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FOLLICULAR LYMPHOMA; UPDATES ON TREATMENT STRATEGIES
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?
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
11. MJRMJR
RESORT: Time to First Cytotoxic Therapy
3-yr Freedom from First Cytotoxic Chemo
MR: 95%
RR: 86%
Median FU : 3.8 yrs
13. 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?
•Role of maintenance rituximab?
14. MJRMJR
RCTs on R-Chemo vs Chemo
Marcus et al Salles et al
Hiddeman et al Harold et alWhich R-Chemo for induction ?
15. MJRMJR
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)
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?
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
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)
43. MJRMJR
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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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
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)
(2%, 3%, and 8% in R-CVP, R-CHOP, and R-FM, respectively).
2 2
2 2
2 2
2 2
2 2
2 2
2 2
2 2
Even in pts with high tum burder.
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.
Some DLBCLs req tonic stimuation of the BCR-BCR signalling is hence an attractv target for amny agents.