprognosticcomorbidityinlongitudinalstudies: developmentandvalidation.JChronicDis.1987;40(5):373–83.