骨髓增生异常综合征的新型治疗方法：超越低甲基化药物

骨髓增生异常综合征的新型治疗方法：超越低甲基化药物OverviewofMyelodysplasticSyndromesAgroupofmalignanthematopoieticstemcelldisorderscharacterizedby[1]BonemarrowfailurewithresultantcytopeniasandrelatedcomplicationsMacrocyticanemiaismostcommonpresentationDysplasticmorphologyisdiseasehallmarkGeneticabnormalities(acquired)arecommonTendencytoprogresstoAMLAge-adjustedincidence4.5/100,000[2]Approximately10,000/yrinUnitedStates(likelyunderestimated)[3,4]1.Greenberg.JNatlComprCancNetw.2013;11:838.2.SEER21Data.2012-2016.

3.Ma.Cancer.2007;109:1536.4.Ma.AmJMed.2012;125:S2.IPSS:AToolforRiskStratificationofMDSPrognosticVariableScoreValue00.51.01.52.0Bonemarrowblasts,%<55-10--11-2021-30Karyotype*GoodIntermediatePoor----Cytopenias†0/12/3------*Good=normal,-Y,del(5q),del(20q);intermediate=otherkaryotypicabnormalities;poor=complex(3abnormalities)orchromosome7abnormalities.

†Hb<10g/dL;ANC<1500/L;platelets<100,000/L.PrognosticVariableTotalScore00.51.01.52.02.5RiskLowIntermediateIIntermediateIIHighMediansurvival,yrs5.73.51.20.4Greenberg.Blood.1997;89:2079.RevisedIPSS:PrognosticValuesandRiskCategories

Greenberg.Blood.2012;120:2454.RiskScoreVerylow≤1.5Low>1.5to3.0Intermediate>3.0to4.5High>4.5to6.0Veryhigh>6PrognosticVariablePrognosticScoreValue00.51.01.52.03.04.0CytogeneticsVerygood--Good--IntermediatePoorVerypoorBMblast,%≤2-->2to<5--5-10>10--Hemoglobin,g/dL≥10--8to<10<8------Platelets,x109/L≥10050to

<100<50--------ANC,x109/L≥0.8<0.8----------SomaticMutationsinMDSPredictPrognosisIndependentoftheIPSS-RAlmost80%ofMDSpatientscarrysomaticgenemutations[1]MDS-associatedsomaticmutationscarryprognosticsignificance,independentofIPSS-R[2]Adverse:TP53,RUNX1,EZH2,NRAS,ASXL1,IDH2,etcFavorable:SF3B1

Prognosticvalueofindividualgenesmayvarybyclinicalcontextandindifferentcombinationsofmultiplemutations1.Papaemmanuil.Blood.2013;122:3616.2.Bejar.ASH2015.Abstr907.CurrentTreatmentOptionsforMDSPatientsPatientswithlower-riskMDSErythropoiesis-stimulatingagentsHypomethylatingagentsLenalidomideImmunosuppressantsPatientswithhigher-riskMDSHypomethylatingagentsAllogeneicstemcelltransplantKim.EMJHematol.2018;6:71.ManagementofPatientsWithLower-RiskMDSAnemiaManagementinLower-RiskMDSWithdel(5q)LenalidomideWithoutdel(5q)+lowserumEPOlevelandlighttransfusionburdenESAfollowedbylenalidomide±EPOorazacitidineWithoutdel(5q)+highserumEPOlevelandheavytransfusionburdenLenalidomide±EPOorazacytidineforolderpatientsIST(ATG+cyclosporinA)foryoungerpatientsScore>+1Score-1to+1Score<-1RA,RARS,RAEBIntermediate(23%,n=31)Poor(7%,n=29)Good(74%,n=34)ResponseProbabilityHellström-Lindberg.BrJHematol.2003;120:1037.PredictiveModelforResponsetoTreatmentWithrhuEPO+G-CSFTreatmentResponseCriteriaCRStableHb>11.5g/dLPRIncreaseinHbwith

>1.5g/dLortotalstopinRBCtransfusionsTreatmentResponseScoreS-EPOIU/L<100100-500>500+2+1-3TransfusionURBC/mo<2U/mo≥2U/mo+2-2LenalidomideorHypomethylatingAgentsinPatientsWithLower-RiskNon-del(5q)MDS17.5%0%26.9%2.5%Placebo(n=79)Lenalidomide(n=160)LineageHIinEvaluablePatients,

n/N(%)5-2-2

(n=50)5-2-5(n=51)5day(n=50)ErythroidMa19/43(44)19/43(44)20/44(46)RBC-TI12/24(50)12/22(55)16/25(64)PlateletMa12/28(43)8/30(27)11/22(50)AnyHI22/50(44)23/51(45)28/50(56)NeutrophilMa

4/23(17)4/23(17)9/24(38)AzacitidineMediandurationofresponse32.9wks

(95%CI:20.7-71.1)amongRBC-TI≥8wksLenalidomideSantini.JClinOncol.2016;34:2988.Lyons.JClinOncol.2009;27:1850.051015202530RBC-TI=8wksRBC-TI=24wksFisherexactP=.001FisherexactP=.001Patients(%)ExcessSmad2/3SignalingSuppressesLate-StageRBCMaturationinMDSTGF-βligands(eg,GDF15,GDF11,BMP6,

activinA)negativelyregulatelateerythropoiesisBonemarrowmicroenvironmentLuspaterceptreleasesmaturationblockOrthoEReticulocyteRBCSCF

IL-3

EPOBFU-ECFU-EEPO

responsiveEPO

dependentEPO8-64cells500cellsSustainedHbincreaseRapidHbincreaseMobilizescellsfromprecursorpoolsintobloodEffectreliesoncontinuousformationoflate-stage

precursorsfromearlierprogenitorsZhou.Blood.2008;112:3434.Luspatercept:MechanismofActionLuspaterceptisaninvestigationalfirst-in-classerythroid-maturationagentItneutralizesselectTGF-βsuperfamilyligandstoinhibitaberrantSmad2/3signalingandenhancelate-stageerythropoiesisinMDSmodels[1]InaphaseIIstudyinlower-risknon-del(5q)MDS,luspaterceptyieldedahighfrequencyoftransfusionreductionorRBC-TIinpatientswithringsideroblastsvsothersubtypes[2]

1.Suragani.NatMed.2014;20:408.2.Platzbecker.LancetOncol.2017;18:1338.Modifiedextracellulardomainof

ActRIIBHuman

IgG1Fc

domainLuspaterceptActRIIB/IgG1Fcrecombinant

fusionproteinPhaseIIIMEDALISTTrialofLuspaterceptvsPlaceboinLower-RiskNon-del(5q)MDSInternational,randomized,double-blind,placebo-controlledphaseIIItrialFenaux.ASH2018.Abstr1.Primaryendpoint:RBCTIfor≥8wksbetweenWk1andWk24Secondaryendpoints:RBCTIfor≥12wksbetweenWk1andWk24,modifiedhematologicimprovement–erythroidresponseperIWG2006criteria,DoR,HbchangefrombaselinePatients≥18yrsofagewith

non-del(5q)MDSandringsideroblastsperWHO2016criteria;IPSS-Rriskthatisverylow,low,orintermediate;refractory,intolerant,orineligibleforESAs;RBCtransfusiondependent

(N=229)Luspatercept

1.0mg/kg*SCQ3Wfor≥24wks(n=153)Placebo

SCQ3Wfor≥24wks(n=76)Randomized2:1*Couldbetitratedupto1.75mg/kgifneeded.TreatmentcontinueduntillackofclinicalbenefitorPDMEDALIST:PatientCharacteristicsCharacteristicLuspatercept(n=153)Placebo(n=76)Medianage,yrs(range)71(40-95)72(26-91)Male,n(%)94(61.4)50(65.8)Mediantimefromdiagnosis,mos(range)44.0(3-421)36.1(4-193)MedianRBCburden,units(range)*≥6units/8wks,n(%)<6units/8wks,n(%)5(1-15)66(43.1)87(56.9)5(2-20)33(43.4)43(56.6)Medianpre-transfusionHb,g/dL(range)7.6(6-10)7.6(5-9)Baselineserumerythropoietin,n(%)<200IU/L≥200IU/L88(57.5)†64(41.8)†50(65.8)26(34.2)IPSS-Rriskcategoryin16wkspriortorandomization,n(%)‡Verylow,LowIntermediate127(83.0)25(16.3)63(82.9)13(17.1)SF3B1mutation,n(%)141(92.2)65(85.5)†Fenaux.ASH2018.Abstr1.*Inthe16weekspriortorandomization.†Dataweremissingfor1patient.‡1(0.7%)patientintheluspaterceptarmwasclassifiedasIPSS-Rhighrisk.MEDALIST:EfficacyAmongprimaryendpointresponders,themediandurationofRBCTIresponsewas30.6wksintheluspaterceptarmvs13.6wksintheplaceboarmOutcome,%Luspatercept

(n=153)Placebo

(n=76)PValueRBCTI≥8wksinWks1-2437.913.2<.0001RBCTI≥12wksinWks1-2428.17.9.0002RBCTI≥12wksinWks1-4833.311.8.0003mHI-E*≥8wksinWks1-24Reductionof≥4RBCunits/8wksHbincreaseof≥1.5g/dL52.948.663.011.814.35.0<.0001mHI-E*≥8wksinWks1-48Reductionof≥4RBCunits/8wksHbincreaseof≥1.5g/dL58.854.269.617.121.45.0<.0001Fenaux.ASH2018.Abstr1.*Definedastransfusionreductionof≥4units/8wksormeanHbincrease≥1.5g/dL/8wksinabsenceoftransfusionsMEDALIST:SafetyTEAEofAnyGrade,%Luspatercept

(n=153)Placebo

(n=76)Fatigue26.813.2Diarrhea22.29.2Asthenia20.311.8Nausea20.37.9Dizziness19.65.3Backpain19.06.6Cough17.613.2Peripheraledema16.317.1Headache15.76.6Dyspnea15.06.6Bronchitis11.11.3Constipation11.19.2UTI11.15.3Fall9.811.8Fenaux.ASH2018.Abstr1.4patientsprogressedtoacutemyeloidleukemia:3inluspaterceptarm,1inplaceboarmThemostcommongrade3/4TEAEsinluspaterceptarmwereanemia(6.5%),fatigue(4.6%),andfall(4.6%)TEAE,%Luspatercept

(n=153)Placebo

(n=76)Patientswith≥1TEAE98.092.1≥1seriousTEAE≥1grade3/4TEAETEAEsleadingtodeath≥TEAEcausingdiscontinuation31.4

42.5

3.3

8.530.3

44.7

5.3

7.9Highertelomeraseactivity,expressionofhTERT,andshortertelomerespredictforshorterOSinlower-riskMDSImetelstatisafirst-in-classtelomeraseinhibitorthattargetscellswithshorttelomerelengthsandactivetelomerase;hasclinicalactivityinmyeloidmalignancies[1-3]FDAgrantedFastTrackdesignationforlower-riskMDS(October2017)IMergeisanongoingglobalphaseII/IIIstudyofimetelstatinRBCTDpatientswithlower-riskMDS(IPSSloworintermediate1)[4]1.Baerlocher.NEJM.2015;373:920.2.Tefferi.NEJM.2015;373:908.

3.Tefferi.BloodCancerJ.2016;6:e405.4.Steensma.ASH2018.Abstr463.Imetelstat:MechanismofActionSingle-arm,open-labelphaseIItrialPhaseIIIMergeTrialofImetelstatinLower-RiskMDSSteensma.ASH2018.Abstr463.Primaryendpoint:RBCTI≥8wksSecondaryendpoints:24-wkRBCTI,timetoTI,andTIdurationHI-E:transfusionreductionby≥4Uover8wks,MDSresponseperIWG,OS,timetoprogressionofAML,andsafetyExploratory:telomeraseactivity,hTERT,telomerelength,andgeneticmutationsPatientswithMDSIPSSloworintermediate1Relapsed/refractorytoESAorineligibleforESATransfusiondependent

(≥4uRBC/8wks)ANC≥1.5x109/LPlatelets≥75x109/LImetelstat

7.5mg/kgIVQ4W(2-hrinfusion)Premedication:diphenhydramine,hydrocortisone100-200mg(orequivalent)Supportivecare:RBCtransfusions,myeloidgrowthfactorsperlocalguidelinesIMerge:BaselineCharacteristics*Ofthe37patientswithsEPOlevelsreported.ParametersN=38Medianage,yr(range)71.5(46-83)Male,n(%)25(66)ECOGPS0/1,n(%)34(89)IPSSrisk,n(%)LowIntermediate1

24(63)14(37)BaselinemedianRBCtransfusionburden,units/8wks(range)8(4-14)WHO2001category,n(%)RARSorRCMD-RSAllothers

27(71)11(29)PriorESAuse,n(%)34(89)sEPO>500mU/mL,n(%)9*(24)Steensma.ASH2018.Abstr463.IMerge:LongestTransfusion-FreeIntervalAmongthepatientsachievingdurableTI,allshowedaHbriseof≥3.0g/dLcomparedwithbaselineduringthetransfusion-freeintervalSteensma.ASH2018.Abstr463.1501257550250Patients24-wkTI8-wkTIHI-E(TR)Noresponse248Treatmentgroup:imetelstat(N=38)100LongestTransfusion-FreeInterval(Wks)ParametersN=38Rateof8-wkTI,n(%)14(37)Rateof24-wkTI,n(%)10(26)MediantimetoonsetofTI,wks(range)8.1(0.1-33.1)MediandurationofTI,wks(range)NE(17.0-NE)IMerge:MostCommonTreatment-Emergent

AdverseEvents19patients(50%)haddosereductionsand26patients(68%)hadcycledelaysReversiblegrade3LFTelevationswereobserved

in3(8%)patientsConsideredtobeunrelatedtostudydrugbyIndependentHepaticReviewCommitteeMostCommonTEAEs051015202521237732012203556Grade1-2eventsGrade≥3events42060606NeutropeniaThrombocytopeniaAnemiaLeukopeniaASTincreasedALTincreasedHeadacheBronchitisNasopharyngitisDiarrheaPeripheraledemaBackpain1NumberofPatientsWith≥1TEAESteensma.ASH2018.Abstr463.IMerge:Occurrence/ReversibilityofGrade3/4Cytopenias2patientshadfebrileneutropenia12patientsreceivedG-CSFforneutropenia7patientsreceivedplatelettransfusions3patientswithgrade1bleedingevents

AllEvents,

n(%)ofPatients(N=38)Recoveredin<4Wks,

n(%)ofPatients

WithanEventNeutrophils,n(%)Grade310(26)8(80)Grade412(32)12(100)Platelets,n(%)Grade314(37)13(93)Grade410(26)9(90)Steensma.ASH2018.Abstr463.IronChelationTherapyinLower-RiskMDSWithIronOverloadChronictransfusionscommonlyleadtoironoverloadinpatientswithMDS[1]Ironchelationtherapyinlower-riskMDShasbeenassociatedwithimprovedOSandotherfavorableoutcomes[2-6]MoststudiesinthissettingareobservationalregistriesorretrospectiveDatafromlargerandomizedtrialsarelackingPhaseIITELESTOstudyevaluatedefficacy/safetyoftheironchelatordeferasiroxvsplaceboinlow-/intermediate-riskMDSwithironoverload[7]1.Gattermann.IntJHematol.

2018;107:55.2.Delforge.LeukRes.

2014;38:557.3.Lyons.LeukRes.

2017;56:88.

4.Neukirchen.

LeukRes.

2012;36:1067.5.Remacha.AnnHematol.

2015;94:779.6.Rose.LeukRes.

2010;34:864.7.Angelucci.ASH2018.Abstr234.PhaseIITELESTOTrialofDeferasiroxvsPlaceboinLower-RiskMDSMulticenter,randomized,double-blindphaseIItrialOriginallydesignedasphaseIIItrial(targetN=630)andrevisedduetolowenrollment;revisedtrialnotdesignedforstatisticalcomparisonsAngelucci.ASH2018.Abstr234.Randomized2:1;stratifiedbyIPSS(lowvsintermediate1),geographicregion(Asianvsnon-Asian)Compositeprimaryendpoint:EFS,definedastimefromrandomizationtodeathorfirstdocumentednonfatalevent(worsenedcardiacfunction,hospitalizationforCHF,impairedliverfunction,livercirrhosis,AMLtransformation)reviewedandconfirmedbyIRCSecondaryendpoints:OS,serumferritinlevelincrease,hematologic(erythroid)response,endocrinefunction(thyroidandglycemiccontrol),safetyPatientswithhematologicallystableIPSSlow-risk/intermediate1–riskMDS,serumferritin>1000ng/mL,ECOGPS≤2,historyoftransfusionwith15-75pRBCunits,nopriorhospitalizationforCHF,LVEF≥50%,

ALT/AST≤3.5xULN,Tbili≤1.5xULN,nolivercirrhosis,CrCl≥40mL/min(N=225)Placebo10-40mg/kgQDbasedondosingguidelines(n=76)Deferasirox10-40mg/kgQDbasedondosingguidelines(n=149)Finalassessmentafter3yrsoftreatmentTELESTO:BaselineCharacteristicsHigherfrequencyofpatientsaged≥75yrsindeferasiroxarmAngelucci.ASH2018.Abstr234.CharacteristicDeferasirox(n=149)Placebo(n=76)Medianage,yrs(range)66(21-88)65(20-80)Agecategory,n(%)<50yrs50to<65yrs65to<75yrs≥75yrs37(24.8)34(22.8)40(26.8)38(25.5)20(26.3)17(22.4)26(34.2)13(17.1)Male,n(%)93(62.4)44(57.9)Race,n(%)WhiteAsianOther68(45.6)66(44.3)15(10.1)36(47.4)34(44.7)6(7.9)MDSriskcategorylow/intermediate1,perIPSS,n(%)41(27.5)/108(72.5)21(27.6)/55(72.4)Priorchelationtherapy,n(%)35(23.5)14(18.4)TELESTO:EFS(PrimaryEndpoint)RiskofEFSeventreducedby36.4%withdeferasiroxvsplaceboBenefitwithdeferasiroxmaintainedinsensitivityanalysesTrendtowardsEFSbenefitwithdeferasiroxacrosssubgroupsMostcommonIRC-confirmedEFSeventsDeferasirox:AMLprogression(6.7%),worseningcardiacfunction(1.3%),hospitalizationforCHF(0.7%),impairedliverfunction(0.7%)Placebo:AMLprogression(7.9%),hospitalizationforCHF(3.9%),worseningcardiacfunction(2.6%),impairedliverfunction(1.3%)Angelucci.ASH2018.Abstr234.EFSOutcomeDeferasirox(n=149)Placebo(n=76)HRFromCoxModel(95%CI)*Events,n(%)62(41.6)37(48.7)0.636(0.42-0.96;

log-rankexploratoryP=.015)MedianEFS,days(95%CI)1440(1167-1559)1091(820-1348)3-yrEFS,%61.547.3*Coxmodelandlog-ranktestbothstratifiedbyIPSSriskcategoryandgeographicregion.TELESTO:OSandSerumFerritinMedianOSlongerby398daysindeferasiroxarmvsplaceboarmAfterdiscontinuingstudytreatment,52.1%ofplacebo-treatedpatientsinitiatedironchelationtherapySerumferritinlevelsdecreasedfrombaselinewithdeferasiroxandcontinuedovertimetobelowerthanwithplaceboSurvivalOutcomeDeferasirox

(n=149)Placebo

(n=76)HRFromCoxModel

(95%CI)*Events,n(%)57(38.3)33(43.4)0.832(0.540-1.279;

log-rankexploratoryP=.200)MedianOS,days(95%CI)1907(1440-NE)1509(1095-1804)*Coxmodelandlog-ranktestbothstratifiedbyIPSSriskcategoryandgeographicregion.Angelucci.ASH2018.Abstr234.TELESTO:Exposure-AdjustedAEsStudydrugexposuremarkedlydifferedbetweenarms,withlowermeandoseofdeferasirox(14.9mg/kg/day)reflectingdoseadjustmentsforserumferritinlevelsvsplacebo(23.5mg/kg/day)Angelucci.ASH2018.Abstr234.Exposure-AdjustedAEsin>10%PatientsinEitherArm,n(IR/100STY)Deferasirox(n=148)Placebo(n=76)AllSevereSeriousAllSevereSeriousDiarrhea53(24.7)4(1.3)5(1.7)20(23.9)2(1.9)4(3.8)Pyrexia51(21.8)11(3.8)14(4.9)17(18.7)3(2.9)5(4.9)Increasedbloodcreatinine38(15.9)*1(0.3)1(0.3)1(0.9)*00UpperRTI37(16.7)*4(1.3)4(1.3)20(22.7)*2(1.9)2(1.9)Cough32(12.6)1(0.3)2(0.7)11(11.3)00Nausea26(10.7)2(0.7)3(1.0)10(10.4)00Peripheraledema22(8.2)0011(10.9)2(1.9)2(1.9)Fatigue21(8.0)*1(0.3)013(13.5)*1(0.9)1(0.9)Constipation19(7.0)*2(0.7)3(1.0)12(12.9)*1(0.9)0Headache17(6.3)*0013(14.6)*2(1.9)0Abdominalpain14(4.9)*1(0.3)1(0.3)10(10.1)*1(0.9)1(0.9)*DifferenceinAEfrequency≥5%betweenarms.ManagementofPatientsWithHigher-RiskMDS01.0510152025303540TimeFromRandomization(Mos)00.10.20.30.40.50.60.70.80.9ProportionSurvivingCCRAzacitidineHR:0.58(95%CI:0.43-0.77;

log-rankP=.0001)24.5mos15mosFenaux.LancetOncol.2009;10:223.AZA-001Trial:AzacitidineSignificantlyImprovesOSinHigher-RiskMDSPhaseIITrialofImmuneCheckpointInhibitorsinMDSExploratoryphaseIIbaskettrial*Patients≥18yrsofagewithWHOMDS,untreatedorHMAfailure;acceptablePS,hepatic,andrenalfunction;nopriorinflammatoryorautoimmunedisease(N=76†)5-azacitidine75mg/m2IVx5daysQ28d+Nivolumab3mg/kgIVDays6,20(n=20)5-azacitidine75mg/m2IVx5daysQ28d+Ipilimumab3mg/kgIVDays6(n=21)*Datafor2cohorts(ipilimumab+nivolumaband5-azacitidine+ipilimumab+nivolumab)notincludedinthisanalysis.†Maximum20patients/cohort.‡5-azacitidineaddedbackifnoresponseafter6cyclesofICI.UntreatedHMAfailureNivolumab3mg/kgIVQ2W‡(n=15)Ipilimumab3mg/kgIVQ3W‡(n=20)StoppingrulesfortoxicityandresponsePrimaryendpoints:ORR(CR+PR+HI)inpatientswithHMAfailureORRinuntreatedpatientsGarcia-Manero.ASH2018.Abstr465.CheckpointInhibitorsinMDS:Response3patientswerenotevaluableMediannumberofcycles:4(range:1-29)Mediannumberofcyclestoresponse:3(range:1-15)Garcia-Manero.ASH2018.Abstr465.Response,n(%)FrontlineHMAFailureNivo+AZA(n=20)Ipi+AZA(n=21)Nivo(n=15)Ipi(n=20)ORR14(70)13(62)06(30)CR8(40)3(14)00mCR+HI2(10)001(5)mCR3(15)7(33)03(15)HI1(5)3(14)03(15)SD01(5)00NR5(25)5(24)15(100)13(65)CheckpointInhibitorsinMDS:OSinUntreatedPatientsGarcia-Manero.ASH2018.Abstr465.MedianOS,Mos

Notreached

11.81-YrOS,%

68

5021

2014

1711

104

80

40

11.000.750.500.250OS0612182430MosP=.36Strata

AZA+ipilimumab

AZA+nivolumabPatientsatRisk,nAZA+ipilimumab

AZA+nivolumabCheckpointInhibitorsinMDS:OSafterHMAFailureGarcia-Manero.ASH2018.Abstr465.1-YrOS,%

45

25MedianOS,Mos

8.5

8.020

1512

79

36

33

20

01.000.750.500.250OS0612182430MosStrata

Ipilimumab

NivolumabP=.48

Ipilimumab

NivolumabPatientsatRisk,nCheckpointInhibitorsinMDS:AdverseEventsOthergrade3/4toxicitiesincludedAKI(2inIpigroup),hemolysis(1inIpigroup),andcolitis(1inNivogroup)Grade2hypophysitis:1eachinIpi,Ipi+AZA,andNivo+AZAgroupsGarcia-Manero.ASH2018.Abstr465.AdverseEvents,n(%)FrontlineHMAFailureNivo+AZA(n=20)Ipi+AZA(n=21)Nivo(n=15)Ipi(n=20)AllGr3/4AllGr3/4AllGr3/4AllGr3/4Infection6(30)5(25)5(24)4(19)6(40)6(40)7(35)6(30)Rash5(25)08(38)1(5)1(7)07(35)1(5)Fatigue6(30)01(5)06(40)05(25)0Musculoskeletalpain7(35)04(19)2(10)004(20)0Pruritus1(5)04(19)01(7)1(7)5(25)0Transaminitis2(10)2(10)2(10)2(10)1(7)03(15)2(10)Constipation3(15)04(19)01(7)000Diarrhea1(5)03(14)01(7)02(10)0Nausea2(10)03(14)01(7)01(5)0Anorexia3(15)01(5)0002(10)0OtherAgentsBeingInvestigatedAfterHMAFailureNovelHMAsGuadecitabine:showedpreliminaryefficacyafterHMAfailureinphaseIIandaphaseIIItrialisongoingASTX727:32%ORRinpatientsafterHMAfailureinphaseIandaphaseIIItrialisongoingTargetedtherapiesEnasidenib:anIDH2inhibitorthathasshownactivityinpretreatedMDSisbeinginvestigatedinaphaseIIItrialenrollinghigh-riskMDSpatientswhoprogressedtoAMLwhilereceivingHMAsH3B-8800:aspliceosomeinhibitorthatisinphaseItrialofAML/MDSpatientswithHMAfailureVenetoclax:aBCL2inhibitorthatisbeinginvestigatedinphaseIItrialsofMDSpatientsafterHMAfailureRigosertib:amultikinaseinhibitorthatwastestedinaphaseIIItrialofMDSpatientsafter

HMAfailurebutthetrialdidnotmeetitsprimaryendpointSantini.Blood.2019;133:521.1.Bejar.NEJM.2011;364:2496.2.Lindsley.NEJM.2017;376:536.

RiskFactorHR(95%CI)PValueAge>55yrsvs

<55yrs1.81(1.20-2.73).004IPSSriskgroupIntermediate1vslow2.29(1.69-3.11)<.001Intermediate2vslow3.45(2.42-4.91)<.001Highvslow5.85(3.63-9.40)<.001MutationalstatusTP53+vsTP53-2.48(1.6-3.84)<.001EZH2+vsEZH2-2.13(1.36-3.33)<.001ETV6+vsETV6-2.04(1.08-3.86).03RUNX1+vsRUNX1-1.47(1.01-2.15).047ASXL1+vsASXL1-1.38(1.00-1.89).049200300250100150050ASXL1PatientsWithMutation(n)FrequencyofDriverMutationsinStudyCohortTP53DNMT3ATET2RUNX1SF3B1U2AF1SRSF2STAG2SETBP1PPM1DBCORNRASETV6EZH2PTPN11GATA2PHF6IDH2CBLJAK2ZRSR2WT1CUX1KRASNF1NPM1DDX41IDH1PRPF8CSF3R0.150.200.050.100FrequencyofCohortOS,AccordingtoTP53MutationStatus801004060020PatientsWhoSurvived(%)012345678YrsSinceTransplantationNo.atRiskNoTP53mutationTP53mutation1224

289757

109529

66370

39261

26183

20109

1453

632

5NoTP53mutationTP53mutationP<0.001OS,AccordingtoTP53MutationStatusandAge801004060020PatientsWhoSurvived(%)012345678YrsSinceTransplantationNo.atRiskNoTP53mutation<40yrsofage

≥40yrsofageTP53mutation<40yrsofage

≥40yrsofageTP53mutation,≥40yrsofageP=.502141010272621595981495133396759115255534100161521781055154267410233043131932TP53mutation,<40yrsofageNoTP53mutation,≥40yrsofageNoTP53mutation,<40yrsofageP<.001TP53MutationIsAssociatedWithInferiorOSOverallandPostAlloSCTinPatientsWithMDS[1,2]MDSWithFounderTP53MutationsAreHighlyResponsivetoDecitabineWelchandcolleagues[1]116patientswithAML(n=90)orMDS(n=26)treatedwithdecitabine(20mg/m2/dayx10daysQ28d)ExomesequencingpretreatmentandseriallyORRhigherinfavorable/intermediatecytogeneticriskvsunfavorable(29/43[67%]vs24/71[34%];P<.001)HigherORRinTP53mutantvswt(21/21[100%]vs32/78[41%];P<.001)CR/CRwithincompletecounthigherinTP53mutantvswt(13/21[62%]vs26/78[33%];P=.04)NorelationbetweenresponseandchangeincytosinemethylationorsubclonalTP53mutationChangandcolleagues[2]109patientswithMDStreatedwithdecitabine(20mg/m2/dayx5daysQ28d)ExomesequencingpretreatmentCRratehigherinTP53mutantvswt(10/15[66.7%]vs20/94[21.3%];P=.001)NodifferenceinORR(TP53mutant,11/15[73.3%]vswt,63/94[67.0%])PoorOSinTP53-mutatedMDS(median,14vs39mos;P=.012)1.Welch.NEJM.2016;375:2023.2.Chang.BrJHaematol.

2017;176:600.

RateofSomaticGeneMutationClearancein

Decitabine-TreatedPatientsWithAMLorMDSWelch.NEJM.2016;375:2023.ChangeinVAFbySomaticMutationClearanceofTP53muClones 100806040200VariantAlleleFrequencyDay0Cycle1,Day28Cycle2,Day28Cycle3,Day28Cycle4,Day281.00.50.0-0.5-1.0-1.5-2.0RateofChangeperDayinCopyNo.–AdjustedVariantAlleleFrequencyduringCycles1-4TP53SRSF2DNMT3AIDH2TET2ASXL1IDH1NRASRUNX1SF3B1OSbyTP53MutationStatusinPatientsWithAMLorMDSWelch.NEJM.2016;375:2023.MedianOSTP53mu12.7mosTP53wt15.4mosOSinPatientsWithTP53Mutationsvs.WildTypeOSWithalloSCTbyTP53MutationStatusSurvival(%)100806040200Days10000200400600800P=.79Wild-type

TP53TP53mutationPatientsatRisk,n

TP53mutation

Wild-typeTP5321

7820

517

312

74

16Survival(%)100806040200Days10000200400600800P=.99TransplantationandTP53mutation7

247

244

162

53

10Transplantationandwild-typeTP53PhaseIb/IITrialofAPR‑246andAzacitidinein

TP53-MutatedMDSandAMLTP53-mutated(mTP53)HMA-naiveMDSandAML(≤30%blasts)Sallman.ASH2018.Abstr3091.DosingDosingScheduleAssessmentSchedulePrimary:

Secondary:EndpointsSafety

ORR,PFS,OS,TP53VAFCRrate

ORR,PFS,OS,TP53VAFPhaseIbPhaseIIAssessment:D(-10)

(PhaseIbonly)C3D21C6D21,C9D21,….Lead-in3cycles3cyclesENROLLAPR-246APR-246

+AZAAPR-246

+AZADrugDoseAdmin.DurationAPR-246Azacitidine75mg/m2SC(orIV)PhIb:50/75/100mg/kgLBM

PhII:4500mgfixeddoseIV6hrsAzacitidineDay:orLead-in(phaseIbonly)