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