1. Richard R. Furman Weill Cornell Medical College
What is the Optimal Therapy for CLL Patients Failing to Achieve PR with CIT?
Richard R. Furman
Weill Cornell Medical College

2. The Evolution of Treatment Options in CLL
Alkylators
CR: 5%
ORR: 30-50%
1970s
Purine Analogs
CR: %
ORR: %
1980s
Purine + alkylators
CR: 35%
ORR: %
1990s
Chemo-immunotherapy
CR: %
ORR: %
2000s
TKIs / SMIs
CR: ???
ORR: %
2010s

3. Fact #1:
Upfront chemoimmunotherapy (FCR) generates high response rates and progression free survival.
Response RR
ORR
95% CR
72%
nPR
10%
PR-i 7%
PR-d 5%
Tam CS. Blood 2008; 112:975.

4. FCR generates excellent time to progression
Fact #2:
FCR generates excellent time to progression
Keating, MJ. JCO 2005; 23:4079.

5. Fact #3: Patients do progress and additional therapy is necessary
Response
TTP
(months) CR 85
nPR 71
PR-i 50
PR-d 19
Tam CS. Blood 2008; 112:975.

6. Response to Second Line BR Chemotherapy Is Poor
Fischer K. JCO 2011; 29:3559.

7. AUSct Toxicity: MDS/AML
Risk of MDS/AML postautograft = 12.4% at 5 years
Incidence of non-MN = 11%
Milligan DW. BJH 2006; 133:173.

8. Overall Survival Post-Auto and Allogeneic Stem Cell Transplant
Gribben JG. Blood 2005; 106:4389.

9. BCR-associated Kinases: Proven Effective Therapeutic Targets
Syk (spleen tyrosine kinase):
fostamatinib
PRT062070
GS-9973
Btk (Bruton’s tyrosine kinase):
ibrutinib
CC-292
ACP-196
PI3K (phosphatidyl 3-kinase:
Idelalisib (GS-1101)
IPI-145
AMG319
Nat Rev Immunol 2:945

10. Targeting the “BCR++” Antigen Pathway:

11. Bruton’s Tyrosine Kinase (Btk)
B-cell antigen receptor (BCR) signaling required for B cell survival
Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway
Inhibitors of Btk block BCR signaling and induces apoptosis

12. Idelalisib: inhibitor of PI3 Kinase-d

13. Same Enzyme - Different Targets
PI3 Kinase
Same Enzyme - Different Targets
PI3K Isoforms
Expression
Broad
Leukocytes
Gene KO effect
Lethal
Benign
Physiological role
Insulin signaling
Angiogenesis
unknown
B-cell signaling, development & survival
Neutrophil,
T-cell development
IC50 (nM)
2154
427 8
182

14. Overall Survival for Idelalisib and Ibrutinib in Relapsed / Refractory Disease

15. PCYC-1102: Overall Response
Among those patients whose initial response was PR-L, the majority achieved classic response by IWCLL criteria:
TN: 9/13 (69%)
R/R: 38/49 (78%)
Combined ORR + (PR-L):
TN = (84%)
R/R = (88%)
Furman RR. IWCLL 2013.

16. PCYC-1102: Progression Free Survival at 26 months
TN: 96.3%
R/R: 73.6%
No del17p/11q: 92.2%
del11q: 72.9%
del17p: 53.1%

17. PCYC-1102: Patient Disposition
TN ≥ 65 Years
n = 31
R/R
n = 85
Median time on treatment, months
 21.3 (0.3, 26.6)
16.3 (0.3, 28.7)
Patients still on treatment, n (%)
26 (84)
53 (62)
Patients discontinuing treatment, n (%)
5 (16)
32 (38)
Reasons for treatment discontinuation, n (%) AE
Treatment-related AE
Death due to AE
2 (6)
1 (3)
10 (12)
1 (1)
1 (1)a
Disease progression*
SCT (while in response)
Investigator decision (not SCT)
Patient decision
Lost to Follow-up
4 (5)
3 (4)
*7 patients (1 TN, 6 R/R) had disease progression with Richter’s transformation
Furman RR. iWCLL 2013

18. Ibrutinib Common AEs (> 20 %)
Treatment Naïve ≥ 65 yrs
Grade 1
Grade 2
Grade 3
Grade 4

19. Rate of > Grade 3 Infections / 100 patient months
Rate of Severe Infections with Ibrutinib (PCYC-1102 Study – Rel/Ref Population)
Rate of > Grade 3 Infections / 100 patient months
First 6 months
>7 months
All Patients (N=85)
7.1
2.6
By duration of exposure:
<12 months (N=22)
17.7
4.1
>12 months (N=63
4.8
Byrd J. NEJM 2013.

20. PCYC-1102: Changes in Median Serum Immunoglobulin Levels – TN + R/R
Furman RR. IWCLL 2013.