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Follicular Lymphoma: Updates on Treatment Strategies Daryl Tan Raffles Cancer Center Visiting Consultant Singapore General Hospital Adjunct Assistant Professor, Duke-NUS Graduate Medical School. Grade 1-2 Follicular Lymphoma. Limited Stage. Advanced Stage, Stage II bulky or ‘ B ’. - PowerPoint PPT Presentation
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Follicular Lymphoma: Updates on Treatment Strategies
Daryl TanRaffles Cancer CenterVisiting Consultant Singapore General HospitalAdjunct Assistant Professor,Duke-NUS Graduate Medical School
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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
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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
MJRMJRTan 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
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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?
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• 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
4.515.8
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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 ChemoMarcus et al Salles et al
Hiddeman et al Harold et al Which 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%
Bendamustine-Rituximab (B-R) vs CHOP-R
Bendamustine-RituximabBendamustine-Rituximab
(N=139)(N=139)- Bendamustine 90 mg/m- Bendamustine 90 mg/m22 day 1+2 day 1+2
-Rituximab 375 mg/mRituximab 375 mg/m22 day 1 day 1
CHOP-Rituximab CHOP-Rituximab (N=140)(N=140)- Cyclophosphamide 750 mg/m- Cyclophosphamide 750 mg/m22 day 1 day 1- Doxorubicin 50 mg/m- Doxorubicin 50 mg/m22 day 1 day 1- Vincristine 1.4 mg/m- Vincristine 1.4 mg/m22 day 1 day 1 - Prednisone 100 mg days 1-5Prednisone 100 mg days 1-5
- Rituximab 375 mg/mRituximab 375 mg/m22 day 1 day 1
FollicularFollicularWaldenströmWaldenström’’ssMarginal zoneMarginal zoneSmall lymphocyticSmall lymphocyticMantle cell (elderly)Mantle cell (elderly)
RRRR
StiL NHL 1-2003StiL NHL 1-2003
Courtesy of Mathias Rummel Lancet 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-R B-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)
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-R B-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
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 value value
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 value value
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 40.9 40.9
Median (months)Median (months)
B-RB-R n. y. r. n. y. r.
CHOP-RCHOP-R 40.9 40.9
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
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 months0 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 46.6 46.6
Median (months)Median (months)
B-RB-R n. y. r. n. y. r.
CHOP-RCHOP-R 46.6 46.6
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
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 months0 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
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 53.4 53.4
CHOP-RCHOP-R 34.9 34.9
Median (months)Median (months)
B-RB-R 53.4 53.4
CHOP-RCHOP-R 34.9 34.9
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months0 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
1.01.0Median (months)Median (months)
B-RB-R 53.6 53.6
CHOP-RCHOP-R 31.5 31.5
Median (months)Median (months)
B-RB-R 53.6 53.6
CHOP-RCHOP-R 31.5 31.5
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
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 months0 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 71.6 71.6
CHOP-RCHOP-R 30.9 30.9
Median (months)Median (months)
B-RB-R 71.6 71.6
CHOP-RCHOP-R 30.9 30.9
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
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 months0 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
Overall survival Overall 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%
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-RB-RB-R
CHOP-RCHOP-RCHOP-RCHOP-R
0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months0 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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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?
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?
The Kiss of Death in Follicular Lymphoma
Ramsay, et al. The Kiss of Death in FL. Blood 2011; 118: 5365-5366Laurent, 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
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
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/MyelomaMD Anderson Cancer Center, Houston, Texas
Courtesy of Nathan Fowler
Study Design
Lenalidomide 20mg Days 1-21 Cycles 1-6*
Months1 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)
Response Rates
SLL (N=30)
Marginal (N=27)*
Follicular(N=46)*
All PatientsEval
(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
PFS (months)
Perc
en
t su
rviv
al
0 12 24 360
20
40
60
80
100
Progression Free Survival
N=10336 mo PFS*:78%
*Projected 3 year PFS
All Evaluable Patients
Courtesy of Nathan Fowler
Grade ≥ 3 Hematologic Toxicity
5 patients developed grade 3 neutropenic fever
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
RELEVANCE Study Design(Rituximab and LEnalidomide versus Any ChEmotherapy)
1st line FL
N=1000R
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
Grade 1-2 Follicular Lymphoma
Advanced Stage, Stage II bulky or ‘B’
Symptomatic,High tumor burden
Chemotherapy/ Immunotherapy
CR or PR Clinical Question :
•Role of maintenance rituximab?Consolidation RIT or
Maintenance Rituximab
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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 Survival Time 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)
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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 B-R is less toxic and more effective than CHOP-R • Impressive data with frontline IMiD + RImpressive data with frontline IMiD + R• Maintance rituximab 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
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Thank You
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Rituximab era
Aggressive chemo/ Purine analogue
Anthracycline
Pre- anthracycline
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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)
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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)
B-Cell Lymphomas Express Several Antigens that can be Targeted
Novel Strategies in B-cell Lymphoma:Targeting B-cell Receptor Signaling
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