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QuébecHighlights

Denis Claude Roy, MD

Director of Research, East Montreal andCentre of Excellence in Cell TherapyHôpital Maisonneuve-RosemontCEO, CellCAN: Regenerative Medicine and Cell Therapy NetworkProf. Medicine, Université de Montréal

TranscriptionalLandscapeofAPLIdentifiesAberrantPodoplanin ExpressionAsaDefiningFeatureandMissingLinkfortheBleedingDisorderofThisDiseaseVincent-PhilippeLavallée,M.D.1,2,MiriamMarquis,Ph.D.3*,Marie-ÈveBordeleau,Ph.D.2*, Jalila Chagraoui,Ph.D.4*, TaraMacRae,M.Sc.4*, IsabelBoivin,M.Sc2*,GenevièveBoucher,M.Sc2*, PatrickGendron,M.Sc2*,SébastienLemieux,Ph.D.5,6*, ArnaudBonnefoy,Ph.D.7,8*,GeorgesE.Rivard,M.D.7,8,JoséeHébert,M.D.1,2,3,8 andGuySauvageau,M.D.,Ph.D1Hematology-OncologyDivision,Maisonneuve-RosemontHospital,Montréal,QC,Canada2TheLeucegene project atInstituteforResearchinImmunology andCancer,UniversitédeMontréal,Montréal,QC,Canada3QuebecLeukemia Cell Bank,Montréal,QC,Canada4InstituteforResearchinImmunology andCancer,Montréal,QC,Canada5InstituteforResearchinImmunology andCancer,UniversitédeMontréal,Montréal,QC,Canada6DepartmentofComputerScienceandOperationsResearch,UniversitédeMontréal,Montréal,QC,Canada7CHUSainte-Justine,M

Monday,December 5,2016:4:30PMMarriottGrand2-4(MarriottMarquisSanDiegoMarina)

TranscriptionalLandscapeofAPLIdentifiesAberrantPodoplanin ExpressionAsaDefiningFeatureandMissingLinkfortheBleedingDisorderofThisDiseaseVincent-PhilippeLavallée

• Acutepromyelocytic leukemia (APL)isafavorable-risksubgroupofAMLcharacterizedbythet(15;17)translocation.

• TheleadingcauseofearlydeathinAPLisuncontrolledbleedingmostlyattributedtoaberrantexpressionoftissuefactor(F3)andannexin A2(ANXA2)onleukemicpromyelocytes leading todisseminated intravascularcoagulationandhyperfibrinolysis,respectively.

• Topreventortreatsuchcomplications,early suspicionofAPLandrapidinitiationoftherapyandsupportivemeasuresarecritical.

• Podoplanin orPDPNisasurfaceglycoproteinexpressed inmostcell types,butnotinbloodcells.• CLEC-2,thePDPNreceptor,isexpressedonnormalplateletsandwasfoundtobenecessary for

theseparationofbloodandlymphaticvesselsduringembryogenesis.• PDPNexpression(whetherendogenousorectopic)incell lines inducesplateletaggregation,

whichcanbeinhibitedbychemical toolcompoundsorbymonoclonalantibodies

• AimsandMethods: Analysisofthetranscriptomeof30APLcomprisedintheLeucegene 430AMLcohort.


• Results: Severalmutatedgenesinthiscohort,mostofwhicharenon-specificandpreviously identified.

• CEBPE mutationsweretheonlyexceptionandwerespecifictoAPLspecimensinthiscohort (2/30vs0/400,p=0.005).

• Authorsidentified PDPN asthesinglemostdifferentiallyoverexpressedgeneinAPL

• PDPN isnotexpressedinwholeblood,bonemarrowandinanysortedcellsubpopulations fromthesenormaltissues,includingpromyelocytes.ThisindicatesthatplateletsareneverexposedtoPDPNintheadultvasculatureandrevealsthatthisgeneisectopicallyexpressedinAPLpromyelocytes.

• Hypothesis:aberrantPDPNexpressiononleukemicpromyelocytes contributestoabnormalplateletaggregationinAPLpatients.High PDPN expressionisassociatedwithlowerplateletcountsatpresentation(18vs34x1012/L,medianPDPN expression≥10vs<10RPKM,p=0.016,FigC).

• Stronginversecorrelationwasobservedbetweenthenumberofestimatedcirculating PDPN+ promyelocytes andplateletcounts

• Byincorporatinganti-PDPNantibody intheEuroFlow protocol,PDPNexpressiontestwas90%sensitiveand100%specificforAPL(n=48and50APLandnon-APLprimaryAML,respectively).Ofnote,5APLcasesconsideredpositiveexpressedlowlevelsofPDPN.

• ComparingexpressionofallcoagulationandfibrinolysisgenesinAPL(n=30)tothatofnon-APLspecimens(n=400),PDPNwasthemostdiscriminatorytranscript.ThisresultstandsinsharpcontrastwiththatfoundwithF3andANXA2whichlargelyoverlapintheseAPLversusnon-APLhumanAML.

769 Chemo-TranscriptomicAnalysisofComplexKaryotypeAMLRevealsIncreasedExpressionofCellCycleComponents andExquisiteDependencyonPolo-likeKinase1

Vincent-PhilippeLavallée,M.D.1,2,ClarisseThiollier,Ph.D.2*, CélineMoison,Ph.D.2*,Marie-ÈveBordeleau,Ph.D.2*,IsabelBoivin,M.Sc2*,GenevièveBoucher,M.Sc2*,PatrickGendron,M.Sc2*,SébastienLemieux,Ph.D.3,4*, AnneMarinier,Ph.D.5,6*, JoséeHébert,M.D.1,2,7,8 andGuySauvageau,M.D., Ph.D.1,6,7,81Hematology-OncologyDivision,Maisonneuve-RosemontHospital,Montréal,QC,Canada2TheLeucegene project atInstituteforResearchinImmunology andCancer,UniversitédeMontréal,Montréal,QC,Canada3DepartmentofComputerScienceandOperationsResearch,UniversitédeMontréal,Montréal,QC,Canada4InstituteforResearchinImmunology andCancer,UniversitédeMontréal,Montréal,QC,Canada5DepartmentofChemistry,UniversitédeMontréal,Montréal,QC,Canada6InstituteofResearchinImmunology andCancer– University ofMontreal,Montreal,QC, Canada7DepartmentofMedicine,FacultyofMedicine,UniversitédeMontréal,Montréal,QC,Canada8QuebecLeukemia Cell Bank,Montréal,QC,Canada

Monday,December5,2016:10:30AMPacificBallroom15-17(MarriottMarquisSanDiegoMarina)

89 TheRiskofMajorBleedingwithLow-Molecular-Weight-Heparins forVenousThromboembolisminDialysisPatients:TheQ-VTEStudy

AdiJ.Klil-Drori,MD1,2,JanieCoulombe,MSc3*,SharonJ.Nessim,MDMSc4,5* andVickyTagalakis,MD,MSc6,71DepartmentofOncology,McGillUniversity,Montreal,QC,Canada2JewishGeneralHospital,Montreal,QC,CAN3CenterforClinical Epidemiology,Jewish GeneralHospital,Montreal,QC,Canada4DivisionofNephrology,Department ofMedicine,Jewish GeneralHospital,Montreal,QC,Canada5DepartmentofMedicine,McGillUniversity,Montreal,QC,Canada6CenterforClinical Epidemiology,LadyDavisInstitute,Montreal,QC,Canada7DepartmentofMedicine,SirMortimerB.DavisJewish GeneralHospital,Montreal,QC,Canada

Saturday,December3,2016:10:30AMRoom31(SanDiegoConventionCenter)


AdiJ.Klil-Drori

• Background:Low-molecularweightheparins(LMWH)arenottraditionallyusedtotreatvenousthromboembolism(VTE)amongdialysispatientsbecausetheir renalclearance mayleadtolesspredictability inthedegreeofanticoagulationforagivendose.

• Theauthorsdetermined theriskofmajorbleedingwithLMWHcomparedwithvitaminKantagonist(VKA)useindialysispatientsdiagnosedwithVTEinarealworldsetting.


AdiJ.Klil-Drori

• Results:Inall,647dialysis patientswith VTEwere identified:467started VKA,82started LMWH,and96started both.Initiators ofLMWHwere 35dalteparin,26tinzaparin,19enoxaparin,and2nadroparin.

• Median (interquartile range,IQR)daily doseswere 12,500(7,500-17,570)IUdalteparin,16,080(13,540-20,000)IUtinzaparin,100(70-120)mgenoxaparin,and15,910(15,200-16,625)IUnadroparin.Median (IQR)durationofLMWHmonotherapy was 37(22-87)days,and132(65-235)forVKAmonotherapy.

• Morethan 90%ofLMWHmonotherapy was from 2004andonwards,and80%ofLMWHusershad cancer.

• Therewere 22majorbleeding events (86%gastrointestinal),20inVKAand2inLMWHusers.

• Nofatalbleeding occurred.

• Compared with VKAmonotherapy,LMWHmonotherapy was notassociated with majorbleeding(adjustedHR,1.21;95%CI:0.20-7.37).

527 TargetingPre-Leukemic StemCells inT-AcuteLymphoblastic Leukemia

BastienGerby,PhD1*,DiogoF.TVeiga,PhD1*,JanaKrosl,PhD1*,JulianneOuellette1*,AndréHaman1*,GenevièveLavoie,PhD1*,ImanFares,MSc1*,MathieuTremblay,Ph.D1*,VéroniqueLitalien1*,ElizabethOttoni1*,MilenaKosic1*,DominiqueGeoffrion1*,JoëlRyan1*,PaulMaddox,PhD2*,JalilaChagraoui,PhD1,AnneMarinier,Ph.D.1*,JoséeHébert,M.D.3,GuySauvageau,M.D.,Ph.D.1,BenjaminHKwok,PhD1*,PhilippePRoux,PhD1* andTrangHoang,PhD1

1InstituteofResearchinImmunology andCancer–University ofMontreal,Montreal,QC,Canada2UniversityofNorth CarolinaatChapelHill,ChapelHill,NC3TheLeucegene projectatInstituteforResearchinImmunology andCancer,UniversitédeMontréal,Montréal,QC,Canada

Sunday,December4,2016:5:30PMRoom10(SanDiegoConventionCenter)

527 Targeting Pre-Leukemic StemCells inT-AcuteLymphoblastic Leukemia

BastienGerby,PhD1

• CurrentchemotherapyofpediatricTcellacutelymphoblasticleukemia (T-ALL)efficientlyreducesthetumormasswith,however,undesirable longtermconsequencesandremainsineffectiveinadolescentandadultT-ALL.

• Furthermore,relapsecanbecausedbypre-leukemicstemcells (pre-LSCs)thatweresparedbycurrentprotocolsandevolvedtomalignancy.

• Adistinctivecharacteristic ofpre-LSCsistheircritical dependenceoninteractionswiththemicroenvironment forsurvival,whichguidedourstrategytotargetpre-LSCsusingniche-basedscreeningassays.


BastienGerby,PhD1

• Usingtransgenicmousemodelsthatcloselyreproducethehumandisease,theauthorshadshowedthattheSCL/TAL1andLMO1oncogenictranscriptionfactorsestablishapre-leukemicstatebyreprogrammingnormalpro-Tcellsintoaberrantlyself-renewingpre-LSCs(Gerbyetal.PloSGenetics,2014).

• Theynowprovidedirectevidencethatpre-LSCsaremuchlesschemosensitive thanleukemicblaststocurrentdrugs,duetoadistinctivelowerproliferativestateasassessedbyreal-timeimaginginacompetitiveassay.

• Theauthorsdesignedarobustprotocolforhigh-throughputscreening(HTS)ofcompoundstargetingprimarypre-LSCsthataremaintainedonstromalcellsengineeredforoptimalNOTCH1activationtomimickthethymic microenvironement.

• Screened1904compoundsandidentifiedUM0119979thatdisruptsbothcellautonomousandnon-cellautonomouspathways:UM0119979abrogatespre-LSCviabilityandself-renewalactivityinvivobyspecificallyinhibitingthetranslationofMYC,adownstreameffectorofNOTCH1,andpreventingSCL/TAL1activity.

• Incontrast:normalhematopoieticstem/progenitorcellsremainfunctional.

• Moreover,invivoadministrationofUM0119979efficientlyreducedtheleukemiapropagatingactivityofprimaryhumanT-ALLsamplesinxenograftedmice.

• Finally,inadditiontoSCL-LMO-inducedT-ALL,theseresultsrevealanovelpossibilityoftherapeuticinterventioninMYC-dependenthematologicmalignancies.


BastienGerby,PhD1

• Conclusion:

• Thisscreeningassay,builtonthegeneticdependenciesofpre-LSCs,revealedtheirvulnerabilitiestocompoundsthatinhibitboththeprimaryoncogenesandnon-cellautonomouspathwaystriggeredbythemicroenvironment.

• Theresultsillustratehowrecapitulatingtissue-likepropertiesofprimarycellsinhighthroughputscreeningisapromisingavenueforinnovationincancerchemotherapy.

75 Endosome-Mitochondria InterfaceControls IntracellularIronTrafficking inErythroidCells

AmelHamdi,PhD1,2,DanielGarcia-Santos,PhD1*,Tariq Roshan,MD3*,AlexSheftel,PhD4,5* andPremPonka,MD,PhD,FCMA1,21LadyDavisInstituteforMedical Research,Montreal,QC,Canada2DepartmentofPhysiologyandMedicine,McGillUniversity,Montreal,QC,Canada3McGillUniversity,Montreal,QC,Canada4SpartanBioscience Inc,Ottawa,Canada5HighImpactEditing,Ottawa,Canada

Saturday,December3,2016:10:00AMRoom3(SanDiegoConventionCenter)

75 Endosome-Mitochondria InterfaceControls Intracellular Iron Trafficking inErythroid Cells

AmelHamdi

• Inerythroidcells,morethan90%oftransferrin-derivedironentersmitochondriawhereferrochelatase insertsFe2+intoprotoporphyrin IX.However,thepathofironfromendosomestomitochondrialferrochelataseremainselusive.

• Theprevailingopinionisthat,afteritsexportfromendosomes,theredox-activemetalspreadsintothecytosolandmysteriouslyfindsitswayintomitochondriathroughpassivediffusion.

• Anopposingviewisthatthehighlyefficienttransportofirontowardferrochelatase inerythroidcellsrequiresadirectinteractionbetweentransferrin-endosomesandmitochondria(“kiss-and-run”hypothesis; PonkaBlood89:1,1997).

• Using3DliveconfocalimagingofreticulocytesfollowingtheirincubationwithMitoTrackerDeepRed(MTDR)andAlexaGreenTransferrin(AGTf),theauthorshavedemonstratedtransientendosome-mitochondriainteractions.

• Theyhavethuslyidentifiedapopulationofparticleslabeledwithbothfluorescentmarkers,representingendosomesinteractingwithmitochondria.FACSfollowedby2Dconfocalmicroscopyconfirmedtheassociationofbothorganellesinthedouble-labeledpopulation.


AmelHamdi

• Theauthorsexaminedwhetherreticulocytemitochondriainteractwithtransferrin(Tf)inacell-freesystem.LysatesofreticulocytespreviouslylabeledwithMTDRwereincubatedwithAGTf forvarioustimeintervals.

• IncreaseinthenumberofmitochondriaincontactwithfluorescentTf.Thiscanbepreventedbythepresenceofexcess,unlabeledFe2-Tf,butnotbyalbumin(Fig.1).Moreover,theadditionofunlabeledFe2-TftoreticulocytelysatesremovedAGTf frommitochondria,indicatingthatmitochondriafromreticulocytelysatesareassociatedwithTfR thatcanreversiblybindTf.


AmelHamdi

• Endosomescontainingmutatedrecombinantholotransferrin,whichcannotreleaseiron,remainassociatedwithmitochondria,whileendosomescontainingmutatedrecombinantapotransferrin,whichcannotbindiron,arenotassociatedwithmitochondria.Thesefindingsindicatethatendosomescontainingholo-Tfpromotetheirattachmentto,anddrivethedetachmentofapo-Tf-endosomesfrom,mitochondria,respectively.

• Byco-immunoprecipitationassay (frommurineeryhroleukemia [MEL]cellsandreticulocyteslysates), theauthorspurified thevoltage-dependentanionchannel2(VDAC2),whichislocatedattheoutermembraneofthemitochondrionwith DMT1.TheyconfirmedthecolocalizationofVDAC2andDMT1inMELcellsandreticulocytesbybothimmunofluorescenceandconfocalmicroscopy.Moreover,theyfoundasignificantdecrease inthenumberofmitochondriaincontactwithTf-endosomesafterdepletionof VDAC2inMELcellsoraftertreatmentofreticulocytelysateswiththemitochondrialuncoupler CCCP, furthersupportingtheconceptofaphysicalinteractionbetweenendosomesandmitochondria.

• DepletedMELcellsofVDAC2orinhibitedVADC2usingerastin (aspecificVDAC2inhibitorthataltersitsgating)andmeasured59Feincorporationfrom59Fe-Tfintoheme.Theyfounddecreased59FeincorporationintohemeofMELcellswithsilencedorinhibitedVDAC2supportstheideathatthisouter-membranemitochondrialproteinisinvolvedintheinteractionofendosomeswithmitochondria.

2306 Bortezomib Consolidation after Nonmyeloablative AllogeneicStemCell TransplantationLeadstoaHighIncidenceofImmunophenotypic CompleteResponse inYoungand/orHigh-Risk MultipleMyeloma Patients

RichardLeBlanc,MD1,ImranAhmad,MD2,Rafik Terra,PhD3*,SéverineLandais,PhD2*,MichaelSebag,MD,PhD4,Emilie Lemieux-Blanchard,MD5,NadiaM.Bambace,MD2,LeaBernard,MD2,SandraCohen,MD1,Jean-SebastienDelisle,MD,PhD6,ThomasKiss,MD2,SilvyLachance,MD6,Denis-ClaudeRoy,MD2,GuySauvageau,MD,PhD7 andJeanRoy,MD81ServiceofHematologyandMedical Oncology,Department ofMedecine,Maisonneuve-RosemontHospital,Montreal,QC,Canada2DivisionofHematologyandMedical Oncology,StemCell TransplantProgram,Department ofMedicine,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEast,Montreal,QC,Canada3ImmunologyLaboratory,Department ofHematologyLaboratory,Maisonneuve-RosemontHospital,Montreal,QC,Canada4McGillUniversityHealthCentre,Montreal,QC,Canada5Hemato-oncologydepartment,CHUM,Montreal,QC,Canada6DivisionofHematologyandMedical Oncology,StemCell TransplantProgram,Department ofMedicine,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEastMontreal,Montreal,QC,Canada7DepartmentofMedicine,IRIC/University ofMontreal,Montreal,QC,Canada8DivisionofHematologyandMedical Oncology,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEastMontreal,Montreal,QC,Canada

Saturday,December3,2016,5:30PM-7:30PMHallGH(SanDiegoConventionCenter)

2306 BortezomibConsolidationafter NonmyeloablativeAllogeneicStemCell TransplantationLeadstoaHighIncidenceofImmunophenotypic CompleteResponse inYoungand/orHigh-RiskMultipleMyeloma Patients

RichardLeBlanc

• Allogeneic stemcelltransplantation(alloSCT)istheonlycurativemodalityfornewlydiagnosedmultiplemyeloma(NDMM)patients(pts).

• Theauthorshavepreviouslyshowninalargecohortof92ptsthatrelapseremainscommon(49%)andtheincidence/severityofchronicGVHDissignificant(79%)aftertandemauto-alloSCTinNDMMpts(Ahmadetal.BMT2016;51:529).

• Theyhypothesizedthatatandemauto-nonmyeloablative (NMA)alloSCT followedbybortezomib (btz)consolidationmightbesafe,whiledecreasingboththeseverity/incidenceofchronicGVHDandtheriskofrelapseinyoungand/orhigh-riskNDMMpts.

• Inaddition,theyhypothesizedthatbortezomibmightfurtherincreasedepthofresponsesafteralloSCT.


RichardLeBlanc

• Methods:NDMMptswitheitherISSstageIII,plasmacellleukemia,abnormalcytogeneticsdefinedast(4;14)withISSIIorIII,t(14;16),t(14;20),17p-,1p-,or1q+in≥10%ofpurifiedplasmacellsorage≤50yearswitha6/6siblingor8/8unrelateddonorwereprospectivelyenrolledinthisphaseIItrial.

• Afterabtz-basedinductionwith≥partialresponseandautologous(A)SCT,outpatientNMAalloSCTwasperformedwitheitheraconditioningoffludarabine30mg/m2 x5daysandcyclophosphamide300mg/m2 x5days(siblingdonor)orfludarabine30mg/m2 x3daysandTBI2Gy(unrelateddonor),followedbyG-CSFmobilizedstemcellsinfusion.

• AcuteGVHDprophylaxisconsistedoftacrolimusandmycophenolatemofetil. Btz 1.3mg/m2 SCevery2weekswasstartedonday+120afteralloSCT for1year.

• BonemarrowaspiratesbeforealloSCT,beforestartingbtz andevery3monthsthereafterwereprospectivelycollectedfor2yearsinordertoassesstheimpactofbtz onminimalresidualdisease(MRD)byahighlysensitive(≥10-5)multiparametric flowcytometryusingthe8-colorEuroflowprotocolevaluating≥10x106cells/specimen.

• MRDnegativitywasdefinedasthedetectionof < 30clonalaberrantplasmacells.ResponseevaluationisbasedonIMWGcriteriaincludingimmunophenotypic completeresponse(iCR)definedasastringentCR(sCR)plusanegativeMRD.Immunophenotypic remission(iR)isdefinedasMRDnegativityregardlessofotherdiseasestatus.


RichardLeBlanc

4677 TandemAutologousFollowedByNonmyeloablative AllogeneicTransplantationinRelapsedHighRisk Follicular Lymphoma LeadstoExcellentLongTerm Progression-FreeSurvival after 8Years ofFollow-upClinical AllogeneicTransplantation:ResultsPosterAbstractsSession: 732.Clinical AllogeneicTransplantation:Results:PosterIII

Monday,December 5,2016,6:00PM-8:00PMHallGH(SanDiegoConventionCenter)

MagalieTardif,MSc,MDStudent1*,ImranAhmad,MD2,NadiaM.Bambace,MD2,LeaBernard,MD2,LambertBusque,MD2,Jean-SebastienDelisle,MD,PhD3,ThomasKiss,MD2,IsabelleFleury,MD2,SilvyLachance,MD3,LuiginaMollica,MD,PhD4,CélineNkoué,MD2*,Denis-ClaudeRoy,MD2,JeanRoy,MD2 andSandraCohen,MD51UniversityofMontreal,Maisonneuve-RosemontHospitalCIUSSSEast,Montreal,QC,Canada2DivisionofHematologyandMedical Oncology,StemCell TransplantProgram,Department ofMedicine,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEast,Montreal,QC,Canada3DivisionofHematologyandMedical Oncology,StemCell TransplantProgram,Department ofMedicine,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEastMontreal,Montreal,QC,Canada4HôpitalMaisonneuve-Rosemont,Montreal,QC,Canada5ServiceofHematologyandMedical Oncology,Department ofMedecine,Maisonneuve-RosemontHospital,Montreal,QC,Canada

4677 TandemAutologousFollowedByNonmyeloablative AllogeneicTransplantationinRelapsedHighRisk FollicularLymphoma LeadstoExcellentLongTerm Progression-FreeSurvival after 8Years ofFollow-up

MagalieTardif,MSc,MDStudent

Prospective protocol initiated in April 2003for pts with high risk relapsed FL as defined by chemorefractory disease, early 1st relapse, >1st relapse or transformation into aggressive histology.

At least one therapy was attempted to document chemosensitivity prior to ASCT.

Rgardless of disease status prior to transplant, pts underwent ASCT followed 3 months later by an outpatient NMT from an HLA-identical sibling.

NMT comprised 5 days of fludarabine 30 mg/m2/day and cyclophosphamide 300mg/m2/day followed by an infusion of >2x106CD34+ cells/kg.

GVHD prophylaxis: tacrolimus starting on day (D) -8 to achieve levels of 8-12 nmol/L then tapered off by D+100 or D+180 depending on disease risk and of

Report on 40 pts with a median f/u of 8 yrs.



• UpuntilJuly2015,40ptswereenrolledwithamedianageof50 yrs (34-65).

• Ptshadpreviouslybeentreatedwithamedianof3linesoftherapy(2-6).

• MediantimefromdiagnosistoASCTwas33months.DiseasestatusatASCTwas:14CR,16PRand10refractory.

• ConditioningforASCTincludedBEAM/BEAC(n=39),andCy-TBI(n=1).

• 4ptsreceivedradiotherapyafterASCTtositesofpreviouslybulkydisease.

• MediantimebetweenASCTandNMTwas138days(75-238).

• PreNMTdiseasestatuswas:25CR,12PRand3refractory.

• EngraftmentwaspromptinallptsafterASCTandmedianneutrophilandplateletrecoverywererespectively13days(0-19)and0day(0-18)postNMT.

1535 Modeling ofPediatric AcuteMegakaryoblastic Leukemia Using CordBloodStem/Progenitor CellsOncogenes andTumor SuppressorsProgram: PosterAbstractsSession: 603.Oncogenes andTumor Suppressors:PosterI

Saturday,December 3,2016,5:30PM-7:30PMHallGH(SanDiegoConventionCenter)SophieCardin,PhD1*,LouiseLaramee2*,TaraMacRae,M.Sc.3*,Jalila Chagraoui,PhD4,GuySauvageau,MD,PhD5,R.KeithHumphries,MD,PhD6,JoséeHébert,M.D.7,BrianT.Wilhelm,PhD8* andSoniaCellot,MD,PhD91Medecine,Universite deMontreal,Montreal,QC,Canada2CHUSJ,Montreal,Canada3InstituteforResearchinImmunology andCancer,Montréal,QC,Canada4LaboratoriesofMolecular Genetics ofHematopoietic StemCells,InstituteforResearchinImmunology andCancer(IRIC),Montreal,QC,Canada5DepartmentofMedicine,IRIC/University ofMontreal,Montreal,QC,Canada6TerryFoxLaboratory,BritishColumbiaCancerAgency,Vancouver,BC,Canada7TheLeucegene project atInstituteforResearchinImmunology andCancer,UniversitédeMontréal,Montréal,QC,Canada8IRIC/University ofMontreal,Montreal,QC,Canada9UniversityofMontreal,Montreal,QC,CAN

1535 Modeling ofPediatric AcuteMegakaryoblastic LeukemiaUsing CordBloodStem/Progenitor Cells

SophieCardin,PhD1*,

• Pediatric acutemegakaryoblasticleukemia (AMKL)accounts for10%ofchildhoodacutemyeloid leukemia (AML)casesandremainsahighfatalitycancer.CBFA2T3-GLIS2,NUP98-KDM5A,RBM15-MKL1andMLLgene rearrangementsarerecurrentaberrationsthat aremutuallyexclusiveandfound atsimilar frequencies inhalf thecasesofpediatric AMKL.

• Therecently identifiedCBFA2T3-GLIS2andNUP98-KDM5Achimeric oncogenesareassociatedwith inferior outcomes (overall survival,OS:~30%)comparedtopatientsharboring theRBM15-MKL1gene fusion(OS~70%).

• ToinvestigateNUP98-KDM5Adriven leukemogenesis,humancell lines andmousemodels wereengineeredusing overexpressionofthechimeric oncogene inCD34+cordblood (CB)stem/progenitor cells.

1535 Modeling ofPediatric AcuteMegakaryoblastic LeukemiaUsing CordBloodStem/Progenitor Cells

SophieCardin,PhD1*,

• cDNAoftheNUP98-KDM5Afusion:nuclearporeproteinnucleoporin98(NUP98)genefusedtothehistonelysinedemethylase5A(KDM5A)gene,wasclonedintoaMNDUlentiviralvectorcarryingaGFPreportergene.

• Usingoptimizedcultureconditions,10,000freshlyisolatedCB-CD34+ (day0)cellswereseededinmultiplewells invitroandtransducedwitheitherNUP98-KDM5Aorcontrol(CTL)vectors.

• Xenotransplantationof75%ofday7cellsinimmunodeficient miceresultedinthedevelopmentofovertAMKLin1of3miceafter32weeks.Recipientmouseboneswerewhiteandbrittle,andthemarrowcavityinfiltratedby30%hCD45loCD61+GFP+ leukemicblasts,withtypicalmegakaryoblasticmorphology.

• Theleukemicblastswerealsodetectedinblood(5%),andinenlargedspleen(0.2%).SecondarytransplantationofisolatedAMKLcells(frombonemarrowandspleen)wasperformed,alongwithexpressionprofilingbyRNAsequencing.

2372 BurdenofRelapseFollowing AllogeneicHematopoietic StemCell TransplantationonHealthCareResourceUtilization intheManagementofAcuteLeukemiaandMyelodysplastic SyndromeHealthServicesResearch—Malignant ConditionsProgram:OralandPosterAbstractsSession: 902.HealthServicesResearch—MalignantConditions:PosterI

Saturday,December 3,2016,5:30PM-7:30PMHallGH(SanDiegoConventionCenter)SilvyLachance,MD1,Joelle Bibeau2*andJeanLachaine3*1DivisionofHematologyandMedicalOncology,StemCell TransplantProgram,Department ofMedicine,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEastMontreal,Montreal,QC,Canada2PeripharmInc,Montreal,QC,Canada3FacultyofPhamacy,Universite deMontréal,Montreal,QC,Canada

2372 Burden ofRelapseFollowing AllogeneicHematopoietic StemCell TransplantationonHealthCareResourceUtilization intheManagementofAcuteLeukemia andMyelodysplastic Syndrome

SilvyLachance

1226 DonorLymphocytesDepletedofAlloreactiveT-Cells(ATIR101) ImproveEvent-FreeSurvival(GRFS)andOverallSurvivalinaT-CellDepletedHaploidenticalHSCT:Phase2TrialinPatientswithAMLandALL

Denis-ClaudeRoy,MD1,SilvyLachance,MD2,JeanRoy,MD3,IrwinWalker,MBBS4,JohanMaertens,MD,PhD5*,Jean-SebastienDelisle,MD,PhD2,StephenRonanFoley,MD6,PhilippeLewalle,MD-PhD7*,EduardoOlavarria8*,DominikSelleslag,MD9,ManfredRüdiger,PhD10*,JurjenVelthuis,PhD10*,LisyaGerez10*,JeroenRovers,MDPhD10*,HalvardBonig,MD,MA11 andStephanMielke,MD121BloodandMarrow TransplantationProgram/DivisionofHematology&Oncology,HopitalMaisonneuve-Rosemont/Universite deMontreal,CIUSSSEastMontreal,Montreal,QC,Canada2DivisionofHematologyandMedicalOncology,StemCell TransplantProgram,Department ofMedicine,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEastMontreal,Montreal,QC,Canada3DivisionofHematologyandMedicalOncology,University ofMontreal,Maisonneuve-RosemontHospitalCIUSSSEastMontreal,Montreal,QC,Canada4JuravinskiHospitalandCancerCentre,McMasterUniversity,Hamilton,ON,Canada5DepartmentofHematology,University HospitalGasthuisberg,Dept.ofHematology,Leuven,Belgium6McMasterUniversity,Department ofMedicine,Juravinski HospitalandCancerCentre,Hamilton,ON,Canada7LaboratoryofExperimentalHematology,JulesBordetInstitut,Bruxelles,BEL8CentreforHaematology,ImperialCollege LondonatHammersmithHospital,London,UnitedKingdom9AZSt-Jan BruggeAV,Brugge,Belgium10KiadisPharma,Amsterdam-Duivendrecht,Netherlands11GermanRed CrossBloodCentreandInstituteforTransfusionMedicine andImmunohematology,Johann-Wolfgang-GoetheUniversity,Hematopoietic Cell ResearchGroup,Frankfurt,Germany12DivisionofHematologyandOncology,Department ofInternalMedicine II,WürzburgUniversity Medical Center,Würzburg,Germany

Monday,December5,2016:6:30PMRoom30(SanDiegoConventionCenter)

ChallengeinHaploidentical DonorTransplantation

HAPLOIDENTICALDONOR

LEUKEMIA PATIENT

XX

XX X

EffectsATIR101procedure• SelectiveremovalofGVHD-causingT-cells

• Preservationoftheimmunerepertoire

• Keyimmunecellsareretainedtoprotectagainstinfections

• T-cellsdirectedagainstleukaemic antigensareretained

• ATIR101manufacturing

Potentialbenefits

• 5daymanufacturingprocess

• Release data

• PerformedinadvanceofHSCT

procedure

• Cells cryopreserveduntil

infusion

1. Immune cells collected and mixed

ex vivo

2. Activation of donor T- cells

GVHD causing T-cells donor cells are activated by patient cells

Patie

ntDo

nor

3. TH9402 addition

Proprietary photosensitizing reagent TH9402 is added.

TH9402 is retained only in activated donor T-cells

4. Exposure to light

Cells are exposed to light, which activates TH9402, generating toxic oxygen radicals

5. ATIR infusion

Cells are formulated for infusion

Infusion done 28-42 days after Haplo HSCT

Day 1 - 4 Day 5

• Phase IIclinical trial• Aimistodevelopanimmunosuppressant-free transplantregimenforhaploidentical donor

transplantation

• BasedonT-celldepletion:CD34+-megadoseapproach (Perugia)

• Pre-emptivepost-HSCTadministrationofdonor lymphocytes(ATIR101)depleted ofalloreactiveT-cells

• AvoidGVHD• Reduceinfections/TRM/relapse

Myeloablativeconditioning

T-cell depleted stem cell graft from family member

Isolation

No prophylactic immunosuppression

CD34+ PBMC graft

Donor lymphocyte infusion

28 – 32 days post-HSCT

Haplo HSCT ATIR101 infusionConditioning

Selective photodepletion to eliminate GVHD-causing T-cells

Donordonor

• 1 Mrozek K, et al. JCO 2012, 30 (36):4515-4523 • 2Armand P, et al. Blood 2014, 123 (23); 3664-3671

• Patient&DonorcharacteristicsDiagnosisPatient & Donor

• N=23patients(HSCT+ATIR101)

• Medianpatientage(range):41years(21–64)

• Gender:13female,10male

• Mediandonorage(range):33years(21- 61)

• HLAmatching(HLA-A,B,DR)

– 3/6match:16

– 4/6match:6 5/6match:1(7/10match)

• Donors:

– Father/mother 4(17%)

– Sibling 9(39%)

– Son/daughter 9(39%)– Other 1(4%)

• Acutemyeloidleukemia–N=16(70%)

– 11inCR1

– 5inCR2

• Acutelymphoblasticleukemia –N=7(30%)

– 4inCR1

– 3inCR2

• Cytogeneticriskprofile1:

– Favorable 0– Intermediate

9(39%)

– Adverse 14(61%)

• Disease-riskindex2:

– Lowriskindex0

– Intermediateriskindex 10(43%)

– Highriskindex13(57%)

• Transplantationcharacteristics(n=23patients)Conditioning

HSCT

HSCT

Prophylaxis GVHD

• TBI(1200cGy;n=11)ormelphalan(120mg/m2;n=12)

• Thiotepa (10mg/kg),fludarabine (30mg/m2x 5d)andATG(2.5mg/kgx 4d)

• CliniMACS®CD34isolationsystem(Miltenyi Biotec)

• Target:8-11x106 CD34+cells/kg,withmax.of3x104

CD3+cells/kg

• NoGVHDprophylaxis

• CMV/EBVmonitoring

• Prophylacticuseofganciclovir /foscarnet (CMV+recipient/donor)

• NoGradeIII-IVGVHD

• GradeIIacuteGVHDin3patients

• ChronicGVHD:1patient

Graft Median(cells/kg)

range

CD34+ 10.9x 106 3.2– 24.4x106

CD3+ 0.28x 104 0– 1.8x 104

Engraftment Median(days) range

Neutrophils 12 8– 34

Platelets 12 9– 35

ASH2016,Session711,OralpresentationonMondayDecember 5,18h30

1226DonorLymphocytesDepletedofAlloreactiveT-Cells(ATIR101)ImproveEvent-FreeSurvival(GRFS)andOverallSurvivalinaT-CellDepletedHaploidenticalHSCT:Phase2Trial inPatientswithAMLandALLDenis-ClaudeRoy

ISCT 2018 GENERAL MEETING

Cell & Gene Therapy RevolutionMontreal: March 9-10, 2017

Invitationtomeetings:

• Québec City: 27 janvier 2017• Montréal: 7 avril 2017

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