急性早幼粒细胞白血病（APL）一线治疗进展

急性早幼粒细胞白血病（APL）一线治疗进展FrontlineclinicaltrialsAPL2006FranceAPL2012ChinaAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCFrontlineclinicaltrialsAPL2006FranceAPL2012ChinaAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCUpdateoftheItalian-GermanstudyAPL0406UpdateoftheItalian-GermanstudyAPL0406

PhaseIIIStudyLow-intermediaterisk

APL0406StudyOutcomesasofSeptember20,2017

OSEFSCIRasofSeptember20–2017

Medianfollow-up:66.2months(0.9-116.7)HaematologicalToxicityNon-haematologicToxicityCONCLUSIONATRA+ATOmustbeconsideredthestandardTreatmentofnewlydiagnosednonhighriskAPLpatients.NextStepPhaseIIIEuropeantrialforhigh-riskAPL(APOLLOstartedonJanuary2017)FrontlineclinicaltrialsAPL2006FranceAPL2012ChinaAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCUpdateofAPL2006trialresultsLionelAdès

HopitalSaintLouis,ParisDiderotUniversityFrenchMDSgroupStandardRiskAPL经典ATRA+蒽环类为基础的化疗治疗标危患者缓解率高，复发率低。含ATO的治疗方案可以减少复发率。HigherRiskAPLTreatmentschedule1、在ATRA+化疗的方案中加入ATO不减少复发，但会增加骨髓抑制。2、巩固治疗中加入ATO去除AraC后不增加复发，但会减少骨髓抑制和缓解后的死亡。3、ATO也适合于高危患者。FrontlineclinicaltrialsAPL2006FranceAPL2012ChinaAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCImprovementswithRisk-adaptedPETHEMAProtocolsinNewDiagnosed

AcutePromyelocyticLeukemiaMiguelA.Sanz

Chairman,SpanishPETHEMAGroupUniversityHospitalLaFeValencia,SpainAll

ages<60Intermediate

riskHigh

riskIDA

5

mg/m2/d×4Ara-c

150mg/m2/8h×4ATRA

45

mg/m2/d×15IDA

5

mg/m2/d×4Ara-c

1

g/m2/d×4ATRA

45

mg/m2/d×15AIDAAgeIDA

12mg/m2

d2，4，6，8ATRA

45

mg/m2/dIDA

12mg/m2

d2，4，6，8ATRA

45

mg/m2/dIDA

12mg/m2

d2，4，6ATRA

45

mg/m2/dIDA

12mg/m2

d2，4，6，8(<70

only

2，4，6)ATRA

45

mg/m2/d≤70>70Relapse-risk

GroupCourse

#1Course

#3Course

#2All

groupsLow

riskIntermediateHigh

riskLow

riskIDA

5

mg/m2/d×4MTZ

10

mg/m2/d×5IDA

12

mg/m2/d×1All

agesIDA

5

mg/m2/d×4MTZ

10

mg/m2/d×5IDA

12

mg/m2/d×1IDA

5

mg/m2/d×4ATRA

45

mg/m2/d×15MTZ

10

mg/m2/d×5ATRA

45

mg/m2/d×15IDA

12

mg/m2/d×2ATRA

45

mg/m2/d×15IDA

5

mg/m2/d×4ATRA

45

mg/m2/d×15MTZ

10

mg/m2/d×3ATRA

45

mg/m2/d×15IDA

12

mg/m2/d×1ATRA

45

mg/m2/d×15IDA

7

mg/m2/d×4ATRA

45

mg/m2/d×15MTZ

10

mg/m2/d×3ATRA

45

mg/m2/d×15IDA

12

mg/m2/d×2ATRA

45

mg/m2/d×15MTZ

10

mg/m2/d×5ATRA

45

mg/m2/d×15LPA96LPA99LPA2005Maintenance

Therapy（2y）Induction

TherapyConsolidation

TherapyHematologicaltoxicityduringconsolidationallpatientshigh-riskpatientsHigherrelapserateinCD56-positivepatientsNodifferencesinrelapseratebyCD56expressionOutcomebyCD56expressionFrontlineclinicaltrialsAPL2006FranceAPL2012ChinaAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCNigelRussell,et

al.onbehalfoftheNCRIAMLWorkingGroupTheFeasibilityofMoreAttenuatedDosageSchedulesofATOinNewlyDiagnosedAndRelapsedAPLTheFeasibilityofMoreAttenuatedDosageSchedulesofATOinNewlyDiagnosedAndRelapsedAPL背景和目的：NCRI

AML17试验---比较AIDA和ATRA+ATO方案治疗低危和高危APL在（Burnett

et

al

Lancet

Oncology

2015）报道基础上，病例增加至235例29例AIDA方案复发患者换用ATO治疗的结果病例：2009-5至2013-10，235例初发APL患者入组（AIDA组119例，ATO+ATRA组116例）随机结束后另有70例予以AIDA方案，复发时使用ATO随访至2017-7，中位随访时间6年AIDA方案后复发患者ATO方案治疗反应AML17研究中共189例予以AIDA方案30例复发（包括5例CNS复发）1例在挽救治疗前死亡29例予以ATO+ATRA方案治疗18在分子复发时开始治疗，显示了MRD监测的价值所有29例患者经ATO+ATRA治疗后重获分子缓解29例中13例获MCR后进行移植（10例自体，3例异体），包括4/5例CNS复发患者16例未用化疗，完成ATO/ATRA治疗（诱导+4疗程巩固治疗）3/16例经ATO+ATRA方案挽救治疗后二次分子复发（1例移植后，2例未移植）29例目前均存活ATO+ATRA挽救治疗后生存情况AML17

APL结论更新数据显示ATO+ATRA较AIDA获得更佳的5y

EFS（93%

vs

79%，p=0.007）ATO+ATRA组无复发（CIMR

0%

vs

21%，p<0.0001）ATO+ATRA方案对于初发和复发APL安全有效ATO组未观察到生存获益，主要是由于多数患者在分子复发时进行ATO挽救治疗，达到了很好的疗效，3y

OS

96%减量方案（n=63

vs

140

dose）&（1190mg

vs

1470mg）/70kg

patient，方便且减少经济负担FrontlineclinicaltrialsAPL2006FranceAPL2012ChinaAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCTheALLGapproachtoincorporatingarsenictrioxideharryilandinstituteofhaematologyroyalprincealfredhospitalsydney,australiaALLGAPML3

vs.APML4ATRA+IDAATRA+CTATRA+MTX+6MPATRA+IDA+ATOATRA+ATOATRA+MTX+6MPAPML42004-2009APML31997-2002InductionConsolidationMaintenanceEFSOSDFSEFSALLGAPML3

vs.APML4DFSOSAPML4

OS-FLT3mutationsAPML4

DFS-whitecellcountPost-hoccomparisonofoutcomesstratifiedbydiseaseriskcategorystandardriskhighriskAPML5

AphaseIpharmacokineticevaluationoforalATOinpreviouslyuntreatedpatientswithAPLTodevelopanoralATOregimenthat:•

isaseffectiveasIVATO•

isatleastassafeasIVATO•

improvestheoveralltreatmentexperience•

isacceptabletoregulatoryagenciesworldwideAimFrontlineclinicaltrialsAPL2006FranceAPL2012ChinaAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCRecentresultsfromtheprospectivestudiesonAPLintheJapanAdultLeukemiaStudyGroup(JALSG)AkihiroTakeshita

theJapanAdultLeukemiaStudyGroup(JALSG)TamibaroteneasMaintenanceTherapyforAPL:PhaseIIIRandomizedControlledTrialResultsofLongTime(10-year)ObservaLon

APL204

Consortdiagramandtreatmentschema5-yearRFSinlow&intermediateriskgroupandhighriskgroupComparisonbetweenpatientstreatedATRAandtamibaroteneShinagawaI,YanadaM,etal,JCO,2014ALL

patients

n=269WBC≥

10×109/L

n=52WBC

<

10×109/L

n=217ResultsofJALSGAPL204Study10年分析显示，Am80维持治疗复发率明显降低，尤其是高危患者ALL

patientsP=0.03WBC

<

10×109/LP=0.263WBC≥

10×109/L

p=0.03410-yearRFS10-yearOS,EFSforallpatientsFollowupperiod11.2yearsat

May31,2017ResultsofAPL204LstudyTotally,CRratewas92%,but87%inhighriskgroupmainlyduetohemorrhagicevents.TamibaroteneissignificantlyalsoeffectiveinhighriskgroupasWBC>10,000/μl.ItmaybenotableaftertheintroductionofATO+retinoidtreatment.Secondaryhematopoieticdisordersandmalignancieswereobservedin12paLentsand9paLents,respectively.TheseshouldbeconsideredinAPL,whichhasimprovedsurvival.Inthefuture,theefficacyofAm80shouldbestudiedininductionsettingforuntreatedAPL.FrontlineclinicaltrialsAPL2006FranceRetinoicAcidandArsenicTrioxidewithorwithoutChemotherapyforAcutePromyelocyticLeukemiawithDifferent

RiskStratifications:

AnInterimAnalysisofChinaAPL2012StudyAPL0406GIMEMA-AMLSG-SALALLGAPML4-APML5NCRIAML17JALSGAPLStudyPETHEMAtrialsATRA+ATO±GOMDACCJunmin

Li

et

al.

Rui

Jin

Hospital

Affiliated

to

Shanghai

Jiao

Tong

University

School

of

Medicine,

Shanghai

Institute

of

HematologyAPL2012ChinaAPL2012StudyA

phase4,prospective,randomized,open-label,multicentertrial.Objectives:If

CHT

could

be

replaced

by

ATO

in

patients

with

low-

and

intermediate-risk

APL

in

post-remission

therapy?If

CHT

could

be

minimized

by

ATO

in

patients

with

high-risk

APL

in

post-remission

therapy?ProtocolofTreatmentLow-riskATRA+ATO±HuIntermediate-riskHigh-riskATRA+ATO±IDAATRA+ATO+IDAATRA+ATOATRA+IDAATRA+ATOATRA+ATOATRA+IDAATRA+ATO+IDAATRA+ATOATRA+IDA+Ara-CATRA+ID

Ara-CATRA→ATO

*3

cyclesATRA→ATO→MTX

*5

cyclesInductionConsolidation/1

&

2Consolidation

3hCRmCRMaintenanceSanz

StratificationRandomizationEnrollment1039

casesscreenedfrom

July

2012

to

Jun

2017.

72

casesexcluded

before

induction:

unqualified

orrefused

to

the

study.967casesenrolled,18

caseswithdrew

due

to

intolerance,

protocolviolation

during

induction.949

cases

eligible

for

analysis.ResultsCR

rate：96.6%

(910/942)Early

death：3.4%

(32/949)Low-risk：1.0%

(n=2)Intermediate-risk：3.6%

(n=18)High-risk：4.6%

(n=12)P

value:

0.106Medianfollow-up：32months(0-58)4-yearOS:Low-risk:

97.9%

Intermediate-risk:95.9%High-risk：90.5%Low-Intermediate

>High

(P=0.006)Post-remissionSurvival4y

DFSLow%Int%High%Exp97.997.593.2Ctrl95.697.191.8P

value0.2950.9830.7704y

OSLow%Int%High%Exp97.910094.7Ctrl10099.595.6P

value0.2980.3210.923Relapse/refractory

22

patients

were

relapsed

and