Post on 19-Feb-2019
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…)