How%20To%20Manage%20p53%20Mutated%20CLL

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How To Managep53 Mutated CLL
Susan OBrien MD Anderson Cancer Center
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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?

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SurveyPrivate Practice MDs (9)

• FCR FR Alemtuzumab BR
• 5 1 2 1
• 3 MD mentioned and then get to SCT
• 4 Houston 1 Florida
• 2 Oklahoma 1 California
• 1 Louisiana

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Survey21 Academic Physicians

• LN large Fludarabine-based 13
• SM R 4
• Alemtuzumab-based 4
• LN small Fludarabine-based 10
• SMR 2
• Alemtuzumab-based 9

17/21 (81) said and proceed to SCT
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GCLLSG SQ Alemtuzumab in Fludarabine
Refractory CLL
Schedule IV 3, 10, 30 mg then SQ 30 mg 3 x / week 4 12 weeks IV 3, 10, 30 mg then SQ 30 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, 273994-4001
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GCLLSG SQ Alemtuzumab Response by Genetics
60,0
40,0
PR
CR
20,0
0,0
All N46
VH unmut
17p-
11q-
13q-
12q
Stilgenbauer et al ASH 2004 Abstract 478
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CAM307 Response to First-line Therapy With
Alemtuzumab vs Chlorambucil (N 297)
IRRP Response Rate to First-line B-CLL Therapy
100
Plt0.0001
83 ORR
90
80
CR
24 CR
70
PR
55 ORR
60
50
Response
40
30
59 PR
52.7
53 PR
20
10
0
Alemtuzumab
Chlorambucil
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CAM307 Overall Response Rates According to
Cytogenetic Abnormality
64
Overall Response Rates ()
P
lt0.0001
1.0000
0.3238
0.0087
0.0805
Data presented according to hierarchical model
of Döhner (NEJM 20003231910-6)
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CAM307 PFS by Cytogenetic Abnormality and
Treatment Arm
Alemtuzumab Alemtuzumab Alemtuzumab Chlorambucil Chlorambucil Chlorambucil
Deletion N Median PFS (mo) 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 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
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Response to FC Rituximab (N300)

• Response No. Pts. Percent
• CR 218 73
• nPR 30 10 95
• PR 37 12
• NR 13 4
• Early Death 2 1

Keating et al JCO 23(18)4070, 2005 updated 2009
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Response to Frontline FCR-based Treatment by
FISH (N169)
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
Overall 100 74 96
P.01
Plt.001
Includes FCR, FCR3, FCMR, FCRGM-CSF
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CLL8 Study Design
Updated results of the 2nd analysis Median
observation time 37.7 months.
Hallek et al Lancet 20103761164-74
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CLL8 Genetic Analyses PFS
FC
FCR
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CLL2O Design
4 week Alem Dexa
4 week Alem Dexa
4 week Alem Dexa
PR SD
PR SD
staging
staging
staging
Alem 30 mg 3x / week, s.c. Dexa 40 mg d 1-4,
d 15-18, p.o.
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CamPred regimen (NCRI CLL206)

• Anti-microbial prophylaxis
• Co-trimoxazole 480mg bd
• Aciclovir 400mg qds
• Itraconazole suspension 200mg bd
• G-CSF when neutrophil count lt 1.0x109/l
• Valganciclovir for CMV viraemia

Pettit et al JCO 2012 30 1647-55
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Comparison of Front-line Regimens in 17p-
FCR CLL8 CAM CAM307 Cam Dex CLL20 CamPred CLL206
CR 5 24 24 65
OR 69 63 98 88
PFS (mos) 11 11 18 18
OS (mos) 23 39
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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
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Frontline Trial Data for 17p-What is the N?

• Regimen 17p- patients
• CLL8 FCR 22
• CAM307 11
• CamPred 17
• CamDex 39
• SMR 1
• 90

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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

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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-?B DNA binding, CpG
  mediated proliferation
• Inhibits CLL cell migration and adhesion
• No cytotoxic effect on T-cells or NK-cells

PCI-32765
Honigberg LA et al Proc Natl Acad Sci U S
A.10713075, 2010 Herman SEM et al Blood 117
6287-6296, 2011 Ponader, et al., ASH Meeting
Abstracts 11645, 2010
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Ibrutinib in Refractory CLL With 11q Deletion
Before
4 weeks
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PCYC-1102-CA Best Overall Response
IWCLL 2013, PCYC 1102, Furman et al.
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PCYC-1102-CA Best Response by Risk Features
Treatment Naive Treatment Naive R/R HR R/R HR
N ORR N ORR
All Patients 31 68 85 71
70 years age 23 61 30 73
ß2 Microglobulin gt 3 mg/L 8 63 39 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 67 44 77
3 prior chemo regimens Not applicable Not applicable 58 69
Purine Analog Refractory Not applicable Not applicable 41 66
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PCYC-1102 Progress-Free Survival
IWCLL 2013, PCYC 1102, Furman et al.
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Idelalisib is an Orally Bioavailable Small
Molecule that Inhibits PI3K Delta Potently and
Selectively
CAL-101
Class IPI3K Isoform
Cell-Based Activity PDGF-induced pAKT LPA-induced pAKT fMLP-induced CD63 Fc?R1-induced CD63
EC50 (nM) gt20,000 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 gt350
  protein kinases (Ambit KINOMEscan)

Lannutti, Blood, 2011
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Marked Reductions in Peripheral Lymphadenopathy
Were Observed
Pretreatment
With Idelalisib Treatment
38 year-old patient with refractory CLL and 5
prior therapies
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Idelalisib Rituximab in Frontline CLL Response
Assessment
All Subjects All Subjects Del(17p) and/or TP53 mutation 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 (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
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Idelalisib Rituximab in Frontline CLL
Progression-Free Survival
PFS at 24 months 93
Idelalisib R (N 64)
ITT analysis of primary extension
studyExtension study assessments based on
standard of care
Lamana et al. iwCLL 2013
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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

ABT-199
Souers AJ, et al. Nature Med. 19(2)202-208. 2013
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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)

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Best Percent Change from Baseline in Lymphocyte
Count and Bone Marrow Infiltrate
Lymphocyte Count 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 gt5
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.
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Responses in ABT-199 Treated CLL Patients
Responses All CLL n () N56 Del 17p n () n17 Fludarabine Refractory n () n18
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)
3 patients had confirmatory CT imaging
assessments at less than an 8 week interval (5,
6, and 7 weeks).
Seymour et al, iwCLL 2013
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Conclusions 17p Deletion

• Small molecule inhibitors will
• become the treatment of choice
• Even for previously untreated patients
• Probably not as single agents