Transcript No Slide Title

How To Manage
p53 Mutated CLL
Susan O’Brien
MD Anderson Cancer Center
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?
Survey
Private Practice MDs (9)
FCR
FR
Alemtuzumab
BR
5
1
2
1
3 MD mentioned “and then get to SCT”
4 Houston
2 Oklahoma
1 Florida
1 California
1 Louisiana
Survey
21 Academic Physicians
LN large:
Fludarabine-based
13
SM + R
4
Alemtuzumab-based 4
LN small:
Fludarabine-based
10
SM+R
2
Alemtuzumab-based 9
17/21 (81%) said “and proceed to SCT”
GCLLSG: SQ Alemtuzumab in
Fludarabine Refractory CLL
Schedule:
IV
SQ
3, 10, 30 mg then
30 mg 3 x / week
4 – 12 weeks
Patients:
Binet C:
No. prior Tx:
Unmutated
17 p -
Stilgenbauer et al JCO 2009, 27;3994-4001
74%
4 (1 – 9)
73%
29%
GCLLSG: SQ Alemtuzumab
Response by Genetics
60,0%
40,0%
20,0%
0,0%
Stilgenbauer et al ASH 2004; Abstract #478
PR
CR
CAM307: Response to First-line Therapy With
Alemtuzumab vs Chlorambucil (N = 297)
IRRP Response Rate to First-line B-CLL Therapy
100
90
P<0.0001
83% ORR
80
% Response
70
24% CR
60
55% ORR
2%
50
40
30
59% PR
53%52.7
PR
20
10
0
Alemtuzumab
Chlorambucil
CR
PR
CAM307: Overall Response Rates According
to Cytogenetic Abnormality
Overall Response Rates (%)
IV Alemtuzumab (N=147)
100
Oral Chlorambucil (N=147)
90
80
70
60
64%
50
40
30
20
10
0
P=
17p del
11q del
0.0805
<0.0001
Trisomy 12
Normal
1.0000
0.3238
Sole del 13q
[Data presented according to hierarchical model of Döhner (NEJM 2000;323:1910-6)]
0.0087
CAM307: PFS by Cytogenetic Abnormality
and Treatment Arm
Alemtuzumab
Chlorambucil
N
Median PFS
(mo)
P-value for
PFS
Deletion
N
Median PFS
(mo)
17p del
11
10.7
10
2.2
0.2034
11q del
(no 17p del)
23
8.5
31
8.5
0.3895
Trisomy 12
(no 17p del,
no 11q del)
24
18.3
10
12.9
0. 0815
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: 1910-6)]
P value is calculated using log-rank test
Response to FC + Rituximab (N=300)
Response
CR
nPR
PR
NR
Early Death
No. Pts.
218
30
37
13
2
Keating et al JCO 23(18):4070, 2005; updated 2009
Percent
73
10
12
4
1
95%
Response to Frontline FCR-based*
Treatment by FISH (N=169)
FISH
% Pts
% CR
% OR
17p del
11
26
74
11q del
21
83
100
+12
21
81
100
None
20
71
97
13q del
26
75
100
100
74
96
Overall
*Includes: FCR, FCR3, FCMR, FCR+GM-CSF
P=.01
P<.001
CLL8 Study Design
Patients with
untreated, active
CLL and
good physical
fitness
(CIRS ≤ 6, creatinine
clearance ≥ 70
ml/min)
FCR
6 courses
R
FC
Updated results of the 2nd analysis
Median observation time 37.7 months.
Hallek et al Lancet 2010;376:1164-74
Follow
up
CLL8 Genetic Analyses: PFS
FC
FCR
13
CLL2O: Design
Off Study
PD
4 week
Alem +
Dexa
staging
PD
PR
SD
Dexa: 40 mg
d 1-4, d 15-18, p.o.
staging
PR
SD
4 week
Alem +
Dexa
CR
CR
Alem: 30 mg
3x / week, s.c.
4 week
Alem +
Dexa
PD
Maintenance:
Option A: alemtuzumab maintenance
(30 mg / 14 d, max. 2 years)
or:
Option B: allo-SCT
staging
SD/PR CR
CamPred regimen (NCRI CLL206)
Weeks 1-4:
IV alemtuzumab
30mg tiw
Weeks 5-16:
SC alemtuzumab
30mg tiw
IV methylprednisolone
1.0 g/m2 day 15
Weeks 1, 5, 9 and 13
Pettit et al JCO 2012: 30: 1647-55
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
Comparison of Front-line Regimens in 17pFCR
CLL8
CAM
Cam Dex CamPred
CAM307
CLL20
CLL206
CR%
5
24
24
65
OR%
69
63
98
88
PFS (mos)
11
11
18
18
OS (mos)
23
39
Comparison of Front-line Regimens in 17pGr 3/4 tox
FCR
CLL8
CAM
Cam Dex CamPred
CAM307
CLL20
CLL206
ANC
34
41
18
67*
Plts
7
12
14
31*
Inf.
21
26
35
71
49*
?
23*
CMV
-
Steroid
-
+Sepsis + NF
8+
53
-
*hematologic, all pts
Frontline Trial Data for 17pWhat is the N?
Regimen
CLL8 FCR
CAM307
CamPred
CamDex
SM+R
17p- patients
22
11
17
39
1
90
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
PCI-32765: First-in Class Inhibitor of BTK
O
NH
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
2
N
N
N
•
N
N
O
PCI-32765
Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010
Herman SEM et al: Blood 117: 6287-6296, 2011
Ponader, et al., ASH Meeting Abstracts 116:45, 2010
Ibrutinib in Refractory CLL With 11q Deletion
Before
4 weeks
PCYC-1102-CA: Best Overall Response
Combined ORR + (PR+L) in TN (84%) and R/R (88%)
IWCLL 2013, PCYC 1102, Furman et al.
PCYC-1102-CA: Best Response by Risk Features
Treatment Naive
R/R + HR
N
ORR %
N
ORR %
All Patients
31
68
85
71
≥ 70 years age
β2 Microglobulin > 3 mg/L
23
8
61
63
30
39
73
72
Rai Stage III/IV
15
60
55
71
IgVH unmutated
17
82
69
77
del(17p13.1) present
2
100
28
68
del(11q22.3) present
1
100
31
77
Bulky disease ≥ 5 cm
6
≥ 3 prior chemo regimens
67
Not applicable
44
58
77
69
Purine Analog Refractory
Not applicable
41
66
PCYC-1102: Progress-Free Survival
IWCLL 2013, PCYC 1102, Furman et al.
Idelalisib is an Orally Bioavailable Small Molecule
that Inhibits PI3K Delta Potently and Selectively
CAL-101
Class I
PI3K
Isoform
Cell-Based
Activity
Alpha
Beta
Gamma
Delta
PDGF-induced
pAKT
LPA-induced
pAKT
fMLP-induced
CD63+
FcR1-induced
CD63+
>20,000
1,900
3,000
8
EC50 (nM)
• 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
Marked Reductions in Peripheral
Lymphadenopathy Were Observed
Pretreatment
With Idelalisib Treatment
38 year-old patient with refractory CLL and 5 prior therapies
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
0
0
Progressive Disease
0
0
Not Evaluable
2
(3)
0
Overall Response
62
(97)
9
• 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
(100)
Idelalisib + Rituximab in Frontline CLL:
Progression-Free Survival*
100
Probability of PFS
80
All Patients N=64
TP53 mutation/ Del (17p) N=9
60
PFS at 24 months: 93%
40
Idelalisib + R
20
(N = 64)
0
BL
5
10
15
Months
*ITT analysis of primary + extension study
Extension study assessments based on standard of care
Lamana et al. iwCLL 2013
20
25
30
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 Bcl2 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
Cl
with greater selectivity
• ABT-199 has shown preclinical activity in a wide range
of Bcl-2 expressing hematologic malignancies as a
single agent
NO2 H
N
O2S
O
NH
O
O
N
N
N
ABT-199
Souers AJ, et al. Nature Med. 19(2):202-208. 2013
N
H
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)
Best Percent Change from Baseline in
Lymphocyte Count and Bone Marrow Infiltrate
Bone Marrow Infiltrate
Median Time to 50% Reduction:
5.6 months (range 1.9 to 17.4)
% Change from Baseline
% Change from Baseline
Lymphocyte Count
Median Time to 50% Reduction:
12 days (range 1 to 43)
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.
500
* ^
Responses in ABT-199 Treated CLL Patients
All CLL
n (%)
N=56
Del 17p
n (%)
n=17
Fludarabine
Refractory
n (%)
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)
1 (6)
Disease progression
1 (2)
1 (6)
-
D/C Prior to first (6W) assessment
4 (7)
1 (6)
3 (17)
Responses
*3 patients had confirmatory CT imaging assessments at less than an 8 week interval (5, 6, and 7 weeks).
Seymour et al, iwCLL 2013
Conclusions – 17p Deletion
Small molecule inhibitors will
become the treatment of choice
- Even for previously untreated
patients
- Probably not as single agents