LEUCEMIA LINFATICA CRONICA

Division of Hematology Department of Translational Medicine

Amedeo Avogadro University of Eastern Piedmont Novara-Italy

Gianluca Gaidano, M.D., Ph.D.

Roche (Advisory Board)

Janssen (Advisory Board)

Amgen (Advisory board, research support)

Novartis (Advisory Board)

Celgene (research support)

GSK (Advisory Board)

Karyopham (Advisory board)

Morphosys (Advisory board)

Gianluca Gaidano - COIs

OUTLINE

•  General concepts (from EHA20 Educational)

•  Ultrastable CLL (Raponi et al, #S125)

•  CLL-International Prognostic Index (Bahlo et al, #S791)

•  FCR predictors (Tausch et al, #LB2070; Ljungström et al, #S121)

•  Novel treatments (Roberts et al, #S431; O’Brien et al, S434)

Font size according to gene mutation prevalence

3601 genes mutated in CLL from the COSMIC v71 database

100 genes mutated in 2 or more CLL

4 genes recurrently mutated in >5% of CLL

Fabbri, J Exp Med 2011; Puente, Nature 2011; Rossi, Blood 2011; Quesada, Nat Genet 2011; Wang, N Engl J Med 2011; Rossi, Blood 2012

CLL MUTATIONS

Survival Treatment tailoring

Prognosticator Factors that provide information on the

likely outcome of CLL

Predictor Factors that provide information on the

likely benefit from a specific CLL treatment

Italiano A, J Clin Oncol 2011

APPLICATIONS OF GENETIC BIOMARKERS IN CLL

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

(%)

Integrating mutation and cytogenetics for CLL survival prognostication

Matched general population

N 10-year OS 10-year relative OS del13q 26% 69% 84%

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

TP53 DIS/BIRC3 DIS 17% 29% 37%

Survival

Rossi et al, Blood 2013

TP53 unmutated Solely subclonal TP53 M Clonal TP53 M

263 122 15 0 18 4 0 0 28 6 0 0

Events Total 5-year OS 95% CI 77 263 75.1% 69.5-80.7% 9 18 46.3% 22.0-70.6% 19 28 34.6% 15.8-53.4%

- .0042 .<.0001 .0042 - .6926

<.0001 .6926 -

p from pairwise comparisons

No. at risk

Small TP53 mutated subclones have the same unfavorable prognostic impact as clonal TP53 defects

Rossi, Blood 2014

-­‐20%0%

20%40%60%80%100%

-­‐10 -­‐5 0 5 10 15 20 25 30 35 40 45

del17p p.G244D

Allele  freq

uency

ID9245

0.9%

66.0%

58.0%

FCR CR

Diagnosis

months

RelapseRefractoriness

TP53M  (p.G244D)

Small TP53 mutated subclone admixed with TP53 wild type clones

Removal of TP53 wild type clones and selection of the

TP53 mutated subclone

Expansion of the TP53 mutated clone

Diagnosis Chemotherapy Progression Chemotherapy Refractoriness

TP53 mutated CLL cell

TP53 unmutated Solely subclonal TP53 M Clonal TP53 M

Poor outcome

Rossi, Blood 2014

Small TP53 mutated subclones are selected by treatment because of their chemoresistance

Summary:  clinical  implica.ons  of  muta.ons  for  the  management  of  CLL  

• Comprehensive  gene.c  assessment  to  sort  out  low  risk  pa.ents  

• NOTCH1  muta.ons  to  iden.fy  pa.ents  at  high  risk  of  RS      • TP53  assessment  for  treatment  tailoring  (chemoimmuno  vs  KI)  

• NGS  as  a  new  tool  for  highly  sensi.ve  detec.on  of  TP53  muta.ons  

• NOTCH1  muta.ons  might  mark  resistance  to  an.-­‐CD20  MoAb  

• Clonal  rela.onship  between  CLL  and  DLBCL  to  iden.fy  prognos.cally  favourable  unrelated  RS  (de  novo  DLBCL)  

• BTK  and  PLCG2  muta.on  tes.ng  to  iden.fy  acquired  resistance  to  KI    

IGHV M IGHV UM/del11q del17p

- 0.004 <.001 0.004 - 0.002 <.001 0.002 -

p from pairwise comparisons

Months

Ove

rall

surv

ival

(%

)

0 12 24 36 48 60 72 84 96 108 120

020

4060

80100

Months 0 10 20 30 40 50 60

0.00

00.

005

0.01

00.

015

0.02

00.

025

Follow-up time (months)

Haza

rd R

ate

del_17pp < 0.001

1

£0 >0

del_11qp = 0.024

2

£0 >0

IGHVp = 0.011

3

£0 >0

Node 4 (n = 86)

0 20 40 60 80 100120

0

0.2

0.4

0.6

0.8

1 Node 5 (n = 233)

0 20 40 60 80 100120

0

0.2

0.4

0.6

0.8

1 Node 6 (n = 54)

0 20 40 60 80 100120

0

0.2

0.4

0.6

0.8

1 Node 7 (n = 30)

0 20 40 60 80 100120

0

0.2

0.4

0.6

0.8

1

No Yes

No Yes

No Yes

Prog

ress

ion

free

su

rviv

al (%

)

Months

IGHV UM and/or del11q

del17p p<0.001

del11q p=0.024

IGHV UM

p=0.011

Months

Months

Months

IGHV M IGHV UM/del11q del17p

N Observed events

Expected events*

5-year OS (%)

5-year relative OS* p*

194 4 2.6 91.3 95.9% 0.364 212 30 7.4 81.8 85.9% <.001 82 14 1.6 57.5 60.4% <0.001

IGHV M IGHV UM/del11q del17p

Haz

ard

of p

rogr

essi

on

Matched general population

IGHV mutated patients devoid of del17p and del11q gain the greatest benefit from FCR

Rossi et al, Blood 2015

•  Quale screening biologico-diagnostico nell'era dei nuovi farmaci, anche alla luce di CLL-IPI?

•  Quale valore di negatività MRD per outcome clinico con nuovi farmaci (eg venetoclax-Rituximab)?

•  Come conciliare “access to all those in clinical need” con sostenibilità? La stratificazione del trattamento è una possibile via?

A FEW QUESTIONS (among the many…)