This document summarizes several presentations from the 2014 American Society of Hematology (ASH) Annual Meeting regarding chronic myeloid leukemia (CML), multiple myeloma, and lymphoma. For CML, early results from the Phase III EPIC trial found that ponatinib resulted in deeper and more rapid responses compared to imatinib but with increased toxicity. Subset analyses of the PACE trial demonstrated that early molecular responses to ponatinib correlated with improved long-term outcomes. For multiple myeloma, updated criteria were presented for diagnosis. The Phase III FIRST trial showed that continuous lenalidomide and dexamethasone improved progression-free survival compared to fixed-duration regimens or melphalan, prednisone

1. ASH 2014 UPDATE
DR. RAJKUMAR M.D., D.M
CONSULTANT MEDICAL ONCOLOGIST
GURU CANCER CENTER

2. OVERVIEW
1. CHRONIC MYELOID LEUKEMIA
2. MULTIPLE MYELOMA
3. CHRONIC LYMPHOCYTIC
LEUKEMIA
4. FOLLICULAR LYMPHOMA

3. CHRONIC MYELOID LEUKEMIA

4.  Early analysis of the randomized, open-label EPIC trial
 Terminated early due to safety concerns in ponatinib clinical program (arterial
thrombotic events)
 Endpoints: BCR-ABLIS < 10% at 3 mos; MMR, MR4, MR4.5; CCyR rates;
safety
Phase III EPIC: Ponatinib vs Imatinib in Pts
With Newly Diagnosed Ph+ CP-CML
Lipton JH, et al. ASH 2014. Abstract 519.
Pts with newly
diagnosed
Ph+ CP-CML
(N = 307)
Stratified by Sokal risk score:
low (< 0.8) vs
intermediate (0.8 to ≤ 1.2) vs
high (> 1.2) Ponatinib 45 mg/day orally
(n = 155)
Imatinib 400 mg/day* orally
(n = 152)
Dose modification allowed in both arms for management of AEs
*Dose escalation allowed for suboptimal response up to 800 mg/day (400 mg BID)

5. EPIC: Ponatinib vs Imatinib in Pts With
Newly Diagnosed CP-CML: Results
 None of the prospectively defined endpoints could be analyzed
due to trial termination
 Deeper, more rapid response rates with ponatinib vs imatinib
– < 10% BCR-ABL transcripts at 3 mos overall
– Ponatinib: 94%
– Imatinib: 68%
– Significantly higher number of patients achieved MMR, MR4,
MR4.5 with ponatinib vs imatinib in all risk groups
– Greater rate of molecular responses at 3, 6, 9, 12 mos with
ponatinib vs imatinib
– Higher percentage of CCyR with ponatinib vs imatinib
Lipton JH, et al. ASH 2014. Abstract 519.

6. EPIC: Ponatinib vs Imatinib in Newly
Diagnosed Ph+ CP-CML: Conclusions
 EPIC: ponatinib showed significantly improved efficacy vs imatinib in
pts with newly diagnosed CP-CML, but with increased toxicity
 < 10% BCR-ABL at 3 mos overall
– Ponatinib: 94%
– Imatinib: 68%
 Better molecular response rates with ponatinib vs imatinib across all
Sokal risk categories and time periods
 Patients experienced greater number of AEs in ponatinib arm
– More grade 3/4 AEs and serious AEs
– More vascular occlusive events
Lipton JH, et al. ASH 2014. Abstract 519.

7. PACE: Effect of Early Response to
Ponatinib on Outcomes in Pretreated Pts
 Objective: subset analysis (n = 267) of association
between early landmark responses with ponatinib and
long-term outcomes in heavily pretreated pts (more than
90% ≥ 2 TKIs) with CP-CML in phase II PACE trial
 Assessment of responses at 3, 6, and 12 mos
– Molecular: BCR-ABLIS ≤ 0.1% (MMR), ≤ 1%, ≤ 10%
– Cytogenetic: MCyR, ≤ 35% Ph+ metaphases; CCyR, ≤ 0%
Ph+ metaphases
 Outcomes: PFS, OS, MR4.5
 Median follow-up: 38.4 mos (range: 0.1-48.6)
Mueller M, et al. ASH 2014. Abstract 518.

8.  ≤ 1% BCR-ABL by 3 mos associated with longer 2-yr PFS, OS vs BCR-ABL > 1% at 3 mos
 Molecular response at 3 mos directly correlated with MR4.5 over time
 Response at 3 and 6 mos associated with significant improvement in 2-yr PFS and OS
PACE: Effect of Early Response to
Ponatinib: 2-Yr PFS, OS
Outcome 2-Yr PFS
Probability, %
P Value 2-Yr OS
Probability, %
P Value
3 mos
MMR 97
.0006
97
.0324
No MMR 67 84
6 mos
MMR 95
< .0001
95
.0428
No MMR 65 88
12 mos
MMR 93
.0010
100
.0089
No MMR 74 93
Mueller M, et al. ASH 2014. Abstract 518.

9. PACE: Effect of Early Response to
Ponatinib: Conclusions
 Early MMR in BCR-ABL with ponatinib in heavily
pretreated pts with CP-CML correlated with improved
long-term outcomes
– 2-yr PFS and OS significantly associated with positive 3-mo,
6-mo, and 12-mo cytogenetic and molecular responses
Mueller M, et al. ASH 2014. Abstract 518.

10. Early Predictors of Survival in Pts With
CML Treated With Imatinib
 Background: BCR-ABLIS > 10% at 3 and 6 mos current
threshold to assess pt response and determine treatment
course
 Current analysis: prognostic significance of 3-mo and
6-mo BCR-ABLIS vs 0.5 log reduction of BCR-ABL* at
3 mos from baseline according to sensitivity and specificity
of BCR-ABL landmarks in pts with imatinib-treated CML in
CML-Study IV
– BCR-ABL landmarks applied to pts with later disease
progression (accelerated phase, blast phase, or death)
– Measured: 8-yr PFS
Hanfstein B, et al. ASH 2014. Abstract 156.
*Calculated from BCR-ABL ratio at 3 mos and at diagnosis.

11. Prognostic Markers for Safely Halting TKI
Therapy in Pts With CP-CML: EURO-SKI
 Background: prospective trials suggest imatinib therapy may be
sustainably and safely discontinued in CML pts with deep and
durable MR (MR4; BCR-ABL <0.01% for at least 1 yr)
 EURO-SKI study: define prognostic markers to identify patients
most likely to retain deep molecular responses after stopping
TKI therapy
 Planned interim analysis: after 200 pts available with eligible
molecular results at 6 mos
 Eligible pts: CP-CML in confirmed deep MR (BCR-ABL < 0.01%
for > 12 mos) while on TKI therapy ≥ 3 yrs
 Primary endpoint: assessment of duration of MR after
discontinuing TKI
Mahon FX, et al. ASH 2014. Abstract 151.

12.  Loss of MMR by TKI duration: > 8 yrs, 29/86 pts (34%); ≤ 8 yrs, 60/114 (53%)
 Loss of MMR by MR4 duration: > 5 yrs, 32/92 pts (35%); ≤ 5 yrs, 57/108 (53%)
 Conclusion: ~ 60% of pts with CP-CML with initial stable, deep MR are likely to remain
in TFR after treatment is stopped
100
80
60
40
20
0
EURO-SKI: Molecular RFS at 18 Mos
Previous TKI Duration MR4 Duration
Mahon FX, et al. ASH 2014. Abstract 151.
Mos From TKI Discontinuation
P = .0122
Mos From TKI Discontinuation
0 6 12 18 24 30
P = .007
MolecularRFS(%)
100
80
60
40
20
0
0 6 12 18 24 30
MolecularRFS(%)
> 8 yrs: 65%
≤ 8 yrs: 47%
> 5 yrs: 65%
≤ 5 yrs: 46%

13. EURO-SKI: Conclusion
 EURO-SKI study suggests ~ 60% of pts with CP-CML with
deep, durable MR (MR4; BCR-ABL <0.01% for at least
1 yr) on TKIs are likely to remain in remission after TKIs
are stopped
Mahon FX, et al. ASH 2014. Abstract 151.

14. MULTIPLE MYELOMA

15. Updated IMWG Criteria For Diagnosis of
Multiple Myeloma
*C: Calcium elevation (> 11 mg/dL or > 1 mg/dL higher than ULN)
R: Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine
> 2 mg/dL)
A: Anemia (Hb < 10 g/dL or 2 g/dL < normal)
B: Bone disease (≥ 1 lytic lesions on skeletal radiography, CT, or PET-CT)
Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.
MGUS
 M protein < 3 g/dL
 Clonal plasma cells in BM
< 10%
 No myeloma defining
events
Smoldering Myeloma
 M protein ≥ 3 g/dL
(serum) or ≥ 500 mg/24
hrs (urine)
 Clonal plasma cells in BM
10% - 60%
 No myeloma defining
events
Multiple Myeloma
 Underlying plasma cell
proliferative disorder
 AND 1 or more myeloma
defining events
 ≥ 1 CRAB* feature
 Clonal plasma cells in BM
≥ 60%
 Serum free light chain
ratio ≥ 100
 >1 MRI focal lesion

16. FIRST: Lenalidomide/Dexamethasone vs
MPT in NDMM SCT-Ineligible Pts
Randomized1:1:1
Arm B
Rd18
Arm C
MPT
Len + LoDex 18 cycles (72 wks)
Lenalidomide 25 mg Days 1-21/28
LoDex 40 mg Days 1, 8, 15, 22/28
Mel + Pred + Thal 12 cycles[2] (72 wks)
Melphalan 0.25 mg/kg Days 1-4/42
Prednisone 2 mg/kg Days 1-4/42
Thalidomide 200 mg Days 1-42/42
PD,OS,and
subsequentanti-MMTx
PDorunacceptabletoxicity
Active treatment + PFS follow-up phase
Pts > 75 yrs: LoDex 20 mg Days 1, 8, 15, 22/28; Thal 100 mg Days 1-42/42;
Mel 0.2 mg/kg Days 1-4. Stratification: age, country, and ISS stage.
Len + LoDex Continuously
Lenalidomide 25 mg Days 1-21/28
LoDex 40 mg Days 1, 8, 15, 22/28
Arm A
Continuous Rd
1. Hulin C, et al. ASH 2014. Abstract 81. 2. Facon T, et al. Lancet. 2007;370:1209-1218. 3. Hulin C, et al.
J Clin Oncol. 2009;27:3664-3670. 4. Benboubker L, et al. N Engl J Med. 2014;371:906-917
Phase III
(N = 1623)

17. FIRST Trial: PFS by Age Stratification
Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.
Aged 75 Yrs or Younger
100
80
60
40
20
0
Pts(%)
0 6 12 18 24 30 36 42 48 54 60
PFS (Mos)
HR (95% CI)
Rd vs MPT: 0.68 (0.56-0.83)
Rd vs Rd18: 0.68 (0.55-0.83)
Rd18 vs MPT: 1.01 (0.84-1.21)
Rd
Rd18
MPT
Median,
Mos
27.4
21.3
21.8
46% (Rd)
25% (Rd18)
23% (MPT)
Aged Older Than 75 Yrs
100
80
60
40
20
0
Pts(%)
0 6 12 18 24 30 36 42 48 54 60
PFS (Mos)
HR (95% CI)
Rd vs MPT: 0.81 (0.62-1.05)
Rd vs Rd18: 0.75 (0.58-0.98)
Rd18 vs MPT: 1.08 (0.83-1.39)
Rd
Rd18
MPT
Median,
Mos
21.2
19.4
19.2
35% (Rd)
19% (Rd18)
22% (MPT)

18. FIRST Trial: OS by Age Stratification
Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.
Aged 75 Yrs or Younger
100
80
60
40
20
0
Pts(%)
0 6 12 18 24 30 36 42 48 54 60
OS (Mos)
HR (95% CI)
Rd vs MPT: 0.77 (0.59-1.01)
Rd vs Rd18: 0.88 (0.67-1.16)
Rd18 vs MPT: 0.88 (0.68-1.14)
Rd
Rd18
MPT
3-Yr OS, %
74
70
67
Aged Older Than 75 Yrs
100
80
60
40
20
0
Pts(%)
0 6 12 18 24 30 36 42 48 54 60
OS (Mos)
HR (95% CI)
Rd vs MPT: 0.80 (0.59-1.09)
Rd vs Rd18: 0.94 (0.69-1.29)
Rd18 vs MPT: 0.85 (0.63-1.15)
Rd
Rd18
MPT
3-Yr OS, %
63
58
54

19. FIRST Trial: Grade 3/4 Adverse Events
Grade 3/4 Treatment-
Emergent AE, %
Dose for Pts Aged ≤ 75 Yrs Dose for Pts Aged > 75 Yrs
Continuous
Rd
(n = 347)
Rd18
(n = 348)
MPT
(n = 357)
Continuous
Rd
(n = 185)
Rd18
(n = 192)
MPT
(n = 184)
Hematologic in ≥ 10% of pts
 Neutropenia 28 25 47 28 29 40
 Anemia 18 12 20 19 23 17
 Thrombocytopenia 8 9 13 9 7 7
 Leukopenia 5 6 11 4 5 8
Nonhematologic
 Infection 29 21 16 29 23 20
 Cardiac disorders 12 6 6 12 9 13
 Fatigue 6 8 5 9 10 8
 Peripheral sensory
neuropathy
1 1 10 1 0 8
 Cataracts 7 3 < 1 3 2 1
 DVT and/or PE 8 5 6 7 6 4
Hulin C, et al. ASH 2014. Abstract 81. Reproduced with permission.

20. FIRST Trial: Conclusions
 Continuous Rd improved PFS vs MPT or 18 cycles of Rd for
newly diagnosed MM regardless of age
– Median and 3-yr PFS both extended with continuous Rd vs MPT or
Rd18 whether pts were younger or older than 75 yrs of age
– 3-yr OS extended with continuous Rd vs MPT whether pts were
younger or older than 75 yrs of age
– Analysis of FIRST results based on age consistent with overall trial
results
 Toxicity profile of Rd similar among pts 75 yrs of age or younger
and older than 75 yrs of age
Hulin C, et al. ASH 2014. Abstract 81.

21. Modified Lenalidomide/Bortezomib/
Dexamethasone in ASCT-Ineligible NDMM
 Phase II trial exploring utility of modified RVD (RVD lite); N = 30
– Lenalidomide: single daily oral dose of 15 mg Days 1-21
– Bortezomib: 1.3 mg/m2 SC once weekly Days 1, 8, 15, 22
– Dexamethasone: 20 mg twice weekly if ≤ 75 yrs or once weekly if > 75 yrs
 RVD lite resulted in 90% ORR (≥ PR), ≥ VGPR: 53%
– 3 pts discontinued study after <1 cycle due to worsening adrenal
insufficiency; rash attributed to lenalidomide; unrelated
 AEs manageable and well tolerated in an older population
– Grade 3 AEs in ≥ 5%: hypophosphatemia (32%), rash (12%), mood
disorder (9%)
– Grade 4 AEs: hypoglycemia (3%), neutropenia (3%), corneal ulcer (3%)
O’Donnell E, et al. ASH 2014. Abstract 3454.

22. Phase III Trial Comparing MPT-T vs MPR-R
in SCT-Ineligible Pts with NDMM
 Joint study of the Dutch-Belgian Cooperative Trial Group for
Hematology Oncology and the Nordic Myeloma Study Group
MPR
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Lenalidomide 10 mg on Days 1-21
(n = 319)
MPT
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Thalidomide 200 mg on Days 1-28
(n = 318)
R Maintenance
Lenalidomide 10 mg
on Days 1-21 q28d
until PD
T Maintenance
Thalidomide
100 mg/day
until PD
Stratified by
center and ISS
28-day cycles x 9
Randomization1:1
Zweegman S, et al. ASH 2014. Abstract 179.
Granulocyte-colony stimulating factor administered if absolute neutrophil count < 0.5 x 109 cells/L or in
event of febrile neutropenia during a cycle.

23. MPT-T vs MPR-R: Efficacy Analysis
 Median follow-up: 33.6 mos
 ORR similar between arms: 81% MPT-T vs 83% MPR-R
 No significant difference in PFS or OS
Zweegman S, et al. ASH 2014. Abstract 179.
Outcome
MPR-R
(n = 319)
MPT-T
(n = 318)
HR (95% CI) P Value
ORR (on protocol), % 83 81
 CR 13 10
 VGPR 32 38
 PR 39 33
Median PFS, mos 22 20 086 (0.72-1.04) .12
Median OS, mos NR NR 0.79 (0.61-1.03) .08
 2-yr OS, % 84 73
 3-yr OS, % 69 64
 4-yr OS, % 55 52

24. MPT-T vs MPR-R: Safety Analysis
*Primarily due to peripheral neuropathy in thalidomide arm, hematologic toxicity in lenalidomide arm
Zweegman S, et al. ASH 2014. Abstract 179.
Treatment Outcome, % MPR-R MPT-T
≤ 75 Yrs > 75 Yrs ≤ 75 Yrs > 75 Yrs
Completed 6 induction cycles 68 73 76 77
Initiated maintenance therapy 59 58 57 39
Discontinued maintenance 43 88
 Due to AEs* 24 31 67 69
Median duration of maintenance, mos
(range)
16 (0-53) 15 (1-52) 5 (0-49) 5 (0-44)
 MPT-T associated with significantly higher rate of grade ≥ 2
neuropathy (45% vs 8%; P < .0001); higher rate of grade 3/4
hematologic AEs (including neutropenia [63% vs 27%],
thrombocytopenia [28% vs 8%], and anemia [14% vs 5%]) vs MPR-R

25. ASPIRE: Phase III Trial Comparing Len/
Dexamethasone ± Carfilzomib in R/R MM
 Randomized, open-label, multicenter phase III trial
KRd* (n = 396)
Carfilzomib 27 mg/m2 IV
Days 1, 2, 8, 9, 15, 16 (20 mg/m2 days 1, 2, cycle 1 only)
Lenalidomide 25 mg Days 1-21
Dexamethasone 40 mg Days 1, 8, 15, 22
Rd (n = 396)
Lenalidomide 25 mg Days 1-21
Dexamethasone 40 mg Days 1, 8, 15, 22
Stratified by β2-microglobulin, prior
bortezomib, and prior lenalidomide
*After cycle 12, carfilzomib given on Days 1, 2, 15, 16. After cycle 18, carfilzomib discontinued.
Stewart AK, et al. ASH 2014. Abstract 79.
Pts with symptomatic
R/R MM after 1-3 prior
treatments with ≥ PR
to ≥ 1 prior regimen
(N = 792)
28 day cycles

26. ASPIRE: PFS in ITT Population (Primary
Endpoint)
KRd Rd
(n = 396) (n = 396)
Median PFS, mos 26.3 17.6
HR (KRd/Rd) (95% CI) 0.69 (0.57-0.83)
P value (1 sided) < .0001
1.0
0.8
0.6
0.4
0.2
0.0
ProportionSurviving
WithoutProgression
KRd
Rd
0 6 12 18 24 30 36 42 48
Mos Since Randomization
Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.
Risk Group by
FISH
KRd (n = 396) Rd (n = 396) HR P Value
n Median PFS, Mos n Median PFS, Mos
High 48 23.1 52 13.9 0.70 .083
Standard 147 29.6 170 19.5 0.66 .004

27. ASPIRE: Interim OS Analysis
 OS results did not meet prespecified statistical boundary (P = .005) at interim
 AEs consistent with previous studies; no unexpected toxicities observed
– Grade ≥ 3 cardiac failure and ischemic heart disease: 3.8% and 3.3% in KRd arm
vs 1.8% and 2.1% in Rd arm, respectively
KRd Rd
(n = 396) (n = 396)
Median OS, mos NR NR
HR (KRd/Rd) (95% CI) 0.79 (0.63-0.99)
P value (1 sided) .018
Median follow-up: 32 months
1.0
0.8
0.6
0.4
0.2
0.0
ProportionSurviving
KRd
Rd
0 6 12 18 24 30 36 42 48
Mos Since Randomization
Stewart AK, et al. ASH 2014. Abstract 79. Reproduced with permission.

28. ASPIRE: Conclusions
 PFS significantly improved by 8.7 mos in pts treated with KRd
vs Rd relapsed/refractory MM (HR: 0.69; P < .0001)
– Median PFS of 26.3 mos with triplet combination unprecedented in
this setting
 Interim OS analysis reveals trend favoring KRd
 Increased ORR with KRd vs Rd: 87.1% vs 66.7%
– More pts achieved CR or better with triplet: 31.8% with KRd vs
9.3% with Rd
 Acceptable safety profile observed with KRd
 KRd potentially new standard of care for treatment of relapsed
MM
Stewart AK, et al. ASH 2014. Abstract 79.

29. CLL

30. CLL10 (Phase III): Final Analysis of FCR vs
BR in Pts With Advanced CLL
Eichhorst B, et al. ASH 2014. Abstract 19
FCR
Fludarabine 25 mg/m2 IV Days 1-3
Cyclophosphamide 250 mg/m2 Days 1-3
Rituximab 375 mg/m2 IV Day 0, cycle 1
Rituximab 500 mg/m2 IV Day 1, cycles 2-6
BR
Bendamustine 90 mg/m2 IV Days 1-2
Rituximab 375 mg/m2 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)
 Primary endpoint: noninferiority of BR vs FCR for PFS HR (λBR/FCR) < 1.388

31. 1.0
0.8
0.6
0.4
0.2
0
FCR vs BR in Pts With Advanced CLL:
PFS
Eichhorst B, et al. ASH 2014. Abstract 19
CumulativeSurvival
ITT PFS = Primary Endpoint
PFS in IGHV-Matched Population
(n = 398; FCR = 201; BR = 197)
0 12 24 36 48 60
Median PFS
FCR: 55.2 mos
BR: 41.7 mos
P < .001
HR: 1.626 CumulativeSurvival
1.0
0.8
0.6
0.4
0.2
0
0 12 24 36 48 60
Median PFS
FCR: NR
BR: 43.1 mos
P < .005
HR: 1.565

32. 1.0
0.8
0.6
0.4
0.2
0
FCR vs BR in Pts With Advanced CLL: OS
Eichhorst B, et al. ASH 2014. Abstract 19
0 12 24 36 48 60
CumulativeSurvival
Mos to Event (OS)
OS at 36 Mos
FCR: 90.6%
BR: 92.2%
P = .897

33. FCR vs BR in Pts With Advanced CLL:
Conclusions
 BR showed inferiority with PFS and CR rate compared
with FCR in the final analysis
 Lower rates of neutropenias and severe infections in
elderly pts associated with BR
 FCR is still standard therapy for fit pts, whereas BR may
be considered in fit, elderly pts as an alternative
Eichhorst B, et al. ASH 2014. Abstract 19

34. RESONATE-17: Phase II Ibrutinib in
del(17p) Relapsed/Refractory CLL/SLL
 CLL/SLL
– Relapsed/refractory disease
after 1-4 prior therapies
– del(17p)13.1 in peripheral
blood*
– ECOG PS 0-1
– Measurable nodal disease
 Primary endpoint: ORR
 Secondary endpoints
– DoR
– Safety
– Tolerability
 Exploratory endpoints
– PFS
– OS
O’Brien SM, et al. ASH 2014. Abstract 327.
Ibrutinib
420 mg/day PO
(N = 144)
*Confirmed by FISH.
Until unacceptable toxicity or disease progression
Primary analysis 12 mos after last enrolled pt

35. Ibrutinib in del(17p) Relapsed/Refractory
CLL/SLL: Main Findings
 Best response (ORR + PR-L) by IRC (no 2nd confirmatory CT scan) was 74%
(95% CI: 66% to 80%)
 Median DOR was not reached at median follow-up of 11.5 mos; 12-mo DOR
was 88.3%
O’Brien SM, et al. ASH 2014. Abstract 327.
Median PFS (Not Reached) Median OS (Not Reached)
100
80
60
40
20
0
0 121 2 3 4 5 6 7 8 9 10 11
Mos
PFS(%)
100
80
60
40
20
0
0 121 2 3 4 5 6 7 8 9 10 11
Mos
OS(%)

36. Ibrutinib in del(17p) Relapsed/Refractory
CLL/SLL: Conclusions
 Ibrutinib showed efficacy with favorable risk–benefit profile
in pts with del(17p) CLL/SLL
 12-mo PFS: 79%, consistent with previous study of 26-mo
PFS (75%)
 PFS outcomes in this relapsed/refractory setting favorable
compared with previous results for frontline FCR regimen
or alemtuzumab in del(17p) CLL (median PFS: 11 mos)
 Safety profile consistent with known profile for ibrutinib
O’Brien SM, et al. ASH 2014. Abstract 327. Byrd JC, et al. N Engl J Med. 2013;369:32-42.

37.  Primary outcome:
– CR/CRu rate assessed at Wk 23, defined according to NCI criteria
– Response assessment
Treatment-naive pts
with grade 1, 2, 3A FL,
in need of therapy
(N = 154)
Rituximab 375 mg/m2 on Day 1 of Wks 1-4,
12-15 +
Lenalidomide 15 mg/day*
(n = 77)
Rituximab 375 mg/m2 on Day 1 of Wks 1-4,
12-15
(n = 77)
*Lenalidomide started 14 days before first administration of rituximab and continued until 14 days after
last rituximab dose.
Stratified by
FL grade 1-2 vs 3a
Bulky vs no bulk
FLIPI score 1, 2 vs ≥ 3
First restaging
Wk 10
Second restaging
Wk 22-24
Kimby E, et al. ASH 2014. Abstract 799.
Phase II Rituximab + Lenalidomide vs
Rituximab Monotherapy in Untreated FL

38. Rituximab + Lenalidomide vs Rituximab in
Untreated FL: Overall Response
Kimby E, et al. ASH 2014. Abstract 799.
ITT population PP population
90
80
70
60
50
40
30
20
10
0
10%
35%
45%
13%
62%
75%
25%
36%
36%
45%
61%
82%
R
(n = 77)
R +
Lenalidomide
(n = 77)
R +
Lenalidomide
(n = 77)
R
(n = 77)
Wk 10 Wk 23
P < .0001 P = .002
PR
CR/CRu
Pts(%)
90
80
70
60
50
40
30
20
10
0
Pts(%)
11%
37%
48%
17%
67%
28%
38%
45%
42%
83%
66%
87%
R
(n = 65)
R +
Lenalidomide
(n = 60)
R +
Lenalidomide
(n = 60)
R
(n = 65)
Wk 10 Wk 23
P < .0001 P = .003
PR
CR/CRu

39. Rituximab + Lenalidomide vs Rituximab
Monotherapy in Untreated FL: Conclusions
 Addition of rituximab to lenalidomide associated with
significantly more CRs vs rituximab alone in untreated FL (36%
vs 25%, respectively)
 Comparison with existing single-arm studies confounded by
differences in pt characteristics and treatment schedules
 Neutropenia was the most common grade 3/4 AE with rituximab
+ lenalidomide; more grade 3/4 AEs seen with combination
– Continuous dosing may contribute to lenalidomide toxicity
 According to investigators, further follow-up needed to
determine if better response translates to improvement in PFS,
OS, and time to next treatment
Kimby E, et al. ASH 2014. Abstract 799.

40. Comparing CTLA-4 and PD-1
PD-1 CTLA-4
Biological function  Inhibitory receptor  Inhibitory receptor
Expression on  Activated T cells, B cells, NK cells
 TILs in different tumor types
 T cells at the time of initial response
to antigen (activated CD8+ T cells)
Major role  Limits T-cell activity in peripheral
tissue after inflammatory response
 Limits autoimmunity
 Regulates the early stage of T-cell
activation
Ligands  PD-L1 (B7-H1/CD274)
 PD-L2 (B7-CD/CD273)
 B7.1 (CD80)
 B7.2 (CD86)
Mechanism of action After ligand binding:
 Recruits inhibitory phosphatase,
SHP-2
 Decreases expression of cell
survival protein Bcl-xL
 Inhibits kinases (PI3K/AKT) involved
in T-cell activation
After ligand binding:
 Binding with PI3K, phosphatases
SHP-2 and PP2A
 Blockade of lipid-raft expression
 Blockade of microcluster formation
Merelli B, et al. Crit Rev Oncol Hematol. 2014;89:140-165.

41. PD-L2–mediated
inhibition of TH2 T cells
Stromal PD-L1
modulation of T cells
Reprinted from Clinical Cancer Research. 2013;19(5):1021-1034. Sznol M, et al. Antagonist antibodies to PD-1 and B7-H1
(PD-L1) in the treatment of advanced human cancer. With permission from AACR.
Blockade of PD-1 Binding to PD-L1 (B7-
H1) and PD-L2 (B7-DC) Revives T Cells
 PD-L1 expression on
tumor cells is induced
by γ-interferon
 In other words,
activated T cells that
could kill tumors are
specifically disabled
by those tumors
PD-1
PD-L1
PD-L2
T-cell receptor
MHC-1
CD28
Shp-2
B7.1
IFN-γ–mediated
upregulation of
tumor PD-L1
PD-L1/PD-1–mediated
inhibition of tumor cell killing
Priming and
activation of
T cells
Immune cell
modulation of T cells
Tumor cell
IFN-γR
IFN-γ
Tumor-associated
fibroblast M2
macrophage
Treg
cell
Th2
T cell
Other NFκB P13K
CD8+ cytoxic
T lymphocyte
T-cell polarization
TGF-β
IL-4/13
Can you generate
tumor-killing T cells?
Dendritic
cell
Antigen priming
Can the T cells
get to the tumor?
T-cell trafficking
Can the T cells
see the tumor?
Peptide-MHC
expression
Can the T cells
be turned off?
Inhibitory cytokines
Can the T cells
be turned off?
PD-L1 expression
on tumor cells

42. CTLA-4 and PD-1/PD-L1 Checkpoint
Blockade for Cancer Treatment
 Immune checkpoint blockade includes agents targeting the
negative regulators CTLA-4 and PD-1
 CTLA-4 attenuates the early activation of naive and memory
T cells in the lymph nodes
– Agents targeting CTLA-4 include ipilimumab and tremelimumab
 In contrast, PD-1 modulates the effector phase of T cell activity
in peripheral tissues via interaction with PD-L1 and PD-L2
– Agents targeting PD-1 include nivolumab and MK-3475
– Agents targeting PD-L1 include MPDL3280A and MEDI4736
Kyi C, et al. FEBS Lett. 2014;588:368-376

43. CTLA-4 and PD-1/PD-L1 Checkpoint
Blockade for Cancer Treatment
 Immune checkpoint blockade includes agents targeting the
negative regulators CTLA-4 and PD-1
 CTLA-4 attenuates the early activation of naive and memory
T cells in the lymph nodes
– Agents targeting CTLA-4 include ipilimumab and tremelimumab
 In contrast, PD-1 modulates the effector phase of T cell activity
in peripheral tissues via interaction with PD-L1 and PD-L2
– Agents targeting PD-1 include nivolumab and MK-3475
– Agents targeting PD-L1 include MPDL3280A and MEDI4736
Kyi C, et al. FEBS Lett. 2014;588:368-376

44. PD-1 and PD-L1 Antibodies Currently
in Phase III Development
Agent Class Disease State
Anti–PD-L1
MPDL3280A Engineered IgG1 NSCLC[1]
MEDI-4736 Modified IgG1 NSCLC[2]
Anti–PD-1
Nivolumab IgG4 Melanoma,[3] NSCLC,[4] RCC[5]
MK-3475
(pembrolizumab)
IgG4 (humanized) Melanoma,[6] NSCLC[7,8]
1. ClinicalTrials.gov. NCT02008227. 2. ClinicalTrials.gov. NCT02125461. 3. ClinicalTrials.gov. NCT01844505.
4. ClinicalTrials.gov. NCT01673867. 5. ClinicalTrials.gov. NCT01668784. 6. ClinicalTrials.gov. NCT01866319.
7. ClinicalTrials.gov NCT01905657. 8. ClinicalTrials.gov. NCT02142738.