HIGHLIGHTS QuesiH aperH nella LLC: IN EMATOLOGIA la ... Zaja.pdf · HIGHLIGHTS IN EMATOLOGIA 23-24...

HIGHLIGHTSINEMATOLOGIA

23-24NOVEMBRE2018TREVISO

SalaConvegniOspedaleCa’Foncello

QuesiHaperHnellaLLC:laprognosiècambiata

ancheperilpazienteanziano?

F.Zaja-Trieste

Epidemiology of CLL

•  Diagnosis is around 72 years of age •  The incidence of CLL increases with age •  Almost 70% of CLL patients are older than 65 years at

the time of diagnosis à 29% diagnosed between 45-64 years of age; à 56% diagnosed between 65-84 years of age; à 13% diagnosed above 85 years of age.

•  More than 50% of patients who require therapy are > 70 years of age

•  Median age at death from CLL is 79 years

Zent CS, et al. Cancer 2001; 92:1325–1330. 2Ries LAG, et al. SEER data 2008. Available at: http://seer.cancer.gov/csr/1975_2008/ (accessed Nov 2011). Jemal A, et al. CA Cancer J Clin 2008; 58:71–96. 4Montillo M, et al. Haematologica 2005; 90:391–399.

‘Slow-go’ ‘No-go’

Stratificazione dei pazienti in diversi gruppi clinici a seconda della presenza o meno di comorbidità loro stato di “fitness”

Eichhorst B, et al. Leuk Lymphoma 2009; 50:171–178; Leblond V. Eur Oncol Haematol 2012; 8:52–57.

•  Completamente indipendenti

•  No comorbidità •  Normale aspettativa

di vita à Approccio

terapeutico intensivo

•  Condizioni generali compromesse

•  Alcune importanti comorbidità

•  Aspettativa di vita ridotta

à Approccio terapeutico palliativo

•  Alcune comorbidità •  Alcune funzioni

d’organo compromesse

•  Performance status alterato

à Approccio terapeutico meno intensivo

‘Go-go’

SurvivalofCLLptscomparedwithage-matchedindividuals

ShanafeltTDetal.,Cancer2010;116:4777–87.

<55yrs 55-64yrs

65-74yrs >74yrs

Medianfollowup:37.1months

MedianPFS(months)

FCR BR P

AllpaFents≤65years>65yearsunmutatedIgHVmutatedIgHVdel(11q)

5554NR42.7NR38

4238.548.5345525

0.0004NS

0.017NS

0.0002

Eichhorstetal.LancetOncol2016

3-yearsOS:•  FCR:91%•  BR:92%

1Lchemoimmunotherapy:FCRvsBR(CLL-10)

CLL11:ObinutuzomabplusChlorambucilinpaHentswithCLLandcoexisHngcondiHons

R-Clb x 6

G-Clb x 6

Clb x 6 (control arm)

R A N D O M I Z E

2:1:2

Stage Ia analysis

G-Clb vs Clb

Stage Ib analysis

R-Clb vs Clb

Stage II analysis

G-Clb vs R-Clb

Additional 190 patients randomized to G-Clb/R-Clb

to complete stage II

Previously untreated CLL

Total CIRS score >6

and/or creatinine Clearance <70 mL/min

N=780 (planned)

•GA101:1000mgdays1,8,and15cycle1;day1cycles2–6,every28days•Rituximab:375mg/m2day1cycle1,500mg/m2day1cycles2–6,every28days•Chlorambucil:0.5mg/kgday1andday15cycle1–6,every28days•PaHentswithprogressivediseaseintheClbarmwereallowedtocrossovertoG-Clb

GoedeVetal.,NEnglJMed2014.

ObinutuzomabasfrontlinetreatmentofChronicLymphocyHcleukemia:updatedresultsofCLL11studywith12monthsmoreoffollow-up

LETTER TO THE EDITOR

Obinutuzumab as frontline treatment of chronic lymphocyticleukemia: updated results of the CLL11 study

Leukemia advance online publication, 17 February 2015;doi:10.1038/leu.2015.14

Obinutuzumab is a novel glycoengineered, humanized, type IIanti-CD20 antibody. In preclinical studies, obinutuzumab

showed greater antileukemic activity than the type I andnon-glycoengineered anti-CD20 antibodies rituximab andofatumumab.1–3 Obinutuzumab recently became available forthe treatment of patients with chronic lymphocytic leukemia(CLL). Approval of the antibody in this indication was based on

1.00.90.80.70.60.50.40.30.20.10.0

Ove

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surv

ival

0

233118

No. at riskR-Clb:

Clb:

3

227110

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

223107

218105

216104

21098

20493

19392

19089

16169

13456

10547

6529

2914

125

00

00

Time (months)

R-ClbClb

HR: 0.6095% CI, 0.38-0.94p=0.0242

1.00.90.80.70.60.50.4

16.3

11.1

0.30.20.10.0

Prog

ress

ion-

free

surv

ival

0

233118

No. at riskR-Clb:

Clb:

3

225101

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

21989

19168

14636

12019

9413

7212

5810

385

264

202

131

40

10

00

Time (months)

R-ClbClb

HR: 0.4495% CI, 0.34-0.56p<0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

238118

No. at riskG-Clb:

Clb:

3

227110

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

224107

222105

217104

21498

20893

20692

19889

16969

14156

10547

7229

3814

95

20

00

Time (months)

G-ClbClb

HR: 0.4795% CI, 0.29-0.76p=0.0014

29.9

11.1

1.00.90.80.70.60.50.40.30.20.10.0

Prog

ress

ion-

free

surv

ival

0

238118

No. at riskG-Clb:

Clb:

3

220101

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

21889

20768

18936

17419

16113

14612

12410

995

754

452

251

120

10

00

Time (months)

G-ClbClb

HR: 0.1895% CI, 0.14-0.24p<0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

333330

No. at riskG-Clb:R-Clb:

3

317320

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

311314

306309

300302

296293

289279

257238

205198

169161

141134

105105

7265

3829

912

20

00

Time (months)

G-ClbR-ClbHR: 0.7095% CI, 0.47-1.02p=0.0632

1.00.90.80.70.60.50.40.30.20.10.0

Prog

ress

ion-

free

surv

ival

15.4 29.2

333330


G-ClbR-ClbHR: 0.4095% CI, 0.33-0.50p<0.001

307317

302309

288273

267204

243160

221128

17282

12459

9938

7526

4520

2513

11

124

00

Time (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Figure 1. Updated PFS and OS for G-Clb versus R-Clb (a, b), G-Clb versus Clb (c, d) and R-Clb versus Clb (e, f) comparisons. G-Clb,obinutuzumab/chlorambucil; R-Clb, rituximab/chlorambucil; Clb, chlorambucil alone; HR, hazard ratio; 95% CI, 95% confidence interval.

Accepted article preview online 30 January 2015

Leukemia (2015), 1–3© 2015 Macmillan Publishers Limited All rights reserved 0887-6924/15

www.nature.com/leu






1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

233118

No. at riskR-Clb:

Clb:

3

227110

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

223107

218105

216104

21098

20493

19392

19089

16169

13456

10547

6529

2914

125

00

00

Time (months)

R-ClbClb

HR: 0.6095% CI, 0.38-0.94p=0.0242

1.00.90.80.70.60.50.4

16.3

11.1

0.30.20.10.0

Prog

ress

ion-

free

surv

ival

0

233118

No. at riskR-Clb:

Clb:

3

225101

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

21989

19168

14636

12019

9413

7212

5810

385

264

202

131

40

10

00

Time (months)

R-ClbClb

HR: 0.4495% CI, 0.34-0.56p<0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

238118

No. at riskG-Clb:

Clb:

3

227110

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

224107

222105

217104

21498

20893

20692

19889

16969

14156

10547

7229

3814

95

20

00

Time (months)

G-ClbClb

HR: 0.4795% CI, 0.29-0.76p=0.0014

29.9

11.1

1.00.90.80.70.60.50.40.30.20.10.0

Prog

ress

ion-

free

surv

ival

0

238118

No. at riskG-Clb:

Clb:

3

220101

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

21889

20768

18936

17419

16113

14612

12410

995

754

452

251

120

10

00

Time (months)

G-ClbClb

HR: 0.1895% CI, 0.14-0.24p<0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

333330


3

317320

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

311314

306309

300302

296293

289279

257238

205198

169161

141134

105105

7265

3829

912

20

00

Time (months)

G-ClbR-ClbHR: 0.7095% CI, 0.47-1.02p=0.0632

1.00.90.80.70.60.50.40.30.20.10.0

Prog

ress

ion-

free

surv

ival

15.4 29.2

333330


G-ClbR-ClbHR: 0.4095% CI, 0.33-0.50p<0.001

307317

302309

288273

267204

243160

221128

17282

12459

9938

7526

4520

2513

11

124

00

Time (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48




www.nature.com/leu






1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

233118

No. at riskR-Clb:

Clb:

3

227110

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

223107

218105

216104

21098

20493

19392

19089

16169

13456

10547

6529

2914

125

00

00

Time (months)

R-ClbClb

HR: 0.6095% CI, 0.38-0.94p=0.0242

1.00.90.80.70.60.50.4

16.3

11.1

0.30.20.10.0

Prog

ress

ion-

free

surv

ival

0

233118

No. at riskR-Clb:

Clb:

3

225101

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

21989

19168

14636

12019

9413

7212

5810

385

264

202

131

40

10

00

Time (months)

R-ClbClb

HR: 0.4495% CI, 0.34-0.56p<0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

238118

No. at riskG-Clb:

Clb:

3

227110

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

224107

222105

217104

21498

20893

20692

19889

16969

14156

10547

7229

3814

95

20

00

Time (months)

G-ClbClb

HR: 0.4795% CI, 0.29-0.76p=0.0014

29.9

11.1

1.00.90.80.70.60.50.40.30.20.10.0

Prog

ress

ion-

free

surv

ival

0

238118

No. at riskG-Clb:

Clb:

3

220101

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

21889

20768

18936

17419

16113

14612

12410

995

754

452

251

120

10

00

Time (months)

G-ClbClb

HR: 0.1895% CI, 0.14-0.24p<0.0001

1.00.90.80.70.60.50.40.30.20.10.0

Ove

rall

surv

ival

0

333330


3

317320

6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

311314

306309

300302

296293

289279

257238

205198

169161

141134

105105

7265

3829

912

20

00

Time (months)

G-ClbR-ClbHR: 0.7095% CI, 0.47-1.02p=0.0632

1.00.90.80.70.60.50.40.30.20.10.0

Prog

ress

ion-

free

surv

ival

15.4 29.2

333330


G-ClbR-ClbHR: 0.4095% CI, 0.33-0.50p<0.001

307317

302309

288273

267204

243160

221128

17282

12459

9938

7526

4520

2513

11

124

00

Time (months)0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48




www.nature.com/leu

OverallsurvivalofG-ClbvsR-ClbProgressionFreesurvivalofG-ClbvsR-Clb

OverallsurvivalofR-ClbvsClb OverallsurvivalofG-ClbvsClb


IbruHnib:indicazioniAIFAperCLL

Primalinea:•  PazienFcon17p-/mutazionep53•  PazienFetà>70anni•  PazienF65–69anni:

o  conclearancecreaFnina<70ml/min

o  PLT<100x109/LoHb<100g/Lo  AHAoITPo  ECOG1o2

Secondalinea:•  Tub

IbruHnibasiniHaltherapyforpaHentswithCLL

BurgeretalNEJM2015

AninternaFonalopen-label,randomizedphase3trialtocompareIbruFnibvsChlorambucilinpreviouslyuntreatedolderpaHents>65yearswithCLLorSLL.(RESONATE-2)

Primaryend-point:progressionfreesurvival

Keyinclusioncriteria:•  Age≥65years•  PreviouslyuntreatedCLLorSLL•  ECOGPS≤2•  Absenceofdel(17p)•  CreaFnineclearance<70mL/min•  PLTcount<100,000/μLorHb<10g/dL•  Autoimmunecytopenia(AIHA,AIT)•  ECOGperformancescore=1or2

136paHentsreceivedIbruHnib:•  MedianAge: 73(65-89)•  ECOGPS0-1 92%•  CLLpaFents 90%•  RAIstageIII-IV 44%•  Del(11q) 21%•  UnmutatedIgHV 43%

269paFentsrandomized1:1toreceiveeitheroralIbruFnib(420mg/day)unFldiseaseprogressionorunacceptabletoxiciFes,orupto12cyclesofChlorambucil

RESONATE-2(PCYC-1115/1116)

Burger J et al. N Engl J Med 2015; 373(25): 2425-37

n.36

RESONATE2:PaHentCharacterisHcs

CharacterisHc ibruHnib(n=136)

chlorambucil(n=133)

Medianage,years(range)≥70years,%

73(65–89)71

72(65–90)70

ECOGperformancestatus,%012

44488

41509

RaistageIIIorIV,% 44 47CIRSscore>6,% 31 33CreaFnineclearance<60mL/min,% 44 50Bulkydisease≥5cm,% 40 30β2-microglobulin>3.5mg/L,% 63 67Hemoglobin≤11g/dL,% 38 41Plateletcount≤100x109/L,% 26 21Del11q,% 21 19UnmutatedIGHV,% 43 45

Burger J et al. N Engl J Med 2015; 373(25): 2425-37

BurgeretalNEJM2015


BurgeretalNEJM2015;Burgeretal.-PCYC1115/1116RESONATE2PosterPF343–EHA2018


PFSbyInvesHgatorforHigh-RiskSubgroups

§  MedianPFSindel11qsubgroup:NRwithibruFnibvs.9monthswithchlorambucil(HR=0.02,P<0.0001)

§  MedianPFSinunmutatedIGHVsubgroup:NRwithibruFnibvs.9monthswithchlorambucil(HR=0.06,P<0.0001)

§  IbruFnib:18-monthPFS92%inIGHVmutated,95%inunmutatedsubgroup

PFSbydel11qstatus PFSbyIGHVmutaHonstatus

TedeschiA.etal,ASH2015Abst495

G-ClbHallekNEJM2014

BREichhorstLancetOnc2016

IbruHnibResonate2

PaFents 333 273 136

Medianage

74>65years=81%>75years=46%

61>65years=81%>70years=22%

73

ORR 77% 98% 86%

CR 22% 31.5% 4%

MRDPB 38% 63%

MedianPFS 29months 43months Notreached

2-yearsPFS 60% 75% 85%

OS 3years:75% 3years:92% 2yearsOS:98%

CLL1Ltherapyinelderly:G-ClbvsBRvsIbruHnib

RESONATEstudy:duraHonofIbruHnibTreatment

•  65%ofpaFentsconFnuedfirst-lineibruFnibtreatmentonstudy•  12%rateofdisconFnuaFonforAes(BarretalHaematologica2018)•  55%ofpaFentscrossedoverfromchlorambuciltoibruFnibfollowingPD

Burgeretal.,EHA2018;PF343(posterpresentaFon)

Barretal.Haematologica2018

UpdateofRESONATEstudy

Ibrutinib discontinuation in CLL: reasons

§  40% of pts discontinued ibrutinib during study period §  Ibrutinib starting dose did not affect d/c rate

Mato AR, et al. ASH 2016. Abstract 3222.

Discontinuation Reason,% Ibrutinib in Frontline Setting Ibrutinib in Relapse Setting Real World

(n = 10) Clinical Trial

(n = 9) Real World

(n = 200) Clinical Trial

(n = 31) AE 50.0 77.7 52.5 38.7 CLL progression 10.0 22.2 19.0 35.5 Other/unrelated death 10.0 0 12.0 12.9 Physician or pt preference 20.0 0 6.0 9.7 RT into DLBCL 0 0 4.5 0 SC transplantation/CAR-T 0 0 3.5 3.2 Financial concerns 0 0 1.0 0 Secondary malignancy 10.0 0 1.0 0 RT into HL 0 0 0.5 0

Ibrutinib discontinuation in CLL: most common AEs causing discontinuation

Mato AR, et al. ASH 2016. Abstract 3222.

Ibrutinib-Associated Toxicity Causing D/c

Ibrutinib in Relapsed Setting, %

Ibrutinib in Frontline

Setting, %

Median Time to D/c, Mos

Atrial fibrillation 12.3 25.0 7.0

Infection 10.7 -- 6.0

Pneumonitis 9.9 -- 4.5

Bleeding 9.0 -- 8.0

Diarrhea 6.6 -- 7.5

Arthralgia -- 41.6 5.0

Rash -- 16.7 3.5

ATRIALFIBRILLATION

BrownJ,Haematologica2017

•  Pooledanalysisof4phase3trials

•  10%aperafollow-upof36months

•  RISKFACTORS:age(inparFcular>75yy),historyofAFandibruFnibtreatment

Robertsetal.NEnglJMed.2015

.Robertsetal.NEnglJMed.2016

*Highriskdefinedas:harbouringdel(17p),ornoresponsetofirst-linechemotherapy-containingregimen,orrelapsedwithin12monthsaperchemotherapyor24monthsaperchemoimmunotherapy.ECOGPS,EasternCooperaFveOncologyGroupperformancestatus.

CharacterisHcs BR(n=195)

VR(n=194)

Age,median,years(range) 66(22–85) 64.5(28–83)

Male,n(%) 151(77.4) 136(70.1)

ECOGPS,n/N(%)012

108/194(55.7)84/194(43.3)2/194(1.0)

111/194(57.2)82/194(42.3)1/194(0.5)

Priorcancertherapies,n(%)123>3

117(60)43(22.1)34(17.4)1(0.5)

111(57.2)57(29.4)22(11.3)4(2.1)

Fludarabinerefractory,n/N(%)

30/194(15.5) 27/191(14.1)

CharacterisHcs BR(n=195)

VR(n=194)

BaselineTLSrisk,n(%)HighMediumLow

55(28.2)104(53.3)36(18.5)

54(27.8)106(54.6)34(17.5)

Highriskstatus,*n(%)

107(54.9) 104(53.6)

del(17p)–centrallab,n/N(%)

46/169(27.2) 46/173(26.6)

TP53mutated,n/N(%)

51/184(27.7) 48/192(25.0)

IGHVn/N(%)UnmutatedMutatedUnknown

123/180(68.3)51/180(28.3)6/180(3.3)

123/180(68.3)53/180(29.4)4/180(2.2)

SeymourJF,etal.NewEnglJMed.2018.

MURANO:PaFentcharacterisFcs

UnstraFfiedp-value<0.0001;HR=0.17.

Time(months)

PFS(%

) Venetoclax+rituximab(n=194)BendamusHne+rituximab(n=195)

StraFfiedp-value<0.0001;HR=0.17(95%CI=0.11–0.25)Medianfollow-up=23.8months(range=0.0–37.4)�

Treatment PaHentswithevents(%)

MedianPFS,months

HR(95%CI) StraHfiedp-value

1-yearPFS(%) 2-yearPFS(%)

VR(n=194) 32(16.5) NE 0.17(0.11–0.25) <0.0001 92.7 84.9BR(n=195) 114(58.5) 17.0 72.5 36.3

0

20

40

60

80

100

0 24 3 9 15 186 12 21 27 30 33 36 39

No.ofpaFentsatrisk

195 35 177 141 102 81163 127 57 12 3 1 0 0 BendamusFne+rituximab 194 76 190 179 173 157185 176 115 33 14 5 3 0 Venetoclax+rituximab

SeymourJF,etal.NewEnglJMed.2018.

MURANO:PFS

ASCOGuidelines2018:TreatmentofPaFentsWithCLLAccordingtoCurrentlyAvailable

Therapies

NiFnJain,PhilipThompson,AlessandraFerrajoli,ChadiNabhan,AnthonyR.MatoandSusanO’Brien–ASCOEducaFonalBook2018

???+Frail/nogo:Clb

QuesiHaperHnellaLLC:laprognosiècambiataancheperilpazienteanziano?

SI,inparHcolareperglianzianiFIT/UNFIT

QuesiHaperHnellaLLC:laprognosiècambiataancheperilpazienteanziano?

•  Rispexoapochiannifa,disponiamodiverseopzioniterapeuFcheperilpazienteanziano•  QuestenuoveopportunitàterapeuFchesicaraxerizzanoper:

•  altotassodirisposta•  significaFvoprolungamentodellaPFS•  prolungamentodell’OS(inalcunigruppidipazienF)

•  possibilitossicità•  cosFmoltoelevaF

•  DifficilepoteroggitraxaretubipazienFanzianiin1Lconinuovifarmaci•  ProbabilechespessoessipossanoessereriservaFneicasiR/R

•  ImportanzadellaselezionedelpazienteanzianosullabasedicaraxerisFche:•  cliniche(fit,unfit,frail)•  biologiche(FISH,IGHV,mutazionigeniche)

HIGHLIGHTS QuesiH aperH nella LLC: IN EMATOLOGIA la ... Zaja.pdf · HIGHLIGHTS IN EMATOLOGIA 23-24...

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