1. MJRMJR
Follicular Lymphoma:
Updates on Treatment
Strategies
Daryl Tan
Raffles Cancer Center
Visiting Consultant
Singapore General Hospital
Adjunct Assistant Professor,
Duke-NUS Graduate Medical School

2. MJRMJR
Grade 1-2 Follicular Lymphoma
Limited Stage Advanced Stage, Stage II bulky or ‘B’
Curative Intent
Radiotherapy
Asymptomatic,
Low tumor burden
Symptomatic,
High tumor burden
Watch and Wait Chemotherapy/
Immunotherapy
CR or PR
Clinical Questions :
•Is there still a role for watch and wait in rituximab era?
•What is the optimal frontline therapy?
Which R-Chemo?
•Role of maintenance rituximab? Consolidation RIT or
Maintenance
Rituximab
GELF Criteria

3. MJRMJR
Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’
Asymptomatic,
Low tumor burden
Watch and Wait
Clinical Questions :
•Is there still a role for watch and wait in rituximab era?

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Horning S, SA Rosenberg. NEJM 1984;311:1471-76
Watch and Wait in FL

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Tan D, Horning S, et al. ASH 2007. Abstract 3428
Overall Survival of 1,333 FL Patients at Stanford
by Time to First Treatment
P<0.001

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Median FU: 32 months

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Time To Initiation of New Therapy
Ardeshna KM et al. ASH 2010 Abstract 6

9. MJRMJR
Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’
Asymptomatic,
Low tumor burden
Watch and Wait
Clinical Questions :
•Is there still a role for watch and wait in rituximab era?
•Role of maintenance rituximab?

10. MJRMJR
• progression within 6 months of
Rtx
• failure to respond to Rtx
• inability to complete protocol
• initiation of alternative therapy.
wks

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RESORT: Time to First Cytotoxic Therapy
3-yr Freedom from First Cytotoxic Chemo
MR: 95%
RR: 86%
Median FU : 3.8 yrs

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Ave Doses of
Rtx Received
4.5
15.8

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Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’
Symptomatic,
High tumor burden
Chemotherapy/
Immunotherapy
Clinical Questions :
•Is there still a role for watch and wait in rituximab era?
•What is the optimal frontline therapy?
•Role of maintenance rituximab?

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RCTs on R-Chemo vs Chemo
Marcus et al Salles et al
Hiddeman et al Harold et alWhich R-Chemo for induction ?

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Federico M, et al. ASCO 2012: Abstract 8006
Phase III Study of R-CVP versus R-CHOP versus R-FM as first-line
therapy for advanced-stage follicular lymphoma: final results of the
FOLL05 trial from the Fondazione Italiana Linfomi (N=534)

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Time-to-Treatment Failure
(R-CHOP vs R-CVP vs R-FM)
Federico M, et al. ASCO 2012: Abstract 8006

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Adverse Events (≥grade 3)
(R-CHOP vs R-CVP vs R-FM)
Federico M, et al. ASCO 2012: Abstract 8006
Second Malignancies: 2% 3% 8%

18. Bendamustine-Rituximab (B-R) vs CHOP-R
Bendamustine-RituximabBendamustine-Rituximab
(N=139)(N=139)
- Bendamustine 90 mg/m- Bendamustine 90 mg/m22
day 1+2day 1+2
-Rituximab 375 mg/mRituximab 375 mg/m22
day 1day 1
CHOP-RituximabCHOP-Rituximab (N=140)(N=140)
- Cyclophosphamide 750 mg/m- Cyclophosphamide 750 mg/m22
day 1day 1
- Doxorubicin 50 mg/m- Doxorubicin 50 mg/m22
day 1day 1
- Vincristine 1.4 mg/m- Vincristine 1.4 mg/m22
day 1day 1
- Prednisone 100 mg days 1-5Prednisone 100 mg days 1-5
- Rituximab 375 mg/mRituximab 375 mg/m22
day 1day 1
FollicularFollicular
WaldenströmWaldenström’’ss
Marginal zoneMarginal zone
Small lymphocyticSmall lymphocytic
Mantle cell (elderly)Mantle cell (elderly)
RRRR
StiL NHL 1-2003StiL NHL 1-2003
Courtesy of Mathias RummelLancet 2012, accepted for publication; J Clin Oncol 30, 2012 (suppl; abstr 3)Lancet 2012, accepted for publication; J Clin Oncol 30, 2012 (suppl; abstr 3)
Median follow-up 45 monthsMedian follow-up 45 months

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Number (%) of patientsNumber (%) of patients
Treatment groupTreatment group Grade 2Grade 2 Grade 3Grade 3 Grade 4Grade 4 Grade 3-4Grade 3-4
LeukocytesLeukocytes CHOP-RCHOP-R 39 (15)39 (15) 110 (44)110 (44) 71 (28)71 (28) 181 (72)181 (72)
(10(1099
/L)/L) B-RB-R 80 (30)80 (30) 85 (32)85 (32) 13 (5)13 (5) 98 (37)98 (37)
NeutrophilsNeutrophils CHOP-RCHOP-R 19 (8)19 (8) 70 (28)70 (28) 103 (41)103 (41) 173 (69)173 (69)
(10(1099
/L)/L) B-RB-R 61 (23)61 (23) 53 (20)53 (20) 24 (9)24 (9) 77 (29)77 (29)
LymphocytesLymphocytes CHOP-RCHOP-R 72 (29)72 (29) 87 (35)87 (35) 19 (8)19 (8) 106 (43)106 (43)
(10(1099
/L)/L) B-RB-R 38 (14)38 (14) 122 (46)122 (46) 74 (28)74 (28) 196 (74)196 (74)
HemoglobinHemoglobin CHOP-RCHOP-R 84 (33)84 (33) 10 (4)10 (4) 2 (<1)2 (<1) 12 (5)12 (5)
(g/L)(g/L) B-RB-R 44 (16)44 (16) 6 (2)6 (2) 2 (<1)2 (<1) 8 (3)8 (3)
PlateletsPlatelets CHOP-RCHOP-R 20 (8)20 (8) 11 (4)11 (4) 5 (2)5 (2) 16 (6)16 (6)
(10(1099
/L)/L) B-RB-R 19 (7)19 (7) 15 (6)15 (6) 2 (<1)2 (<1) 13 (5)13 (5)
Worst CTCAE Grades for Hematology Tests ResultsWorst CTCAE Grades for Hematology Tests Results
Courtesy of Mathias Rummel

20. ToxicitiesToxicities (all CTC-grades)(all CTC-grades)
B-R (n=261)B-R (n=261) CHOP-R (n=253)CHOP-R (n=253)
(no. of pts)(no. of pts) (no. of pts)(no. of pts) PP valuevalue
AlopeciaAlopecia -- ++++++ < 0.0001< 0.0001
ParesthesiasParesthesias 1818 7373 < 0.0001< 0.0001
StomatitisStomatitis 1616 4747 < 0.0001< 0.0001
Skin (erythema)Skin (erythema) 4242 2323 = 0.0122= 0.0122
Allergic reaction (skin)Allergic reaction (skin) 4040 1515 = 0.0003= 0.0003
Infectious complicationsInfectious complications 9696 127127 = 0.0025= 0.0025
- Sepsis- Sepsis 11 88 = 0.0190= 0.0190
Courtesy of Mathias Rummel

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B-RB-R CHOP-RCHOP-R
(n=261)(n=261) (n=253)(n=253) PP valuevalue
ORRORR 92,7 %92,7 % 91,3 %91,3 %
CRCR 39,8 %39,8 % 30,0 %30,0 % = 0.021= 0.021
SDSD 2,7 %2,7 % 3,6 %3,6 %
PDPD 3,5 %3,5 % 2,8 %2,8 %
Results Response ratesResults Response rates
Lancet 2012 in press; J Clin Oncol 30, 2012 (suppl; abstr 3)Lancet 2012 in press; J Clin Oncol 30, 2012 (suppl; abstr 3)

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PFS: follicular (n=279)PFS: follicular (n=279) 45 months follow-up45 months follow-up
Median (months)Median (months)
B-RB-R n. y. r.n. y. r.
CHOP-RCHOP-R 40.940.9
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
Hazard ratio, 0.61 (95% CI 0.42 - 0.87)Hazard ratio, 0.61 (95% CI 0.42 - 0.87)
p = 0.0072p = 0.0072
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months
Courtesy of Mathias Rummel

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PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)
Median (months)Median (months)
B-RB-R n. y. r.n. y. r.
CHOP-RCHOP-R 46.646.6
Hazard ratio, 0.56 (95% CI 0.31 - 0.98)Hazard ratio, 0.56 (95% CI 0.31 - 0.98)
p = 0.0428p = 0.0428
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months
Courtesy of Mathias Rummel

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PFS: follicular, FLIPI high (3-5) (n=127; 45.5%)PFS: follicular, FLIPI high (3-5) (n=127; 45.5%)
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
Hazard ratio, 0.63 (95% CI 0.38 - 1.04)Hazard ratio, 0.63 (95% CI 0.38 - 1.04)
p = 0.0679p = 0.0679
Median (months)Median (months)
B-RB-R 53.453.4
CHOP-RCHOP-R 34.934.9
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months
Courtesy of Mathias Rummel

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0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
Median (months)Median (months)
B-RB-R 53.653.6
CHOP-RCHOP-R 31.531.5
Age: 61 yrs and older ( n = 315 )Age: 61 yrs and older ( n = 315 )
Hazard ratio, 0.62 (95% CI 0.45 - 0.84)Hazard ratio, 0.62 (95% CI 0.45 - 0.84)
p = 0.0022p = 0.0022
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months
Courtesy of Mathias Rummel

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0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
Age: 60 yrs and younger ( n = 199 )Age: 60 yrs and younger ( n = 199 )
Median (months)Median (months)
B-RB-R 71.671.6
CHOP-RCHOP-R 30.930.9
Hazard ratio, 0.52 (95% CI 0.33 - 0.79)Hazard ratio, 0.52 (95% CI 0.33 - 0.79)
p = 0.0022p = 0.0022
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months
Courtesy of Mathias Rummel

27. MJRMJR
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
Overall survivalOverall survival
2 yrs2 yrs 3 yrs3 yrs 4 yrs4 yrs 5 yrs5 yrs 6 yrs6 yrs 7 yrs7 yrs
89.7%89.7% 85.6%85.6% 82.3%82.3% 80.1%80.1% 80.1%80.1% 75.9%75.9%
89.5%89.5% 86.7%86.7% 84.2%84.2% 77.8%77.8% 75.5%75.5% 59.5%59.5%
B-RB-R
CHOP-RCHOP-R
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months
Courtesy of Mathias Rummel

28. MJRMJR
Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’
Symptomatic,
High tumor burden
Chemotherapy/
Immunotherapy
Clinical Questions :
•Is there still a role for watch and wait in rituximab era?
•What is the optimal frontline therapy?
– Which R-Chemo ? BR >RCHOP> RCVP
– DO WE REALLY NEED CHEMO UPFRONT ?
•Role of maintenance rituximab?
•What is the optimal sequence of treatment?

30. MJRMJR
?

31. The Kiss of Death
in Follicular Lymphoma
Ramsay, et al. The Kiss of Death in FL. Blood 2011; 118: 5365-5366
Laurent, et al. Distribution, function, and prognostic value of cytotoxicT lymphocytes in FL. Blood 2011;118(20):5371-5379
CTL: Cytotoxic T lymphocyte, FL: follicular lymphoma

32. Lenalidomide:
Mechanisms of Action in Lymphoma
1. Ramsay AG, et al. Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with
lenalidomide: implications for the tumor microenvironment and immunotherapy. Blood. 2009;114(21):4713-4720.
2. Lei W, et al. Lenalidomide Enhances Natural Killer Cell and Monocyte-Mediated Antibody-Dependent Cellular Cytotoxicity of
Rituximab-Treated CD20+ Tumor Cells. Clin Cancer Res 2008;14:4650-4657

33. Lenalidomide and Rituximab for
Untreated Indolent Lymphoma:
Final Results of a Phase II Study
Nathan Fowler, Sattva Neelapu, Frederick Hagemeister, Peter McLaughlin,
Larry W Kwak, Jorge Romaguera, Michele Fanale, Luis Fayad, Robert
Orlowski, Michael Wang, Francesco Turturro, Yasuhiro Oki, Linda Lacerte,
Felipe Samaniego
Department of Lymphoma/Myeloma
MD Anderson Cancer Center, Houston, Texas
Courtesy of Nathan Fowler

34. Study Design
Lenalidomide 20mg Days 1-21 Cycles 1-6*
Months
1 2 3 4 5 6
Rituximab 375mg/M2
Day 1 of Cycles 1-6
If clinical benefit,
can proceed to 12
cycles
•Phase II, single institution
•Planned Enrollment
•N= 50 Follicular lymphoma (grade I/II)
•N=30 Small lymphocytic lymphoma
•N=30 Marginal zone lymphoma
•Groups analyzed independently for response and toxicity
R= RESTAGING R
Lenalidomide 20mg Days 1-21 Cycles 7-12*
Rituximab 375mg/M2
Day 1 of Cycles 7-12
R RR
7 8 9 10 11
12
*SLL patients: Dose escalation of lenalidomide
starting with cycle 1: (10mg, 15mg, 20mg)

35. Response Rates
SLL
(N=30)
Marginal
(N=27)*
Follicular
(N=46)*
All Patients
Eval
(N=103)
ITT
(N=110)
ORR, n (%) 24 (80) 24(89) 45(98) 93(90) 93(85)
CR/Cru 8(27) 18(67) 40(87) 66(64) 66(60)
PR 16(53) 6(22) 5(11) 27(26) 27(25)
SD, n (%) 4(13) 3(11) 1(2) 8(8) 8(7)
PD, n (%) 2(7) 0 0 2(2) 2(2)
*7 pts not evaluable for response:
• 5 due to adverse event in cycle 1
• 1 due to non-compliance
• 1 due to withdrawal of consent Courtesy of Nathan Fowler

36. PFS (months)
Percentsurvival
0 12 24 36
0
20
40
60
80
100
Progression Free Survival
N=103
36 mo PFS*:78%
*Projected 3 year PFS
All Evaluable Patients
Courtesy of Nathan Fowler

37. Grade ≥ 3 Hematologic Toxicity
5 patients developed grade 3 neutropenic fever

38. Grade ≥ 3 Non Hematologic
Adverse Events (>1 pt.)
• Five secondary malignancies reported
• 75 yo: recurrent bladder cancer
• 53 yo: localized melanoma
• 53 yo: stage 0 DCIS of breast
• 81 yo: multiple myeloma
• 75 yo: recurrent localized prostate cancer

39. RELEVANCE Study Design
(Rituximab and LEnalidomide versus Any ChEmotherapy)
1st
line
FL
N=1000
R
R2
R +
Chemo
R2
Maintenance
Rituximab Maint.
• R+Chemo:
•Investigator’s choice of R-CHOP, R-CVP, BR
• Lenalidomide 20mg for 6 cycles, then 10mg if CR
• LYSA (PI: Morschhauser) + North America (PI: Fowler)
Courtesy of Nathan Fowler

40. Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’
Symptomatic,
High tumor burden
Chemotherapy/
Immunotherapy
CR or PRClinical Question :
•Role of maintenance rituximab?
Consolidation RIT or
Maintenance
Rituximab

41. MJRMJR
Salles G, et al. Lancet 2010; 377: 42–51
R-Maintenance vs Observation After R-Chemo
Induction (PRIMA)

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Time to next lymphoma treatment
Overall SurvivalTime to next Chemotherapy
Progression Free Survival
Median follow-up: 36 months
75%
58%
Salles G, et al. Lancet 2010; 377: 42–51

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45. MJRMJR
Salles G, et al. Lancet 2010; 377: 42–51
Grade 3 / 4 Adverse Events
P=0.0026
Fulminant
Hep B (n=1)

46. MJRMJR
Conclusions
-BTG 2013
• Certainly still a role for watchful waiting
• R-FM a/w increased toxicity
• B-R is less toxic and more effective than CHOP-RB-R is less toxic and more effective than CHOP-R
• Impressive data with frontline IMiD + RImpressive data with frontline IMiD + R
• Maintance rituximabMaintance rituximab
– Observed improvements in PFS and Time to Next Tx
not been shown to translate into OS benefit
– MR should be weighed against increased risk of toxicity,
other potential complications, resources and pt’s
preference

47. MJRMJR
Thank You

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51. MJRMJR
Rituximab era
Aggressive chemo/ Purine analogue
Anthracycline
Pre- anthracycline

52. MJRMJR
Comparison of Observed vs Expected survival
in follicular lymphoma
Tan D, et al. J Clin Oncol 2008 (suppl; abstr 8535)J Clin Oncol 2008 (suppl; abstr 8535)

53. MJRMJR
Impacts of Frontline and Salvage Tx on OS-
The Stanford Experience
EFS1 OS-post first relapse
Tan D, et al. J Clin Oncol 2008 (suppl; abstr 8535)J Clin Oncol 2008 (suppl; abstr 8535)

54. B-Cell Lymphomas Express Several
Antigens that can be Targeted

55. Novel Strategies in B-cell Lymphoma:
Targeting B-cell Receptor Signaling