1. Follicular Lymphoma Transformed Lymphoma Diffuse Large B-Cell Lymphoma
John P. Leonard, M.D.
Richard T. Silver Distinguished Professor of Hematology
and Medical Oncology
Professor of Medicine, Weill Cornell Medical College
Associate Director, Weill Cornell Cancer Center

2. Interest in Topics Related to the Treatment of Patients with FL (Percent Responding 9 or 10)
New agents/regimens
52%
Initial therapy for patients <70 yo
35%
“Watch and wait” vs rituximab
34%
monotherapy
Initial therapy for patients >70 yo
33%
Rituximab maintenance
32%
Treatment of relapsed FL
30% 0%
10%
20%
30%
40%
50%
60% 2

3. Interest in Topics Related to the Treatment of Patients with DLBCL (Percent Responding 9 or 10)
Therapy for relapsed
48%
DLBCL
New agents/regimens
38%
Cell origin
36%
biomarkers/risk
Post-transplant
35%
relapse
R-CHOP alternatives
31%
Radioimmunotherapy
31% 0%
10%
20%
30%
40%
50%
60% 3

4. What is your usual induction regimen for an otherwise healthy 60-year-old patient who requires initial systemic treatment for FL?
R-CHOP
20%
BR (B at 120 mg/m2 d1, d2 q4wk) 1%
BR (B at 120 mg/m2 d1, d2 q3wk) 9%
BR (B at 90 mg/m2 d1, d2 q4wk)
21%
BR (B at 90 mg/m2 d1, d2 q3wk) 9%
R-CVP
24%
Rituximab monotherapy 8%
FCR 5%
Other 3% 0% 5%
10%
15%
20%
25%
30% 4 4

5. Do you generally recommend R maintenance after R-chemotherapy?5 5

6. Follicular Lymphoma Transformed Lymphoma Diffuse Large B-Cell Lymphoma
John P. Leonard, M.D.
Richard T. Silver Distinguished Professor of Hematology
and Medical Oncology
Professor of Medicine, Weill Cornell Medical College
Associate Director, Weill Cornell Cancer Center

7. 2 opposite FL management approaches:
Aggressive strategies
Objective of treatment – cure or extended survival
CHOP-R (B-R) + R maintenance or RIT or other
Hoping that more intensive strategy will pay off
Downside – more toxicity in short term
Gentler strategies
Objective of treatment – disease control, less toxicity
Rituximab + other biologics
Hoping that less intensity will improve QOL
Downside – is it less effective in long term?

8. Bendamustine-Rituximab (B-R) vs CHOP-R
StiL NHL
Bendamustine-Rituximab
Follicular
Waldenström‘s
Marginal zone
Small lymphocytic
Mantle cell R
CHOP-Rituximab
Bendamustine 90 mg/m2 day R day 1, max 6 cycles, q 4 wks.
CHOP-R, max 6 cycles, q 3 wks.
Rummel et al.: Blood 114: 168 (abstr #405), 2009

9. B-R vs CHOP-R - Toxicities (all CTC-grades)
B-R (n = 260)
CHOP-R (n = 253)
(no. of pts)
p-value
Alopecia –
+++
<
Paresthesias 18 73
Stomatitis 16 47
Skin (erythema) 42 23 =
Allergic reaction (skin) 40 15 =
Infectious complications 96
127 =
- Sepsis 1 8 =

10. Rummel et al.: Blood 114: 168 (abstr #405), 2009
Median Progression-Free Survival
BR, 54.9 months vs CHOP-R, 34.8 months
Hazard ratio, 0.57
p-value =
Rummel et al.: Blood 114: 168 (abstr #405), 2009

11. Rummel et al.: Blood 114: 168 (abstr #405), 2009
Progression-Free Survival: Subentities
BR vs CHOP-R:
Follicular, p =
Mantle cell, p =
Marginal zone, p =
Waldenström, p =
Rummel et al.: Blood 114: 168 (abstr #405), 2009

12. Randomized Trial of Rituximab Versus Watch-and-Wait in Stage II-IV Asymptomatic Nonbulky Follicular Lymphoma: Study Design
Arm A
Watch-and-Wait R A N D O M I Z E
(n = 187)
Eligibility criteria:
Stage II-IV FL
Grade 1-3a
Asymptomatic
ECOG PS 0/1
Low tumor burden
Arm B
Rituximab 375 mg/m2/week × 4
(n = 84)
Arm C
Rituximab 375 mg/m2/week × 4→375 mg/m2 q 2 months × 12
(n = 192)
Primary endpoint: time to initiation of new therapy
Ardeshna et al. ASH 2010; abstract 6.

13. 95% (no significant difference)
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL: Efficacy and safety
Response at 25 months
Arm A
(N = 187)
Arm B
(N = 84)
Arm C
(N = 192)
ORR 8%
53%
79%
CR/CRu 4%
40%
70% PR
13% 9%
Initiated new treatment
44%
23%
10%
HR for median TTNT
0.37
(34 months)
0.20
0.57
No treatment at 3 years
48%
80%
91%
3-year PFS
33%
60%
81%
(P < vs. A)
3-year OS
95% (no significant difference)
Safety
Serious adverse events 14 6 25
Ardeshna et al. ASH 2010, Abstract 6.

14. Proportion of patients with no new treatment initiated
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL
Proportion of patients with no new treatment initiated
HR (Rituximab vs W+W) = 0.37, 95% CI = 0.25, 0.56, p < HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p < HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p = 0.10
With permission from Ardeshna et al. ASH 2010, Abstract 6.

15. Preliminary analysis of rituximab vs
Preliminary analysis of rituximab vs. watch and wait in stage II-IV, asymptomatic, non-bulky FL
HR (Rituximab vs W+W) = 0.46, 95% CI = 0.33, 0.65, p < HR (Rituximab + M vs W+W) = 0.21, 95% CI = 0.15, 0.29, p < HR (Rituximab + M vs Rituximab) = 0.43, 95% CI = 0.24, 0.72, p = 0.001
With permission from Ardeshna et al. ASH 2010, Abstract 6.

16. Rituximab maintenance
PRIMA: Study design
INDUCTION
MAINTENANCE
Rituximab maintenance
375 mg/m2 every 8 weeks
for 2 years‡
Registration
High
tumor burden
untreated
follicular
lymphoma
Immunochemotherapy
8 x Rituximab
+ 8 x CVP or
6 x CHOP or
6 x FCM
CR/CRu PR
Random 1:1*
Observation‡
PD/SD
off study
* Stratified by response after induction, regimen of chemo and geographic region
‡ Frequency of clinical, biological and CT-scan assessments identical in both arms
Five additional years of follow-up
Salles et al, ASH 2010.

17. Primary endpoint (PFS): 36 months follow-up
Observation
n = 513
R Maintenance
n = 505
3-yr progression-free survival (PFS)
58%
75%
Hazard ratio (95% CI)
0.55 ( )
p-value
<0.0001
Salles GA et al. Proc ASH 2010;Abstract 1788.

18. Safety during rituximab maintenance
Observation n = 508
Rituximab n = 501
Any adverse event
35%
52%
Grade ≥2 infections
22%
37%
Grade 3/4 adverse events
16%
23%
Grade 3/4 neutropenia
<1% 4%
Grade 3/4 infections
Salles GA et al. Proc ASH 2010;Abstract 1788.

19. FIT Study Schema 90Y-ibritumomab (n = 207)
Rituximab 250 mg/m2 IV on day −7 and day Y-ibritumomab MBq/kg (0.4 mCi/kg) [max 1184 MBq (32 mCi)] on day 0
CONSOLIDATION
Start of study R
ANDOMI
ZAT I ON
Patients with previously untreated FL
First-line therapy with chlorambucil, CVP, CHOP, CHOP-like, fludarabine combination, or rituximab combination
6-12 weeks after last dose of induction
CR/CRu or PR
INDUCTION
No further treatment (n = 202)
CONTROL NR PD
Not eligible
CVP = cyclophosphamide, vincristine, prednisone; CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CR = complete response; CR/u = unconfirmed CR; PR = partial response; NR = no response; PD = progressive disease.
Morschhauser et al. J Clin Oncol 2008;26:
Hagenbeek et al, ASH 2010.

20. Overall PFS for Treatment Groups
The 5-year overall PFS was 29% in the control arm compared with 47% in the 90Y-ibritumomab arm HR = 1.95 (95% CI: 1.52 – 2.50); P < 0.001
100 75
90Y-ibritumomab: n = 207 Median PFS: 49 mo
Cumulative Percentage 50 25
Control: n = 202 Median PFS: 15 mo N F
90Y-ibritumomab
207
108
Control
202
144 12 24 36 48 60
PFS from Time of Randomization (Months)
At risk:
90Y-ibritumomab
207
174
133
113 98 80
Control
202
117 83 67 65 46
With permission from Hagenbeek et al, ASH 2010.

21. R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1)
R-ACVBP (every two weeks)
PDN: 60 mg/m2; d1-d5
Ritux: 375 mg/m2 ; d1
Doxo: 75 mg/m2; d1
CPM: 1200 mg/m2; d1
Vindesine: 2 mg/m2; d1 & d5
Bleomycin 10 mg; d1 & d5
Methotrexate (IT) 15 mg; d1
G-CSF 5 µg/kg/d; d6-d13
Methotrexate
3 g/m2; d1-d15
R-Ifosfamide-VP16
Ritux: 375 mg/m2; d1
Ifosfamide: 1.5g/m2; d1
VP16: 300 mg/m2; d1
Ara-C
100 mg/m2 sc, d1-d4
Increased dose-intensity (mg/ m2.wk) compared to R-CHOP
Sequential consolidation using  second-line agents
Ifosfamide, VP16, Ara-C
CNS prophylaxis
High-dose IV Methotrexate
Intrathecal Methotrexate
R-ACVBP
x 2.25
x 2.4
x 1.5
Doxo: 37,5
CPM: 600
Rituximab: 187
Doxo: 16.7
CPM: 250
Rituximab: 125
R-CHOP

22. LNH 03-2B study R-ACVBP 14 R R-CHOP 21 *No radiotherapy in both arms
New DLBCL
Age 18-59
aaIPI 1 R 6 3 12 15 18 9 21
R-ACVBP 14
R-CHOP 21
Wks
MTX
R-IFM-VP16
Ara-C 2 4 10 14 24
4 IT-MTX
380 patients have been included:
196 (R-ACVBP) and 184 (R-CHOP)
Pathological review: 344 patients (91%)
Median follow-up: 44 months
Analyses are on an intent-to-treat basis.
*No radiotherapy
in both arms
ClinicalTrials.gov: NCT

23. R-ACVBP (vs R-CHOP in DLBCL < 60 aaIPI = 1) ORR 92% vs 88%
3-Year Progression-Free Survival:
R-ACVBP (n = 196), 87%
R-CHOP (n = 183), 73%
p =
HR = 0.482
3-Year Overall Survival:
R-ACVBP (n = 196), 92%
R-CHOP (n = 183), 84%
p =
HR = 0.439
Recher et al, ASH 2010.

24. 5/196 (2.6%) in the R-ACVBP arm vs 3/184 (1.6%) in the R-CHOP arm
Toxicity (grade ≥ 3)
R-ACVBP
R-CHOP
Toxic deaths:
5/196 (2.6%) in the R-ACVBP arm vs 3/184 (1.6%) in the R-CHOP arm
Recher et al, ASH 2010.

25. Beyond R-CHOP-21 in younger patients with DLBCL
R-ACVBP
R-EPOCH
R-CHOP-14
Auto SCT in first remission
R-CHOP + novel agents
Epratuzumab
Bortezomib
Lenalidomide
Enzastaurin
Azacitidine

26. What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, :00 PM – 9:30 PM Chicago, Illinois
Moderator
Neil Love, MD
Faculty
Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD
Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek 26 26

27. What schedule of R maintenance do you use?27 27

28. What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, :00 PM – 9:30 PM Chicago, Illinois
Moderator
Neil Love, MD
Faculty
Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD
Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek 28 28

29. Do you use interim PET scans in diffuse large B-cell lymphoma?29 29

30. What Clinicians Want to Know A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic Cancers Sunday, June 5, :00 PM – 9:30 PM Chicago, Illinois
Moderator
Neil Love, MD
Faculty
Sergio Giralt, MD John P Leonard, MD Lauren C Pinter-Brown, MD
Antonio Palumbo, MD Susan M O’Brien, MD Professor Michael Hallek 30 30