1. Can Kinase Inhibitors and Immunomodulators Replace Chemotherapy? No
Michael J. Keating
MD Anderson Cancer Center
Presented by:
Susan O’Brien

2. Response to FC + Rituximab (NCI-WG: 300 Patients)
Response* # Pts. ( % )
CR (72%)
Nodular PR (10%) %
PR (12%)
No Response ( 4%)
Early Death ( 1%)
* Evaluated 6 months after last course

3. CLL8 Study Design 6 courses FCR R FC
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
Updated results of the 2nd analysis
Median observation time 37.7 months.
Hallek et al. Lancet. 2010;376:

4. FC (%) FCR (%) P FC vs FCR: Response CR 23 45 <0.01 CRu 5 3 0.22
CRi 2
0.52
nPR
0.15 PR 50 40 OR 85 93
Hallek et al. Lancet. 2010;376:

5. CLL8 Update PFS N-817 Median PFS: FC: 32,9 months FCR: 57,9 months
HR: 0,56
95%CI: ;
P<0.0001
Fink, et al. ASH 2011, Abstract 977

6. CLL8 Trial: 1st Line FC vs. FCR
Overall survival:
HR= 0.68; p= .001
Median follow-up= 70 months
Fischer et al. Updated, ASH 2012, Abstract 435

7. Are there any patients with CLL for whom FCR is NOT the Standard of Care?

8. CLL8 Genetic Analyses: PFS
EHA Educational Talk 2013
21 September 2008
CLL8 Genetic Analyses: PFS FC
FCR
CLL8 Investigator Meeting 21 September 2008

9. CLL8 Study Design 6 courses FCR FC Follow R up
Patients with untreated, active
CLL and
good physical fitness
(CIRS  6,
Creatinine clearance
 70 ml/min)
Updated results of the 2nd analysis
Median observation time 37.7 months.
Hallek et al Lancet 2010;376:

10. CLL8: Side Effects: the Effect of AgeFC
FCR
< 70 yrs n = 359
 70 yrs n = 37 p
< 70 yrs n = 361
 70 yrs n = 43
Total AEs gr 3/4
61.0%
78.4%
0.04
75.6%
83.7%
0.24
Anemia
6.7%
8.1%
0.74
5.5%
4.7%
0.81
AIHA
1.1%
0.0%
0.52
0.6%
2.3%
0.20
Leukocytopenia
12.0%
13.5%
0.79
24.9%
16.3%
0.21
Neutropenia
19.5%
35.1%
0.03
32.4%
44.2%
0.12
Thrombopenia
11.4%
5.4%
0.26
7.8%
0.46
Infections, unspecified
9.5%
13.0%
18.6%
0.31
Infections, bacterial
0.7%
0.02
1.9%

11. SOB’s Quick Survey All patients with CLL > 70 years seen
by me in clinic last month: N = 14
Eligible for CLL8 trial?
3 too old, > 80 years, so N = 11
Meet creatinine clearance requirement?
N = 4
So 4/14 = 29% eligible
Not counting CIR score

12. FCR300: Progression-free & Overall Survival
Median follow up time
All yrs
Alive yrs
Proportion Surviving
Events Total Median
yrs
yrs
Months

13. First-line FCR: NCI-WG Response & Bone Marrow MRD-free Status
% of Patients
% MRD- Negative* CR
153 65 75
nPR 29 12 4 PR 48 20 44 NR 7 3
Overall MRD
220 93 59
* Bone marrow evaluation by 4-color flow cytometry (sensitivity .01%)

14. First-line FCR: PFS & OS by MRD Status
Progression-free Survival
Overall Survival
Proportion of Patients
p<.0001
p=.0004
Months

15. First-line FCR: Multivariable Model for BM MRD-free Status (N=181)
Pretreatment
Characteristic
p-value
IGHV – Mutated
.003
Rai Stage – 0-II
.016
Trisomy 12
.02
No 17p del
.04

16. FCR300: PFS by IGHV Mutation Status
Group Events Total
IGHV-M
IGHV-UM
Unknown
Proportion Progression-free
P<.0001
Months

17. 53rd ASH Annual Meeting, 10.-13. Dec. 2011, San Diego
Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG)
Anna Fink, MD1, Raymonde Busch2, Natali Pflug, MD1, Sebastian Boettcher, MD3, Dirk Winkler, MD4, Andreas Buehler, MD4, Matthias Ritgen, MD3, Kirsten Fischer, MD1, Barbara Eichhorst, MD1, Clemens-Martin Wendtner, MD1,5, Myriam Mendila, MD6, Michael K. Wenger, MD6, Hartmut Doehner, MD4, Michael Kneba, MD3, Stephan Stilgenbauer, MD4 and Michael Hallek, MD1
1Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University Hospital, Cologne, Germany; 2Institute for Medical Statistics and Epidemiology, Technical University Munich, Germany; 3Campus Kiel, 2nd Dept. of Internal Medicine, University of Schleswig-Holstein, Kiel, Germany; 4Internal Medicine III, University of Ulm, Germany; 5Department of Hematology, Oncology, Immunology, Palliative Care, Infectiology and Tropical Medicine, Hospital Munich-Schwabing, Munich, Germany; 6Pharmaceutical Division/Global Drug Dev., F. Hoffmann-La Roche Ltd., Basel, Switzerland;
53rd ASH Annual Meeting, Dec. 2011, San Diego
Fink, et al. ASH 2011, Abstract 977

18. Defining High-risk for Early Progression in Patients Treated with First-line FCR (CLL8)
Early progression defined as progression within 24 months of FCR
MRD level of >10-2 OR
MRD level of >10-4 to <10-2
plus at least one of the following three parameters
(del(17p) OR
TP53 mutation OR
unmutated IGHV-status
Fink, et al. ASH 2011, Abstract 977

19. PFS and OS in High-risk vs. Low-risk First-line FCR (CLL8)
Progression Free Survival
Low risk
High risk
Low risk
High risk
Proportion without progression
Total n=143, HR n=40, LR n=103
OS High risk vs low risk
Total n=143, HR n=40, LR n=103
Time since randomization in months
Fink, et al. ASH 2011, Abstract 977

20. FCR300: Progression-free & Overall Survival
Median follow up time
All yrs
Alive yrs
Proportion Surviving
Events Total Median
yrs
yrs
Months