making sense of novel prognostics: notch1, sf3b1 jennifer r brown, md phd director, cll center...
Post on 14-Dec-2015
220 Views
Preview:
TRANSCRIPT
Making Sense of Novel Prognostics: NOTCH1, SF3B1
Jennifer R Brown, MD PhDDirector, CLL Center
Dana-Farber Cancer Institute
October 24, 2014
What is High Risk CLL?
• Historically defined solely by clinical features:– Stage, lymphocyte doubling time, b2m– Therapy resistance
• Biologic prognostic factors are increasingly important:
• IGHV, FISH, somatic mutation profile
Immunoglobulin VH Gene Mutation
Years from DiagnosisBlood 94: 1840, 1999
Med Surv 9 yrs
Med Surv>24 yrs
Overall Survival by FISH
100
80
60
40
20
00 12 24 36 48 60 72 84 96 120 144 168
Pa
tie
nts
su
rviv
ing
(%
)
Months
17p-11q-12q trisomyNormal13q deletion assole abnormality
NEJM 2000;343:1910
Del 17p: 32 m
Del 11q: 79 m
IGHV Mutation and Cytogenetics: Independent Predictors
Blood 100: 1410, 2002
Insights from Sequencing: NOTCH Mutations
NOTCH1: recurrent mutation (2 bp deletion; P2515fs)
-Fabbri et al:
-15.1% overall, assoc with UM IGHV and TP53 disruption
-21% in chemorefractory
-31% in Richter’s transformation
-predictor poor OS in MVA
-Puente et al:
-12.2% overall, assoc with UM IGHV, ZAP70, CD38
-23% in RT; poor OS 21% at 10 yrs Fabbri et al. J Exp Med. 2011 Jul 4;208(7):1389-401.
Puente et al. Nature. 2011 Jun 5;475(7354):101-5.
NOTCH Mutations: Short TFS and Higher Risk RT
Blood 119: 521, 2012
Mutation Discovery Through Sequencing a Large Initial Sample Set
• Increases detection of the full range of mutated genes
• Enables reconstruction of gene pathways underlying disease pathogenesis
• Reveals associations between genetic events and clinically important disease features
NEJM 365:2497, 2011
Sequencing CLL Reveals 9 Significantly Mutated Genes
Recently associatedEstablished
Novel
0 4 8 12 16
MAPK1
DDX3X
ZMYM3
NOTCH1
FBXW7
ATM
MYD88
SF3B1
TP53
Sig
nif
ican
tly
mu
tate
d g
enes
# mutations / 91 CLLs
NEJM 365:2497, 2011
SF3B1 Mutated in 15% of CLLs
SF3B1 chromosome 2 q33.1
1 2222 PP2A repeats
R62
5LN
6 26H
K70
0 E (7
)G
740E
K74
1NG
742D
(2
)
Q90
3R
1 1304 aa
• At the catalytic core of U2 snRNP
• 14 mutations in 14 CLL patients in a restricted region of the C-terminal domain
- K700E was recurrent
• Mutations in SF3B1 also seen in myelodysplasia
Yoshida et al, Nature 2011; Papaemmanuil et al, NEJM 2011
The Significantly Mutated Genes Associate with Known Prognostic
Markers
P<0.001
P=0.004
P=0.009
P=0.009
P=0.001
del(13q)
Trisomy 12
del(11q)
del(17p)
TP53
SF3B1
MYD88
NOTCH1
FISH Cytogenetic Features
Significantly mutated genes
IGHV mutational Status
1 91
MAPK1
FBXW7
ATM
DDX3X
ZMYM3
RNA processing
Notch1 signaling
Inflammatory pathway
Cell cycle or DNA damage
NEJM 365:2497, 2011
SF3B1 Mutation Independently Predicts Poor Prognosis
Months from diagnosis to first therapyNEJM 365:2497, 2011
SF3B1 Mutations Confer Poor Prognosis
Rossi et al Blood 2011;118:6904-8
BIRC3 Mutation Associated with Poor OS
Blood 119:2854
Fre
qu
enc
y o
f C
E (
%)
N=202 casesN=469 samplesMedian interval between sampling: 62 months
Inclusion criteria:• >2 years of follow-up • >2 sequential samples collected at the following time points:
a. Diagnosisb. Progression requiring treatment in progressive
casesc. Last follow-up in non-progressive/untreated cases
New NOTCH1, SF3B1 and BIRC3 Lesions are Developed During the CLL Clinical Course
N=3618%
N=136%
N=94%
N=105%
N=105% N=8
4%
N=105%
N=52%
N=63%
N=52%
N=42% N=1
0.5% N=0 N=0
High risk clonal evolution(TP53, NOTCH1, SF3B1, BIRC3)
24% at 10 years
Blood 2013;121(8):1403–1412
16 previously reported CLL driversWang et al., NEJM, 2011Quesada et al., Nat Gen, 2011Fabbri et al., JEM, 2011Brown et al., Clin Can Res, 2011Edelmann et al., Blood 2012
25 Recurrent Drivers in CLL
(n=160 Patients)
82/160 WES used in Wang et al. NEJM 2011
* 9 novel putative CLL drivers identified
Landau et al Cell 2013
NOTCH1 Mutation Status: High Risk Patient Characteristics
All WES NOTCH1 wt NOTCH1 p.P2514fs deletion# of patients 160 145 (91%) 15 (9%)Median age at diagnosis 54 53 58Male 99 (62%) 90 (62%) 9 (60%)Ever treated 33 (21%) 28 (19%) 5 (33%)IGHV unmut 60 (38%) 47 (32%) 13 (87%)Zap70 + 56 (35%) 50 (49%) 6 (40%)
Cytogenetics (Döhner hierarchy):17p- 18 (11%) 13 (9%) 5 (33%)11q- 25 (16%) 24 (17%) 1 (7%)Trisomy 12 16 (10%) 13 (9%) 3 (20%)normal 16 (10%) 14 (10%) 2 (13%)13q- 68 (43%) 64 (44%) 4 (27%)
Number affected
% of affected samples that are clonal
100
0
* Higher rate of clonal
frequencies, q<0.1
Inferring Earlier and Later Drivers in CLL
Landau et al Cell 2013;152:714–726
Biology of High Risk CLL • Clinical significance of del17p/TP53 mutation >
del11q > UM IGHV is well established
• Genomic complexity (FISH, karyotype or CN) associates with prognosis and appears quite adverse– but has not been routinely studied – Not analyzed in multivariable analyses
• Sequencing data suggest SF3B1, NOTCH1 and subclonal driver mutations associate with poor prognosis– Increasing data on TP53, SF3B1 and NOTCH1
in clinical cohorts
Recurrent Mutations Refine Prognosis
Balakas et al. Leukemia 2014: 1-8.
Balakas et al. Leukemia 2014: 1-8.
Recurrent Mutations Refine Prognosis
Recurrent Mutations Correlated to Cytogenetics
Jeromin et al. Leukemia 2014: 108-117
Balakas et al. Leukemia 2014: 1-8.
Recurrent Mutations Refine Prognosis
del13q14Normal/+12
NOTCH1 M/SF3B1 M/del11q22-q23TP53 DIS/BIRC3 DIS
del13q14Normal/+12
NOTCH1 M/SF3B1 M/del11q22-q23TP53 DIS/BIRC3 DIS
OS Treatment
Integrated Mutational and Cytogenetic Model for CLL Prognostication
N % 10-years OS155 26% 69%228 39% 57%99 17% 37%
101 17% 29%
p<0.0001 p<0.0001
N % Treated at 10 years155 26% 41%228 39% 50%99 17% 83%
101 17% 100%
Rossi et al. Blood 2013;121(8):1403
80%
14%6%
del13q14
NOTCH1 M/SF3B1 M
TP53 M/BIRC3 DIS
81%
14%5%
Normal
NOTCH1 M/SF3B1 M
TP53 M/BIRC3 DIS
70%
23%
7%
+12
NOTCH1 M/SF3B1 M
TP53 M/BIRC3 DIS
+12 by FISH
By Integrating Mutations, ~20% Low Cytogenetic Risk CLL are Reclassified into
High Risk Subgroups
del13q14 only by FISH Normal by FISH
Rossi et al
What About After Therapy?
CLL8 Study Design
817 patients with untreated, active CLL and good physical fitness (CIRS ≤
6, creatinine clearance ≥ 70
mL/min)
R
FCR
FC
6 courses
Follow up
C1 C2 C3 C4 C5 C6
Median observation time 5.9 years
Demographics similar between two treatment arms
Hallek M, et al: Lancet. 376:1164, 2010
CLL8: Addition of Rituximab to FC
CLL8: Addition of Rituximab to Fludarabine and Cyclophosphamide
CLL8: Survival after FCR by FISH
17p deletion
Lancet 2010: 376: 1164
+12q
13q-single
11q-
Not 17p-/11q-/+12q/13q-
17p-
MDACC: TTF after FCR Based on FISH (2004-2010)
0 12 24 36 48 60 72Months
0.0
0.2
0.4
0.6
0.8
1.0
Pts. Failed FISH 36 23 17p- 75 30 11q- 67 18 Trisomy 12 100 18 13q- 70 19 Negative
Pro
port
ion
Courtesy of M Keating
0 12 24 36 48 60 72 84
Months
0.0
0.2
0.4
0.6
0.8
1.0
Pts. Relapsed Status FISH 79 5 Mutated 54 20 Unmutated 11q- 104 20 Unmutated Other
MDACC: TTP for FCR Responders by IGHV and 11q
Pro
port
ion
Incidence of Genetic Lesions
CLL8: CLL3X:* CLL2H:# 1st Line High-Risk F-refractory
(FC vs. FCR) (Allo-SCT) (Alemtuzumab)n=635 n=80 n=97
TP53mut 11.5 30.0 37.4
NOTCH1mut 10.0 13.8 13.4
SF3B1mut 18.4 26.3 17.5
IGHV UM 63.0 95.6 76.3
17p- 8.2 18.1 30.1
11q- 24.6 36.1 19.4
*Dreger et al. abstract 966, Tue 8:45, #Schnaiter et al. abstract 710, Mo 4:45
Cox regression including: FC, FCR, age, sex, stage, ECOG, B-symptoms, WBC, TK, β2MG, 11q-, +12, 13q-, 17p-, IGHV, TP53, NOTCH1, SF3B1
CLL8 Multivariable Analysis: PFS
PFS: HR p-value
FCR 0.510 <.001
TK>10 1.367 0.019
IGHV UM 1.727 <.001
11q- 1.536 <.001
17p- 2.949 <.001
TP53mut 2.113 <.001
SF3B1mut 1.348 0.024
OS: HR p-value
FCR 0.652 0.006
Age>65 y. 1.467 0.018
ECOG>0 1.609 0.002
ß2MG>3.5 1.493 0.014
TK>10 1.961 0.003
IGHV U 2.125 <.001
17p- 3.175 <.001
TP53mut 2.852 <.001
CLL8 Multivariable Analysis: OS
CLL8: Impact of TP53 Mutation on OS
FCRFC
TP53: wild type mutated
Therapy:
Cox regression including: FC, FCR, TP53, NOTCH1, SF3B1, and treatment interaction
CLL8 Multivariable Analysis: Predictive Factors
PFS: HR p-value
FCR 0.544 <.001
TP53mut 3.607 <.001
SF3B1mut 1.355 0.012
NOTCH1mut 1.652 0.022Interaction
OS: HR p-value
FCR 0.654 0.002
TP53mut 4.470 <.001
NOTCH1mut 1.331 0.344Interaction
CLL8: NOTCH1 as Predictive Marker
FCRFC
NOTCH1: wild type mutated
Therapy:
Mutation Frequency in Fludarabine Refractory CLL
Rossi et al. Blood 2013;121:1403
TP53, SF3B1, and NOTCH1 Mutations and Outcome of Allotransplantation
Dreger et al. Blood 2013: 121 (16); 3284-3286
Summary
• SF3B1 mutation: associated with 11q deletion, UM IGHV, and shorter TTFT and PFS, ?OS
• NOTCH1 mutation: associated with trisomy 12, UM IGHV, shorter TTFT and Richter’s transformation– ? No benefit of anti-CD20 antibody
• Genomic complexity is adverse but requires further analysis in large trials
Summary
• Deletion of 17p or TP53 mutation predict highest risk CLL, followed by 11q deletion (NOTCH1, SF3B1) and Unmutated IGHV– Early data suggest high response but
shorter PFS with 17p or 11q deletion even with BCR pathway inhibitors
– No good data with BCR inhibitors for NOTCH1, SF3B1
• AlloSCT may overcome poor prognosis of these somatic mutations
What is Actionable?
• 17p / TP53: prognosis; therapy selection (TP53 independent: BCR, ?SCT)
• 11q: prognosis; FC-based CIT
• Mutated IGHV (esp trisomy 12): FCR
• SF3B1, NOTCH1, BIRC3: prognosis
Acknowledgments
DFCI BiostatisticsDonna NeubergLillian WernerHaesook Kim Kristen Stevenson
Brown Lab, DFCIBethany TesarStacey FernandesSasha VartanovReina ImprogoJosephine Klitgaard
NIH, NHGRICLL Research Consortium
Okonow-Lipton FundMelton Fund Rosenbach Fund
Lymphoma Program, DFCIArnold S FreedmanDavid C FisherAnn S LaCasceEric Jacobsen Philippe ArmandMatthew Davids
Clinical ResearchKaren FrancoeurKaren CampbellShannon MililloHazel Reynolds
Center for CancerGenome Discovery, DFCIMegan HannaLaura Macconaill
Wu Lab, DFCICatherine WuDan-Avi LandauLili WangYouzhong Wan
Broad Institute Eric LanderGaddy GetzCarrie SougnezNir HacohenStacey GabrielMike LawrencePetar StojanovAndrey SivachenkoKristian CibulskisDavid Deluca
top related