1. 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. Grade 1-2 Follicular Lymphoma
Limited Stage
Advanced Stage, Stage II bulky or ‘B’
GELF Criteria
Curative Intent Radiotherapy
Asymptomatic,
Low tumor burden
Symptomatic,
High tumor burden
Watch and Wait
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?
Role of maintenance rituximab? .
CR or PR
Consolidation RIT or Maintenance Rituximab

3. 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? .

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

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

7. Median FU: 32 months

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

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

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

12. Ave Doses of Rtx Received
4.5
15.8

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

14. RCTs on R-Chemo vs Chemo Which R-Chemo for induction ?
Marcus et al
Salles et al
Which R-Chemo for induction ?
Hiddeman et al
Harold et al

15. 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) .
Federico M, et al. ASCO 2012: Abstract 8006

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

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

18. Bendamustine-Rituximab (B-R) vs CHOP-R
StiL NHL
Bendamustine-Rituximab
(N=139)
- Bendamustine 90 mg/m2 day 1+2
Rituximab 375 mg/m2 day 1
Follicular
Waldenström’s
Marginal zone
Small lymphocytic
Mantle cell (elderly) R
CHOP-Rituximab (N=140)
- Cyclophosphamide 750 mg/m2 day 1
- Doxorubicin 50 mg/m2 day 1
- Vincristine 1.4 mg/m2 day 1
Prednisone 100 mg days 1-5
Rituximab 375 mg/m2 day 1
Median follow-up 45 months
Lancet 2012, accepted for publication; J Clin Oncol 30, 2012 (suppl; abstr 3)
Courtesy of Mathias Rummel

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

20. Toxicities (all CTC-grades)
B-R (n=261) CHOP-R (n=253)
(no. of pts) (no. of pts) P value
Alopecia <
Paresthesias <
Stomatitis <
Skin (erythema) =
Allergic reaction (skin) =
Infectious complications =
- Sepsis 1 8 =
Courtesy of Mathias Rummel

21. Results Response rates
B-R CHOP-R (n=261) (n=253) P value
ORR 92,7 % 91,3 %
CR 39,8 % 30,0 % = 0.021
SD 2,7 % 3,6 %
PD 3,5 % 2,8 %
Lancet 2012 in press; J Clin Oncol 30, 2012 (suppl; abstr 3) 2 2

22. PFS: follicular (n=279) 45 months follow-up
1.0
Median (months)
B-R n. y. r.
CHOP-R
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio, 0.61 (95% CI )
p =
0.1
0.0
months
Courtesy of Mathias Rummel 2 2

23. PFS: follicular, FLIPI low (0-2) (n=152; 54.5%)
1.0
Median (months)
B-R n. y. r.
CHOP-R
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio, 0.56 (95% CI )
p =
0.1
0.0
months
Courtesy of Mathias Rummel 2 2

24. PFS: follicular, FLIPI high (3-5) (n=127; 45.5%)
1.0
Median (months)
B-R
CHOP-R
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio, 0.63 (95% CI )
p =
0.1
0.0
months
Courtesy of Mathias Rummel 2 2

25. Age: 61 yrs and older ( n = 315 ) Median (months) 1.0 B-R 53.6
CHOP-R
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio, 0.62 (95% CI )
p =
0.1
0.0
months
Courtesy of Mathias Rummel 2 2

26. Age: 60 yrs and younger ( n = 199 )
1.0
Median (months)
B-R
CHOP-R
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio, 0.52 (95% CI )
p =
0.1
0.0
months
Courtesy of Mathias Rummel 2 2

27. Overall survival 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs 1.0 0.9 0.8 B-R
0.7
0.6
CHOP-R
0.5
0.4
2 yrs 3 yrs 4 yrs 5 yrs 6 yrs 7 yrs
89.7% 85.6% 82.3% 80.1% 80.1% 75.9%
89.5% 86.7% 84.2% 77.8% 75.5% 59.5%
0.3
0.2
0.1
0.0
months
Courtesy of Mathias Rummel 2 2

28. Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’
Symptomatic,
High tumor burden
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?
Chemotherapy/ Immunotherapy
Even in pts with high tum burder.

30. ?

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

32. Lenalidomide: Mechanisms of Action in Lymphoma
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):
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:

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. Lenalidomide 20mg Days 1-21 Cycles 1-6*
Study Design
Months
Lenalidomide 20mg Days 1-21 Cycles 1-6*
Lenalidomide 20mg Days 1-21 Cycles 7-12*
Rituximab 375mg/M2 Day 1 of Cycles 7-12 R
Rituximab 375mg/M2 Day 1 of Cycles 1-6 R R
R= RESTAGING
If clinical benefit, can proceed to 12 cycles
*SLL patients: Dose escalation of lenalidomide starting with cycle 1: (10mg, 15mg, 20mg)
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

35. Response Rates *7 pts not evaluable for response:
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)
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. Progression Free Survival
All Evaluable Patients
N=103
36 mo PFS*:78%
*Projected 3 year PFS
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
Clinical Question :
Role of maintenance rituximab?
CR or PR
Consolidation RIT or Maintenance Rituximab

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

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

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

46. 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-R
Impressive data with frontline IMiD + R
Maintance 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. Thank You

48. This is the 2013 NCCN hot off the press
This is the 2013 NCCN hot off the press. Prob not surprising that flu now no longer recommended upfront . Options have been narrowed down.
In terms of efficacy, we know that BR> RCHOP> RCVP, Before we jump in and hail BR king of the hill, let me ask a more provocative question.

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

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

53. 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)

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

55. Novel Strategies in B-cell Lymphoma:
Targeting B-cell Receptor Signaling
Some DLBCLs req tonic stimuation of the BCR-BCR signalling is hence an attractv target for amny agents.

56. Follicular Lymphoma Response: Tumor Burden, Molecular Response
BY GELF CRITERIA N=46
GELF (+) HIGH TUMOR BURDEN N=22 (48%)
GELF (-) HIGH TUMOR BURDEN N=24 (52%) SD PR
CR/Cru
ORR
1 (5%)
21(95%)
100%
1(4%)
4(17%)
19 (79%)
96%
BY BULK OF DISEASE N=46
BULKY N=13 (28%)
NON-BULKY N=33 (72%) SD PR
CR/CRu
ORR
1(8%)
12(92%)
100%
1(3%)
4 (12%)
28 (85%)
97%
MOLECULAR RESPONSE N=44 (eval)
PCR POSITIVE
PCR NEGATIVE
PRETREATMENT
17(41%)
26(59%)
POST CYCLE 3
5(11%)
39(89%)
POST CYCLE 6
2(5%)
42(95%)
Bone marrow and peripheral blood for major or minor breakpoint
1. Brice P, et al. JCO 1997: 15:1110–1117.