maria rosaria villa u.o.c. ematologia p.o. ascalesi … · published: 27 june 2017. authors: esmo...

L’approccioterapeu-co

MariaRosariaVillaU.O.C.Ematologia

P.O.AscalesiASLNA1Centro

DISCLOSURE

Nome:MariaRosariaCognome: VillaImpiegonell’industriafarmaceu7canegliul7mi5anni:NOInterssifinanziarinelcapitalediun’industriafarmaceu7ca:NOAltrirappor7conl’industriafarmaceu7ca:NO

§  Treatment decisions

§  Patients with del 17p/TP53 mutations

§  Complex Karyotype/NOTCH1

§  IGHV mutational status

§ Outcomes in 1 line and R/R

AGENDA

•  Alargenumberofbiological,gene-candmolecularmarkersofprognosisinCLLhavebeeniden-fied1

•  Ofthese,IGHVmuta7onstatusanddel(11q)areamongthemostwell-studied1

•  Recentevidenceindicatesthattes-ngforIGHVmuta-onstatusanddel(11q)shouldbeperformedasstandardforallpa-entswithnewly-diagnosedCLLpa-ents1

•  Astheseareconsistentandrobustprognos7cmarkers,independentofclinicalstage,whichprovidescomplementaryinforma7ononPFSandOS1

•  ESMOguidelinesrecommendanalysisforthedetec-onofdel(11q)andofIGHVmuta-onstatusas‘desirable’beforethestartoftherapy2,3

Treatment decisions

CLLPrognos7cMarkers

Serummarkers

FISHcytogene7cs[del(11q)Del(17P)]

IGHVmuta7onstatus

CD38expression

ZAP-70expression

Experimentalmarkers

MRDnega7vity

1.  ParikhS,etal.SeminOncol2016;43(2):233-40.2.  Stra7P,etal.Blood2015;126(4):454-462.3.  EichhorstB,etal.AnnOncol2015;26(Suppl5):v78-v84.

Published: 27 June 2017. Authors: ESMO Guidelines Committee

•  ESMO guidelines recommend analysis for the detection of del(11q) and of IGHV mutation status as ‘desirable’ before the start of therapy

•  Only patients with

del(17p) and/or TP53 mutation are highlighted as needing specific regimens

Published: 27 June 2017. Authors: ESMO Guidelines Committee

•  Current ESMO treatment guidelines do not recommend treatments according to IGHV or del(11q) mutational status

•  Only patients with del(17p) and/or TP53 mutation are highlighted as needing specific regimens



§  Complex Karyotype



AGENDA

Background: UpdatedresultsfromCLL8trial(FCvsFCR):ByFISH

Overall Survival Progression Free Survival

Del17p: patients treated with FC /FCR PFS less than 12 months!³

Patients with TP53 aberrations respond less well to treatment than do those without this high-risk genetic lesion, resulting in early relapse and inferior survival1,2

1. Hallek M, et al. Lancet. 2010;376:1164-1174. 2. Stra7 P, et al.Haematologica. 2014;99:1350-1355. 3. Stilgenbauer et al., Blood 2014

BR is Less Effective in Relapsed or Refractory CLL With Del17p

FischerKetal.JClinOncol.2011;29:3559-3566

Event-FreeSurvival

Cytogene-csbyFISH

OverallResponseRate

Notabnormal 62.5%

Del17p 7.1%*

Del11q 92.3%

12qtrisomy 100.0%

Del13q 75.0%

*P=0.006vsnotabnormal.

del17p

Del17p:median=4.8

months

Notabnormal:median=13.8

months

Mul7center,phase2study78pa7ents

Jonesetal.,EHA2016

CLL R/R patients with del17p patients treated with ibrutinib

Idelalisib+OfatumumabvsOfatumumabinR/Rpa-entswithdel17p/TP53muta-on

Jonesetal.LancetHematology2017O’Brienetal.,LancetOncol.2016

Ibru-nibinR/Rpa-entswithdel17p/TP53muta-on(theRESONATE-17™Study)

VenetoclaxinR/Rpa-entswithdel17pCLL

PFS@2yrs=63% Med.PFS=15.5months

IBRUTINIB IDELALISIB VENETOCLAX

New agents in R/R patients with del 17p/TP53 mutations

Stilgenbauer et al., iwCLL 2017, abstract 420

Med.PFS=27.2months

VenetoclaxinR/RCLLwith17pdele-on:PFSandOS

S7lgenbaueretal.,PresentedatEHA2017(abstractS771,oralpresenta7on)

Median:27.2months24-monthes7mate:54%

24-monthes7mate:73%

Resonate 17 Fup 27.6 months

PFSat24monthsof63%

24-monthOSwas75%

Ibru-nibinR/RCLLwith17pdele-on:PFSandOS

Susan O’Brien et al. Published online September 13, 2016 http://dx.doi.org/10.1016/S1470-2045(16)30212-1






AGENDA

FCR:ComplexKaryotypesensi-vitywithoutChr17abnormali-es-benefitspa-entswith≤3priortreatments

ap<0.05vs.≤3priortherapiesbp<0.001vs.notFrefractoryC:cyclophosphamide;Chr17:chromosome17;CI:confidenceinterval;CLL:chroniclymphocy7cleukaemia;F:fludarabine;OR:overallresponse;PFS:progression-freesurvival;R:rituximabBadouxXC,etal.Blood2011;117:3016–3024.

Phase II, single-arm trial in patients with relapsed/refractory CLL (N=284)

n= 116 80 46 42 230 54

Median PFS All patients: 20.9 months Chr17 abnormalities: 5 months HR 4.6 (95% CI: 2.5, 8.2) p<0.001

OR rate (all patients): 74%

1 2 3 ≥4 No Yes Prior treatment

regimens Fludarabine refractory

PFS (subgroup analysis)

1.0

0.8

0.6

0.4

0.2

0.0 0 24 48 84 108 12 36 60 96 72

Karyotype n Failed MedianChr17 20 17 5Complex 22 21 911q– 13 12 12+12 16 12 20Dip/13q– 97 66 27Others 14 10 27

Time (months)

FCR:NOTCH1muta-ons

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

PFSMonths

S7lgenbauerSetal.Blood2013

GCLLSGCLL8

PFSMonths

GCLLSGCLL11

EstenfelderSetal.Blood2016128:3227

RossiD.,iwCLL2017(invitedoralpresenta7on)

IdelalisibinptswithComplexKaryotypestatus

Karl-AntonKreuzeretal.ASH2016Poster

ThemedOSwasNRvsNRinCKTvsnon-CKT,HR=1.78(95%CI

0.69-4.64;p=0.23).

themedianPFSwas20.9monthsinCKTvs19.4innon-CKT,HR=1.18(p=0.63);

Thepresenceorabsenceofdel(17p)/TP53mutandCKTstatusdidnotsignificantlyaffectPFSorOS

inptsrandomizedtoIDELA

OSwasNR

PFS20.9months

•  Retrospec7veexploratoryanalysisofStudy1116(Idelal+RvsR)

•  UpdateontheOSdataatASH2016•  NowwithmedianFU25months

•  Con7nuestoshownosignificantadverseeffectofCKinIdela-treatedpa7ents(HR1.97,p=0.10),withthecaveatoflimitedsamplesize

Kreuzeretal.iwCLL2017,poster410

Pa-entswithComplexKaryotype(CK)treatedwithIdela+R

OS28.3months

PFSNR

Ibru-nibinComplexKaryotype

GenomicRiskFactorsarenotAssociatedWithInferiorResponseRatesinIbru7nib-TreatedPa7ents

Medianfollow-up36.4months(95%CI35.8-37.1)

ThomasJ.Kipps–iwCLLNewYork2017






AGENDA

IGVHmutated54%Prog-free@13yrs

curveplateauedbeyond10.4yrs

IGVHmutated>50%Prog-free@6yrs

Thomsonetal.,Blood2015 Fisheretal.,Blood2015

PFS by IGHV after front-line FCR: FCR300 and CLL8 trials

EichhorstB,etal.LancetOncol2016;17(7):928-42.

FCRCLL10

IGHV-unmutatedN=152

IGHV-mutatedN=123

MedianPFS 42.7months Notreached

MedianOS Notreported Notreported

FCRCLL10

Del(11q)presentN=68

Allpa-entsN=282

MedianPFS 37.8months 55.2months


FrontlineCLL

FCRPFSbyunmutatedIGHVordel(11q):CLL10

EichhorstB,etal.LancetOncol2016;17(7):928-42.

BRCLL10

IGHV-unmutatedN=183

IGHV-mutatedN=87



BRCLL10

Del(11q)presentN=63

Allpa-entsN=279



FrontlineCLLCLL10:BRPFSbyunmutatedIGHVordel(11q)

CLL 11: Chl + Ofatumumab efficacy by IGHV muta8onal status

HillmenP,etal.Lancet2015;385:1873-83.

FrontlineCLL

O+ClbvsClbComplement-1

IGHV-unmutatedN=114vs113

IGHV-mutatedN=87vs90

Reduc-oninriskofPDordeathwithO+ClbvsClb

HRforPFSisimprovedwithO+ClbvsClbregardlessofIGHVstatusButthereisatrendsugges7ngoutcomesarereducedinpa7entswithunmutatedIGHVvsmutatedIGHV(ForrestPlotonright)

TreatmentEffectonPFSbyIGHVstatus-(HR,95%CI)

CLL 11: Chl + Obinutuzumab PFS is decreased by unmutated IGHV

TreatmentEffectofG+ClbvsClbonPFSbyIGHVstatus-(HR,95%CI)G+ClbvsClbCLL11



PFS,HR(95%CI) 0.23(0.16-0.34) 0.11(0.06-0.22)

Reduc-oninriskofPDordeathwithG+ClbvsClb 77% 89%

CLL: Chl + Rituximab PFS is decreased by unmutated IGHV TreatmentEffectofR+ClbvsClbonPFSbyIGHVstatus-(HR,95%CI)

R+ClbvsClbCLL11



PFS,HR(95%CI) 0.54(0.38-0.76) 0.25(0.15-0.41)

Reduc-oninriskofPDordeathwithR+ClbvsClb 46% 75%

GoedeV,etal.NEnglJMed2014;370(12):1101-10.

Ibru-nibPFSbenefitismaintainedinpresenceofunmutatedIGHV

BarrPetal.Oralpresenta7onatASH2016

Ibru-nibvsClb

RESONATE-2



PFS,HR(95%CI) 0.082(0.039-0.173)P<0.0001

0.166(0.068-0.406)P<0.0001

Reduc-oninriskofPDordeathwithIbru-nibvsClb

92% 83%

FrontlineCLL

Ibrutinib PFS benefit vs FCR and BR in presence of unmutated IGHV

Ghia P et al. Poster 188 presented at XVII iwCLL 2017.

Ibru-nibvsBRandFCR

IGHV-unmutated

IGHV-mutated

30-monthPFSrates:

CLL8FCR(N=197)

64%

84%

CLL10FCR(N=155)BR(N=190)

65%59%

87%83%

RESONATE-2Ibru-nib(N=58)

87%

81%

Frontline CLL

Nintheabovetabledenotesthenumberofpa>entswithunmutatedIGHV

Progression-freesurvivalbyIGHV:front-lineCITandibru-nib

100-Outcomeofibru-nib-treatedpa-entswithCLL/SLLwithhigh-riskprognos-cfactorsinanintegratedanalysisof3randomizedphase3studies

Kippsetal.ICML2017;Abstract100(Oralpresenta7on)

Genomicabnormali7esdel17panddel11q,aswellasunmutIgHV,areprognos7cfactorsforpooroutcomestochemoimmunotherapyforptswithCLL/SLL

Thisisapooledanalysison3phaseIIIstudies(RESONATE2,RESONATE,HELIOS)toassessoutcomesbasedongenomicabnormali7es(FU:36,4months)

IgHV (mut vs unmut) Trisomy 12 (with vs without)

PFS@36m:70%unmutvs77%mut PFS@36m:73%inbothgroupsComplex cariotype (with vs without)

PFS@36m:65%withCKvs72%withoutCK

Del11q (with vs without)

PFS@36m:74%withdel11qvs68%nodel11q






AGENDA

AllPa-ents

FCRN=408

FCRN=404

FCRN=282

BRN=279

BR(elderly)N=70

BR(elderly)(n=279)

BR(elderly)N=121

CHL-OBI(elderly)N=330

Ibru-nib(elderly)N=136

Ibru-nib(elderly)N=31

Age,median(range)

61(36-81)

Notreported

62.1(55-67)

61(54-69)

72(65-87)

70.0(43-86)

75(approx)

74(39-88)

73(65-89)

71(65-84)

PFS,median

56.8mo 54.8mo 57.6mo 42.3mo 35mo 40.0mo 40mo 26.7mo NR89%at2Yr

NR92%at5Yr

OS,median NR78.7%at5Yr

Notreached

NR80.9%at5Y

NR80.1%at5Y

55mo89.6%at2Yr

NR94.3%at2Yr 44mo Notreached NR

95%at2YrNR

92%at5Yr

MedianFu 5.9yrs 70mo 58.2mo 58.2mo Nrep. 24m 24mo 18.8mo 28.6mo 62mo

Reference CLL8Fischeretal2016

Rossi2015Retrospec7ve

CLL10Eichhorst,etal.

ASH2016.Abstract4382

CLL10Eichhorst,etal.

ASH2016.Abstract4382

Lauren72015LeukRes

Retrospec7v“RealLife”

Gen7leMetal.EurJCancer

2016“RealLife”

MABLEMichalletiwCLL2015

#178

CLL11GoedeV,etal.NEnglJMed.2014;

RESONATE-2Barretal.ASH

2016

PCYC-1102SusanM.O'Brienetal.ASH2016

ORAL

1LCLL

Cau-on:NaiveComparison

BR Chl-Obi

NeedlongerfollowuptodrawanyconclusionsfromnaïvecomparisonsagainstFCRorBRin1LCLLcohorts

FCR IBRUTINIB

IBRUTINIB BR FCR Ide Ven

Comparators

ibru-nibR/RPCYC-1102

O'BrienASH2016

ibru-nibR/R

RESONATEJ.ByrdASCO2017

BRFisheretal.JCO2011

BRHELIOS(n=289)

FraseriwCLL2017

BRA.Cuneoetal.ASH2017

FCRBadouxBlood

2011

FCRRobakJCO

2010REACH

IDELA+RSharmanASH2014

VenetoclaxRoberts2016

MedianPFS,months 52

NR3-yearPFS

ratewas59%

15.2 14.3 25 20.9 30.6 19.4 66%at15mo

MedianOS,months

NR57%at60

mp

NR3-yearOSrate

was74%33.9 NR

NR92.7%at12mo

46 NR NR NR

ORR,% 86% 91% 59% 66.1% 82.3% 74% 69.9% 81%1interimanalysis

77%

mFUp 5-year(60month)

4-year(44month) 24 34.8 37.1 43 25 13 16.7

Susan M. O'Brien et al. ASH 2016 ORAL John C. Byrd et al. ASCO 2017 Poster 272 - RESONATE 4 Year Follow-Up PCYC Fisher et al. JCO 2011 Fraser et al., iwCLL 2017, abstract 400 (poster presentation) Badoux C. et al. Blood March 17, 2011

R/RCLL

Roback et al. JCO 2010 Sharman et al. ASH 2014; Abstract 330 (Oral Presentation) Andrew W. Roberts et al. ASH 2016 POSTER Roberts A.W. et al. – NEJM 2016 A.Cuneo et al. Abstract 642 - ASH 2017

DISCUSSION

§  Cytogenetic: When? Who? Where? Why?

§  IGHV mutational status When? Who? Where? Why?

§  Therapeutic Algorithm

§  New drugs alone or combination?

Grazie……

maria rosaria villa u.o.c. ematologia p.o. ascalesi … · published: 27 june 2017. authors: esmo...

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