1. CLL/SLL: New Therapeutic Strategies for the Practicing Clinician
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3. Faculty Jennifer R. Brown, MD, PhD Associate Professor of Medicine
Department of Hematologic Malignancies
Dana-Farber Cancer Institute
Harvard Medical School
Director, CLL Center
Department of Medical Oncology
Boston, Massachusetts
Jennifer R. Brown, MD, PhD, has disclosed that she has received consulting fees from Celgene, Gilead Sciences, Infinity, Janssen, Pharmacyclics, ProNai, Roche/Genentech, and Sun BioPharma.
This slide lists the faculty who were involved in the production of these slides.

4. Chronic Lymphocytic Leukemia
~ 15,000 new cases per yr
Most common adult leukemia
Chronic, incurable, mature B-cell neoplasm
Most pts present with asymptomatic increase in lymphocyte count
Many asymptomatic pts do not initially require therapy
Therapy required once symptoms, cytopenias, or large lymphadenopathy occur
Slide credit: clinicaloptions.com

5. CLL: Incidence of Genetic Lesions
Treatment naïve CLL[1]
(n = 452)
CLL8[2]
Frontline
FC vs FCR (n = 635)
CLL3X[3,4]
High-Risk
AlloSCT (n = 80)
CLL2H[5,6]
F-Refractory Alemtuzumab (n = 97)
TP53mut
5.3
11.5
30.0
39.0
NOTCH1mut
12.6
10.0
14.0
13.4
SF3B1mut
8.6
18.4
26.0
17.5
IGHV UM
32.8
63.0
96.0
79.0
del(17p)
8.4
18.1
30.1
del(11q)
16.0
24.6
36.1
19.4
F, fludarabine.
1. Puente XS, et al. Nature. 2015;526:
2. Stilgenbauer S, et al. Blood. 2014;123: Dreger P, et al. ASH Abstract Dreger P, et al. Blood. 2013;121: Schnaiter A, et al. Blood. 2013;122: Schneiter A, et al. ASH Abstract 710.
Slide credit: clinicaloptions.com

6. Estimate of OS According to Cytogenetics
Median OS, yrs NR
5.0
Events, n 27 53
41 57
Total, n 155
228 99
101
95% CI
Del(13q14) Normal/+12 NOTCH1 M/SF3B1 M/del(11q22-q23)
TP53 DIS/BIRC3 DIS
100 80 60
Del(13q14) vs normal/+12
Normal/+12 vs NOTCH1 M/SF3B1 M/del(11q22-q23)
NOTCH1 M/SF3B1 M/del(11q22-q23)
vs TP53 DIS/BIRC3 DIS
P = .0406
P = .0082
P = .0196
Cumulative Probability of OS (%) 40 20
P < .0001 5 10 15
Yrs From Diagnosis
Slide credit: clinicaloptions.com
Rossi D, et al. Blood. 2013;121:

7. Initial Management of Patients With Untreated CLL

8. Case 1: First-line Treatment
Your 58-yr-old pt was diagnosed with asymptomatic CLL and you recommended observation
1 yr later, monitoring revealed worsening disease
WBC 123,000 cells/mm3, ANC 1700 cells/mm3, ALC 119,000 cells/mm3, Hb 10.1 g/dL, hematocrit 30.2%, platelet count 99,000 cells/mm3
Spleen tip was enlarged to 3 cm beneath the left costal margin
FISH testing reveals presence of trisomy 12, and IGHV status was mutated
CT scan confirmed splenomegaly and showed diffuse adenopathy including bilateral axillary, subcarinal, retroperitoneal, right external iliac, and 8-cm mesenteric mass
Slide credit: clinicaloptions.com

9. Based on available data, which of the following would you recommend for this pt?
Continued observation
Fludarabine, cyclophosphamide, and rituximab
Bendamustine and rituximab
Obinutuzumab and chlorambucil
Idelalisib and rituximab
Ibrutinib
Unsure
Slide credit: clinicaloptions.com

10. Based on available data, which of the following would you recommend for this pt?
Continued observation
Fludarabine, cyclophosphamide, and rituximab
Bendamustine and rituximab
Obinutuzumab and chlorambucil
Idelalisib and rituximab
Ibrutinib
Unsure
Slide credit: clinicaloptions.com

11. Phase III CLL10: Final Analysis of FCR vs BR in Pts With Advanced CLL
Fludarabine 25 mg/m2 IV Days Cyclophosphamide 250 mg/m2 Days Rituximab 375 mg/m2 IV Day 0, cycle 1 + Rituximab 500 mg/m2 IV Day 1, cycles 2-6
Pts with untreated, active CLL without del(17p) and good physical fitness (CIRS ≤ 6, creatinine clearance ≥ 70 mL/min) (N = 564) BR
Bendamustine 90 mg/m2 IV Days Rituximab 375 mg/m2 Day 0, cycle 1 + Rituximab 500 mg/m2 IV Day 1, cycles 2-6
BR, bendamustine, rituximab; CIRS, Cumulative Illness Rating Scale; CLL, chronic lymphocytic leukemia; FCR, fludarabine, cyclophosphamide, rituximab; IV, intravenously; PFS, progression-free survival.
Primary endpoint: noninferiority of BR vs FCR for PFS with HR (λBR/FCR) < 1.388
Slide credit: clinicaloptions.com
Eichhorst B, et al. ASH Abstract 19.

12. CLL10: Response with FCR vs BR in Pts With Advanced CLL
FCR (n = 282)
BR (n = 279)
P Value
CR (CR + CRi)
39.7
30.8
.034 CR
35.1
30.4
CRi
4.6
0.4 PR
55.7
64.9
ORR
95.4
95.7
1.0
MRD Negativity, %
FCR (n = 282)
BR (n = 279)
BM at final restaging
26.6
11.1
PB at final restaging
48.6
38.4
PB 12 mos after final restaging
19.7
9.0
PB 18 mos after final restaging
18.0
8.5
Slide credit: clinicaloptions.com
Eichhorst B, et al. ASH Abstract 19.

13. (> 1.388 non-inferiority cut-off)
CLL10: PFS (Primary Endpoint) and OS With FCR vs BR in Pts With Advanced CLL
PFS OS
1.0
Median
PFS, Mos
1.0
FCR BR
0.8
0.8
P = .897
0.6
0.6
Cumulative Survival
0.4
0.4
OS at
36 Mos, %
0.2
0.2
P < .001
HR: 1.626
(> non-inferiority cut-off)
FCR BR 12 24 36 48 60 12 24 36 48 60
Mos
Mos to Event (OS)
Slide credit: clinicaloptions.com
Eichhorst B, et al. ASH Abstract 19.

14. CLL10: Adverse Events With FCR vs BR in Pts With Advanced CLL
P Value
Neutropenia
84.2
59.0
< .001
Anemia
13.6
10.4
.20
Thrombocytopenia
21.5
14.4
.03
Infection
39.1
26.8
Secondary neoplasm*
6.1
3.6
.244
Treatment-related mortality
4.6
2.1
.107
Infections
2.5 --
Secondary neoplasm
1.1
Other
1.0
*sAML/MDS: FCR = 6, BR = 1
Slide credit: clinicaloptions.com
Eichhorst B, et al. ASH Abstract 19

15. CLL10 Trial: Conclusions
Compared with BR, FCR increases CR rate and median PFS, but not OS
While achieving those improvements, FCR causes increased adverse events, including neutropenia, thrombocytopenia, and infections
Slide credit: clinicaloptions.com

16. Pts Progression Free (%)
FCR300 Phase II Trial: Plateau in PFS with FCR as Initial Therapy for CLL
With extended follow-up, PFS shows plateau at Yrs 10-11
Last relapses occurred around Yr 10, with a plateau in PFS for IGHV-mutated pts
Progression Free N
Event Free N OS
PFS
IGHV mutated IGHV unmutated
100
100 75 75
Pts (%) 50
Pts Progression Free (%) 50
FCR, fludarabine/cyclophosphamide/rituximab; OS overall survival; PFS, progression-free survival. 25 25
P < .0001 2 4 6 8 10 12 14 16 2 4 6 8 10 12 14 16
Yrs
Yrs
Slide credit: clinicaloptions.com
Thompson PA, et al. Blood Oct 22.

17. Use of MRD Assessment in CLL
MRD assessment important surrogate endpoint in clinical trials
Important predictor of efficacy for new agents in CLL
Outside of a trial setting, not yet routine
MRD Assessment
Results
Peripheral blood[1]
Statistically significant difference in PFS between MRD- CR or PR and MRD+ CRs
(P = .001 and .008, respectively)
Bone marrow[2]
Independently associated with significantly longer PFS and OS (P = .03 and .02, respectively)
1. Kovacs G, et al. ASH Abstract Strati P, et al. Blood. 2014;123:
Slide credit: clinicaloptions.com

18. What About Treatment for Older Patients With CLL?

19. Case 2: Frontline Therapy
A 78-yr-old pt with progressive fatigue and 4-kg weight loss
Multiple comorbidities and CRI (CrCl 32 mL/min)
Nonetheless, she lives alone and can take care of her ADL with the aid of a companion
She is found to have CLL
Labs show WBC 43,200 cells/mm3, ANC 1300 cells/mm3, ALC 39,700 cells/mm3, Hb 8.9 g/dL, hematocrit 26.4%, platelet count 89,000 cells/mm3
Exam reveals a thin woman (height 155 cm, weight 43.6 kg) with small volume axillary and inguinal adenopathy, and palpable spleen 4 cm beneath the left costal margin
Evaluation reveals mutated IGHV and FISH trisomy 12
Slide credit: clinicaloptions.com

20. Which of the following would you recommend for this pt?
Ofatumumab and chlorambucil
Obinutuzumab and chlorambucil
Ibrutinib
Idelalisib and rituximab
Bendamustine and rituximab
Fludarabine and rituximab
Fludarabine, cyclophosphamide, and rituximab
Unsure
Slide credit: clinicaloptions.com

21. Goals of Frontline Treatment for Older Pts With CLL
Pts with comorbidities, reduced organ function, unfavorable performance status
Fit pts with longer life expectancy (unrelated to CLL prognosis)
Deep remission
Effective but less toxic
Do no harm
Goal: MRD negative Good response Palliation
Priority: Efficacy Efficacy and tolerability Low toxicity
Shanafelt T. Hematology Am Soc Hematol Educ Program ;2013:
Slide credit: clinicaloptions.com

22. Mos Since Randomization
Complement-1 Phase III Trial: Ofatumumab + Chlorambucil vs Chlorambucil Alone
Ofatumumab + chlorambucil
mPFS: 22.4 mos
(95% CI: )
HR: 0.57; P < .001
Chlorambucil
mPFS: 13.1 mos
(95% CI: )
1.0
8.0
6.0
4.0
2.0
Probability of PFS*
M, median; PFS, progression-free survival.
Median follow-up: mos 4 8 12 16 20 24 28 32 36 40 44 48 52
Mos Since Randomization
*As assessed by an independent review committee.
Slide credit: clinicaloptions.com
Hillmen P, et al. ASH Abstract 528.

23. Phase III CLL11 Trial: Chlorambucil Alone vs With Obinutuzumab vs With Rituximab
0.5 mg/kg PO on Days 1, 15 x 6 cycles
(n = 118)
Previously untreated
CLL pts with
comorbidities
(CIRS score > 6 and/or
CrCl < 70 mL/min)
(N = 781)
Obinutuzumab
1000 mg IV cycle 1 on Days 1, 8, 15; cycles 2-6 on Day 1 Chlorambucil
(n = 333)
Rituximab
375 mg/m2 IV cycle 1 on Day 1; 500 mg/m2 cycles 2-6 on Day 1 Chlorambucil
(n = 330)
Goede V, et al. ASH Abstract 6. Goede V, et al. N Engl J Med. 2014;370:
Slide credit: clinicaloptions.com

24. CLL11: Survival with Clb/Obinutuzumab vs Clb Alone or Clb/Rituximab in CLL
HR: 0.18 (95% CI: ; P < .001)
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR: 0.41 (95% CI: ; P < .002)
Probability of PFS
Probability of OS
O-Clb Clb
26.7
O-Clb Clb
11.1 6 12 18 24 30 36 6 12 18 24 30 36
1.0
0.8
0.6
0.4
0.2 6 12 18 24 30 36 39
1.0
0.8
0.6
0.4
0.2 6 12 18 24 30 36 39
HR: 0.39 (95% CI: ; P < .001)
HR: 0.66 (95% CI: ; P = .08)
Probability of PFS
Probability of OS
O-Clb R-Clb
O-Clb R-Clb
26.7
15.2
Mos
Mos
Slide credit: clinicaloptions.com
Goede V, et al. N Engl J Med. 2014;370:

25. CLL11: Response with Clb/Obinutuzumab vs Clb Alone or Clb/Rituximab in CLL
O-Clb (n = 238)
Clb (n = 118)
R-Clb (n = 233)
ORR
77.3
31.4
75.7 CR
22.3
7.3 PR
55.0
58.4
Pts With MRD-Negative Test, %
O-Clb
R-Clb
P Value
Bone marrow
19.5
2.6
< .001
Blood
37.7
3.3
Slide credit: clinicaloptions.com
Goede V, et al. N Engl J Med. 2014;370:

26. CLL11: Safety of Clb/Obinutuzumab vs Clb/Rituximab in CLL
Adverse Event, %
O-Clb (n = 336)
R-Clb (n = 321)
Any grade ≥ 3 70 55
Infusion-related reaction 20 4
Neutropenia 33 28
Anemia
Thrombocytopenia 10 3
Leukopenia 1
Infection 12 14
Pneumonia 5
Slide credit: clinicaloptions.com
Goede V, et al. N Engl J Med. 2014;370:

27. CLL11: Conclusions
Adding anti-CD20 antibody to chlorambucil improves response rates and PFS vs chlorambucil alone
Adding obinutuzumab to chlorambucil improves response rates and PFS vs adding rituximab to chlorambucil
Adding obinutuzumab to chlorambucil improves OS vs chlorambucil alone, trend for OS improvement vs rituximab-chlorambucil
Obinutuzumab produces more infusion reactions and thrombocytopenia than rituximab
Slide credit: clinicaloptions.com

28. RESONATE-2: Ibrutinib vs Chlorambucil in Pts ≥ 65 Yrs of Age With Tx-Naive CLL/SLL
An international, randomized phase III trial
Primary endpoint: PFS
Secondary endpoints: OS, ORR, EFS, rate of hematologic improvement, and safety
Ibrutinib
420 mg/day until progression
Pts 65 yrs of age or older with treatment-naive CLL/SLL; no warfarin use; no del(17p) (N = 269)
Crossover upon PD (n = 43)
Chlorambucil
0.5 mg/kg (up to maximum of 0.8 mg/kg)
on Days 1, 15 of 28-day cycle
for up to 12 cycles
Slide credit: clinicaloptions.com
Burger JA, et al. N Engl J Med. 2015;[Epub ahead of print].

29. RESONATE-2: Superior Efficacy With Ibrutinib vs Chlorambucil for Elderly Pts
PFS OS
Ibrutinib
100
100
Ibrutinib 80 80
Chlorambucil 60
Chlorambucil 60
Pts With PFS (%)
Pts Who Survived (%) 40 40
Clb
18.9
Ibrutinib NR 20 20
Median, mos HR: 0.16 (95% CI: ; P < .001)
HR: 0.16 (95% CI: ; P < .001 by log-rank test) 6 12 18 24 6 12 18 24
Mos
Mos
AEs Summary
Ibrutinib
Chlorambucil
Most frequent AEs
Diarrhea, fatigue, cough and nausea
Nausea, fatigue, neutropenia, anemia, and vomiting
AEs leading to discontinuation, % 9 23
Slide credit: clinicaloptions.com
Burger JA, et al. N Engl J Med. 2015;[Epub ahead of print].

30. Frontline CLL Therapy in 2016
Clinical trial should be considered for all pts with CLL
Population
Initial Therapy
Younger, fit pts
FCR (especially mutated IGHV)
Older pts with comorbidities
Bendamustine/Rituximab
Chlorambucil/Obinutuzumab
Chlorambucil/Ofatumumab
Ibrutinib
Pts with del(17p) or
TP53 mutation
AlloSCT?
Slide credit: clinicaloptions.com

31. Optimal Treatment for Relapsed/Refractory CLL

32. Case 2: Management at Relapse
Your 78-yr-old pt is treated with obinutuzumab and chlorambucil
She tolerates 4 cycles of treatment before she developed prolonged cytopenias after therapy
On exam, there is no adenopathy or splenomegaly
The CBC reveals WBC 2,300 cells/mm3, ANC cells/mm3, ALC 100 cells/mm3, Hb 9.2 g/dL, hematocrit %, platelet count 100,000 cells/mm3
You choose to observe
Initial visit: 78-yr-old, thin woman diagnosed with CLL; small volume axillary and inguinal adenopathy, and palpable spleen 4 cm beneath left costal margin; mutated IGHV and trisomy 12 by FISH
Slide credit: clinicaloptions.com

33. Case 2: Management at Relapse
Initially in follow-up, cytopenias gradually resolve
6 mos after therapy: WBC 5100 cells/mm3, ANC 2500 cells/mm3, ALC 2,100 cells/mm3, Hb 10.9 g/dL, hematocrit 32.9%, platelet count 132,000 cells/mm3
However, over the next 12 mos, the pt has a rising ALC and develops progressive anemia and thrombocytopenia
Current labs: WBC 32,100 cells/mm3, ANC 1300 cells/mm3, ALC 29,100 cells/mm3, Hb 9.1 g/dL, hematocrit 27.4%, platelet count 97,000 cells/mm3
Repeat FISH shows trisomy 12; TP53 status is negative
During treatment, she developed atrial fibrillation and was started on apixaban
Slide credit: clinicaloptions.com

34. What treatment would you recommend for this pt now?
Continued observation
Ibrutinib
Idelalisib with rituximab
Bendamustine and rituximab
Fludarabine and rituximab
Fludarabine, cyclophosphamide, and rituximab
Unsure
Slide credit: clinicaloptions.com

35. What treatment would you recommend for this pt now?
Continued observation
Ibrutinib
Idelalisib with rituximab
Bendamustine and rituximab
Fludarabine and rituximab
Fludarabine, cyclophosphamide, and rituximab
Unsure
Slide credit: clinicaloptions.com

36. Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies
BCR signaling is required for tumor expansion and proliferation
BCR signaling up- regulated in CLL
New inhibitors are targeting multiple components of BCR signaling including PI3K delta, BTK, and Syk
BCR
LYN
SYK
Idelalisib
Duvelisib
Pilaralisib ┬
BCR, B-cell antigen receptor; BTK, Bruton’s tyrosine kinase; GSK-3, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; NF-kβ, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphatidylinositide 3-kinases; PKC, protein kinase C; PLC, phospholipase C; Syk, spleen tyrosine kinase. ┬
PI3K
delta
Ibrutinib
BTK
PLCγ2
AKT
GSK-3
NF-kβ
pathway ┬
PKC
mTOR
Everolimus
p70s6k
elf4E
Slide credit: clinicaloptions.com

37. Phase II (PCYC-1102/PCYC-1103) Ibrutinib Monotherapy Trial in CLL/SLL
Pts with CLL/SLL: tx naive (n = 31) and R/R with PD < 24 mos after chemoimmunotherapy or failure to respond (n = 101)
Pts received ibrutinib 420 or 840 mg/day PO
Best response to ibrutinib improves over time
100
100
ORR:
90%
ORR:
89%
CR PR PR-L
ORR:
84% 90
ORR:
80% 7 11 80 76 77 76 80 73 6 69 71 23
CR PR PR-L SD PD 70 63 74 56 60 60 48
Pts With Response (%) 50
Pts (%)
ANC, absolute neutrophil count; CLL, chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization; PD, progressive disease; R/R, relapsed/refractory; SD, stable disease; SLL, small lymphocytic leukemia; TN, treatment naive. 40 80 65 74 40 42 42 55 29 30 20 20 20 21 15 12 5 10 9 11 8 4 12 2 10 8 10 4 5 6 5 3 2 9 3 4 1 2 5 4 5 4 4
Untreated ≥ 65 Yrs of Age (n = 31)
R/R (n = 101)
R/R del(17p) (n = 34)
Total (N = 132) 3 6 9 12 15 18 24 30 36 42
Mos From Initiation of Study Treatment
Slide credit: clinicaloptions.com
Byrd JC, et al. Blood. 2015;125:

38. Ibrutinib Monotherapy 3 Yrs Postinitiation in CLL/SLL: PFS, OS by Cytogenetics
1.0
1.0
0.8
0.8
0.6
0.6
Proportion Achieving PFS
del(17p) del(11q) No del(17p) or del(11q)
Proportion Achieving OS
del(17p) del(11q) No del(17p) or del(11q)
0.4
0.4
0.2
0.2
Log-rank P = .0327
Log-rank P = .0031
0.0 6 12 18 24 30 36 42 6 12 18 24 30 36 42
Mos From Initiation of Study Treatment
Mos From Initiation of Study Treatment
del(17p) R/R (n = 34)
del(11p) R/R (n = 28)
No del(17p/11q) R/R (n = 34)
30-mo PFS, % (95% CI) 48
(29-65) 74
(53-87) 87
(68-95)
Median PFS, mos (95% CI)
28 (18.2-NE)
38.7 (31.2-NE) NR
(NE-NE)
del(17p) R/R (n = 34)
del(11p) R/R (n = 28)
No del(17p/11q) R/R (n = 34)
30-mo OS, % (95% CI) 65
(46-79) 85
(65-94) 90
(73-97)
Median OS, mos (95% CI)
NR (21.5-NE)
NR (41.4-NE) NR
(NE-NE)
Slide credit: clinicaloptions.com
Byrd JC, et al. Blood. 2015;125:
17/06/ :56

39. Phase III RESONATE: Ibrutinib vs Ofatumumab in Previously Treated CLL/SLL
Ibrutinib 420 mg/day PO until PD or unacceptable toxicity (n = 195)
CLL/SLL diagnosis
≥ 1 prior therapy
ECOG PS 0-1
Measurable nodal disease by CT
Ofatumumab IV starting dose of 300 mg followed by 2000 mg x 11 doses for 24 wks (n = 196)
Crossover = 122 pts
To Ibrutinib 420 mg/day following PD
CLL, chronic lymphocytic leukemia; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; IV, intravenously; PD, progressive disease; PO, orally; PS, performance status; SLL, small lymphocytic lymphoma
Primary goal: updated efficacy results, with median treatment duration of 16 mos, relative to genetic features and prior treatment exposure, and updated AE data
Brown JR, et al. ASH Abstract Byrd JC, et al. N Engl J Med. 2014;371:  
Slide credit: clinicaloptions.com

40. RESONATE: Ibrutinib vs Ofatumumab in Previously Treated CLL/SLL
100 80
HR: 0.215
(95% CI: )
Log-rank P < .0001 60
PFS (%) 40
Median
PFS, mos
NR 8.08 20
Ibrutinib Ofatumumab 3 6 9 12 15
Mos
Richter’s transformation confirmed in 2 pts on each arm; 1 additional pt on ibrutinib experienced disease transformation to prolymphocytic leukemia
Slide credit: clinicaloptions.com
Byrd JC, et al. N Engl J Med. 2014;371:  

41. RESONATE: PFS by del(17p) With Ibrutinib vs Ofatumumab in CLL/SLL
Ibrutinib del(17p) ibrutinib no del(17p)
Ofatumumab del(17p)
Ofatumumab no del(17p)
Median
PFS, mos NR
5.9
8.2
HR: (95% CI:
; P = .396)
HR: (95% CI:
; P = .039)
100 80 60
PFS (%) 40 20 3 6 9 12 15 18 21 24
Mos
For ibrutinib, no significant difference in PFS with or without del(17p)
Slide credit: clinicaloptions.com
Brown JR, et al. ASH Abstract 3331.

42. Survival After Discontinuing Ibrutinib Is Poor
100
Deaths/Total 25/33 Median OS: 3.1 mos 80 60
Survival (%) 40 30 10 20 30 40 50
Mos
Slide credit: clinicaloptions.com
Jain N, et al. Blood. 2015;125:

43. Retrospective Study: Time to Discontinuation of Ibrutinib
Single institution retrospective analysis of 308 pts participating in 4 sequential trials of ibrutinib
Cumulative Incidence,
% (95% CI)
12 Mos
18 Mos
Other event
13.5 ( )
15.6 ( )
Richter’s transformation
4.5 ( )
6.5 ( )
CLL progression
0.3 (0-1.0)
2.4 ( ) 30 25 20 15 10 5
Cumulative Incidence of Discontinuation of Ibrutinib Therapy (%) 48 6 12 18 24 30 36 42
Mos
Slide credit: clinicaloptions.com
Maddocks KJ, et al. JAMA Oncol. 2015;1:80-87.

44. Ibrutinib: Toxicities
Hemorrhage: fatal bleeding events have occurred
Grade ≥ 3: 6% of pts
Any grade, including bruising and petechiae: ~ 50% of pts
Recommendation: hold tx for days pre/postsurgery depending on the type of surgery and the risk of bleeding
Atrial fibrillation: 6% to 9% of pts
Increased in pts with cardiac risk factors, acute infections, and history of atrial fibrillation
Cytopenias, grade 3/4
Neutropenia (19% to 29%); thrombocytopenia (5% to 17%); anemia (0% to 9%)
Tumor lysis syndrome
Monitor closely, particularly pts with high tumor burden
Most common AEs (≥ 25%): thrombocytopenia, neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, URI, and rash
Slide credit: clinicaloptions.com
Ibrutinib [package insert]

45. Ibrutinib: Conclusions
Ibrutinib is very active in pts with R/R CLL
Produces ORR of 80% to 90%, with CR of 6% to 7%, and 53% of pts remain on ibrutinib at median 3-yr follow-up
No significant difference in PFS, regardless of del(17p) status
Ibrutinib can result in various AEs
Rate of atrial fibrillation is less than 10%
Increases bleeding risk, but most bleeding is mild and not serious
Use caution when combining with anticoagulants or in pts with predisposing risk factors
Slide credit: clinicaloptions.com

46. PI3K Signaling Pathway as a Target in B Cells
BCR
PI3K
Delta
PIP2
LYN
PTEN
SYK P
AKT P
p110
p85 P
p27kip1
IKK
NF-kB pathway
Proliferation
GSK-3ß
ASK
SAPK/JNK
pathway
Cyclin-D
Bad
mTOR
FoxO
Protein synthesis
Cell survival
Slide credit: clinicaloptions.com

47. Phase III Study 116/117: Rituximab ± Idelalisib in Relapsed CLL
Primary Study 116
Extension Study 117
Double blind
Blinded dose
Open label
Idelalisib 150 mg BID
Idelalisib 300 mg BID
Rituximab* (n = 110)
Pts with relapsed CLL, not appropriate for cytotoxic therapy; ≥ 1 prior anti-CD20 or ≥ 2 prior cytotoxic therapies PD
Idelalisib 150 mg BID
Placebo BID
BID, twice daily; CLL, chronic lymphocytic leukemia; OS, overall survival; PD, progressive disease; PFS, progression-free survival.
Rituximab* (n = 110)
Interim analysis; unblinding
Independent review
Blinded, independent review
Primary endpoint: PFS, OS by subgroup analysis
*Rituximab given in 8 doses; first dose 375 mg/m2, then 500 mg/m2 every 2 wks x 4, then every 4 wks x 3
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

48. Phase III Study 116/117: PFS With Rituximab ± Idelalisib in Relapsed CLL
100 80 60
PFS (%) 40 20
Idelalisib + R (n = 110)
Placebo + R* (n = 110) 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
Median PFS, Mos (95% CI)
HR (95% CI)
P Value
Idelalisib + R
19.4 (16.6-NR)
0.25 ( )
< .0001
Placebo + R
7.3 ( )
*Placebo + R includes those pts who received open-label idelalisib after unblinding without prior progression (n = 42).
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

49. Idelalisib + Rituximab in Relapsed CLL: PFS Subgroup Analysis*
IGHV: Unmutated vs Mutated
del(17p)/TP53mut: Present vs Not Present
100
100 80 80 60 60
PFS (%)
PFS (%) 40 40 20 20 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
CLL, chronic lymphocytic leukemia; NR, not reached; PFS, progression-free survival.
Mos
Mos
Mutated (n = 19)
Unmutated (n = 91)
No del(17p)/TP53mut (n = 64)
del(17p)/TP53mut
(n = 46)
Median PFS, Mos (95% CI)
P Value
Mut
NR (10.7-NR )
.75
Unmut
19.4 (16.6-NR )
Median PFS, Mos (95% CI)
P Value
No del
20.3 (19.4-NR)
.94
Del
16.6 (13.9-NR)
*Including extension study.
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

50. Idelalisib + R vs Placebo + R ➞ Idelalisib in Relapsed CLL: OS
All Pts
IGHV Unmutated
100 80 60 40 20
100 80 60 40 20
OS (%)
OS (%)
Idelalisib + R (n = 110) Placebo + R (n = 110)
P = .0001
Idelalisib + R (n = 91) Placebo + R (n = 93)
P = .0003 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
Mos
del(17p)/TP53 Mutation (Either)
del(11q) Positive
100 80 60 40 20
100 80 60 40 20
CLL, chronic lymphocytic leukemia; OS, overall survival; R, rituximab.
OS (%)
OS (%)
Idelalisib + R (n = 46) Placebo + R (n = 49)
P = .001
Idelalisib + R (n = 25) Placebo + R (n = 23)
P = .21 2 4 6 8 10 12 14 16 18 20 22 24 26 2 4 6 8 10 12 14 16 18 20 22 24 26
Mos
Mos
Slide credit: clinicaloptions.com
Sharman JP, et al. ASH Abstract 330.

51. Idelalisib: Toxicities
Diarrhea:
occurs in 2 forms
Transaminase elevations: generally reversible
Pneumonitis: consistent with reports with mTOR inhibitors
Self-limiting: usually mild; early onset (median 1.5 mos); responds to common antidiarrheal agents
Severe diarrhea: late onset (median 7 mos); responds poorly to antimotility agents but appears to be responsive to budesonide and/or systemic corticosteroids
Usually occurs within first 12 wks
74% of pts with treatment interruption able to resume idelalisib at a lower dose without recurrence
Permanently discontinue idelalisib if ALT/AST > 20 x ULN
Any pt who presents with pulmonary symptoms should be evaluated for pneumonitis
Hold idelalisib with any symptomatic pneumonitis
Often treated with corticosteroids in addition to continuing antibiotics and holding idelalisib if no improvement
Slide credit: clinicaloptions.com
Coutre SE, et al. Leuk Lymphoma. 2015;56:

52. New Approval for Relapsed/Refractory CLL

53. Which of the following novel agents inhibits BCL-2 overexpression to induce apoptosis?
Acalabrutinib
Duvelisib
Pembrolizumab
Venetoclax
Unsure
Slide credit: clinicaloptions.com

54. Which of the following novel agents inhibits BCL-2 overexpression to induce apoptosis?
Acalabrutinib
Duvelisib
Pembrolizumab
Venetoclax
Unsure
Slide credit: clinicaloptions.com

55. Venetoclax: Mechanism of Action1 2 3
An Increase in BCL-2 Expression Allows the Cancer Cell to Survive
Venetoclax Binds to and Inhibits Overexpressed BCL-2
Apoptosis is Initiated
Active caspase
Apoptosome
Venetoclax
Proapoptotic
proteins
(BAX, BAK)
Antiapoptotic
proteins
(BCL-2)
APAF-1
BH3-only
Cytochrome C
Procaspase
BAK
BAX
BCL-2
BCL-2
Mitochondria
Mitochondria
Mitochondria
Kumar S, et al. ASCO Abstract 8576.
Reproduced with permission.
Slide credit: clinicaloptions.com

56. Venetoclax Monotherapy: Phase II Trial in Ultrahigh-Risk R/R CLL With del(17p)
Pts received venetoclax monotherapy once daily with dose ramp-up ( mg over 5 wks) with TLS prophylaxis (N = 107)
Outcome
Pts (N = 107)
Overall response, %
CR or CRi
nPR PR
79.4
7.5
2.8
69.2
Pts with MRD- test, % 40
Time to first response,
mos (range)
0.8 ( )
Time to CR/CRi,
8.2 ( )
1-yr PFS, % (95% CI)
72 ( )
1-yr OS, % (95% CI)
86.7 ( )
Tx-Emergent AE,* %
Any Grade
Grade 3/4
Any 96 76
Neutropenia 43 40
Diarrhea 29
Nausea 1
Anemia 27 18
Fatigue 22
Pyrexia 20
Thrombocytopenia 19 15
Hyperphosphatemia 16
Vomiting
Infection 72
Slide credit: clinicaloptions.com
Stilgenbauer S, et al. ASH Abstract LBA-6.

57. CLL Therapy in 2016
Clinical trial should be considered for all pts with CLL
Population
Initial Therapy
Relapsed Therapy
Younger, fit pts
FCR (especially mutated IGHV)
Ibrutinib
Idelalisib + R
Older pts with comorbidities
Bendamustine/rituximab
Chlorambucil/obinutuzumab
Chlorambucil/ofatumumab
Pts with del(17p)
or TP53 mutation
AlloSCT?
Venetoclax
Slide credit: clinicaloptions.com

58. Future Directions: New Combinations for Treatment

59. or unacceptable toxicity
HELIOS: Study Design
An international, double-blind, placebo-controlled phase III trial
Primary endpoint: PFS (independent review)
Secondary endpoints: ORR (independent review), OS, MRD-negative response rate, safety
Bendamustine-R +
Ibrutinib 420 mg orally QD
(starting Day 2, cycle 1)
(n = 289)
Pts with previously treated R/R
CLL/SLL,
ECOG PS 0-1,
measurable LN, no del(17p)
(N = 578)
Treat to PD
or unacceptable toxicity
Crossover to ibrutinib arm permitted
after confirmed progression
Bendamustine-R +
Placebo orally QD
(starting Day 2, cycle 1)
(n = 289)
CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; LN, lymph node; MRD, minimum residual disease; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; QD, once daily; R, rituximab; R/R, relapsed/refractory.
Chanan-Khan AAA, et al. Lancet Oncol. 2015;[Epub ahead of print]. Chanan-Khan AAA, et al. ASCO Abstract LBA7005.
Slide credit: clinicaloptions.com

60. HELIOS: Survival Outcomes (ITT)
PFS OS
100
100
Ibrutinib + BR
Ibrutinib + BR
(mPFS: NR) 80 80
Placebo + BR 60 60
PFS (%)
OS (%) 40
Placebo + BR
(mPFS: 13.3 mos) 40 20 20
Median OS NR in either arm
HR: (95% CI: ; P = .0598)
HR: (95% CI: ; P < .0001)
BR, bendamustine/rituximab; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; NR, not reached. 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32
Mos
Mos
ORR higher with ibrutinib + BR vs placebo + BR: 82.7% vs 67.8% (P < .0001)
% MRD- higher with ibrutinib + BR vs placebo + BR: 12.8% vs 4.8% (P = .001)
Chanan-Khan AAA, et al. Lancet Oncol. 2015;[Epub ahead of print]. Chanan-Khan AAA, et al. ASCO Abstract LBA7005.
Slide credit: clinicaloptions.com

61. HELIOS: Safety Outcome, % Ibrutinib + BR (n = 289)
Placebo + BR (n = 289)
Treatment discontinuation
Progression or relapse AE
29.1
4.8
14.2
64.7
45.0
11.8
Grade 3/4 treatment-emergent AE ≥ 5% of pts
Neutropenia
Thrombocytopenia
Anemia
(n = 287)
53.7
15.0
3.5
50.5
8.0
Any grade bleeding
Major hemorrhage
31.0
3.8
14.6
1.7
Atrial fibrillation
Grade 3/4
7.3
2.8
0.7
AE, adverse events; BR, bendamustine/rituximab.
Chanan-Khan AAA, et al. Lancet Oncol. 2015;[Epub ahead of print]. Chanan-Khan AAA, et al. ASCO Abstract LBA7005.
Slide credit: clinicaloptions.com

62. Followed for PD with post-study therapy at investigator’s discretion
Study 115: Study Design
Randomized, double-blind, placebo-controlled phase III study
Primary endpoint: PFS
Secondary endpoints: ORR, nodal response, CR, OS
Idelalisib 150 mg BID +
Bendamustine 70 mg/m2 D1,2 q4w, C1-6 +
Rituximab 375 mg/m2 C1, 500 mg/m2 C2-6
(n = 207)
CLL* with measurable disease, no history of CLL transformation or prior BTK/PI3Kδ/SYK inhibitor use
(N = 416)
Followed for PD with post-study therapy at investigator’s discretion
Placebo BID +
Bendamustine 70 mg/m2 D1,2 q4w, C1-6 +
Rituximab 375 mg/m2 C1, 500 mg/m2 C2-6
(n = 209)
BTK, Bruton's tyrosine kinase; C, cycle; CLL, chronic lymphocytic leukemia; IGHV, immunoglobulin heavy chain variable region; PD, progressive disease; PI3Kδ, phosphoinositide-3-kinase delta; R/R, relapsed/refractory; SYK, spleen tyrosine kinase.
*Progression < 36 mos from last therapy, requiring treatment, but no progression within 6 mos of last bendamustine.
Slide credit: clinicaloptions.com
Zelenetz AD, et al. ASH Abstract LBA-5.

63. Study 115: Survival Outcomes
100
100
IDELA + BR
(mOS: NR)
HR: 0.33 (95% CI: ;
P < .0001) 80 80 60 60
PFS (%)
OS (%) 40
Placebo + BR
(mOS: NR) 40
IDELA + BR
(mPFS: 23.1 mos)
Placebo + BR
(mPFS: 11.1 mos) 20 20
HR: 0.55 (95% CI: ;
P = .008 [stratified] or .023 [unstratified])
BR, bendamustine, rituximab; IDELA, idelalisib. 6 12 18 24 30 6 12 18 24 30
Mos
Mos
ORR higher with idelalisib + BR vs placebo + BR: 68% vs 45%
Slide credit: clinicaloptions.com
Zelenetz AD, et al. ASH Abstract LBA-5.

64. Study 115: Safety Characteristic, % Idelalisib + BR (n = 207)
Placebo + BR (n = 209)
Any Grade
Grade ≥ 3
Any AE
Neutropenia
Pyrexia
Diarrhea
Febrile neutropenia
Pneumonia
Rash
ALT elevation
100 63 42 35 22 17 16 15 93 60 7 20 11 3 97 54 30 12 1 76 46 2 6
< 1
AEs leading to dose reduction
AEs leading to discontinuation 26 13
Deaths 10
AE, adverse event; ALT, alanine aminotransferase; BR, bendamustine, rituximab; IDELA, idelalisib.
Slide credit: clinicaloptions.com
Zelenetz AD, et al. ASH Abstract LBA-5.

65. Future Directions: Emerging Treatment Options

66. Venetoclax Monotherapy: Phase II Trial in Pts Who Are R/R to Ibrutinib or Idelalisib
Pts received venetoclax monotherapy starting at 20 mg followed by a 5-step weekly ramp-up to a final daily dose of mg (N = 28)
Wk 8 Response Assessment
PR SD PD
100 80 50 53 60
Pts (%) 40 25 20 40 25
Arm A: Relapsed After or Refractory to Ibrutinib (n = 15)
Arm B: Relapsed After or Refractory to Idelalisib (n = 4)
Slide credit: clinicaloptions.com
Jones J, et al. ASH Abstract 715.

67. Venetoclax Combinations in R/R CLL
Agents
Phase
Setting
Results
Venetoclax +
rituximab[1] Ib
Pts with R/R CLL/SLL
(n = 49)
ORR: 86% (MRD- in 53%)
PFS at 1 yr: 87%; OS at 1 yr: 94%
Tolerable safety profile
obinutuzumab[2]
Pts with R/R or treatment-naive CLL
(n = 32)
ORR: 100% (24% CR/CRi)
AEs appear to be manageable
Cytopenia is most frequent AE, but no pt discontinued tx due to AEs
TLS prophylaxis effective even in patients with higher disease burden
BR[3]
(n = 30)
ORR: 100% (15% CR)
Most common AEs: neutropenia and diarrhea
1. Ma S, et al. ASH Abstract Flinn IW, et al. ASH Abstract Salles GA, et al. ASH Abstract 829.
Slide credit: clinicaloptions.com

68. Critical Signaling Pathways and New Targeted Agents in B-Cell Malignancies
BCR
LYN
SYK
Idelalisib
Duvelisib
Pilaralisib ┬ ┬
PI3K
Delta
BCR, B-cell antigen receptor; BTK, Bruton’s tyrosine kinase; GSK-3, glycogen synthase kinase 3; mTOR, mammalian target of rapamycin; NF-kβ, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphatidylinositide 3-kinases; PKC, protein kinase C; PLC, phospholipase C; Syk, spleen tyrosine kinase.
Ibrutinib
Acalabrutinib (ACP-196)
BTK
PLCγ2
AKT
GSK-3
NF-kβ
pathway ┬
PKC
mTOR
Everolimus
p70s6k
elf4E
Slide credit: clinicaloptions.com

69. Acalabrutinib Monotherapy: Phase I/II Trial in Relapsed CLL
Pts received oral acalabrutinib QD with dose-escalation ( mg) for phase I cohort or 100 mg BID for phase II (N = 61)
Median number of prior therapies: 3 (range: 1-13)
Most AEs observed were grade 1/2 and resolved over time
PR with lymphocytosis PR SD
100
100 90
100 25
100
100 90 10 80 13 80 85 70 70 75 77 60 60
Best Response (%) 50
Pts With PFS (%) 50 40 40 30 20 30 10 5 10 20 10
All Cohorts (N = 60)
175 mg QD (n = 8)
250 mg QD (n = 7)
400 mg QD (n = 6)
100 mg BID (n = 31)
100 mg QD (n = 8) 2 4 6 8 10 12 14 16 18 20
Mos
Slide credit: clinicaloptions.com
Byrd JC, et al. N Engl J Med. 2015;[Epub ahead of print].

70. Ongoing Clinical Trials and Emerging Agents in CLL
MOA
Initial Therapy
Relapsed Therapy
Duvelisib
PI3K-δ,γ
inhibitor
Duvelisib vs ofatumumab
(phase III)
Duvelisib/obinutuzumab after BCRi
Acalabrutinib
(ACP-196)
Bruton
tyrosine
kinase
Inhibitor
Acalabrutinib alone vs
acalabrutinib + obinutuzumab
vs obinutuzumab + chlorambucil
Acalabrutinib vs ibrutinib
Pembrolizumab
PD-1 inhibitor
Relapsed/refractory CLL including RS (phase II)
Slide credit: clinicaloptions.com
ClinicalTrials.gov.

71. CLL Therapy in the Future
Clinical trial should be considered for all pts with CLL
Population
Initial Therapy
Relapsed Therapy
Younger, fit pts with low risk
FCR (especially mutated IGHV)
Ibrutinib
Idelalisib + R
Ibrutinib + BR*
Idelalisib + BR*
Venetoclax*
Older pts with comorbidities
Bendamustine/rituximab
Chlorambucil/obinutuzumab
Chlorambucil/ofatumumab
Pts with del(17p)
or TP53 mutation
AlloSCT?
Venetoclax
*Not currently approved by the FDA.
Slide credit: clinicaloptions.com

72. Go Online for More CCO Coverage of CLL!
Downloadable slidesets on CLL Additional Webcast on CLL with expert faculty commentary on all the key studies
clinicaloptions.com/oncology