autologous stem cell transplant in aml: the … · autologous stem cell transplant in aml: the...

AUTOLOGOUSSTEMCELLTRANSPLANTINAML:THECINDERELLASTORY

FrancescoSaraceniHematologyandSCT,Ravenna

Ravenna,27-Oct-2016

Auto-SCT in AML

PasswegJR,BoneMarrowTransplantaFon2017

EBMTsurvey:IndicaFonsforauto-SCTinEUROPE-2015

…andwhataboutAML??

Auto-SCT in AML

NCCNGuidelinesVersion3,2017:AML

…andwhataboutAuto-SCT??

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

Auto-SCT in AML: WHAT

1970• Auto-SCTasbackupforpaFentslackingasiblingdonor

2000

• Developementsinallo-SCT:• nMAC,RIC• AlternaFvedonors

• Auto-SCThasfallenoutoffavour

2010• Developementsinauto-SCTpracFce:SCsource,condiFoning• MRD

Re-discoveryofauto-SCTinAML?

Auto-SCT in AML: WHAT

RandomizedAuto-SCTvsCHT

•  LowerRIvshigherNRM•  Be\erLFS•  SimilarOS

VellengaE,Blood2011

Zi\ounRA,NEngJMed1995HarousseauJL,Blood1997Burne\AK,Lancet1998SlovakML,Blood.2000

RandomizedAuto-SCTvsAllo-SCT

•  HigherRIvslowerNRM•  InferiorLFS•  SimilarOS

Cassileth,NEngJMed1998

Koreth,JAMA2009Suciu,Blood2003

Auto-SCT in AML: WHAT

Improvementsinauto-SCT

•  Grabsource:BMàPBSC•  CondiFoning:TBI-basedàBuCyàBuMel

GorinNC,Cancer2017

74%at3y

BuMel

BuCyBuMel

BuCy

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

Auto-SCT in AML: WHY

KeaFngA,Haematologica2013CornelissenJ,Leukemia2014

Overall survival

Auto-SCT in AML: WHY

MizutaniM,Bonemarrowtransplant2016

1998=2016: Auto-SCT vs sibling allo-SCT: similar survival

Auto-SCT vs 10/10 or 9/10 UD allo-SCT: ALWP-EBMT study

SaraceniF,JHematolOncol2016

PaDentcharacterisDcs auto-SCT 10/10UD 9/10UD

Totaln.2879 1202 1302 375

CytogeneFcrisk,n(%)

good 518(43) 608(47) 187(50)

intermediate 624(51) 550(42) 165(44)

poor 186(16) 615(47) 184(49)

Age 49(18-78) 51(18-76) 49(18-69)

Stemcellsource BM 53(4) 258(20) 58(16)

PBSCs 1149(96) 1044(80) 317(84)

CondiFoningintensity MAC - 619(48) 194(52)

RIC - 677(52) 180(48)

And what if compare auto-SCT vs MUD and MMUD?

3-yearsPS-weightedNRMrates

auto-SCT 4±2%

10/10UD 13±2%

9/10UD 21±2%

3-yearsPS-weightedRIrates

auto-SCT 49±3%10/10UD 29±3%9/10UD 23±5%

auto10/10UD

9/10UD

auto

10/10UD

9/10UD

COXLR10/10UDvsauto:p<10-5COXLR9/10UDvsauto:p<10-5

COXLR10/10UDvsauto:p<10-5COXLR9/10UDvsauto:p=0.0016

SaraceniF,JHematolOncol2016

Auto-SCT vs 10/10 or 9/10 UD allo-SCT: ALWP-EBMT study

auto

10/10UD

9/10UD

auto

10/10UD

9/10UD

3-yearsPS-weightedLFSrates

auto-SCT 48±3%

10/10UD 58±3%

9/10UD 55±3%

3-yearsPS-weightedOSrates

auto-SCT 64±3%10/10UD 63±3%9/10UD 58±4%

COXLR10/10UDvsauto:p=0.0016COXLR9/10UDvsauto:p=ns

COXLR10/10UDvsauto:p=nsCOXLR9/10UDvsauto:p=ns

SaraceniF,JHematolOncol2016

Auto-SCT vs 10/10 or 9/10 UD allo-SCT: ALWP-EBMT study

CzerwT,Cancer2016

Auto-SCT in AML: WHY

MessererD,Haematologica2008

Auto-SCT in AML: WHY

Lateeffectsfollowingallo-SCT

•  Immunedeficiency,endocrine,ocularandsalivaryglanddisfuncFon,skeletaldisorders,respiratorytract,dental,liver,sexualdisfuncFon,secondarycancers

• RRofgrade3–4chronichealthcondiFonsx2.65aberASCT,vsx4.5aberallo-HSCTcomparedwithsiblingsofthesurvivors

HoltanSG,Blood2015

Auto-SCT in AML: WHY

PROs CONs

OSabove60%longterm RIabout50%longterm

LowNRM(3-4%) LFS40-50%

NoGVHD NoGVL

Lowincidenceoflateeffects ManyptsfailtocollectPBSCs

Be\erQoLvsalloTheoreFcpossibilityof

grabcontaminaFonbyblastsAvailableinmostcenters

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

FirstdesignedforpaFentslackinganavailabledonor,isnowstrugglingtofindanupdatedroleinAML

SimilarOSvsmatchedallo-SCT;maybebe\erthanMMUD;lowerincidenceoflateeffects,be\erQoL

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

Auto-SCT in AML: WHO

DohnerH,Blood2017

Auto-SCT in AML: WHO: Good risk?

SchlenkRF,JClinOncol2004RolligC,JClinOncol2015

CBF-AML NPM1mutated/FLT3wt

Auto-SCT in AML: WHO: Good risk – CBF AML?

Burne\AK,Lancet1998SlovakML,Blood2000

CBF-AML

auto

allo

cht

VellengaE,Blood2011

Auto-SCT in AML: WHO: Good risk – CBF AML?

SchlenkRF,JClinOncol2004

So,isauto-SCTbe\erthanjustchemoterapyinCBF-AML?

Auto-SCT in AML: WHO: Good risk – CBF AML?

GorinNC,JClinOncol2008FernandezHF,Blood2011

Surelywedonotneedallo-SCTinCBFAML

Auto-SCT in AML: WHO: Good risk – CBF AML?

Auto-SCT in AML: WHO: Good risk – NPM1 mutated AML?

FerraraF,BiolBloodMarrowTransplant2010

NPM1+/FLT3wt

NPM1mutatedAML

Allothers

SchlenkRF,Blood2013

CEBPAdmAML

Auto-SCT in AML: WHO: Good risk – CEBPAdm AML?

Auto-SCT in AML: GITMO AML CR1 auto-SCT study

SaraceniF,BoneMarrowTransplant2017

RIGoodrisk

2y 27.7%(20.7-36.9)

5y 32.9%(25.3-42.7)

PaDentsn.809AMLautograbedinCR1

CytogeneFcsavailable

Auto-SCT in AML: GITMO AML CR1 auto-SCT study

LFSGoodrisk

2y 64.4(56.4-73.4)

5y 55.1(46.6-65.1)

SaraceniF,BoneMarrowTransplant2017

Auto-SCT in AML: ALWP-EBMT study-good risk subgroup

3-yearsPS-weightedKaplanMeierNRM RI LFS OS

auto 4±2% 36±5% 59±5% 78±4%

10/10UD 9±3% 19±5% 72±6% 77±5%

SaraceniF,JHematolOncol2016

Auto-SCT in AML: WHO: Good risk

VersluisJ,Leukemia2017

NPM1m/FLT3wt

Auto-SCT in AML: WHO

DohnerH,Blood2017

Auto-SCT in AML: WHO: Intermediate risk

CornelissenJ,Leukemia2014

VersluisJ,Leukemia2017

NPM1wt/FLT3wt

«[…]autologousisanopFonforpaFentslackingamatcheddonor»

Auto-SCT in AML: WHO: Intermediate risk

NRM RI LFS OS

auto 4±2% 51±4% 45±4% 60±4%

10/10UD 16±3% 30±5% 54±4% 60±5%

9/10UD 34±5% 21±4% 45±5% 48±4%

HR 95%CI p-value

NRM10/10 3,6 2-6,4 <10-4

9/10 9,4 4.9-18 <10-5

RI10/10 0,5 0,4-0,7 <10-59/10 0,4 0,3-0,8 0,004

HR 95%CI p-value

LFS10/10 0,7 0,6-0,9 0,019/10 1,1 0,7-1,6 0,7

OS10/10 0,98 0,7-1,3 0,99/10 1,6 1,001-2,5 0,049

PS–weightedCOX(autoasreference)

auto

10/10UD

9/10UD

auto

10/10UD

9/10UD

COXLR10/10UDvsauto:p=0.01COXLR9/10UDvsauto:p=ns

COXLR10/10UDvsauto:p=nsCOXLR9/10UDvsauto:p=0.049

3-yearsPS–weightedKaplanMeier

SaraceniF,JHematolOncol2016

Auto-SCT in AML: ALWP-EBMT study-int risk subgroup 1339intermediateriskAML

NRM RI LFS OS

auto 4±2% 51±4% 45±4% 60±4%

10/10UD 16±3% 30±5% 54±4% 60±5%

9/10UD 34±5% 21±4% 45±5% 48±4%

HR 95%CI p-value

NRM10/10 3,6 2-6,4 <10-4

9/10 9,4 4.9-18 <10-5

RI10/10 0,5 0,4-0,7 <10-59/10 0,4 0,3-0,8 0,004

HR 95%CI p-value

LFS10/10 0,7 0,6-0,9 0,019/10 1,1 0,7-1,6 0,7

OS10/10 0,98 0,7-1,3 0,99/10 1,6 1,001-2,5 0,049

PS–weightedCOX(autoasreference)

auto

10/10UD

9/10UD

auto

10/10UD

9/10UD

3-yearsPS–weightedKaplanMeier

COXLR10/10UDvsauto:p=0.01COXLR9/10UDvsauto:p=ns

COXLR10/10UDvsauto:p=nsCOXLR9/10UDvsauto:p=0.049

Auto-SCT in AML: ALWP-EBMT study-int risk subgroup

NRM RI LFS OS

auto 4±2% 51±4% 45±4% 60±4%

10/10UD 16±3% 30±5% 54±4% 60±5%

9/10UD 34±5% 21±4% 45±5% 48±4%

HR 95%CI p-value

NRM10/10 3,6 2-6,4 <10-4

9/10 9,4 4.9-18 <10-5

RI10/10 0,5 0,4-0,7 <10-59/10 0,4 0,3-0,8 0,004

HR 95%CI p-value

LFS10/10 0,7 0,6-0,9 0,019/10 1,1 0,7-1,6 0,7

OS10/10 0,98 0,7-1,3 0,99/10 1,6 1,001-2,5 0,049

PS–weightedCOX(autoasreference)

auto

10/10UD

9/10UD

auto

10/10UD

9/10UD

3-yearsPS–weightedKaplanMeier

autoLFS

COXLR10/10UDvsauto:p=0.01COXLR9/10UDvsauto:p=ns

COXLR10/10UDvsauto:p=nsCOXLR9/10UDvsauto:p=0.049

Auto-SCT in AML: ALWP-EBMT study-int risk subgroup

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

FirstdesignedforpaFentslackinganavailabledonor,isnowstrugglingtofindanupdatedroleinAML

SimilarOSvsmatchedallo-SCT;maybebe\erthanMMUD;lowerincidenceoflateeffects,be\erQoL

Favourablerisk.Intermediaterisk(??)

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

Auto-SCT in AML: WHEN

GorinNC,Leukemia1991.“Lateautograb”be\eroutcomeascomparedto“Earlyautograb”

Vendi{A,Leukemia2003MaurilloL,JClinOncol2008

MRDstatus!

Auto-SCT in AML: WHEN

Buccisano,BoneMarrowTransplant2017

MRD+

Auto-SCT in AML: WHEN

GorinNC,AmJHematol2017

FavourableriskMRDneg

Intermediate-2riskMRDneg

Auto-SCT in AML: WHEN

YaoJ,LeukRes2017

FavourableandintermediateriskAML,MRDneg

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

FirstdesignedforpaFentslackinganavailabledonor,isnowstrugglingtofindanupdatedroleinAML

SimilarOSvsmatchedallo-SCT;maybebe\erthanMMUD;lowerincidenceoflateeffects,be\erQoL

Favourablerisk.Intermediaterisk(??)

MRDnegaFve

Auto-SCT in AML: Overview

WHAT

WHY

WHO

WHEN

WHATNEXT

Auto-SCT in AML: WHAT NEXT

MuraroPA,NatRevNeur2017

The immune resetting following auto-SCT

Auto-SCT in AML: WHAT NEXT

Strategiestopreventrelapsefollowingauto-SCT

• Maintenance(inALLdoeswork!)• HypometylaFngagents• Deacetylaseinhibitors•  Targetedagents:FLT3-ITDinhibitors,IDH-1,IDH-2inhibitors,BCL2-BCLXinhibitors

•  AdopFvecelltherapy•  ImmunotherapyWetzlerM,Haematologica2013

GoodyearOC,Blood2012

BugG,Blood2013

ChenYB,Blood2014

SandmaierB,Blood2014

SteinEM,Blood2017

CurFA,Blood2011

Te\amanFS,BrJHaematol.2013

Al-Hussaini,Blood2016

SmithBD,Blood2014

Auto-SCT in AML: Conclusion

WHAT

WHY

WHO

WHEN

WHATNEXT

FirstdesignedforpaFentslackinganavailabledonor,isnowstrugglingtofindanupdatedroleinAML

SimilarOSvsmatchedallo-SCT;maybebe\erthanMMUD;lowerincidenceoflateeffects,be\erQoL

Favourablerisk.Intermediaterisk(??)

MRDnegaFve

Posttransplantstrategiestopreventrelapse

Aknowledgements

ArnonNagler

MyriamLabopin

Norbert-ClaudeGorin

AcuteLeukemiaWorkingPartyoftheEBMT

BipinN.Savani FrancescoLanza

HematologyandSCTRavennaHospitalMohamadMohty

GITMO

A{lioOlivieri

FrancescaBonifazi

EmmanuellePolge

Auto-SCT in AML: CONCLUSIONS

Mario Giacomelli - Campagna Marchigiana, Presa di coscienza sulla natura, 1977

Thankyou