How to Treat CLL in 2014:
Overview of CLL
Steven E. Coutre, MD
Professor of Medicine
Department of Hematology
Stanford University School of Medicine
Stanford, California
This activity is supported by educational grants from Infinity
Pharmaceuticals Inc.; Janssen Biotech Inc., Pharmacyclics Inc.; TG
Therapeutics.
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Faculty Disclosures
Steven E. Coutre, MD, has disclosed that he has received funds for
research support from AbbVie, Celgene, Gilead Sciences, and
Pharmacyclics and has served on advisory boards for AbbVie, Celgene,
Gilead Sciences, and Janssen Biotech, and Pharmacyclics.
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Initial Diagnosis: Questions You Will Need
to Consider
 What is the prognosis?
– Should you do additional prognostic testing?
 When should treatment start?
– Is watch and worry still appropriate for many patients?
 What type of therapy should you choose?
 What is your goal of therapy?
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Risk Assessment
 Stage (Rai, Binet)
 Age
 “Fitness”
– Performance status
– CIRS
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Prognostic vs Predictive Factors
 Prognostic factor: predicts an event (eg, progression)
in untreated patients
 Predictive factor: anticipates response to a given event
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Prognostic Factors
 Traditional
– Advanced stage, older age, males
– Short lymphocyte doubling time, increased b2m
 Newer
– Increased CD38, ZAP70
– Cytogenetic (FISH) abnormalities
– IGVH mutational status
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ZAP-70 Expression and Prognosis
Risk of Disease Progression
Likelihood of Survival
100
< 20% ZAP-70–positive cells
100
 20% ZAP-70–positive cells
80
% of Cells
% of Cells
80
60
< 20% ZAP-70–positive cells
40
20
P = .009
0
60
 20% ZAP-70–positive cells
40
20
P = .01
0
0
2
4
8 10 12
6
Yrs After Diagnosis
14
16
Crespo M, et al. N Engl J Med. 2003;348:1764-1775.
0
4
8
12 16 20 24 28 32 36
Yrs After Diagnosis
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IgVH Mutation Status and Prognosis:
Pts With Mutated vs Unmutated VH Genes
Median survival 8-9 yrs in “unmutated” vs > 24 yrs in mutated
Patients With Stage-A CLL (n = 62)
100
100
80
80
Surviving (%)
Surviving (%)
All Patients (N = 84)
Mutated
60
P = .001
40
Unmutated
20
0
Mutated
60
P = .0008
40
Unmutated
20
0
0
50
100
150 200
Mos
250
300
0
50
100
150 200
Mos
250
1. Damle RN, et al. Blood. 1999;94:1840-1847. 2. Hamblin TJ, et al. Blood. 1999;94:1848-1854.
300
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Probability of Disease Progression
Patients Treated (%)
100
80
60
17p deletion
11q deletion
12q trisomy
Normal
13q deletion as
sole abnormality
40
20
0
0 12 24 36 48 60 72 84 96 108120132 144156 168 180
Mos
Döhner H, et al. N Engl J Med. 2000;343:1910-1916.
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Point Mutations May Carry Prognostic
Significance, but Are Not Assessed by FISH
Mutation
Prevalence, %
P53
~ 10
NOTCH1
~ 10
SF3B1
~9
BIRC3
~5
MYD88
~3
Rossi D, et al. Expert Rev Hematol. 2012;5:593-602.
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Notch1 Mutations Occur in ~ 10% Cases
1. Wang L, et al. N Engl J Med. 2011;365:2497-2506. 2. Rossi D, et al. Expert Rev Hematol. 2012;5:593602. 3. Vallamor N, et al. Semin Hematol. 2013;50:286-295.
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Notch1 Mutations and Prognosis
100
Time to Treatment
80
80
70
70
60
50
40
wt (n = 644)
30
40
30
10
10
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Yrs
Jeromin S, et al. Leukemia. 2014;28;108-117.
wt (n = 648)
50
20
0
P = .016
60
20
mut (n = 93)
Overall Survival
90
P < .001
Overall Survival
Time to Treatment
90
100
mut (n = 101)
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Yrs
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Notch1 Mutations and Prognosis
Time to Rx (+12 Cohort)
100
90
P = .002
90
80
80
70
70
60
50
NOTCH1wt (n = 69)
40
30
Overall Survival
Time to Treatment
100
60
NOTCH1wt (n = 69)
50
40
30
20
20
10
10
NOTCH1mut (n = 29)
Overall Survival (+12 Cohort)
P = .155
NOTCH1mut (n = 31)
0
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Yrs
Jeromin S, et al. Leukemia. 2014;28;108-117.
0 2 4 6 8 10 12 14 16 18 20 22 24 26
Yrs
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Treatment Selection
 Age
 “Fitness”
– Performance status
– CIRS, renal function
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Phase III CLL8 Trial
 First-line FC ± rituximab in previously untreated CLL
Pt Population
Physically fit
CIRS ≤ 6
Normal CrCl
N = 817
Fludarabine + Cyclophosphamide
(FC)
R
FC + Rituximab (Anti-CD20)
(FCR)
Fischer K, et al. ASH 2012. Abstract 435. Cramer P, et al. Leuk Lymphoma. 2013;54:1821-1822.
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Efficacy vs Toxicity
FCR1
58 mos
Efficacy
PCR2; FR2
Fludarabine1;
42 mos BR2; FC1 bendamustine1
Chlor34 mos alemtuzumab1
rituximab1;
20-23 mos
16 mos
PFS/TFS
Toxicity
% Grade 3+ Adverse Event
Chlorambucil1
FCR1; FR2
76%
BR2; FC2
64% to
65%
PCR2
Fludarabine1
Chlor40%
rituximab1
46% to
47%
1 Phase
III data.
2 Phase II data.
Shanafelt T. Hematology 2013;2013:158-167.
Chlorambucil1;
12 mos
Alemtuzumab1
27%
Rituximab2
11%
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Prognostic vs Predictive Factors
 Prognostic factor: predicts an event (eg, progression) in
untreated patients
 Predictive factor: anticipates response to a given
event
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Poor Prognostic Impact of 11q- May Be
Overcome by Addition of Rituximab
100
FCR
Proportion Surviving (%)
90
80
70
60
50
40
30
+12q
13q-single
11qNot 17p-/11q-/+12q/13q-
20
10
0
0
6
12 18 24 30 36 42 48 54 60 66
Mos Since Randomization
Hallek M, et al. Lancet. 2010;376:1164-1174.
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Notch1 Mutations May Confer Lack of
Benefit to Anti-CD20 mAb Therapy

123 CLL symptomatic patients homogeneously treated with first-line fludarabine
followed by consolidation rituximab in responding patients

NOTCH1mut
̶
Significant associations with trisomy 12 (P = .03) and unmutated IGHV (P = .0001)
̶
20 of 123 pts (16.3%).
̶
Associated with inferior response rates, PFS
Response Duration by Unconsolidated vs
NOTCH1 wt and NOTCH1 Mut Consolidated Pts
Unconsolidated
Consolidated
NOTCH1 wt
n = 49
Consolidated
n = 10
NOTCH1 mut
1.0
0.8
P = .00004
NOTCH1 wild type
NOTCH1 mutated
n = 103
0.6
0.4
n = 20
0.2
0
0
24
48
72
96
120
144
168
Mos From the End of Induction Therapy
Del Poeta G, et al. 2013 EHA. Abstract P102
Cumulative Proportion
Progressing
Cumulative Proportion
Progressing
Response Duration by NOTCH1 Mutations
1.0
0.8
0.6
P = .0007
0.4
P = .004
n = 21
0.2
0
0
24
48
72
96
120
144
168
Mos From the End of Induction Therapy
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Frontline Treatment of CLL: Past
“iwCLL active
disease”
Diagnosis
Performance
status?
Good/moderate
Poor
Chlorambucil
(del)17p?
Yes
No
Alemtuzumab
Fludarabine,
cyclophosphamide,
and rituximab
(FCR)
Allo-SCT
Gribben JG. Blood. 2010;115:187-197.
How to Treat CLL in 2014: Making Sense of the Changing Landscape
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Frontline Treatment Algorithm for CLL Pts
Stage
Binet A-B,
Rai 0-II,
inactive
Active disease or
Binet C or
Rai III-IV
Fitness
del(17p)
p53mut
Therapy
Irrelevant
Irrelevant
None
No
FCR
Yes
Allo-SCT
No
CLB + anti-CD20-mAb
Yes
Al, HD R or O
Go go
Slow go
Hallek M. Hematology. 2013;2013:138-150.
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