Myron Czuczman, M.D., Professor Chief, Lymphoma/Myeloma Service, Dept. of Medicine Head, Lymphoma Translational Research Laboratory Dept. of Immunology Roswell Park Cancer Center Evolving Management of Follicular Lymphoma Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

1. Evolving Management of Follicular Lymphoma
HUMC Oncology Fall Conference
November 3, 2011
Hackensack, NJ
Myron S. Czuczman, MD
Chief, Lymphoma/Myeloma Service
Head, Lymphoma Translational Research Laboratory
Professor of Medicine and Oncology
Roswell Park Cancer Institute
Buffalo, NY

2. Disclosure Information
Myron S. Czuczman, MD
I have the following financial relationships to disclose:
Membership on advisory committees or consultant/review
panels for: Celgene, Cephalon, Genentech, Genmab,
GlaxoSmithKline
Honorarium from: Celgene, Cephalon, GlaxoSmithKline,
MundiPharma
I will include discussion of investigational or off-label use of
products in my presentation (i.e. numerous agents are
currently in clinical trials and not yet FDA-approved)

3. Outline
• Background
• Approach to Rx of Advanced-stage FL
– Rapidly changing terrain
• Who When and Why Treat? Goals?
• What Rx to use?
– Frontline?
– Post-induction
– In Relapsed/Refractory disease?
• Where are we now?
• Future Directions / Conclusions

4. Characteristics of Follicular Lymphoma
Clinical Pattern:
• Indolent clinical course (typical)
• Highly responsive to therapy but relapse is likely
Treatment decisions based on:
• Stage and Bulk
• FL IPI
• Transformation
• Sites of involvement
• Prior therapy
• Time from prior therapy
Current Treatment Approach:
• Frontline: Rituximab +/- chemotherapy (R-CHOP, R-Benda, R-CVP, etc)
• Consolidation: Rituximab, Radioimmunotherapy (RIT)
• Salvage: Clinical trial, chemoimmunotherapy; HDT/SCT; RIT

5. Current Lymphoma Field:
Rapidly Changing Landscape
• Heterogeneity/complexity of FL will not change
– We are developing scientific tools to better understand it:
• Biologic, genetic, and clinical features
• Results from targeted therapies (e.g. mAbs, RIC’s,
etc.) and novel Rx approaches are promising
• Historical approaches need to be critically reviewed
and retested and will require data from well-
designed clinical trials:
– Optimal combination(s) of old and new agents?
– Optimal timing and sequencing of specific therapies?
– Surrogate end-points other than OS?
– Are cures possible in a significant subset of patients?

6. New directions in the treatment of follicular
lymphoma (FL) in 2011
• The successful use of mAbs in B-cell malignancies is inducing a
paradigm shift in attitudes toward treatment:
– Therapeutic goals are moving from palliation to prolonged remission
durations
– Therapeutic principles are changing from “watchful waiting” to
“earlier” therapy and/or consolidation strategies designed to induce
complete remissions of long duration
– Development and testing of novel targeted agents, both alone and in
combination, enhance B-cell killing and improve response and survival
rates… POSSIBLY EVEN CURE RATES!

7. What are our treatment goals in FL patients?
• Increased CR and PFS rates were associated with
improved survival:
1.0
CR
PR
0.8
Survival probability
0.6
0.4
0.2
0
0 5 10 15 20
Overall survival (y)
Bachy E, et al. J Clin Oncol 2010; 8:822–829

8. Indications for Rx* on FL clinical trials (an example)
 B-symptoms
 Hematopoietic failure
(Hb < 11 g/dl, granulocytes < 1.500 /µl, thrombocytes < 100.000 /µl)
 Large tumor burden
(3 areas > 5 cm or 1 area > 7.5 cm)
 Rapid progression
(increase of tumor mass > 50% within 6 months)
 Complications due to disease
(pain, infarction of spleen, hyperviscosity syndrome, etc.)
 * NEEDS RE-EXAMINED IN 2011!!!
 * THESE PATIENTS MAY BE ALREADY INCURABLE!
references.

9. What Rx to Use @ Presentation?
@ Relapse?
• Answer: “Varies”
• Need additional information to gain a better
understanding of how to attain optimal anti-
tumor activity (i.e. optimal “sequencing”) for
a given “subset” of FL pts
• Choice of Rx dependent on:
• Tumor characteristics (e.g. rate of growth,
tumor size/bulk), histology,
cytogenetic/molecular abnormality)
• Clinical/laboratory characteristics (e.g.
FLIPI score, LDH, B-2 microglobulin)
• Patient characteristics (e.g. co-morbid
conditions, Rx goals, patient’s wishes)

10. Suggested Treatment Regimens
(in alphabetical order)
First-line Therapy
• Bendamustine + R
• CHOP (cyclophosphamide, vincristine, prednisone) + R (category 1)
• CVP (cyclophosphamide, vincristine, prednisone) + R (category 1)
• FND (fludarabine, mitoxantrone, dexamethasone) + R
• Radioimmunotherapy (category 2B)
• Rituximab
First-line for Elderly or Infirm (if none of the above are tolerable)
• Radioimmunotherapy
• Rituximab, preferred
• Single agent alkylators (e.g. chlorambucil or cyclophosphamide)
First-line Consolidation or Extended Dosing
• Chemotherapy followed by radioimmunotherapy (category 1)
• Rituximab maintenance (category 1)
NCCN Clinical Practice Guidelines in Oncology v.1.2010; FOLL-B

11. Suggested Treatment Regimens
(in alphabetical order)
Second-line and Subsequent Therapy
• Chemoimmunotherapy (as in first-line therapy)
• FCMR (fludara, cyclophosphamide, mitoxantrone, R) (category 1)
• High dose therapy with autologous stem cell rescue
• High dose Rx with allogeneic stem cell rescue, (highly selected pts)
• Radioimmunotherapy (category 1)
• Fludarabine + R
• See Second-line therapy for DLBCL (e.g. DHAP; ICE; ESHAP +/- R)
Second-line Extended dosing
• Rituximab maintenance (category 1)
For patients with locally bulky or symptomatic disease, consider IFRT 4-
30 Gy + additional systemic therapy
NCCN Clinical Practice Guidelines in Oncology v.1.2010; FOLL-B

12. NEW
INFORMATION PRESENTED
IN 2010 and 2011
in FL

13. Biomarkers in FL
Relander et al, J Clin Oncol 28(17), 2902-2913 , 2010

14. Bendamustine Chemical Structure
Bendamustine cross-links DNA single and double strands, inhibiting DNA
replication, repair, and transcription*
ClH2C
Bendamustine
Carboxylic acid
N N
ClH2C COOH
Nitrogen mustard N Benzimidazole ring
CH3 NH2
Cl N
N
Cyclophosphamide
Cl N N
O O
N P HOCH2
Cl O
N Cladribine
H
MOA: Leads to mitotic catastrophe in cells OH
* Ghandi et al. Semin Oncol. 2002;29:4

15. Phase III Study of First-line
Bendamustine/Rituximab (B-R) Versus R-
CHOP in Indolent NHL: Efficacy
B-R R-CHOP
P Value HR
(n = 260) (n = 253)
Overall Response Rate 93% 91% – –
Complete response 40% 30% .0262 –
Median Progression-Free Survival 54.9 months 34.8 months .00012 0.57
Median Time to Next Treatment Not reached 37.5 months .00002 0.52
Rummel et al. ASH 2009; abstract 405

16. Phase III Study of First-line B-R vs. R-CHOP in
Indolent NHL: Safety
Cycles
B-R (n = 1450) R-CHOP (n = 1408)
Grade 3/4 Leukocytopenia 12% 38%
Grade 3/4 Neutropenia 11% 46.5%
G-CSF Administered 4% 20%
Number of Patients
B-R (n = 260) R-CHOP (n = 253)
Infectious Complications (All Grades) 96 127
Skin (Erythema, All Grades) 42 23
Allergic Skin Reactions (All Grades) 40 15
Thoughts/Questions:
•Will B+R replace (or has it already replaced) upfront R+CHOP/CVP?
•Trial did not include FL, grade 3 histologies
•PR and CR in B-R arm have identical outcomes…Why?
•Await formal publication and more in depth analysis of Rummel trial…
•Long-term F/U? Rummel et al. ASH 2009; abstract 405

17. Maintenance Therapy
 First-line consolidation or extended dosing
– Chemotherapy followed by radioimmunotherapy
– Rituximab maintenance up to 2 yrs
 Second-line consolidation or extended dosing
– High-dose therapy with autologous stem cell
rescue
– AlloSCT for highly selected patients
– Rituximab maintenance

18. FIT (Front-Line Indolent Trial)
Enroll CONSOLIDATION
90Y-Ib consolidation
R
INDUCTION (n = 208)
A
First-line therapy with CVP, N Rituximab 250 mg/m2
6–12 wks IV Day 0, 7 +
CHOP-like, fludarabine D 90Y-Ib 14.8 MBq/kg
combinations, chlorambucil, O
or rituximab combination M
CR/CRu I
or PR Z
A
T
Primary end point: PFSa
I
O CONTROL
NR N
PD No further treatment
(n = 206)
Off Study
aCalculation
of PFS starts at enrollment, not from induction.
90Y-Ib
= Y-90 ibritumomab tiuxetan; IV = intravenous.
Morschhauser et al, 2008.

19. Median PFS for All Patients
36.5 mos (90Y-Ib) Vs. 13.3 mos (Control; p < .0001)
100 2-sided log-rank p < .0001
HR 0.465
95% CI: 0.357–0.605
80
90Y-Ib
(n = 208)
Median 36.5 mos
PFS (%)
60
40
Control (n = 206)
Median 13.3 mos
20
0
0 6 18 18 30 30 42 42 54 54 66 66
Time After Random Assignment (mos)
Morschhauser et al, 2008

20. FIT Trial: Conclusions…
• 90Y-Ibritumomab consolidation resulted in:
– High conversion rates from PR to CR/CRu: 78%
– High overall CR rate: 87%
• Significantly prolonged median PFS
• 90Y-Ibritumomabconsolidation was well-tolerated with manageable
hematologic adverse events
• Confers a durable PFS benefit for patients with advanced FL
• No unexpected toxicities emerging
• For patients who relapse:
– 90Y-Ibritumomab consolidation does not (appear to) rule out any
second-line treatment approach, including ASCT
• At current follow-up: no significant difference in OS between Rx arms
Morschhauser et al. J Clin Oncol . 2008;26:5156-5164

21. SWOG/CALGB Trial 0016
Untreated Advanced Stage FL
CHOP x 6 CHOP x 6 CHOP x 6 +
+ Rituximab 131ITositumomab
(Bexxar)
•Update: Results Pending
•ASH 2011 abstract accepted as an oral presentation

22. Rituximab Maintenance for 2 Years in Patients with High Tumor
Burden FL responding to R-chemotherapy (PRIMA):
A phase 3 randomized control trial
Patientswere required to have at least one of the following:
B-symptoms
Bulky disease at study entry (nodal or extranodal mass >7cm)
Symtomatic splenomegaly, compressive syndrome, pleural/peritoneal effusion
Involvement of > 3 nodal sites (each > 3cm)
Elevated LDH (>ULN) or β2-microglobulin (>3mg/L)
Gilles Salle et al. ASCO 2010; Abstract 8004

23. Primary Rituximab and Maintenance study: PRIMA
Rituximab maintenance
Immunochemotherapy 375 mg/m2 q8w for 2
High tumor 8 x rituximab years
burden + CR/CRu
untreated 8 x CVP or Randomize 1:1
PR
follicular 6 x CHOP or
lymphoma 6 x FCM Observation
1.0 PFS
Progression-free rate
82%
0.8 Rituximab maintenance
n=505
0.6 Observation
66% n=513
0.4 Stratified HR=0.50
95% CI 0.39; 0.64
0.2 P<0.0001
0.0
0 6 12 18 24 30 36
Time (mo)
Salles GA, et al. J Clin Oncol 2010;28(Suppl.): Abst. 8004

24. Rituximab Maintenance: Do the Results of
the PRIMA Study Define a New Standard of Care?
• Current results of the PRIMA study do not allow us to
evaluate a possible impact on overall survival or
“responsiveness” to subsequent Rx…
• Must balance the benefits/risks (i.e. rituximab resistance
or chronic B-cell depletion) and costs when using
rituximab
• Novel agents (eg, different mAbs; immunoconjugates;
RIT; IMiDs, etc) and/or different maintenance strategies
need to be evaluated as well

25. An Intergroup Randomized Trial of Rituximab vs. a Watch
& Wait Approach in Patients with Advanced Stage,
Asymptomatic, non-Bulky FL
Study Schema F
ARM A
O
R Watch and Wait
Clinic visits L
A L
N ARM B O
D Rituximab Induction W
O
M ARM C U
I Rituximab Induction P
Z & maintenance
A
T Progressive disease
Compulsory CT scan Compulsory
I requiring therapy stops CT scan if clinical CR CT scan
O protocol treatment
N
Bone marrow for histology and MRD only if CT shows CR
Ardeshna et al. Blood 116: Abstract 6, 2010

26. Primary Endpoint: Time to
initiation of next therapy
– Symptomatic enlarged LN or spleen
– ‘B’ symptoms or severe pruritus Limitation of
– Lymphomatous mass > 7cm Study:
provided size increased by 25%
“At the time of
– >3 nodal sites with nodes >5cm
progression,
– Significant effusions rituximab
– Lymphoma-related cytopenias monotherapy
– Near-critical organ was not an
involvement/compression option!”
– Histological transformation
Ardeshna et al. Blood 116: Abstract 6, 2010

27. Benefit of early rituximab ± maintenance over
watch & wait in asymptomatic non-bulky FL
1.0
TTNT: PFS:
Group 3y-PFS (%)
0.8
Proportion of pts with
Watch & Wait (WW) 33
no new Tx initiated
Rituximab (R) 60
0.6
Rituximab 81
maintenance (M)
0.4 Events Totals
WW: 83 187
Pts not requiring Rx (%):
0.2 R: 19 84 W+W=48
R=80%
R+M: 19 192 R+M=91%
0.0
0 1 2 3 4 5
Time from randomization (y)
No difference in OS between treatment arms
• Is this clinically meaningful?
• Cost versus benefit?
Ardeshna KM, et al. Blood 2010;116: Abstract 6

28. The duration of rituximab benefit is limited!
100
Progression-free survival (%)
80 P=0.937
60
Maintenance
40
20
Retreatment
0
0 12 24 36 48 60
Time (mo)
•Within 3 yrs, the majority of patients become refractory to rituximab
•New treatments are still needed for follicular NHL
•Unlikely that R maintenance will be utilized with each course of Rx
Hainsworth JD, et al. J Clin Oncol 2005;23:1088–1095

29. Risks Associated with Prolonged
B-cell Suppression*
• Hypogammaglobulinemia
• Delayed neutropenia
• Viral reactivation (Hepatitis B; JC virus)
• Increased infections associated with
rituximab maintenance
• Restricted response to vaccinations
• Development of acquired rituximab
resistance (under investigation)
* Presentation by M. S. Czuczman, ASCO 2010

30. Next generation anti-CD20 mAbs
Name Comparison to Rituximab Status
Ofatumumab1,2 •Human mAb •FDA-approved in r/r CLL
•Novel membrane proximal •S/P Ph III in rituximab-refractory FL
CD20 epitope •Ph III: in CLL, FL, DLBCL
•Stronger CDC •Several Ph II trials (also RA and
•Slower dissociation rate MS)
•Stronger binding to B-cells
GA1011 •Type II anti-CD20 (glycol- •S/P Ph I trials
engineered Fc Region) •Ph III Benda vs. Benda + GA101 in
•Increased ADCC/Apoptosis rituximab-refractory indolent NHL
•Stronger binding to effectors •Several Ph II trials
•Limited CDC
Veltuzumab1 •Humanized IgG1 mAb •S/P Ph I/II studies (IV)
•Single a.a. change in CDR3- •Phase I/II sub q in NHL/CLL
VH (Asn to Asp) •Phase I subq in ITP
•Epratuzumab framework
•Slower dissociation rate
•Stronger CDC
•Enhances epratuzumab
activity
•Low-dose subq formulation
1. Robak T & Robak E. Biodrugs 2011;25:13–25. 2. Lin TS. Pharmacogenomics and Personalized Medicine 2010;3:51–59.

31. B-Cells: Express Many Surface Antigens That May
Serve as Targets for mAbs
Marker
 Antigen expression variable1,2
B-cell receptor
(BCR)
 Most involved in B-cell growth,
differentiation, proliferation,
CD19
and activation; other functions
CD20
include1,2:
CD21
CD22
B-Cell CD23 – Immune regulation
CD38 – Complement inhibition
CD40
CD52  Many are targets of therapeutic
CD46, CD55, CD59
mAbs for current or potential
CD74
use in B-cell malignancies1,2
CD80
1Bello C, Sotomayor EM. Hematology Am Soc Hematol Educ Program. 2007;2007:233-242
2Hotta T. Acta Histochem Cytochem. 2002;35(4):275-279 31

32. NHL: emerging agents
Microenvironment Surface markers
CD22
Bevacizumab1 CD40
Anti-CD20 mAb/
radioimmunotherapy
CD20
Lenalidomide2* CD80
(RIT)2*
Anti-CD19 mAb4
Chemotherapy Anti-CD22 mAb/
immunoconjugates/
Bendamustine3* RIT1,2*
“Pathways”
Bcl-2 family Proteasome PKC inhibitors: HDAC inhibitors:
inhibitors: inhibitors: mTOR Enzastaurin6,7 Vorinostat (SAHA)6
ABT-263,5 Bortezomib;2,5,6 inhibitors:
6,7
Panobinostat (LBH589)6
2nd generation6 Everolimus 6,7 BCR-signaling
7
GX 15-0706
Temsirolimus BTK inhibitor
*Denotes agent is licensed for a B-cell NHL indication
1. Kahl B. SeminHematol 2008;45:90–94. 2. Gregory SA, et al. Oncology 2010;24:5. 3. Cheson BD, et al. Clin
Lymphoma Myeloma Leuk 2010;10:452–457. 4. Gerber H-P, et al. Blood 2009;113:4352–4361. 5. Tageja N, et
al. J Hematol Oncol 2009;2:50. 6. Delmonte A, et al. Oncologist 2009;14:511–525. 7. Witzig TE & Gupta M.
Hematology Am Soc Hematol Educ Program 2010;2010:265–270. Adapted slide courtesy of DeVos, UCLA

33. Novel Therapies in FL: Select Clinical Trials
Veungopal; 3rd Annual Considerations in Lymphoma 3(2):5-10, 2011

34. Effects of lenalidomide on tumor cells
and their microenvironment
Chanan-Khan and Cheson. J Clin Oncol 26:1544; 2008

35. Future approach?: High CR rate with lenalidomide
plus rituximab in stage III/IV iNHL (incl. FL)
● Interim results of phase II trial (n=19) assessed after 3 cycles; 10
patients with FL had achieved a CR at 6 cycles (below)
● Updated data at ASCO 2010 (n=30): 16 of 17 FL pts (94%) CR rate
100 84% 79% High CR/CRu rate
Response (%)
80
60
40 16%
16%
20 5%
5%
0
ORR CR/CRu PR SD
Adverse events: Well-tolerated
• Rash in 10 patients (erythematous and transient; Grade3/4 n=6)
Fowler N, et al. Blood 2009;114: Abst 1714; Updated at ASCO 2010, Abst 8036

36. FL-001: Phase 3 Study Design
Primary end-point: PFS
R2 R2 maintenance
1st line
FL S R CR, CRu, PR
n = 1000
R-Chemo Rituximab maintenance
• R2 = Rituximab + Lenalidomide
• R-Chemo
─ investigator choice of R-CHOP, R-CVP, R-B
• Lenalidomide 20 mg x 6 cycles, if CR then 10 mg
─ subjects with PR after 6 cycles receive additional 3–6 m of lenalidomide 20 mg
• Co-primary endpoints
─ surrogate endpoint (for initial approval): CR/CRu rate at 1.5 years
─ PFS

37. PI3K Delta Inhibition Offers a Novel Targeted
Therapy in B-Cell Malignancies
Courtesy of Calistoga Pharmaceuticals

38. PI3K Promotes Survival and Growth of Cancer
Okkenhaug Nat Rev Immunol, 2003

39. BTK* Regulates Multiple Cellular Processes in B-cell neoplasms
•B-cell receptor (BCR)
signaling
•PCI-32765** blocks BCR
signals and induces
apoptosis
•Chemokine-mediated
lymphocyte migration
and adhesion
•PCI-32765 reduces
lymphadenopathy
•Cytokine secretion
•PCI-32765 blocks
CCL3/4, TNFα
•*Btk = Bruton’s tyrosine kinase
•**PCI-32765 = Btk inhibitor
•Burger JA and Gandhi V. Blood 2009 114(12):2560-1

40. Targeted Therapy, Novel Agents
Being Tested in FL
• Btk inhibition in B-cell malignancies
– PCI-32765 shows clinical benefit with single-agent PO dosing1
– 52% ORR in 48 evaluable pts
• 78% in MCL; 29-33% in FL, DLBCL, MZL, MALT
– Well tolerated, minimal toxicities at <12.5 mg/kg/day
• CAL -101: Oral PI3K inhibitor
– Clinical benefit in pts with r/r indolent NHL, MCL, and CLL2
– Well tolerated with minimal hematologic toxicity
– Most frequent AE: reversible increase in ALT/AST
– 55% ORR in indolent NHL (n=24); 62% in MCL (N=16)
1Fowler KH et al. ASH 2010 Abst 964
2Kahl B et al. ASH 2010 Abst 1777

41. Where are we going? / Conclusions
 Use of “risk analysis” to “individualize” Rx in future
 Ongoing translational research will identify additional novel
therapeutic targets; Biomarkers associated with response
to a given agent are needed
 “Targeted” combo therapies increase direct anti-tumor
activity while decreasing non-specific toxicities
 Problem: How to best combine active agents?... Improve
induction? Concurrent vs sequential? Role of
“maintenance” (especially with new agents!)
• Need well-designed clinical trials and participation by a
large number of pts…
 Achieveable Goal: Prolongation of life and quality-of-life in
patients with novel non-cross-resistant
targeted agents!