w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Special
article
Guidelines
on
the
treatment
of
acute
myeloid
leukemia:
Associac¸ão
Brasileira
de
Hematologia,
Hemoterapia
e
Terapia
Celular
Project
guidelines:
Associac¸ão
Médica
Brasileira
–
2015
Rosane
Bittencourt
a,
Teresa
Cristina
Bortolheiro
b,
Maria
de
Lourdes
Lopes
Ferrari
Chauffaille
c,
Evandro
Maranhão
Fagundes
d,
Katia
Borgia
Barbosa
Pagnano
e,
Eduardo
Magalhães
Rego
f,∗,
Wanderley
Marques
Bernardo
gaUniversidadeFederaldoRioGrandedoSul(UFGRS),PortoAlegre,RS,Brazil
bIrmandadedaSantaCasadeMisericórdiadeSãoPaulo,SãoPaulo,SP,Brazil
cUniversidadeFederaldeSãoPaulo(UNIFESP),SãoPaulo,SP,Brazil
dUniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil
eUniversidadeEstadualdeCampinas(Unicamp),Campinas,SP,Brazil
fUniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil
gUniversidadedeSãoPaulo(USP),SãoPaulo,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received12January2016 Accepted12January2016 Availableonline5February2016
Introduction
Theguidelines projectisa jointinitiative ofthe Associac¸ão MédicaBrasileira andtheConselhoFederaldeMedicina.Itaims to bring together information in medicine to standardize conductinordertohelpdecision-makingduringtreatment. The data contained in this article were prepared by and
∗ Correspondingauthorat:DepartamentodeClínicaMédica,FaculdadedeMedicinadeRibeirãoPreto,UniversidadedeSãoPaulo(USP),
14048-900RibeirãoPreto,SP,Brazil.
E-mailaddress:[email protected](E.M.Rego).
arerecommendedbytheAssociac¸ãoBrasileiradeHematologia,
HemoterapiaeTerapiaCelular(ABHH).Evenso,allpossible con-ducts shouldbeevaluated bythe physicianresponsiblefor treatmentdependingonthepatient’ssettingandclinical sta-tus.
Thisarticlepresents theguidelines forthetreatmentof acutemyeloidleukemia(AML).TheexpertgroupoftheABHH mainly focusedon issuesrelatedtochemotherapyand the
http://dx.doi.org/10.1016/j.bjhh.2016.01.001
selectionofpatient subgroups forwhich thereare specific recommendationsfortreatment.Theindications,butnotthe actualtreatmentprotocolsforbonemarrowtransplantation, wereanalyzed.
Description
of
the
method
used
to
gather
evidence
These Guidelines were drafted by elaborating 12 clinically relevant questions related to the treatment of AML. The questionswere structuredusingthe Patient/Problem, Inter-vention,Comparisonand Outcome (PICO)system,allowing thegenerationofevidencesearchstrategiesinthekey sci-entificdatabases(MEDLINEPubMed,Lilacs,SciELO,Embase, Cochrane Library, Premedline via OVID). The data recov-eredwascriticallyanalyzedusingdiscriminatoryinstruments (scores)accordingtothe typeofevidence–JADADfor ran-domizedclinical trials and the Newcastle Ottawa scale for non-randomizedstudies.Afteridentifyingstudiesthat poten-tially substantiate recommendations, the level ofevidence and degree of recommendation were calculated using the OxfordClassification.1
Summary
of
the
degree
of
recommendation
and
level
of
evidence
A:Majorexperimentalandobservationalstudies
B:Minorexperimentalandobservationalstudies
C: Casereports(non-controlledstudies)
D:Opinionwithoutcriticalevaluationbasedonconsensus, physiologicalstudiesoranimalmodels
Aims
Theaimoftheseguidelinesistocontributetodecisionmaking inthetreatmentofAML.
Which
anthracycline
agent
is
the
most
effective
in
inducing
remission
of
acute
myeloid
leukemia?
P–PatientsundergoinginductiontreatmentforAML I–Anthracyclineagent(daunorubicin,doxorubicin, idaru-bicin)
C–
O–Completeremissionrate,overallsurvival,and disease-freesurvival
Two different induction treatments were compared in under18-year-oldpatients(meanage:7.9years)withdenovo
AML:cytarabine,idarubicinandetoposide(AIE)and cytara-bine, daunorubicin and etoposide (EDA). The AIE regimen wascytarabine(100mg/m2/day)asacontinuousinfusionon
Days1and2and30-mininfusionsonDays3–8,idarubicin (12mg/m2/day)as30-mininfusionsonDays3–5and
etopo-side(150mg/m2/day)as120-mininfusionsonDays6–8.The
EDAregimenwascytarabine(100mg/m2/day)ascontinuous
infusionsonDays1and2,and30-mininfusionsonDays3–8), daunorubicin(30mg/m2)as30-min infusionsevery12hon
Days3–5)andetoposide(150mg/m2/day)as120-mininfusions
onDays6–8.Aftertheexclusionofpatientswith myelosar-coma,secondaryAML,myelodysplasticsyndrome(MDS)and Downsyndrome,andwith22%ofpatientshavingfavorable karyotypes,asignificantlyhigherpercentageofpatientshad blastcounts≤5%bythe15thdayafterinductionwiththeAIE regimencomparedtotheADEregimen(83%vs.69%, respec-tively;p-value=0.01)(A).2
Therewasnosignificantdifferencesbetweenthegroups inrespectto complete remission(CR) (87%forAIE andfor ADE),deaths(5%forAIEand3%forADE;p-value=0.41), car-diacorhematologictoxicityorforthepresenceofgrade3and 4mucositisafterinductiontherapy(A).2
Onanalyzingunder65-year-oldadultpatientswithdenovo
AMLstratifiedintotwoinductiontreatmentgroups:idarubicin (12mg/m2/day)forthreedaysordaunorubicin(50mg/m2/day)
forfivedaysbothassociatedwithcytarabine(100mg/m2/day)
by 24-h continuous infusions for seven days, the CR was similarafterthefirstcycle(64.1%vs.61.1%,respectively;p -value=0.39). Thesame regimenwas repeated at3–4-week intervalswhenpatientsdidnotachieveCRafterthefirstcycle withtheoverallCRrateincreasingto77.9%(78.2%for idaru-bicinvs.77.5%fordaunorubicin;p-value=0.79).Althoughfew patientswerecharacterizedasM6bythe French-American-Britishclassification(FAB)system(3.12%),thisgroupresponds bettertotheidarubicinregimenafterthefirstcycle[oddsratio (OR):78%vs.38%;p-value=0.037].However,thereisno signif-icantdifferencebetweenthetwoanthracyclinesinrespectto theotherFABsubtypesofAML,cytogeneticriskgroups,age, theinitialwhitebloodcellcount,thepercentageofpositive myeloperoxidaseblastsorperformancestatus(A).3
Induction treatment with daunorubicin (50mg/m2/day),
mitoxantrone(12mg/m2/day)oridarubicin(10mg/m2/day)on
Days1,3and5associatedwithcytarabine(100mg/m2/day)as
aten-daycontinuousinfusionandetoposide(100mg/m2/day)
asa1-hinfusionforfivedaysresultsinaCRof63.6%in 15-to60-year-oldpatientswithprimaryorsecondaryAML.There isnoevidence ofserious cardiac,pulmonary, neurologicor metaboliccomorbiditiesoruncontrolledinfectionsand nor-malhepaticandrenalfunctionwiththisregimen.Incasesof partialresponse,asecondcycleisperformedusingthesame regimenasthefirstcycleandtheCRincreasesto68.5%with nosignificantdifferencesbetweenthetreatmentarms (mitox-antronevs.daunorubicin:p-value=0.63;anddaunorubicinvs. idarubicin:p-value=0.49)(A).4
PatientswithdenovoAMLorsecondaryAMLduetoMDS and normal heart functionstratified into threeage groups (15–50years,51–60yearsandover60yearsold)were evalu-atedinrespecttoinductionregimens.Theuseofidarubicin (IDA–12–13mg/m2/dayforthreedays)ordaunorubicin(DNR
– 45mg/m2/day for three days), both in combination with
cytarabine(100mg/m2/daybyseven-daycontinuousinfusion)
(70–74%vs.57–59%;p-value=0.032–0.09).Whenevaluated sep-arately,therewasnosignificantdifferencebetweenthegroups afterthefirstandafterthesecondcycle.Whentheevaluation wasperformedforthethreeagegroups,lowerCRrateswere observedastheageincreased(15–50years:86–91%vs.70–80%; 51–60years:67–71%vs.45–65%;>60years:50–68%vs.44–53% fortheIDAandDNRgroups,respectively).Therewasno signif-icantdifferenceinhematologicandnon-hematologictoxicity forbothgroupsregardlessofage(A).5–8
Oncomparingdaunorubicin(DNR–80mg/m2/dayforthree
days), idarubicin (IDA4– 12mg/m2/day for four days), and
idarubicin(IDA3–12mg/m2/dayforthreedays),allassociated
withcytarabine (200mg/m2/dayas aseven-day continuous
infusion) in50- to70-year-oldpatients, the overall CRwas 66%.CR rates of61%, 67% and 70% were recorded forthe DNR,IDA4andIDA3arms,respectively(p-value=0.25). How-ever,whenpatientsreceivedasecondinductioncycle,allwith mitoxantrone(12mg/m2/day for two days)associated with
cytarabine(1g/m2over1hevery12hforfourdays),the CR
increasedto77%.Thedifferencebetweenthethree compar-isonarmswassignificant(p-value=0.04)withtheCRbeing 70%,78%and83%fortheDNR,IDA4andIDA3arms, respec-tively.TheCRwassignificantlyhigherintheIDA3armwhen comparedtothe high-dose DNR arm(p-value=0.007), with atendencyofbetterratesinthesubgroupwithunfavorable cytogenetics(74%vs.48%;p-value=0.07).Consequently,the CRwashigherinpatientsreceivingidarubicinthaninthose receiving daunorubicin (80% vs. 70%; p-value=0.03). There werenosignificantdifferencesinthemortalityrates,lengthof hospitalization,cytopenias,grade3or4infectionrates, bleed-ingepisodesorthedurationofantibiotictherapybetweenthe threegroupsduringinduction(A).9
Inductiontherapy forde novo AMLin55- to75-year-old patientsusingcytarabine(100mg/m2/day)asaseven-day
con-tinuousinfusionassociatedwithidarubicin(8mg/m2/day)for
fivedaysordaunorubicin(50mg/m2/day)forthreedayswas
compared. Therewere nosignificant differences in the CR (IDA:67.9%vs.DNR:61.1%;p-value=0.29)orhematologicor non-hematologicaltoxicity(A).10
Inover65-year-oldpatientswithdenovoAMLorAML sec-ondarytoMDS(FAB:refractoryanemiawithexcessblastsin transformation –RAEB-T), daunorubicin(45mg/m2/day) for
four days wascompared withidarubicin (9mg/m2/day) for
fourdaysbothassociatedwithcytarabine(200mg/m2/day)by
aseven-daycontinuousinfusion.Aftertheinitialinduction chemotherapycycle,asecondcycleofcytarabine(500mg/m2)
ina1-h infusionevery 12hforthreedays associatedwith mitoxantrone(12mg/m2/day)fortwodayswasadministered
whenCRwasnotachieved.TheoverallCRratewas57%(53.8% afterthefirstinductioncycle);theCRratefortheDNRarm was54%andfortheIDAarmitwas59%(p-value=0.28).The mortalityrateinbothgroupswas10%(A).11
Three induction therapies were compared in over 55-year-old treatment-naive AML patients without serious heart conditions, and normal liver and kidney function: daunorubicin (45mg/m2/day) for three days or idarubicin
(12mg/m2/day)forthreedaysormitoxantrone(12mg/m2/day)
forthree days, associated with cytarabine (100mg/m2/day)
by seven-day continuous infusion. The overall CR rate was 39.7–42%, with no significant difference between the
anthracyclinesused.However,whenonlyunder70-year-old patientsofthatgroupwere evaluated,theCRofthe idaru-bicinarmwasbetterthanthedaunorubicinarm(55%vs.46%, respectively;p-value=0.04)(A).12
Recommendations:Oncomparingtheefficacyof
induc-tion therapy using the anthracyclines, idarubicin and
daunorubicininAMLpatientsofdifferentages,although
thereductionintheblastcountwasfasterwiththefirst
cycleofidarubicin,therewerenosignificantdifferences
intheCRortoxicityofthetwodrugs.
What
dose
(100
mg/m
2/day
and
200
mg/m
2/day)
of
cytarabine
(Ara-C
or
Arabinoside-C)
is
the
most
effective
in
the
induction
therapy
of
acute
myeloid
leukemia
patients?
P–PatientsundergoinginductiontreatmentforAML
I–Cytarabine(Ara-CorArabinoside-C)–100mg/m2/day
C–Cytarabine(Ara-CorArabinoside-C)–200mg/m2/day
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Oncomparing inductiontherapyforAMLpatientsusing
cytarabine(100mg/m2/day)orcytarabine(200mg/m2/day)as
a seven-day continuous infusionassociated with
daunoru-bicin (45mg/m2/day) in under 60-year-old patients or
(30mg/m2/day)inover60-year-oldpatients,theCRwas61%
withnosignificantdifferencebetweendoses(p-value=0.29).
There was also no significant difference in the CR rate
when the over and under60-year-old patients were
evalu-atedseparately(p-value=0.68vs.p-value=0.08,respectively).
However,therewasa7%lower riskofdeathduring
induc-tiontherapyfortheunder60-year-oldpatientsinthegroup
thatreceived100mg/m2/day[neededtoharm(NNH):15;p
-value=0.04]anda6%decreaseinover60-year-olds(NNH:17;
p-value=0.51).Themaincauseofdeathwasinfectionsinboth
the100mg/m2/dayandthe200mg/m2/daygroups(A).13
Two induction regimens were evaluated in 18- to 60-year-oldpatientswithdenovoAML.Thefirstgroupreceived cytarabine(200mg/m2/day)duringthefirstcycleand
cytara-bine (1g/m2) every 12h as a 3-h continuous infusion in
a second cycle, and the second group received cytarabine (1g/m2)every 12h inthefirstcycle and cytarabine(2g/m2)
every12hinthesecondcycle.Therewasnosignificant differ-enceinCR(34%vs.35%,respectively)andoverallsurvival(OS) betweenthetwogroups(40%vs.42%,respectively).Thehigher doseofcytarabineresultedinahigherincidenceofgrade3and 4toxicity,longerhospitalstayandlongerdelaysinneutrophil andplateletengraftment(A).14
TwodifferentinductionregimenswerecomparedinAML patients aged 16–60 years old. The first, TAD cycle was cytarabine(100mg/m2/day)ascontinuousinfusionsonDays
1 and 2 and then cytarabine (200mg/m2/day) as 30-min
thioguanine (100mg/m2/day) orally on Days 3 and 9. This
was followed by another cycle using the same doses. The second regimen was one TAD cycle, followed by a second HAMcyclewithcytarabine(3g/m2)in3-hinfusionsevery12h
onDays1–3associatedwithmitoxantrone(10mg/m2/day)in
30-mininfusionsonDays3–5.Therewasnosignificant dif-ferencebetweenthetwogroupsinrespecttotheCR(67%vs. 71%,respectively;p-value=0.072).Thetimestoneutrophiland plateletengraftmentwerelowerforthegroupthatreceived theTAD-TADregimenthanthosethatreceivedtheTAD-HAM regimen(16days vs.20 days, respectively; p-value=0.0001) (A).15
A continuous seven-day infusion of cytara-bine (100mg/m2/day) associated with daunorubicin
(50mg/m2/day) Days 1–3 and etoposide (75mg/m2/day)
on Days 1–7 was compared with cytarabine (3g/m2) every
12h on Days 1, 3, 5 and 7, associated with daunorubicin (50mg/m2/day)onDays1–3andetoposide(75mg/m2/day)on
Days1–7.CRwasattainedin74%[95%confidenceinterval(CI): 66–81%]ofthegroupsubmittedtostandarddosecytarabine and71%(95%CI:63–78%)ofthegroupsubmittedtohigh-dose cytarabine (p-value=0.7).Significantlymorepatients inthe high-dose cytarabine group discontinued induction ther-apyduetotoxicity(1% vs.9%, respectively;p-value=0.003) (A).16
Theuseofcytarabine(10mg/m2)subcutaneouslyevery12h
for21dayswascomparedwithcytarabine (200mg/m2/day)
asaseven-daycontinuousinfusionassociatedwith rubida-zone(100mg/m2/day–derived fromdaunorubicin)forfour
daysasinductiontherapyinover65-year-oldpatientswith
denovoAML.TheoutcomeswereCR,partialremission, treat-mentfailure,anddeathin32%,22%,36%and10%,respectively ofpatientsreceivingsubcutaneouscytarabine,and52%,2%, 15%and31%,respectivelyofthosereceivingintensive ther-apy.Thatis,thenumberofCRpatientsanddeathswerehigher inthegroupthatreceivedhigh-dosecytarabine,whilepartial remissionandtreatmentfailureweremorefrequentinthose submittedtolow-dosecytarabine(p-value<0.001).Grade3and 4toxicity,infectiouscomplicationsandprolongedcytopenias weresignificantlyhigherinthe intensivetherapygroup(p -value<0.01)(A).17
Recommendations: Due to the lower risk of death
using 100mg/m2/day of cytarabine compared to
200mg/m2/day of cytarabine in the induction
ther-apy of AML patients and no significant difference in
theCRbetweenthetwogroups,thelowerdoseismore
appropriate.Thisistrueforallagegroups.
What
dose
of
daunorubicin
(45,
60
or
90
mg/m
2/day)
is
the
most
effective
for
induction
therapy
of
acute
myeloid
leukemia
in
young
patients
(<60
years)?
P–Under60-year-oldpatientsundergoinginduction
treat-mentforAML
I–Daunorubicin(45,60or90mg/m2/day)
C–Daunorubicin(45,60or90mg/m2/day)
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Oversixyears,17-to60-year-oldpatientswithAMLwere
treated withcytarabine (100mg/m2/day)by seven-day
con-tinuous infusion associatedwith daunorubicin atdoses of
45mg/m2/dayor90mg/m2/dayforthreedays.Bonemarrow
biopsieswereperformedbetweenDay12and14after
induc-tiontherapy,andifthepatientcontinuedwithleukemicblasts
inthebonemarrow,asecondcyclewasadministeredwiththe
samedosesofcytarabineanddaunorubicin(45mg/m2/day).
Theoverall CR ratewas 63.9%(95% CI:59.9–67.8),57.3%in
the group that received a dose of 45mg/m2 and 70.6% in
thegroupthatreceivedahighdoseofdaunorubicin(p-value
<0.001).Ofthepatientsinthisstudy,72%ofthe45mg/m2/day
groupand83.3%ofthehigh-dosegroupachievedCRafterthe
firstinductioncycle(p-value=0.01);thusonly11.4%achieved
CR after the second cycle of chemotherapy. There was no
significantdifference intherateofhematologicaland
non-hematologicaltoxicity(grades3–5)orthedeathratesduring
inductionbetweenthetwogroups(A).18
Two doses of daunorubicin, 45mg/m2/day and
90mg/m2/day for three days, associated with cytarabine
(200mg/m2/day) by seven-day continuous infusion were
comparedinapopulationof15-to60-year-oldAMLpatients. PatientswithCMLintheblastphaseandthosewith prom-yelocytic leukemia were excluded and all participants had adequate renal and hepatic function and normal heart function. The CR was superior in the group that received thehighdoseofdaunorubicin(72%vs.82.5%;p-value=0.01) with a significant difference afterthe first induction cycle (56.1% vs. 71.1% for45mg/m2 and high-dose, respectively; p-value=0.04), and therefore a 15% reduction in the need to perform a second cycle of chemotherapy. There was no significant difference regarding the hematological and non-hematological adverse eventsbetween the twogroups (A).19
One study compared daunorubicin (45mg/m2/day) for
threedays,andasecondcyclewhennecessaryatthesame dose,withdaunorubicin(75mg/m2/day)forthreedays,and
asecondcycleof60mg/m2/daywhenthereweremorethan
5% of blasts in the bone marrow. All cycles were associ-atedwithcytarabine(100mg/m2/day)bycontinuousinfusion
andetoposide(100mg/m2/day)in30-mininfusions,bothfor
sevendays.Theparticipantswere13-to67-year-oldpatients (mean33 years)withdenovoAML.Patientswithsecondary AMLor promyelocytic leukemia accordingto the FAB clas-sification were excluded, as were patients with severely impairedheartfunction.TheoverallCRwas65%,58.9%inthe groupthatreceivedtwocyclesof45mg/m2/dayof
daunoru-bicinand77%inthegroupthatreceived75mg/m2/dayand
60mg/m2/dayofdaunorubicin(p-value=0.04).WhentheCR
Recommendations: In adult patients with AML, high
doses of daunorubicin (60–90mg/m2/day) associated
withcytarabine(100or200mg/m2/day)increasetheCR
rateininductiontherapy,bothafterthefirstandsecond
cyclesofchemotherapywithoutincreasingthe
hemato-logicornon-hematologictoxicitywhencomparedtoa
doseof45mg/m2/dayofdaunorubicin.
What
dose
of
daunorubicin
(45,
60
or
90
mg/m
2)
is
the
most
effective
for
induction
therapy
of
acute
myeloid
leukemia
in
elderly
patients
(>60
years)?
P– Over60-year-old patients undergoinginduction
treat-mentforAML
I–Daunorubicin(45,60or90mg/m2)
C–Daunorubicin(45,60or90mg/m2)
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Elderly AML patients (61–75 years old) not including
patientswiththeM3subtypewereevaluatedusingtwo
induc-tion regimens. All patients had normal liver and kidney
function,norecenthistoryofmyocardialinfarctionorother
severecardiovasculardiseaseandhadnodocumentedactive
infection.Cytarabine(100mg/m2/day)wasadministeredasa
seven-daycontinuousinfusionforallpatientsbutonegroup
receiveddaunorubicin(45mg/m2/day)forthreedaysandthe
other,liposomaldaunorubicin(80mg/m2/day)forthreedays
withrepeatedsecondcyclesusingthesamedosesasthefirst
cycleifthepatientdidnotachieveCR.Ofthepatients
receiv-ing the standard dose of daunorubicin, 11.5% achieved CR
afterthesecondcycleofchemotherapycomparedto9.6%of
patientsreceivingthehighdoseliposomaldaunorubicin
reg-imen.There wasno significant difference inrespectto CR
betweenthegroups(p-value=0.94) (A).21 Considering
treat-mentfailure includingcasesofdrugresistanceand deaths during the induction period, there was no significant dif-ferencebetweenthegroups(p-value=0.33)withtheleading causeofdeathbeinginfections(A).21
Two induction regimens were evaluated in 60- to 83-year-old patients (mean: 67 years old) with de novo or secondary AML and a performance status ≤2 according to the World Health Organization (WHO) classification. Daunorubicin(45mg/m2/day)in3-hinfusionsforthreedays
was compared with daunorubicin (90mg/m2/day) in 3-h
infusions for three days, both associated with cytarabine (200mg/m2/day)inaseven-daycontinuousinfusionfollowed
by a second cycle where both groups received cytarabine (1g/m2)every 12h forsixdays.Theoverall CR was54% in
thegroupthatreceivedtheconventionaldoseand64%forthe high-dosegroup(p-value=0.002)(A).22
When each cycle was evaluated, the CR rate after the firstcycleusinghighdosesofdaunorubicinwasbetterthan in the group that received the conventional dose (52% vs. 35%respectively; p-value<0.001),withnosignificant differ-ence after the second cycle. There was alsono significant
differencebetweenthetwogroupsinrespecttohematologic andnon-hematologictoxicity,andmortalityafterinduction therapy(A).22
Recommendations: Thereiscontroversyaboutthe use
ofconventionaldosesandhighdosesofdaunorubicinin
inductiontherapyinrelationtotheCRofelderlyAML
patients.However,increasingthedosedoesnotincrease
thehematologicalandnon-hematologicaltoxicity,orthe
numberoftreatment-relateddeaths.
What
is
the
number
of
induction
cycles
(1
or
2)
that
is
the
most
effective
in
the
induction
of
acute
myeloid
leukemia
patients?
P–PatientsundergoinginductiontreatmentforAML
I–Onecycleofchemotherapy
C–Twocyclesofchemotherapy
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Under65-year-oldadultpatientswithdenovoAMLstratified
intotwoinductiontherapygroups–idarubicin(12mg/m2/day)
for three days or high-dose daunorubicin (50mg/m2/day)
for five days, both regimens associated with cytarabine
(100mg/m2/day)asaseven-daycontinuousinfusion,had
sim-ilar CR afterthe firstcycle (64.1% vs.61.1%;p-value=0.39).
If the patient did not achieve CR after the first cycle, the
sameregimenwasrepeatedata3-to4-weekintervalwhich
increasedtheoverallCRrateto77.9%(78.2%foridarubicinand
77.5%fordaunorubicin;p-value=0.79)(A).6
Regimens using daunorubicin (80mg/m2/day) for three
days(DNR),idarubicin(12mg/m2/day)forfourdays(IDA4),and
idarubicin(12mg/m2/day)forthreedays(IDA3),allassociated
withcytarabine (200mg/m2/day)inaseven-day continuous
infusionwerecomparedin50-to70-year-oldpatients.There wasanoverallCRrateof66%withnosignificantdifference betweenthegroups(61%DNR,67%IDA4, and70%IDA3;p -value=0.25).However,whenpatientsreceivedasecondcycle ofmitoxantrone(12mg/m2/day)fortwodaysassociatedwith
cytarabine (1g/m2/day)in 1-h infusionsevery 12hfor four
days, the CR rate increased to 77% with a significant dif-ference (p-value=0.04)betweenthe threegroups(70%, 78% and 83% for the DNR, IDA4 and IDA3 arms, respectively) (A).7
Three inductionregimens were compared in 15- to 60-year-oldpatientswithprimary orsecondaryAMLandwith no evidence of severe heart, pulmonary, neurological or metabolic disease or uncontrolled infection, and with nor-malhepaticandrenalfunction.TheCRratewas63.6%after aninductioncycleofdaunorubicin(50mg/m2/day)or
mitox-antrone(12mg/m2/day)oridarubicin(10mg/m2/day)onDays
1, 3and 5associatedwithcytarabine (100mg/m2/day) ina
ten-daycontinuousinfusionandetoposide(100mg/m2/day)
firstcycle,andtheCRrateincreasedto68.5%,withno signif-icantdifferencebetweenthetreatmentarms(mitoxantrone vs.daunorubicin:p-value=0.63;idarubicinvs.daunorubicin:
p-value=0.49)(A).23
A large number of over 18-year-old, treatment-naive patientswithdenovoorsecondaryAMLwasassessedafter being grouped in several therapeutic induction schemes: cytarabine (100–200mg/m2/day) as a continuous infusion
associatedwithdaunorubicin(45–60mg/m2/day), idarubicin
(12mg/m2/day)ormitoxantrone(12mg/m2/day).Theoverall
CRratewas64%;74%ofthetotalenteredintoremissionafter thefirstinductioncycleand26%oftheremainingafterthe secondcycle;thisrepresentsa16.5%increaseintheCRafter thesecondcycleofinductionchemotherapy(p-value=0.001) (A).23
Recommendations:Itiscommon toperformasecond
inductioncycleofchemotherapyinpatientswithAML
whohave5%ormoreblastsinthebonemarrow10–14
days after the first cycle; the complete response rate
increasessignificantly afterthe second chemotherapy
cycle.
What
dose
of
cytarabine
(400
mg/m
2or
1
g/m
2or
1.5
g/m
2or
3
g/m
2)
is
the
most
effective
in
the
consolidation
treatment
of
young
acute
myeloid
leukemia
patients?
P–PatientsundergoinginductiontreatmentforAML
I – Use of cytarabine (400mg/m2/day, 1g/m2, 1.5g/m2 or
3g/m2)
C–
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Youngpatients(16–60yearswithameanof47yearsold)
withde novo orsecondary AMLwere evaluatedforOS and
disease-freesurvival(DFS)usingdifferentdosesofcytarabine
duringconsolidationtreatment.
All patients took the same drugs during the induction
phaseandthosewhoachievedCRwerestratifiedaccordingto
prognosticfactorsbycytogenetics.High-riskor
intermediate-riskpatientswithmatcheddonorswerereferredforallogeneic
bonemarrowtransplantation.However,low-riskpatientsand
thosewhodidnothaveHLA-compatibledonorswere
submit-tedtoconsolidation.
Consolidation chemotherapy was performed in 52% of
thepatients whowere inCR aftertwocycles ofinduction.
Cytarabine (1g/m2) every 12h for six days (total 12g/m2)
orcytarabine (3g/m2)every12hforsixdays(total36g/m2)
wasadministeredassociatedwithmitoxantrone10g/m2 for
three days in both cases. There was no significant
differ-enceinthenon-hematologicalgrade3and4toxicitybetween
thetwogroups.However,thegroupthatreceived36g/m2of
cytarabine presentedneutropenia (24days – 95% CI:22–26
days)longer than the grouptaking 12g/m2 (18 days –95%
CI:17–19days;p-value=0.004), buttherewasno difference
in the infectious complications rate between groups (A).24
Patients who used the highestdose ofcytarabine required more red blood cell transfusions (8 vs. 6; p-value=0.03), but there was no difference in the need for platelet con-centratetransfusions (A).24 Inthe analysisofintention to treat,theestimated5-yearOSwas30%(95%CI:25–35%)for the group that received intermediate-dose cytarabine and 33% (95%CI:28–38%)forthegroupthatreceivedhigh-dose cytarabine(p-value=0.77).The5-yearDFSwasestimatedat 37% (95% CI:31–44%) for the intermediate-dose group and 38%(95%CI:31–45%)forthehigh-dosegroup(p-value=0.86) (A).24
Twodifferentconsolidationchemotherapyregimenswere compared in 15- to60-year-old patients with de novo AML (except promyelocytic leukemia) with favorable cytogene-tics,whoreceivedoneortwoinductioncyclesandachieved CR. Arm 1 of the trial was mitoxantrone (12mg/m2/day)
on Days 1–3, cytarabine (500mg/m2/day) on Days 1–3 and
on Days8–10and etoposide(200mg/m2/day) onDays 8–10.
Arm2comprisedcytarabine(3g/m2/day)onDays1,3and5
forfourcycles followedbymaintenancewithdaunorubicin (45mg/m2/day)onDay1andcytarabine(100mg/m2/day)on
Days1–5.
Relapseoccurredin52%ofpatientssubmittedto consoli-dationtherapy;51.6%inArm1and48.3%inArm2(meantime: 9.9monthsvs.10.7months,respectively)(A).25DFSwas13.7 months(95%CI:11.3–22.5months)inArm1and23.3months (95%CI15.7–47months)inArm2,withthe5-yeardisease-free survival(DFS)being6%higherinArm2(p-value=0.24).TheOS was55.6monthsinArm1and62.9monthsinArm2,witha 5-yearOS2%higherinArm2(p-value=0.82).Thus,therewas nosignificantdifferencebetweenthetwoarmsinrespectto thecumulativeincidenceofrelapseandmortalityrelatedto consolidationtherapy(A).25
Arm 1 was associated with greater non-hematological grade3or4toxicitycomparedtoArm2(maximum percent-ages:diarrhea24%vs.3%,nausea/vomiting,26%vs.3%,and seriousinfection39%vs.19%,respectively).Severeheartand lungsideeffectswereobservedmainlyinArm1.Concerning hematologicaltoxicity,patientsinArm2receivedmore trans-fusionsthanArm1duetorepeatingcyclesofchemotherapy (A).25
Twoconsolidationtherapieswereevaluatedin15-to 65-year-oldpatientswithAML,includingthosewith promyelo-cyticleukemia.GroupAreceivedcytarabine(100mg/m2/day)
in a seven-day continuous infusion and Group B received cytarabine (3g/m2)in1-h infusionsevery 12h forsixdays,
bothassociatedwithdaunorubicin(45mg/m2/day)forthree
days.Thecytogeneticriskwasnotclassifiedandallpatients achieved CRaftertwo inductionchemotherapycycles.The toxicity,DFSandOSwereevaluated.
Grade3and4toxicitywas36.6%higherinGroupB(NNH:3;
Of693over16-year-oldpatientswithdenovoAMLinfirstCR afterinductionwithcytarabineanddaunorubicinatstandard doses, 596 were randomized to one of three regimens of fourconsolidationcycles.Thefirstgroupreceivedcytarabine (100mg/m2/day)bycontinuousintravenousinfusionforfive
days,thesecondreceivedcytarabine(400mg/m2/day)by
con-tinuousinfusionforfivedays, andthethirdgroupreceived cytarabine(3g/m2)ina3-hinfusionevery12honDays1,3and
5.Overa52-monthfollow-up,theprobabilityofsurvivalinCR forunder60-year-oldpatientswas24%forthe100mg/m2/day
cytarabinegroup,29%forthe400mg/m2/daycytarabinegroup
and44%forthe6g/m2/daycytarabinegroup(p-value=0.002)
(A).27
Recommendations: There is no significant difference
between different doses of cytarabine in the
consol-idation therapy of AML in respect to DFS and OS.
However,thestudythatcomparedstandard-dose
cytara-bine (100mg/m2/day) with high dose (6g/m2/day) did
notinform the cytogenetic risk. There are no studies
comparingdosesof1g/m2/day,1.5g/m2/day,2g/m2/day
and3g/m2/day.Thetotaldose of6g/m2/day forthree
daysseemstobeassociatedwithgreater hematologic
toxicity, and compared with the standard regimen of
100mg/m2/day, it is also associated withhigher
non-hematologictoxicity.
What
dose
of
cytarabine
(400
mg/m
2/day,
2
g/m
2/day,
3
g/m
2/day,
4
g/m
2/day
or
6
g/m
2/day)
is
the
most
effective
in
consolidating
young
acute
myeloid
leukemia
patients
with
favorable
prognosis
[<60
years,
leukocyte
count
at
diagnosis
<30,000
or
<50,000/mm
3with
cytogenetics:
t(8;21)/AML1-ETO/RUNX1-RUNX1T1,
inv(16)/t(16;16)/CBFbeta/MYH11,
core
binding
factor
leukemia,
FLT3-negative
or
FLT3-ITD-negative/NPM1-mutated]?
P – AML patients with favorable prognosis [<60 years,
with white blood cell count at diagnosis <30,000 or
<50,000/mm3 with cytogenetics
t(8;21)/AML1-ETO/RUNX1-RUNX1T1, inv(16)/t(16;16)/CBFbeta/MYH11, core binding
factorleukemia,FLT3-negativeor
FLT3-ITD-negative/NPM1-mutated]
I – Use of cytarabine (400mg/m2, 2g/m2/day, 3g/m2/day
4g/m2/day,or6g/m2/day)
C–
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Patients(16–60 years;meanof47 years)withde novoor
secondaryAMLwereevaluatedforOSandDFSusing
differ-entdoses ofcytarabine duringconsolidationtreatment.All
patientshadthesameregimenduringinductionandthose
who achievedCR were stratified byprognosis according to
cytogenetics. High-risk and intermediate-risk patients who
hadHLA-compatibledonorswerereferredforallogeneicbone
marrowtransplantation.Low-riskpatientsandthosewhohad
nocompatibledonorunderwentconsolidationchemotherapy.
Consolidationchemotherapywasadministeredto52%of
thepatientswhowereinCRaftertwoinductioncycles.The
regimensusedwerecytarabine1g/m2every12hforsixdays
(total12g/m2)orcytarabine3g/m2every12hforsixdays(total
36g/m2),bothassociatedwithmitoxantrone10g/m2/dayfor
threedays.
There was no significant difference in the
non-hematological grade 3 and 4 toxicity between the two
groups.However,thegroupthatreceived36g/m2presented
neutropenialongerthanthegroupofpatientswhoreceived
12g/m2[24days(95%CI:22–26)vs.18days(95%CI:17–19);
p-value=0.004].However,therewasnodifferenceinthe
infec-tious complicationsrate betweenthe two groups. Patients
who usedthehighestdoseofcytarabinerequiredmorered
bloodcelltransfusions(8vs.6;p-value=0.03)buttherewasno
difference inthe needforplatelet concentratetransfusions
(A).24
Chemotherapyconsolidationwasevaluatedin15-to 60-year-old patients with de novo AML (except promyelocytic leukemia) withfavorablecytogenetics, whoreceivedoneor twochemotherapyinductioncyclesandachievedCR.Two dif-ferentgroupswerecompared.Arm1receivedmitoxantrone 12 (mg/m2/day) on Days 1–3 associated with cytarabine
(500mg/m2/day)onDays1–3andetoposide(200mg/m2/day)
on Days 8–10 associated with cytarabine (500mg/m2/day)
also on Days 8–10. Arm 2 received cytarabine (3g/m2/day)
onDays1,3and5forfourcyclesfollowedbymaintenance withdaunorubicin(45mg/m2/day)on Day1and cytarabine
(100mg/m2/day)onDays1–5.
Fifty-twopercentofpatientswhoweresubmittedto con-solidationtherapyrelapsed,51.6%inArm1and48.3%inArm 2(9.9monthsvs.10.7months,respectively).ThemeanDFS was13.7months(95%CI:11.3–22.5months)inArm1and23.3 months(95%CI:15.7–47months)inArm2,witha5-yearDFS 6%higherinArm2(p-value=0.24).TheOSwas55.6monthsin Arm1and62.9monthsinArm2,withthe5-yearOSbeing2% higherinArm2(p-value=0.82).Thus,therewasnosignificant differencebetweenthetwoarmsinrespecttothe cumula-tiveincidenceofrelapseandmortalityrelatedtoconsolidation (A).25
Arm1hadmorenon-hematologicalgrade3or4toxicity thanArm2:diarrhea24%vs.amaximumof3%ineachcycle, respectively, nausea/vomiting26%vs.amaximumof3%in eachcycle,respectively,andsevereinfection39%vs.nomore than19%ineachcycle,respectively.Severecardiacand pul-monaryeffectswereobservedmainlyinArm1.Inregardsto hematologicaltoxicity,patientsinArm2receivedmore trans-fusionsthan thoseinArm1duetotherepeatingcyclesof chemotherapy(A).25
Thehigh-dosegroupreceived2g/m2in3-hinfusionsevery
12h(total4g/m2)forfivedayswitheachcyclestartingone
weekaftertherecoveryofneutrophil,leukocyte,andplatelet countstomorethan1.5×109/L,3.0×109/Land100.0×109/L,
respectively.Thestandard-dosegroupincludedseveral regi-mens: mitoxantrone (7mg/m2/day) as 30-min infusions
for three days or daunorubicin (50mg/m2/day) as 30-min
infusionsforthreedays,oraclarubicin(20mg/m2/day)as
30-mininfusionsforfivedaysoretoposide(100mg/m2/day)as1-h
infusionsforfivedays,togetherwithvincristine(0.8mg/m2)
boluson Day 8 and vindesine (2mg/m2)bolus on Day 10.
All the above regimens were associated with cytarabine (200mg/m2/day)asa24-hcontinuousinfusionforfivedays.
Eachconsolidationcyclewasstartedassoonaspossibleafter therecoveryoftheneutrophil,leukocyteandplateletcounts. The5-yearDFSforthehigh-doseandstandard-dosegroups were 43% and 39%, respectively (p-value=0.724). However, when patients with favorable cytogenetics were evaluated alone, the DFS was 18% higherin the high-dose group (p -value=0.05).Therewasnosignificantdifferenceinthe5-year OSbetweenthe consolidationregimens forthetotalgroup of patients or for patients with favorable cytogenetics (p -value=0.954andp-value=0.174,respectively)(A).28
Whencytarabine100mg/m2/dayasaseven-day
continu-ousinfusionwascomparedwithcytarabine3g/m2every12h
asacontinuousinfusionforsixdays,bothassociatedwith daunorubicin45mg/m2/dayforthreedays,therewasgreater
grade3and4toxicity(infection,gastrointestinaleffects,and neurologicaleffects)inthehigh-dosegroup(p-value=0.0001). However,therewasnosignificantdifferencebetweenthetwo groupsinrespecttothemeanOSandDFSof15-to 65-year-oldpatientswithdenovoAMLduringafollow-upof85months (A).26
Recommendations:Theoverallsurvivalanddisease-free
survivalof15-to65-year-oldAMLpatientswitha
favor-ableprognosisdoesnotimproveusingahigherdoseof
cytarabineintheconsolidationregimen.However,
hema-tologicalandnon-hematologicalgrade3and4toxicity
increasesasthedoseincreases.
What
dose
of
cytarabine
(400
mg/m
2/day,
2
g/m
2/day,
3
g/m
2/day,
4
g/m
2/day
or
6
g/m
2/day)
is
the
most
effective
in
the
consolidation
of
young
acute
myeloid
leukemia
patients
with
poor
or
intermediate
prognosis
[leukocyte
count
at
diagnosis
≥
30,000/mm
3,
complex
karyotypes
(
≥
3
chromosomal
abnormalities),
secondary
acute
myeloid
leukemia,
changes
in
chromosome
3
or
7]?
P–AMLpatientswithpoororintermediateprognosis[≤60
years,withwhitebloodcellcountatdiagnosis≥30,000/mm3,
complex karyotypes(≥3chromosomalabnormalities),
sec-ondary AML,changes in chromosome 3or 7) undergoing
consolidationtherapy.
I–Useofcytarabine(400mg/m2/day,2g/m2/day,3g/m2/day,
4g/m2/day,or6g/m2/day)
C–
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Youngpatients, aged15–64years old,withde novoAML
(exceptpromyelocyticleukemiabytheFABclassification),who
achievedCRafteroneortwochemotherapyinductioncycles
weredividedintotwogroupsforconsolidationtherapy.The
high-dosegroupreceivedhighdosesofcytarabinerepeatedfor
threecyclesandthestandard-dosegroupreceivedstandard
doses ofcytarabineforfour cycles.Patientswere evaluated
over a mean follow-up period of 48 months (range: 5–78
months).
Thehigh-dosegroupreceived2g/m2in3-hinfusionsevery
12h for five days with each cycle starting one weekafter
neutrophil, leukocyte and platelet countsrecoverytomore
than1.5×109/L,3.0×109/Land100.0×109/Lrespectively.The
standard-dosegroupreceivedseveralregimens:mitoxantrone
(7mg/m2/day)ina30-mininfusionforthreedaysor
daunoru-bicin(50mg/m2/day)ina30-mininfusionforthreedays,or
aclarubicin(20mg/m2/day)ina30-mininfusionforfivedays
oretoposide(100mg/m2/day)ina1-h infusionforfivedays
togetherwithvincristine(0.8mg/m2)bolusonDay8and
vin-desine(2mg/m2)bolusonDay10.Alloftheaboveregimens
were associatedwith cytarabine (200mg/m2/day) asa 24-h
continuousinfusionforfivedays.Eachconsolidationcyclewas
startedassoonaspossibleaftertherecoveryoftheneutrophil,
leukocyteandplateletcounts.
The5-yearDFSforthehigh-doseandstandard-dosegroups
were 43% and 39%, respectively (p-value=0.724). However,
when patientswithintermediate prognosiswere evaluated
alone,the5-yearDFSwas38%forthehigh-dosegroupand39%
forthestandard-dosegroup(p-value=0.403)andthe5-yearOS
were53%and54%,respectively(p-value=0.482).Forpatients
withunfavorablecytogenetics,the5-yearDFSwas19%higher
inthehigh-dosegroup(33%vs.14%;p-value=0.364)andthe
5-yearOSwere39%(high-dose)and21%(standard-dose)(p
-value=0.379)(A).28
Two other consolidation regimens (IcE and ICE) were evaluated in 15- to60-year-old patients with de novo AML (exceptpromyelocyticleukemia)whoachievedCRafterone ortwoinductioncycles.TheIcEregimencomprisesidarubicin (12mg/m2/day)onDays 1and2associatedwithcytarabine
(100mg/m2/day)in acontinuous infusionon Days 1–5 and
etoposide (75mg/m2/day) in a 1-h infusion on Days 1–7.
ICEcomprisesidarubicin(9or12mg/m2)bolusonDays 1–3
associatedwithcytarabine(3g/m2)asa3-hinfusionsevery
12honDays 1,3,5and7andetoposide(75mg/m2/day)on
Days1–5.
Recommendation:Intheconsolidationof15-to
64-year-oldpatientswithAMLandintermediateorunfavorable
prognosis,thereisnosignificantdifferenceinoverall
sur-vivalordisease-freesurvivalusingthedifferentdosesof
cytarabineevaluated.
Which
chemotherapy
regimen
(cytarabine
with
or
without
anthracycline
and
dose
of
cytarabine)
is
the
most
effective
in
the
consolidation
of
elderly
acute
myeloid
leukemia
patients
(>60
years)?
P–Elderlypatients(>60years)withAMLundergoing
consol-idationtreatment
I–Cytarabinewithanthracycline
C–Cytarabinewithoutanthracycline
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
Over60-year-old patients (61–87 years) withprimary or
secondary AML (excluding those with severe
comorbidi-ties)werefollowedup foramedianof68months.Patients
receivedtwoinductioncyclesofcytarabine(100mg/m2/day)
inaseven-daycontinuousinfusion,associatedwith
daunoru-bicin(45mg/m2/day)onDays3–5,andaconsolidationcycle
ofcytarabine(1g/m2)every12honDays 1–5andansacrine
(100mg/m2/day)onDays1–5.TheOSandDFSwere9.7%and
14%,respectively(B).30
Afterinductiontherapy withcytarabine (100mg/m2/day)
as a seven-day continuous infusion and daunorubicin (45mg/m2/day)oridarubicin(12mg/m2/day)forthreedays,
AMLpatients in CR received consolidation treatment with cytarabine(100mg/m2)every12hforfivedays,thioguanine
(100mg/m2) orally every 12h for five days and
daunoru-bicin(50mg/m2)oridarubicin(15mg/m2)onthefirstdayof
chemotherapy.Thecycleswererepeatedat3-to4-week inter-valsforthreecycles.Over60-year-oldPatientshadameanOS of235daysinthegroupthatreceivedidarubicinintheir con-solidationregimenand209daysinthe groupthatreceived daunorubicin,withnosignificantdifferencebetweenthetwo groups(p-value=0.58)(A).11
Elderlypatients(55–75yearsold)withdenovoAML, exclud-ingthosediagnosedwithmyeloproliferativesyndromes,were evaluatedafterinductiontherapywithcytarabineassociated with daunorubicin or idarubicin, and consolidation ther-apywithcytarabine(50mg/m2/day)subcutaneously forfive
daystogetherwithdaunorubicin(30mg/m2/day)oridarubicin
(8mg/m2/day)forthreedays.Therewasnosignificant
differ-encebetweenthetwogroupsinrespecttonon-hematological toxicity,includingsepsisandinfectiouscomplications,except forfeverthatwashigherinthegroupofpatientswhoreceived idarubicin (p-value=0.001). The three-year DFS was signif-icantly higher (p-value=0.016) in the group that received idarubicinratherthandaunorubicin(meanof647daysvs.283 days)inthesubgroupof65-to75-yearolds(A).8
Cytarabine(1g/m2)asa1-hcontinuousinfusionevery12h
forfourdaysassociatedwithdaunorubicin(80mg/m2/day)or
idarubicin(12mg/m2/day)onDay1ofthefirstcycleandDays
1and2ofthesecondcyclewereadministeredin50-to 70-year-oldpatientswithdenovoAML(exceptAMLM3according totheFABclassification).Theestimatedevent-freesurvival attwoyearswas23.5%(95%CI:19.5–28%)andatfouryears itwas18%(95%CI:14–22%).ThemedianOSwas17months, withestimatesfortwoyearsof38%(95%CI:34–44%)andfour yearsof26.5%(95%CI:22–32%)(A).7
Of416patientsaged65yearsorolder(median:72years) withdenovoorAMLsecondarytoMDS(FAB:refractory ane-mia with excess blasts in transformation – RAEB-T), 236 achievedCRafterinductionwithcytarabine(200mg/m2/day)
forsevendaysanddaunorubicin(45mg/m2/day)oridarubicin
(9mg/m2/day)forfourdays.IfaCRwasnotachievedbythe
firstinductioncycle,asecondcycleofcytarabine(500mg/m2)
wasinfusedover1hevery12hforthreedaysassociatedwith mitoxantrone(12mg/m2)every12hfortwodays.
Granulocyte-colonystimulatingfactorwasusedfromDay9oftreatment until recoveryof the bonemarrow. Among patientsin CR, 164wererandomizedbetweentwoconsolidationgroups.The first regimen consisted of one cycle similar to the induc-tion regimenand thesecondcomprisedsixmonthlycycles ofdaunorubicin(45mg/m2)oridarubicin(9mg/m2)onDay1
andcytarabine(60mg/m2)subcutaneouslyevery12honDays
1–5.Multivariateanalysisshowedthatthechanceofstaying aliveandinCRwere1.59and1.51timeshigherforthegroup receiving sixcycleswithlow-dosecytarabine (p-value=0.04 andp-value=0.05,respectively)(A).4
Of693over16-year-oldpatientswithdenovoAMLinfirst CR after induction with standard doses of cytarabine and daunorubicin,596wererandomizedtooneofthreeregimens offourconsolidationcycles.Thefirstgroupreceived Cytara-bine(100mg/m2/day)bycontinuousintravenousinfusionfor
fivedays,thesecondreceivedCytarabine(400mg/m2/day)by
continuousinfusionforfivedays,andthethirdgroupreceived 3g/m2)ina3-hinfusionevery12honDays1,3and5.Aftera
follow-upof52months,theprobabilityofCRforover 60-year-oldpatientswas16%orlessforthethreecytarabinegroups (p-value=0.19)(A).27
Recommendations: Thereisnoconsensusonthe best
consolidationstrategyforelderlypatients.
Is
allogeneic
transplant
more
effective
than
chemotherapy
in
the
consolidation
of
young
acute
myeloid
leukemia
patients
with
favorable
prognoses
and
with
unfavorable
or
intermediate
prognoses?
P–YoungpatientswithAMLfavorable,intermediaryor
unfa-vorableprognosisundergoingconsolidationtreatment
I–Chemotherapy
C–Allogeneictransplantation
O–Completeremissionrate,overallsurvival,and
ThemajorityofpatientswithAML,whoachieveCR,relapse afterconventionalchemotherapy.Sofar,allogeneicbone mar-row transplantation (BMT) is considered the only curative treatment. This procedure influences the OS, but depends onthe existenceofan HLA-compatibledonorand is asso-ciated with considerable morbidity and mortality. In this scenario,thedefinitionoftowhomreceivesandwhen allo-geneictransplantisindicatedbecomesanimportantissuein themanagementofAMLpatients;cytogeneticandmolecular factorsguidethisdecision.
A randomized study published by the European Group showedthat16-to67-year-oldpatientswithadvancedMDSor MDStransformingintoAML,orAMLsecondarytoMDSwith intermediateorunfavorablecytogeneticsafter83monthsof follow-up,who underwent oneor twoinductioncycles fol-lowedbyaconsolidationcyclewithidarubicin10mg/m2/day
onDays4–6andcytarabine500mg/m2asa2-hinfusionevery
12h on Days 1–6 were divided into two groups after CR. Patientsinfirst remissionwhohad HLA-compatibledonors underwent allogeneic BMT and those without compatible donorsweresubmittedtoasecondconsolidationcycle fol-lowedbyautologousBMT.Theresultswerebetterforpatients whoperformed allogeneicBMTwitha hazardratio (HR)in multivariateanalysisof0.58(99%CI:0.22–1.5;p-value=0.14) forOSand0.46(95%CI:0.22–1.5;p-value=0.08)forDFS(A).31
Inameta-analysis,Korethetal.evaluatedtheDFSandOS ofunder 60-year-oldAMLpatientswithfavorable, interme-diate and unfavorable cytogeneticssubmitted toallogeneic BMTinthe first CR afterstartingchemotherapy compared topatientswhocontinuedinchemotherapy.Aftera follow-up of 19–222 months, no benefit was seen in relation to DFSfortheAMLgroupwithfavorablecytogenetics(HR:1.06; 95%CI:0.80–1.42),howevertheresultswerebetterafter allo-geneic BMTcompared to chemotherapyalone forpatients withintermediate(HR:0.76;95%CI:0.68–0.85)and unfavor-ablecytogenetics(HR:0.69;95%CI:0.57–0.84)(A).32TheOS wasbetterafterBMTcomparedtochemotherapyalone for theintermediatecytogenetics(HR:0.83;95%CI:0.74–0.93)and unfavorablecytogeneticsgroups(HR:0.73;95%CI:0.59–0.90), butnotforthefavorablecytogeneticsgroup(HR:1.07;95%CI: 0.83–1.38)(A).32
TheGermangroupmonitored18-to60-year-oldpatients withdenovoorsecondary AMLand trisomy8(+8) aloneor withanadditionalaberration,exceptt(8;21),inv(16),t(16;16), t(15;17), 11q23 abnormalities or complex karyotypes, who receivedtwocyclesofinductionchemotherapy,followedby (a)high-dosecytarabine(60%),(b)autologousBMT(14%),or(c) allogeneicBMT(16%)(A).33Thepatientswhoweresubmitted toallogeneic BMTwere youngerthantheother twogroups [32(range:18–55)vs.51(range:19–59)years;p-value=0.001] but there was no significant difference inthe OS between thedifferentconsolidationtreatmentstrategies.The3-year OSratewas37%(95%CI:23–52%)forhigh-dose cytarabine, 34% (95%CI: 3–65%)forautologous BMTand 45% (95% CI: 22–68%) for allogeneic BMT (p-value=0.63) (A).33 However, treatment-relatedmortalitywashigherforpatients submit-tedtoallogeneicBMTcomparedtothosewhowerenot(27% vs.4%;p-value=0.01),despitethe 3-yearrelapse ratebeing lower(27%vs.69%;p-value=0.002).Thislowerprobabilityof relapsewasseeninagreater3-yearDFS;49%(95%CI:25–72%)
forthosewhounderwentallogeneicBMT,23%(95%CI:0–51%) forthosewhoreceivedhigh-dosecytarabineand28%(95%CI: 14–41%)forthosesubmittedtoautologousBMT(p-value<0.05) (A).33
Sevenhundredandthirty-four16-to60-year-oldpatients werefollowedupintheEuropeanOrganizationforResearch and Treatment of Cancer-Gruppo Italiano Malattie Emato-logichedell’Adulto(EORTC-GIMEMA)AML-10study.Afterone ortwoinductiontreatmentcycles,thepatientsreceiveda con-solidationchemotherapycycle,andwhileunder46-yearolds withHLA-identicaldonorsweresubmittedtoallogeneicBMT, the remainingpatients underwent autologousBMT.The 4-year DFSwas 52.2%forpatients whounderwent allogeneic BMTcomparedto 42.2%forthose submittedtoautologous BMT (HR: 0.80; 95% CI: 0.64–0.99; p-value=0.44). The inci-dence of relapse was 30.4% for the allogeneic BMT group comparedto52.5%afterautologousBMT.TheOSwas58.3% vs.50.8%forallogeneicandautologousBMT,respectively.The DFS inpatients with or without HLA-identicaldonors was similarinpatientswithlow-andintermediate-risk cytogene-tics.However,theDFSwas43.4%and18.4%forallogeneicand autologousBMT,respectivelyinpatientswithhigh-risk cyto-genetics.Thisdifferencewasevenmorepronouncedinyoung (15–35yearsold)patients(p-value=0.036)(A).34Therefore,the strategytoperformallogeneicBMTearlyinfirstCRhasledto betterresultsofsurvival,especiallyinyoungerpatientsand thosewithunfavorableriskcytogenetics(p-value=0.18)(A).34 Brunetetal.evaluated16-to60-year-oldpatientswithAML (exceptM3byFABclassification) withnohistoryofMDSor previous use of cytotoxic drugsor radiation. Patientswere submittedtoinductiontherapywithoneortwocyclesofICE chemotherapy[idarubicin(10mg/m2/day)as30-mininfusions
on Days1,3and 5,cytarabine(100mg/m2/day)as
continu-ousinfusionsonDays1–10andetoposide(100mg/m2/day)as
1-h infusionsonDays1–5]. Thiswasfollowedbya consoli-dationcyclewithintermediate-dosecytarabine (500mg/m2)
as 2-h infusions every 12h on Days 1–6 associated with mitoxantrone (12mg/m2/day) over 15min onDays 4–6 and
then patients were stratified into different intensification treatmentsdependingonageand cytogeneticrisk.Patients withlow-riskcytogeneticsreceivedtwocyclesofcytarabine (3mg/m2)as2-hinfusionsevery12honDays1,3and5.
Allo-geneicBMTwasperformedinunder50-year-oldpatientswith intermediate- or high-risk cytogenetics and HLA-identical donors,andautologousBMTwasperformedinover50-year oldsorthosewithoutHLA-identicaldonors.Thegroupswere evaluatedfortreatment-relatedmortality,OSandDFS.
Recommendation:Allogeneictransplant ismore
effec-tivein young patientswith HLA-identical donorsand
unfavorable or intermediate-risk cytogenetics.
Candi-datesforallogeneicBMTaredefinedasindividualsinfirst
completeremissionaftertheinitiationoftreatmentwith
unfavorable or intermediate-risk cytogenetics; these
patientshaveevidentimprovementinoverall survival
ratesanddisease-freesurvival.Thereisnoprovenbenefit
forpatientswithfavorablecytogenetics.
Is
autologous
transplant
more
effective
than
chemotherapy
in
the
consolidation
of
young
acute
myeloid
leukemia
patients
with
favorable
prognosis
and
in
patients
with
unfavorable
or
intermediate
cytogenetic?
P–YoungpatientswithAMLfavorable,intermediaryor
unfa-vorableprognosisundergoingconsolidationtreatment
I–Chemotherapy
C–Autologoustransplantation
O–Completeremissionrate,overallsurvival,and
disease-freesurvival
ThebeststrategyafterintensificationofremissionforAML
patientswithfavorableriskorintermediateriskandwithout
acompatiblebonemarrowdonorisstillwidelydebated,given
thatthere isnorobustevidencefor therapeuticmodalities
apartfromallogeneictransplantation,whichisconsideredthe
onlycurativealternative.
Nathan et al. published a meta-analysis comparing a
groupofpatientsinfirstremissionsubmittedtoautologous
hematopoieticstem cell transplantation (HSCT)to agroup
who received intensive chemotherapy. Six studies totaling
1044patientsrandomizedforautologousHSCTorintensive
chemotherapywereincludedthemeta-analysis.Theauthors
concludedthatpatientswhoreceivedautologousHSCThad
betterDFS,buttheOSwassimilarinbothgroups(A).36
Another randomizedstudy evaluated16- to 67-year old patientswithadvancedMDS,MDStransformingintoAMLor AMLsecondarytoMDS,whoafterachievingCR,received con-solidationtherapyofhigh-dosecytarabine.Patientswhodid nothaveaHLA-compatibledonorweresubmittedto autol-ogousHSCTorasecondcycle ofhigh-dosecytarabine. The 4-yearOSofpatientssubmittedtoautologousHSCTora sec-ondconsolidationcycleofhigh-dosecytarabinewas37%and 27%,respectively.TheHRsinmultivariateanalysiswere1.22 (95%CI:0.65–2.27)forOSand1.02(95%CI:0.56–1.85)forDFS (A).31
Anotherpublicationanalyzed18-to60-year-oldpatients with de novo or secondary AML and trisomy 8 (+8) alone or with an additional aberration (except t(8;21), inv(16), t(16;16), t(15;17) abnormality11q23, or complex karyotype), whoreceivedtwoinductioncycles,followedbyahigh-dose cytarabine(60%),autologousHSCT(14%)orallogeneicHSCT (16%).TherewasnosignificantdifferenceintheOSbetween thethreeregimens.The3-yearOSwas37%(95%CI:23–52%)for high-dosecytarabine,34%(95%CI:3–65%)forautologousBMT
and45%(95%CI:22–68%)forallogeneicBMT(p-value=0.63) (A).32 However,the treatment-related mortalitywas higher forpatientssubmittedtoallogeneic BMTthan thoseofthe otherregimens(27%vs.4%;p-value=0.01),despitethe3-year relapse ratebeing lower(27% vs.69%;p-value=0.002).This lowerprobabilityofrelapseisseeninthehigher3-yearDFS: 49% (95% CI:25–72%) forthose who underwent allogeneic BMT,23%(95%CI:0–51%)forthose whoreceivedhigh-dose cytarabineand28%(95%CI:14–41%)forthosesubmittedto autologousBMT(p-value<0.05)(A).33
Morethetal.,inasystematicreview,analyzed24clinical trialsinvolvingunder60-year-oldpatientswithdenovoor sec-ondaryAMLwithfollow-upsof1–222months.Patientswitha HLA-compatibledonorafterthefirstCRunderwentallogeneic BMT,whilethosewithoutaHLA-compatibledonorreceived autologousBMTorchemotherapyorboth.Thethreegroups werecomparedandtheHRforrelapseanddeathdueto allo-geneicBMTwas0.80(95%CI:0.74–0.86).TheallogeneicBMT procedureprovidedsignificantbenefitsinrespecttotheDFS inhigh-risk(HR0.69;95%CI:0.57–0.84)andintermediate-risk cytogenetics patients(HR0.76;95%CI:0.68–0.85),but there wasnosignificantbenefitforlow-riskpatients(HR:1.06;95% CI:0.80–1.42)(A).32
Inaprospectivestudyof16-to60-year-oldAMLpatients (exceptM3bytheFABclassification)withnohistoryofMDS orprevioususeofcytotoxicdrugsorradiation,patientswere stratifiedbyriskrelatedtocytogeneticsandageafter induc-tion therapy. Favorable cytogenetics was defined as t(8;21) andinv(16),andthecutoffpointforindicatingforallogeneic HSCTwas50yearsold.Afterstratificationdependingonage andcytogeneticrisk,patientswereevaluatedfor treatment-relatedmortality,OSandDFS.Low-riskpatientsreceivedtwo cyclesofcytarabine(3g/m2)as2-hinfusionsevery12honDays
1,3and5.Under50-year-oldpatientswithintermediate-or high-riskcytogeneticsandHLA-identicaldonorswere submit-tedtoallogeneicBMT,andover50-yearoldsandindividuals without HLA-identical donors underwent autologous BMT. The treatment-relatedmortality was23±9%for allogeneic BMT,3±3%forautologousBMTin under50-year olds and 23±6% for over 50-year olds and 14±7% for those who receivedhigh-dosecytarabine.Therewasnosignificant differ-enceinthe4-yearOSbetweenthedifferentregimens(41±9%, 52±8%,38±8and61±6%,respectively).Asignificant differ-ence was observed forthe DFS only forunder 50-year-old patientswho underwentautologousBMTcomparedtoover 50-year oldsalsosubmittedtoautologousBMT(48%±8vs. 17±9%, respectively; p-value=0.03) (A).35 Thisstudy found that age, cytogenetics and white blood cell count at diag-nosisare theadverse factorsmostassociatedwithrelapse. Of the low-risk cytogenetics patients who did not receive transplants, those with t(8;21) had higher DFS than those withinv(16). Intermsofleukemia-freesurvival,theresults ofautologousandallogeneictransplantsweresimilarwhen the mortalityassociatedwithallogeneic BMTisconsidered (A).35
