1. 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
CLL, chronic lymphocytic leukemia.
This activity is supported by educational grants from Infinity Pharmaceuticals Inc.; Janssen Biotech Inc., Pharmacyclics Inc.; TG Therapeutics.

2. About These Slides
Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent
These slides may not be published or posted online without permission from Clinical Care Options (
Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. 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.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

4. 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?

5. Risk Assessment Stage (Rai, Binet) Age “Fitness” Performance status
CIRS
CIRS, cumulative illness rating scale.

6. Prognostic vs Predictive Factors
Prognostic factor: predicts an event (eg, progression) in untreated patients
Predictive factor: anticipates response to a given event

7. Prognostic Factors Traditional Newer Advanced stage, older age, males
Short lymphocyte doubling time, increased b2m
Newer
Increased CD38, ZAP70
Cytogenetic (FISH) abnormalities
IGVH mutational status
FISH, fluorescence in situ hybridization; IGVH, immunoglobulin heavy chain variable gene, β2m, beta-2-microglobulin.

8. ZAP-70 Expression and Prognosis
4/25/2017 6:14 PM
ZAP-70 Expression and Prognosis
Risk of Disease Progression
Likelihood of Survival
< 20% ZAP-70–positive cells
100
100
 20% ZAP-70–positive cells 80 80 60 60
% of Cells
% of Cells
< 20% ZAP-70–positive cells
 20% ZAP-70–positive cells 40 40
ZAP-70, zeta chain-associated protein kinase 70.
Kaplan–Meier Estimates of the Actuarial Risk of Disease Progression (Panel A) and the Likelihood of Survival (Panel B) among Patients with Binet Stage A Chronic Lymphocytic Leukemia, According to the Level of Expression of ZAP-70. In Panel A, the median time to progression among 26 patients with a high level of ZAP-70 expression (20 percent or more) was 29 months, whereas it was not reached in 18 patients with a low level of ZAP-70 expression (less than 20 percent) (P=0.009). In Panel B, the probability of survival at 10 years was 90 percent among patients with a low level of ZAP-70 expression. The median survival was 90 months among the patients with a high level of ZAP-70 expression, whereas it was not reached among patients with a low level of ZAP-70 expression (P=0.01). Tick marks indicate censored data. 20
P = .009 20
P = .01 2 4 6 8 10 12 14 16 4 8 12 16 20 24 28 32 36
Yrs After Diagnosis
Yrs After Diagnosis
Crespo M, et al. N Engl J Med. 2003;348:
\\ \ART Direct\ART DIRECT SLIDES\Berlex 2003\BL 7606 Slides\PACT Exprests Roundtable G3

9. Patients With Stage-A CLL (n = 62)
4/25/2017 6:14 PM
IgVH Mutation Status and Prognosis: Pts With Mutated vs Unmutated VH Genes
Median survival 8-9 yrs in “unmutated” vs > 24 yrs in mutated
All Patients (N = 84)
Patients With Stage-A CLL (n = 62)
100 20 40 60 80
100 80
Mutated
Mutated 60
Surviving (%)
Surviving (%)
IgVH, immunoglobulin heavy chain variable gene; CLL, chronic lymphocytic leukemia.
In this patient population, median survival was significantly shorter for patients with unmutated VH genes than for those with mutated VH genes (117 months vs 293 months, respectively; P=0.001). However, this comparison may be skewed, because in this population, a greater number of patients with unmutated VH genes had advanced disease. A comparison of survival times of patients with Binet stage A CLL is provided on the following slide.
In patients with Binet stage A CLL, median survival was once again significantly shorter for patients with unmutated VH genes than for those with mutated VH genes (95 months vs 293 months, respectively; P=0.0008). This indicates that mutation of VH genes in CLL is an effective prognostic factor and suggests that CLL arising from naïve B cells is more malignant than disease arising from memory B cells.
P = .001
P = .0008 40
Unmutated
Unmutated 20 50
100
150
200
250
300 50
100
150
200
250
300
Mos
Mos
1. Damle RN, et al. Blood. 1999;94: Hamblin TJ, et al. Blood. 1999;94:
Hamblin et al. Blood. 1999;94:
\\ \ART Direct\ART DIRECT SLIDES\Berlex 2003\BL 7606 Slides\PACT Exprests Roundtable G3

10. Probability of Disease Progression
4/25/2017 6:14 PM
Probability of Disease Progression
100 80 60 40 20
Patients Treated (%)
17p deletion
11q deletion
12q trisomy
Normal
13q deletion as
sole abnormality
The figure depicts the probability of disease progression, as indicated by the treatment-free interval in the patients in the 5 genetic categories. The median treatment-free intervals for those with 17p deletion, 11q deletion, 12q trisomy, normal karyotype, and 13q deletion as the sole abnormality were 9, 13, 33, 49, and 92 months, respectively. The differences between the curves were significant (P<0.001). Twenty-five patients with various other chromosomal abnormalities are not included in the analysis.
In patients with 13q deletion alone, the time from first diagnosis to first treatment was prolonged (92 months). About one third of patients with this abnormality did not require therapy during the course of this study. 12 24 36 48 60 72 84 96
108
120
132
144
156
168
180
Mos
Döhner H, et al. N Engl J Med. 2000;343:
Döhner et al. N Engl J Med. 2000;343:
\\ \ART Direct\ART DIRECT SLIDES\Berlex 2003\BL 7606 Slides\PACT Exprests Roundtable G3

11. Point Mutations May Carry Prognostic Significance, but Are Not Assessed by FISH
Prevalence, %
P53
~ 10
NOTCH1
SF3B1
~ 9
BIRC3
~ 5
MYD88
~ 3
FISH, fluorescence in situ hybridization.
Rossi D, et al. Expert Rev Hematol. 2012;5:

12. Notch1 Mutations Occur in ~ 10% Cases
1. Wang L, et al. N Engl J Med. 2011;365: Rossi D, et al. Expert Rev Hematol. 2012;5: Vallamor N, et al. Semin Hematol. 2013;50:

13. Notch1 Mutations and Prognosis
100
Time to Treatment
100
Overall Survival
P = .016 90
P < .001 90 80 80
wt (n = 648) 70 70 60 60
Time to Treatment 50
Overall Survival 50 40 40
wt (n = 644) 30
Mut, mutation; wt, wild type. 30
mut (n = 101) 20 20 10 10
mut (n = 93) 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
Yrs
Yrs
Jeromin S, et al. Leukemia. 2014;28;

14. Notch1 Mutations and Prognosis
100
Time to Rx (+12 Cohort)
100
Overall Survival (+12 Cohort)
P = .155 90 90
P = .002 80 80 70 70 60 60
NOTCH1wt (n = 69)
NOTCH1wt (n = 69)
Time to Treatment 50
Overall Survival 50 40 40 30
Mut, mutation; wt, wild type. 30 20 20
NOTCH1mut (n = 31) 10
NOTCH1mut (n = 29) 10 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
Yrs
Yrs
Jeromin S, et al. Leukemia. 2014;28;

15. Treatment Selection Age “Fitness” Performance status
CIRS, renal function

16. Fludarabine + Cyclophosphamide
Phase III CLL8 Trial
First-line FC ± rituximab in previously untreated CLL
Fludarabine + Cyclophosphamide
(FC)
Pt Population
Physically fit
CIRS ≤ 6
Normal CrCl
N = 817 R
FC + Rituximab (Anti-CD20)
(FCR)
FC, fludarabine/cyclophosphamide; FCR, FC + rituximab; Pt, patient; CIRS, cumulative illness rating scale; CrCl, creatinine clearance; CLL, chronic lymphocytic leukemia.
Fischer K, et al. ASH Abstract 435. Cramer P, et al. Leuk Lymphoma. 2013;54:

17. Efficacy vs Toxicity FCR1 58 mos PCR2; FR2 42 mos
Fludarabine1; bendamustine1
alemtuzumab mos
BR2; FC1 34 mos
Chlor- rituximab1; 16 mos
Chlorambucil1; 12 mos
Efficacy
PFS/TFS
Toxicity
% Grade 3+ Adverse Event
Rituximab2 11%
Alemtuzumab1 27%
PCR2 Chlor- rituximab1 46% to 47%
Chlorambucil1 Fludarabine1 40%
FCR, fludarabine/cyclophosphamide/rituximab; PCR, pentostatin/cyclophosphamide/rituximab; BR, bendamustine/rituximab; FR, fludarabine/rituximab; FC, fludarabine/cyclophosphamide; PFS, progression-free survival; TFS, treatment-free survival.
The tight link between efficacy and toxicity with historical CLL therapy. This figure is a summary illustrating the link between efficacy and toxicity with historical CLL treatments. It cannot be used to compare regimens directly because results are drawn from across trials with different patient characteristics. In some cases, multiple trials testing the same regimen found slightly different PFS and rates of grade 3/4 toxicity; the representative experience is indicated in such cases.
BR2; FC2 64% to 65%
FCR1; FR2 76%
1 Phase III data.
2 Phase II data.
Shanafelt T. Hematology 2013;2013:

18. Prognostic vs Predictive Factors
Prognostic factor: predicts an event (eg, progression) in untreated patients
Predictive factor: anticipates response to a given event

19. Mos Since Randomization
Poor Prognostic Impact of 11q- May Be Overcome by Addition of Rituximab
100 90 80 70 60
FCR
Proportion Surviving (%) 50 40
FCR, fludarabine/cyclophosphamide/ritixumab. 30
+12q 13q-single 11q- Not 17p-/11q-/+12q/13q- 20 10 6 12 18 24 30 36 42 48 54 60 66
Mos Since Randomization
Hallek M, et al. Lancet. 2010;376:

20. 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
Response Duration by NOTCH1 Mutations
1.0
1.0
NOTCH1 wild type
NOTCH1 mutated
Unconsolidated
Consolidated NOTCH1 wt Consolidated
NOTCH1 mut
0.8
mAB, monoclonal antibody; CLL, chronic lymphocytic leukemia; IGHV, immunoglobulin heavy variable group gene; PFS, progression-free survival; mut, mutated; wt, wild type.
0.8
P =
n = 49
Cumulative Proportion Progressing
0.6
n = 103
Cumulative Proportion Progressing
0.6
n = 10
0.4
0.4
P = .0007
n = 20
0.2
0.2
n = 21
P = .004 24 48 72 96
120
144
168 24 48 72 96
120
144
168
Mos From the End of Induction Therapy
Mos From the End of Induction Therapy
Del Poeta G, et al EHA. Abstract P102

21. Frontline Treatment of CLL: Past
“iwCLL active
disease”
Performance status?
Diagnosis
Poor
Good/moderate
Chlorambucil
(del)17p?
CLL, chronic lymphocytic leukemia; iwCLL, International Workshop on CLL; del, deletion; Allo-SCT, allogeneic stem cell transplant.
Yes No
Alemtuzumab
Fludarabine,
cyclophosphamide, and rituximab
(FCR)
Allo-SCT
Gribben JG. Blood. 2010;115:

22. Frontline Treatment Algorithm for CLL Pts
Stage
Fitness
del(17p)
p53mut
Therapy
Binet A-B,
Rai 0-II,
inactive
Irrelevant
None
Active disease or Binet C or
Rai III-IV
Go go No
FCR
Yes
Allo-SCT
Slow go
CLB + anti-CD20-mAb
Al, HD R or O
CLL, chronic lymphocytic leukemia; Allo-SCT, allogeneic stem cell transplant; CLB, chlorambucil; Al, alemtuzumab; HD R, high-dose rituximab; O, ofatumumab.
Hallek M. Hematology. 2013;2013:

23. Go Online for More CCO Education in CLL!
ClinicalThought blog posts
Downloadable and CME-certified slidesets
Educational videos
Text modules
Interactive Virtual Presentations
Conference Coverage
CML, chronic myeloid leukemia; TKI, tyrosine kinase inhibitor.
clinicaloptions.com/oncology