3 Davide Rossi - ER Congressi · R/R CLL Not suitable for cytotoxic Tx: • del17p Idelalisib-R (116) ORR: 81% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 0 20 40 60 80 100 Time (months)

Predic'vebiomarkers

Hematology IOSI - Oncology Institute of Southern Switzerland

IOR - Institute of Oncology Research Bellinzona - Switzerland

Davide Rossi, M.D., Ph.D.

•  Newlypresentedpts

•  Firstlinepts

•  Relapsedpts

CLLsubgroups

Predic'vebiomarkers Prognos'cbiomarkers

Progression

Treatmenttailoring Pa'entcounseling

Frequencyoffollow-up

Iden'fythoseapropriateforearlyinterven'ontrials

Clinicalapplica'onsofpredic'veandprognos'cbiomarkersinCLL

HostFactors:Age,sex,etc

DiseaseMarkers:Stage,lymphocytecount,LDT,etc

Agexpression:CD38,Zap70,CD49d,etcSerology:β2M,TK,LDH,sCD23,etc

Gene'cs:del17p,TP53muta

Biomarker ScoreAge

65years 3

Sex Male 0Female 1

Raistage 0-II 0III-IV 1

Involvednodalareas 7 55%

MDACCscore

Wierdaetal,Blood2007

Themuta'onallandscapeofCLL

ThewordcloudshowsthegenesthatarereportedasmutatedinCLLbythev77oftheCatalogueofSomaJcMutaJonsinCancer(COSMIC).ThesizeofthefontisproporJonaltothemutaJonfrequency

0 2 4 6 8 10 12 14

0.0

0.2

0.4

0.6

0.8

1.0

Years from diagnosis

Cum

ulat

ive

prob

abili

ty o

f OS

(%)

Integra'ngmuta'onandcytogene'csforCLLsurvivalprognos'ca'on

MatchedgeneralpopulaJon

N 10-year OS 10-year relative OS Terated at 10 tears del13q 26% 69% 84% 41%

Normal/+12 40% 57% 70% 50% NOTCH1 M/SF3B1 M/del11q 17% 37% 48% 83%

TP53 DIS/BIRC3 DIS 17% 29% 37% 100%

Survival Treatment

Rossietal,Blood2013

CLL-IPI

Variable Adverse factor Coeff. HR

TP53 (17p) deleted and/or mutated 1.442 4.2

Grading

4

Prognostic Score 0 – 10

IGHV status Unmutated 0.941 2.6

B2M, mg/L > 3.5 0.665 2.0

Clinical stage Binet B/C or Rai I-IV 0.499 1.6

Age > 65 years 0.555 1.7

2

1

2

1

Risk group Score PatientsN (%)

5-year OS, %

HR (95% CI) p value

Very High 7 – 10 62 (5) 23.3 3.6 (2.6 - 4.8) < 0.001

High 4 – 6 326 (27) 63.6 1.9 (1.5 - 2.3) < 0.001

Intermediate 2 – 3 464 (39) 79.4 3.5 (2.5 - 4.8) < 0.001

Low 0 – 1 340 (29) 93.2

InternaJonalCLL-IPIworkinggroup.LancetOncol2016

Time (months)

Ove

rall

surv

ival

Low

Intermediate

HighVery high

Overallsurvival(allpa'ents)

Clinicalapplica'onsofbiomarkersinCLL

W&W

Asymptoma'c Symptoma'c

ClinicalstageiwCLLcriteria

Treatment

HallekiwCLL2017

Predic'vebiomarkers Prognos'cbiomarkers

Progression

Treatmenttailoring Pa'entcounseling

Frequencyoffollow-up

Iden'fythoseapropriateforearlyinterven'ontrials

Clinicalapplica'onsofpredic'veandprognos'cbiomarkersinCLL


•  Firstlinepts

•  Relapsedpts

CLLsubgroups

•  Predic'vebiomarkesinthe1stlinese^ng§  Ptsfitness§  TP53§  IGHV

•  Predic'vebiomarkesintherelapsedse^ng§  Remissiondura'on§  TP53§  Histology

Outline

MDACC ↑myelosuppression/dosereducJonsinpaJents>60yrs1

↑earlytreatmentdisconJnuaJonsinpaJents≥70yrs2

CLL8 ↑hematologicaltoxicityinpaJents≥65yrs3

↑adverseeventsinptswithincreasedCIRS4

CLL10 ↑infecJonsinpaJents>65yrs5

REACH ↑adverseeventsinpaJentswithdecreasedCrCl61KeaJngetal. JClinOncol.2005; 2TFerrajoliA,etal. LeukLymphoma.2005:S86; 3Halleketal. Lancet.2010 ; 4Goedeetal.Haematologica (EHAmeeJngabstracts).2012;5Eichhorstetal.Blood.2014(ASHmeeJngabstracts);6Robaketal.JClinOncol.2010

Biomarkersthatiden'fyunfitpa'ents

SIOGrecommenda'onfortheidenJficaJonofptslessfitforFCR:

–  Olderage(e.g.≥65years)–  Highercomorbidityburden(e.g.CIRS>6)–  ImpairedrenalfuncJon(e.g.CrCl



Outline

TP53abnormali'esinCLL

5’ 3’

1 DNABINDING

EX4 EX9

393

Missense Nonsense Frameshift

TP53

Freq

uency

0%10%20%30%40%50%60%70%80%90%

100%

MBL Early stage CLL

CLL requiring treatment

F-refactory CLL

Richter syndrome

TP53 Mdel17p13TP53 M/del17p13

N=1/63(1.5%)

N=30/318(9.4%)

N=44/99(44.4%)

N=25/38(65.7%)

N=13/268(4.8%)

Dohneretal,NewEnglJMed2000;Rasietal,Haematologica2012;Zainuddinetal,LeukRes2011;ZenzetalJClinOncol2010;RossietalBlood2011;RossietalBlood2014

Chr17

DNA damage

P

p53P

p21cyclin B

p53P

cyclin B

cdc2 p21

BAXCaspase 9

Apoptosis

Cell cycle arrest

M P

del(17p) p53wt

(rare)

M P

del(17p)p53mut

(>80%)

P P

LOHp53mut

M P

p53wt/mut

(rare)

M P

normal

p armp53

q arm

BadouxBlood2011;FisherJClinOncol2011;O’Brien,ASH2014;SharmanASH2014;ByrdASH2015;SJlgenbauer,ASH2015

Chemoimmunotherapy(CIT)vsnovelagentsinTP53disruptedCLL

0%

20%

40%

60%

80%

100%

Respon

sera

te

0%

20%

40%

60%

80%

100%

CR PR PR-L

35%

7%

83% 78% 79%

12-m

onthsP

FS

18% 22%

80% 79% 72%

Responserate PFS

CIT Novelagents CIT Novelagents

Relapsed/RefractoryCLL

‡



Outline

IGHVmutatedpa'entsgainthegreatestbenefitfromFCR

1.ThompsonPA,etal.Blood2016;127:303–309.2.FischerK,etal.Blood2016;127:208–215.3.RossiDetal.Blood2015;1261921–1924,4.KippsTetal.ICML14..

2 4 6 8 10 12 140 16

p

aInpaJentswhoarenoteligibleforanyothertherapiesChl:chlorambucil;CIRS:CumulaJveIllnessRaJngScale;Cr:creaJnine PersonalcommunicaJon.

Chl+an'-CD20

TP53

Chemo+an'-CD20Age;CIRS;

Crclearance

BR

Ibru'nibIdelalisib+Ra

IGHV Ibru'nib

Mutatedand/ordeleted

Wildtype

Unmutated

Mutated

Canfirstlinetreatmentbeinformedbybiomarkers?

FCR


•  Firstlinepts

•  Relapsedpts

CLLsubgroups



Outline

FC,fludarabine+cyclophosphamide;FCR,FC+rituximab;MDACC,MDAndersonCancerCenter.

1.TamCS,etal.Blood2014;124:3059–3064;2.SJlgenbauerSandZenzT.HematologyAmSocHematolEducProgram2010;2010:481–488

Laterelapseaierfirst-linechemoimmunotherapysupportsmaintainedsensi'vity

SurvivalaierfirstsalvageaierFC/FCRfirst-linefailure:CLL8data2

SurvivalaierfirstsalvageaierFCRfirst-linefailure:MDACCdata1

36-monthcutoff

0.0

0.2

0.4

0.6

1.0

0.8

Cumula'

vesu

rvival

≥6years(n=46),5-yearOS:71%

Time(months)0 24 48 72 96 120 144

3–5.9years(n=61),mOS:54months1–2.9(n=34),mOS:27months24monthsPFS12–24monthsPFS

ByrdJCetal.NewEnglJMed2014371:213-2

SalvagetreatmentinCLLnotsuitableforchemoimmunotherapy

R/RCLLNotsuitableforF-basedTx•  PFS



Outline

Ibru'nib Venetoclax

Even

t-freesu

rvival

(propo

r'on

al)

0.0

0.2

0.4

0.6

0.8

1.0

PFS:6.8months2

Time(months)

del(17p)median

0 6 12 18 24 30 36 42

del(11q)del(17p)

Trisomy12qdel(13q)singleOther*

Bendamus'ne-R

0

20

40

60

80

100

0 2 4 6 8 101214161820222426

Progression-freesu

rvival(%

)

Time(months)

Del(17p)/TP53mut

Nodel(17p)/TP53mut

Idelalisib-R

P=0.94

Event-freesurvivalinrelapsedTP53disruptedpa'ents

HistologyofprogressedCLL

GinèE,etal.Haematologica2010;95:1526–1533.

Richtersyndrome

‘Progressive’CLL

(months)

SurvivalProba

bility

0.0

0.2

0.4

0.6

0.8

1.0

0 24 48 72 96 120 144 168

Richter’s syndrome DLBCL variant

Overallsurvival

0.8

0.6

0.4

0.2

0.0

1.0

(months)0 6048362412

CwynarskiK,etal.JClinOncol2012;30:2211–2217.

Richtersyndromesurvival

Aierallo-SCT

Can treatment of R/R CLL be informed by biomarkers?

BCR: B-cell receptor; R-chemo: rituximab chemotherapy; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone; RIC-allo-SCT: reduced-intensity conditioning allogeneic stem cell transplant; RT: Richter transformation Personal communication.

Histology: CLL

Previous Tx: R-chemo and BCR inhibitor

Previous Tx: R-chemo

BR

Ibrutinib Idelalisib + R Venetoclax

Histology: RT

Venetoclax R-CHOP

RIC-allo-SCT RIC-allo-SCT

TP53 wt

Long remission duration

TP53 mutated and/or deleted or

Short remission duration

RIC-allo-SCT

LymphomaUnitBernhardGerberAldenMocciaAnastasiosStathisGeorgStüssiEmanueleZucca

NuclearMedicineLucaCeriani

MicheleGhielmini

ClaraDeambrogiLorenzoDePaoliFaryDiopGianlucaGaidano

ExperimentalHematologyAlessioBruscagginClaudiaCirilloAdalgisaCondoluciGabrielaFores'eriFrancescaGuide^LodovicoTerzidiBergamoValeriaSpina

Lymphoma&GenomicsFrancescoBertoni

FrancoCavalli

UnrestrictedresearchgrantfromGileadandAbbvie

IlariaDelGiudiceMonicaMessinaAnnaGuarini

RobinFoà

Documents

3 Davide Rossi - ER Congressi · R/R CLL Not suitable for cytotoxic Tx: • del17p Idelalisib-R (116) ORR: 81% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 0 20 40 60 80 100 Time (months)