1. How To Manage p53 Mutated CLL
Susan O’Brien
MD Anderson Cancer Center

2. Survey 9 physicians in private practice 21 physicians in academics
US and Canada
Question: If you have a patient with CLL requiring treatment and that patient has 17p- what treatment would you use?

3. Survey Private Practice MDs (9)
FCR FR Alemtuzumab BR
3 MD mentioned “and then get to SCT”
4 Houston 1 Florida
2 Oklahoma 1 California
1 Louisiana

4. Survey 21 Academic Physicians
LN large: Fludarabine-based 13
SM + R
Alemtuzumab-based 4
LN small: Fludarabine-based 10
SM+R
Alemtuzumab-based 9
17/21 (81%) said “and proceed to SCT”

5. GCLLSG: SQ Alemtuzumab in Fludarabine Refractory CLL
Schedule:
IV , 10, 30 mg then
SQ mg 3 x / week
4 – 12 weeks
Patients:
Binet C:
74%
No. prior Tx:
4 (1 – 9)
Unmutated
73%
17 p -
29%
Stilgenbauer et al JCO 2009, 27;

6. GCLLSG: SQ Alemtuzumab Response by Genetics
60,0%
40,0% PR CR
20,0%
0,0%
All
N=46 VH
unmut
17p-
11q-
+12q
13q-
Stilgenbauer et al ASH 2004; Abstract #478

7. IRRP Response Rate to First-line B-CLL Therapy
CAM307: Response to First-line Therapy With Alemtuzumab vs Chlorambucil (N = 297)
IRRP Response Rate to First-line B-CLL Therapy
100
P<0.0001 90
83% ORR 80 CR
24% CR 70 PR
55% ORR 60 2%
% Response 50 40 30
59% PR
53% PR
52.7 20 10
Alemtuzumab
Chlorambucil

8. CAM307: Overall Response Rates According to Cytogenetic Abnormality
IV Alemtuzumab (N=147)
Oral Chlorambucil (N=147)
64%
Overall Response Rates (%)
P =
0.0805
<0.0001
1.0000
0.3238
0.0087
[Data presented according to hierarchical model of Döhner (NEJM 2000;323:1910-6)]

9. CAM307: PFS by Cytogenetic Abnormality and Treatment Arm
Alemtuzumab
Chlorambucil
Deletion N
Median PFS (mo)
P-value for PFS
17p del 11
10.7 10
2.2
0.2034
11q del
(no 17p del) 23
8.5 31
0.3895
Trisomy 12
(no 17p del,
no 11q del) 24
18.3
12.9
Normal 25
19.9 26
14.3
0.3477
Sole 13q del 33
24.4 34
13.0
0.0107
[Data presented according to hierarchical model of Döhner (NEJM 2000; 343: )]
P value is calculated using log-rank test

10. Response to FC + Rituximab (N=300)
Response No. Pts Percent CR
nPR % PR NR
Early Death
Keating et al JCO 23(18):4070, 2005; updated 2009

11. Response to Frontline FCR-based* Treatment by FISH (N=169)
% Pts
% CR
% OR
17p del 11 26 74
11q del 21 83
100
+12 81
None 20 71 97
13q del 75
Overall 96
P=.01
P<.001
*Includes: FCR, FCR3, FCMR, FCR+GM-CSF

12. CLL8 Study Design 6 courses FCR Follow R up 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:

13. CLL8 Genetic Analyses: PFS
21 September 2008
CLL8 Genetic Analyses: PFS FC
FCR
17p Deletion - How to Treat

14. CLL2O: Design Off Study PD 4 week Alem + Dexa 4 week Alem + DexaPR SD PR SD
staging
staging
staging
Option B: allo-SCT
Option A: alemtuzumab maintenance
(30 mg / 14 d, max. 2 years)
Maintenance: CR
SD/PR CR
or:
Alem: 30 mg
3x / week, s.c.
Dexa: 40 mg
d 1-4, d 15-18, p.o.

15. CamPred regimen (NCRI CLL206)
Weeks 1-4:
IV alemtuzumab
30mg tiw
Weeks 5-16:
SC alemtuzumab
IV methylprednisolone
1.0 g/m2 day 15
Weeks 1, 5, 9 and 13
Anti-microbial prophylaxis
Co-trimoxazole 480mg bd
Aciclovir 400mg qds
Itraconazole suspension 200mg bd
G-CSF when neutrophil count < 1.0x109/l
Valganciclovir for CMV viraemia
Pettit et al JCO 2012: 30:

16. Comparison of Front-line Regimens in 17p-
FCR
CLL8
CAM
CAM307
Cam Dex
CLL20
CamPred
CLL206
CR% 5 24 65
OR% 69 63 98 88
PFS (mos) 11 18
OS (mos) 23 39

17. Comparison of Front-line Regimens in 17p-
Gr 3/4 tox
FCR
CLL8
CAM
CAM307
Cam Dex
CLL20
CamPred
CLL206
ANC 34 41 18
67*
Plts 7 12 14
31*
Inf. 21 8+ 26 35
CMV - 53 71
49*
Steroid ?
23*
+Sepsis + NF *hematologic, all pts

18. Frontline Trial Data for 17p- What is the N?
Regimen 17p- patients
CLL8 FCR
CAM
CamPred
CamDex
SM+R 90

19. Conclusions – So Far
All available treatments for CLL stink in the 17p- patients
Since there is no clear winner there is no “standard”
Even frontline patients are good candidates for investigational treatments

20. PCI-32765: First-in Class Inhibitor of BTK
Forms a specific and irreversible bond with cysteine-481 in BTK
Highly potent BTK inhibition at IC50 = 0.5 nM
Orally administered with once daily dosing resulting in 24-hr target inhibition
In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG mediated proliferation
Inhibits CLL cell migration and adhesion
No cytotoxic effect on T-cells or NK-cells N H 2 O
PCI-32765
Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010
Herman SEM et al: Blood 117: , 2011
Ponader, et al., ASH Meeting Abstracts 116:45, 2010

21. Ibrutinib in Refractory CLL With 11q Deletion
Before
4 weeks

22. PCYC-1102-CA: Best Overall Response
Combined ORR + (PR+L) in TN (84%) and R/R (88%)
IWCLL 2013, PCYC 1102, Furman et al.

23. PCYC-1102-CA: Best Response by Risk Features
Treatment Naive
R/R + HR N
ORR %
All Patients 31 68 85 71
≥ 70 years age 23 61 30 73
β2 Microglobulin > 3 mg/L 8 63 39 72
Rai Stage III/IV 15 60 55
IgVH unmutated 17 82 69 77
del(17p13.1) present 2
100 28
del(11q22.3) present 1
Bulky disease ≥ 5 cm 6 67 44
≥ 3 prior chemo regimens
Not applicable 58
Purine Analog Refractory 41 66

24. PCYC-1102: Progress-Free Survival
IWCLL 2013, PCYC 1102, Furman et al.

25. Idelalisib is an Orally Bioavailable Small Molecule that Inhibits PI3K Delta Potently and Selectively
CAL-101
Alpha
Beta
Gamma
Delta
Class I PI3K Isoform
Cell-Based Activity
PDGF-induced pAKT
LPA-induced pAKT
fMLP-induced CD63+
FcR1-induced CD63+
EC50 (nM)
>20,000
1,900
3,000 8
Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions
No off-target activity against Class II or III PI3K, mTOR, or DNA-PK
No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)
Lannutti, Blood, 2011

26. Marked Reductions in Peripheral Lymphadenopathy Were Observed
Debates and Didactics 2013
November 18
Marked Reductions in Peripheral Lymphadenopathy Were Observed
Pretreatment
With Idelalisib Treatment
38 year-old patient with refractory CLL and 5 prior therapies

27. Idelalisib + Rituximab in Frontline CLL: Response Assessment
All Subjects
Del(17p) and/or TP53 mutation
N = 64
(%)
N = 9
Complete Response 12
(19) 3
(33)
Partial Response 50
(78) 6
(67)
Stable Disease
Progressive Disease
Not Evaluable 2
(3)
Overall Response 62
(97) 9
(100)
Median Time to Response 1.9 months
24/26 patients with B symptoms resolved by week 16
No on-study progression
Lamana et al. iwCLL 2013

28. Idelalisib + Rituximab in Frontline CLL: Progression-Free Survival*
PFS at 24 months: 93%
Idelalisib + R
(N = 64)
*ITT analysis of primary + extension study Extension study assessments based on standard of care
Lamana et al. iwCLL 2013

29. Souers AJ, et al. Nature Med. 19(2):202-208. 2013
Background: ABT-199
Bcl-2 expression is uniformly high in CLL:
enabling inappropriate survival through evasion of
apoptosis
contributing to resistance to cytotoxic agents
ABT-199 is a selective, potent, orally bioavailable Bcl-2 inhibitor
ABT-199 binds Bcl-2 with high affinity and with substantially lower affinity to Bcl-xL, Bcl-w and MCL-1
ABT-199 mimics BH3-only proteins (Bim, Bad), but with greater selectivity
ABT-199 has shown preclinical activity in a wide range of Bcl-2 expressing hematologic malignancies as a single agent O N H 2 S Cl
ABT-199
Souers AJ, et al. Nature Med. 19(2):

30. Best Percent Change from Baseline in Nodal Size by CT Scan
N = 52 evaluable (at minimum, 6 weeks assessment)
Median Time to 50% Reduction = 1.4 months (range 0.7 to 13.7)

31. Best Percent Change from Baseline in Lymphocyte Count and Bone Marrow Infiltrate
Median Time to 50% Reduction:
12 days (range 1 to 43)
Bone Marrow Infiltrate
Median Time to 50% Reduction:
5.6 months (range 1.9 to 17.4)
500
* ^
% Change from Baseline
% Change from Baseline
Data represents patients with lymphocyte count >5 x 109/L
at baseline.
N = 32 evaluable
*Patient had 70% infiltrate at baseline and at Week 24.
^Patient did not have CLL infiltrate at baseline.
N = 34 evaluable
Anti-tumor activity of ABT-199 was observed in all tumor compartments.

32. Responses in ABT-199 Treated CLL Patients
All CLL
n (%)
N=56
Del 17p
n=17
Fludarabine
Refractory
n=18
Overall Response Rate
47 (84)
14 (82)
14 (78)
Complete response / Cri
11 (20)
2 (12)
3 (17)
Partial response*
36 (64)
12 (71)
11 (61)
Stable disease
4 (7)
1 (6)
Disease progression
1 (2) -
D/C Prior to first (6W) assessment
*3 patients had confirmatory CT imaging assessments at less than an 8 week interval (5, 6, and 7 weeks).
Seymour et al, iwCLL 2013

33. Conclusions – 17p Deletion
Small molecule inhibitors will
become the treatment of choice
Even for previously untreated patients
Probably not as single agents