Follicular Lymphoma Laurie H. Sehn, MDCM, MPH BC Cancer Agency Vancouver, Canada.
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Transcript of Follicular Lymphoma Laurie H. Sehn, MDCM, MPH BC Cancer Agency Vancouver, Canada.
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Follicular Lymphoma
Laurie H. Sehn, MDCM, MPHBC Cancer Agency
Vancouver, Canada
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Pathogenesis of Follicular LymphomaPathogenesis of Follicular Lymphoma
t(14;18)
t(14;18) B cell
GC reaction
SHM machinery
Additional genetic alterations
6q- -1p36.3 +der18 +7, +8Additional genomic alterations
Immune Response 2
Immune Response 1
B cell
Adverse Course Favorable Course
Ag
Host Genetics
Host Genetics
Bcl-2
N-glycosylation
RFH
FL
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Dave, NEJM, 2004;351:2159
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Reported Molecular Markers in FL Favorable Unfavorable
Bcl-6 expression
CD-10 expression
MUM1 negative
PU.1
Cyclin B1
Immune response IR-1
Chromosomal gains (+7, +12q13-14, +18q)
Chromosomal losses(del6q, -9p21, -17p13)
Bcl-2 expression
BCL-6 translocation
MDM2 expression
Bcl-XL
Macrophage content
Microvessel density
81-gene predictor (variable)
Immune response IR-2
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Follicular Lymphoma Grades
X
Grade 1 Grade 2
Grade 3a
Grade 3b
MIB1
MIB1
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WHO Lymphoid Neoplasm ClassificationRevisions 2008
Maintains Grading Grade 1/2 (low grade) 0-15 centroblasts/hpf – Grade 1 0-5 centroblasts/hpf – Grade 2 6-15 centroblasts/hpf
Grade 3– Grade 3A > 15 centroblasts/hpf – Grade 3B solid sheets of centroblasts
Any diffuse areas with >15 centroblasts/hpf is now called DLBCL with follicular lymphoma
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Follicular Lymphoma International Prognostic Index (FLIPI)
Factor Adverse
Nodal Sites ≥5
LDH >Normal
Age ≥60
Stage III-IV
Hemoglobin <12 g/dL
PrognosisNumber of Factors
Patients (%)
5-year OS(%)
10-year OS(%)
Good 0-1 36 91 71
Intermediate 2 37 78 51
Poor ≥3 27 53 36
Solal-Celigny et al, Blood 2004
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Comparison of IPI and FLIPI Indices
IPI
FLIPI
Perea, Annals Oncol 2005
HR
HRHR
HR
IR
IR
IR
IR
LR
LR
LR
LR
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TTF According to FLIPI Following R-CHOP
Buske, Blood 2006
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Indolent LymphomaAge Adjusted Mortality vs Normal
Indolent LymphomaAge Adjusted Mortality vs Normal
Agegroup
U.S. populationexpected %1-yr
mortality
LGL 60% 1-yr
mortality
60-64 1.62 29.5
65-69 2.60 26.0
70-75 5.33 45.1
75 6.87 65.9
Overall 2.52 32.1
Weisdorf, J Clin Oncol 1992;10:942
Indolent lymphoma
> 75
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Treatment Options for Follicular Lymphoma
Interferon
Autologous
Allogeneic(full or non-
myeloablative)
Alkylator-based treatment
CVPChlorambucil
CHOP
Specific Nonspecific
Purine analogsFludarabine
Fludarabine-basedcombination
Chemotherapy-based
Antibody-basedRituximab alone
Chemo-immunotherapy
RadioimmunotherapyTositumomab
Ibritumomab tiuxetan
Biologic-based Transplantation
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Optimal Therapy in FL Should be Individualized
Curative therapy has not been identified
Treatment decisions must be individualized and should consider:– Goal of therapy– Efficacy of therapy– Toxicity– Patient’s medical condition– Patient preferences– Lifelong management– Appropriate sequencing
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Watch and Wait
No survival advantage to starting therapy early– Young, RC et al. Semin Hematol 1988– Brice, P et al. J Clin Oncol 1997– Ardeshna, KM et al. Lancet 2003
Avoids unnecessary toxicity and maintains QOL
Allows new information and therapies to emerge
Not yet tested in era of immuno-chemotherapy
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Randomized Trials of Rituximab and Chemotherapy in Untreated Follicular NHL
Trial Treatment CR%ORR
%Results
MarcusBlood 2005, JCO 2008
CVP vs
R-CVP
10
41
57
81Improved TTP
and OS
Hiddemann Blood 2006
CHOP vs
R-CHOP
17
20
90
96Improved TTF
and OS
HeroldASH 2005, ASH 2006
MCP vs
R-MCP
25
50
75
92Improved EFS
and OS
Salles, Foussard
J Clin Oncol 2008
CHVP/IFN vs
R-CHVP/IFN
63
79
73
84Improved EFS
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Time to Treatment FailureR-CVP versus CVP
Time to Treatment FailureR-CVP versus CVP
Study month
Ev
en
t-fr
ee
pro
ba
bil
ity
06 12 18 24 30 36 42 48 540 60
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
R–CVP: median 27 months
CVP: median 7 months
66 72
159CVP
R–CVP
Patients at risk:
162
86
123
51
113
34
98
30
93
21
76
17
69
14
63
10
53
6
37
3
14
1 0
3 0
p<0.0001
Median FU: 53 months
Marcus et al, ASH 2006
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Marcus, R et al. J Clin Oncol 2008
Overall survival R CVP versus CVP
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Do we need to use an Anthracycline?
No survival advantage to using an anthracycline– Dana, et al. J Clin Oncol 1993 – Peterson, et al. J Clin Oncol 2003
Greater Toxicity
Variable results reported with R-CHOP– Czuczman, et al. J Clin Oncol 2004– Hiddemann, et al. Blood 2005
Consider lifelong management (transformation risk)
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Risk of Transformation by Initial Treatment
Al-Tourah et al. J Clin Oncol, 2008
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Follicular Lymphoma GradingGrade 1 FL Grade 3a FL
Grade 2 FL
The spectrum of FL is a continuum from grade 1 grade 3a
Increasing Proliferation
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Overall Survival of Grade 3A FL According to Treatment
1614121086420
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Time (years)
1614121086420
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Time (years)
Overall Survival Disease Specific Survival
Anthracycline (n=32)
Anthracycline (n=32)
No Anthracycline (n=67)
No Anthracycline (n=67)
Shustik et al, Lugano 2008
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MJRMJR
PFS : Bendamustine-R vs R-CHOPPFS : Bendamustine-R vs R-CHOP
B-RB-R
CHOP-RCHOP-R
p = 0,11p = 0,11
00 1212 2424 36360.00.0
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
Pro
babi
lity
Pro
babi
lity
48 months48 months
Median observation period 18 monthsMedian observation period 18 months
Rummel et al, ASH 2007
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Randomized Maintenance Rituximab Trials in Indolent NHL
Trial Patients Induction Results
HochsterJ Clin Oncol 2009
Untreated CVP Improved EFS
Ghielmini Blood 2004
Untreated/
RelapsedRituximab Improved EFS
HainsworthJ Clin Oncol 2005
Relapsed Rituximab Improved PFS
Forstpointner Blood 2006
Relapsed FCM v R-FCMImproved
Response Duration
van OersBlood 2006, ASH 2009
Relapsed CHOP v R-CHOPImproved PFS
and ?OS
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RANDOMISE
CHOP q21dmaximum 6 cycles
R-CHOP q21dmaximum 6 cycles
RANDOMISE
Observation
Rituximab maintenance
therapy*
* 375 mg/m2 every 3 months for 2 years or until relapse
CRPR
n = 234
n = 231
n = 167
n = 167
van Oers M, et al. Blood 2006
Rituximab in Induction and Maintenance Treatment of Relapsed Follicular NHL- EORTC Trial
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Rituximab maintenance prolongs PFS by more than 3 years
Rituximab maintenance median: 51.5 months
Observation median: 14.9 months
p < 0.001
Years0 1 2 3 4 5
0
10
20
30
40
50
60
70
80
90
100
Pat
ien
ts (
%)
PFS > 3 years
PFS after R-CHOP/CHOP induction in EORTC 20981 trial
van Oers M, et al. Blood 2006
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Rituximab maintenance improves PFS irrespective of induction regimen
PFS after CHOP induction PFS after R-CHOP induction
ObservationMedian: 23.0 months
MaintenanceMedian: 51.8 months
p = 0.004
Maintenancemedian: 42.2 months
Observationmedian: 11.6 months
p < 0.001
Years0 1 2 3 4 5
0
20
40
60
80
100
Years0 1 2 3 4 5
0
20
40
60
80
100
van Oers M, et al. Blood 2006
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Rituximab maintenance significantly improves overall survival
Years0 1 2 3 4 6
0
10
20
30
40
50
60
70
80
90
100
Pa
tie
nts
(%
)
p = 0.011HR: 0.52
5
Rituximab maintenance: 3 years 85.1%
Observation: 3 years 77.1%
OS after CHOP/R-CHOP induction in EORTC 20981 trial
van Oers M, et al. Blood 2006
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Vidal et al, J Natl Cancer Inst 2009
Meta-Analysis: Overall Survival with Rituximab Maintenance versus Observation
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Vidal et al, J Natl Cancer Inst 2009
Meta-Analysis: Infection-Related Adverse Events with Rituximab Maintenance
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FIT Study Design
ZEVALIN (n = 208)
Rituximab 250 mg/m2 IV day -7 and day 0 +Zevalin 14.8 MBq/kg (max 1184 MBq/kg)
day 0
Advanced Stage FLFirst-line CVP, CHOP-
like, fludarabine combinations,
chlorambucil, or rituximab combination
INDUCTION
CONSOLIDATION
No further treatment (n = 206)
NRPD
CR/CRu or PR
No inclusion
RANDOMIZATION
CONTROLCONTROL
Start of study
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Morschhauser et al, J Clin Oncol 2008
Progression-Free Survival 90Y-ibritumomab tiuxetan versus Observation
90Y-ibritumomab tiuxetan (n=208) Median 36.5 mos
P<0.0001
Control (n=206) Median 13.3mos
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Overall Survival 90Y-ibritumomab tiuxetan versus Observation
Morschhauser et al, J Clin Oncol 2008
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Ladetto et al, Blood 2008
Overall Survival Event-Free Survival
Outcome in Untreated FL Following CHOP-R versus Rituximab and ABMT
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Rezvani, et al. J Clin Oncol 2008
Outcome Following Reduced-Intensity
Allogeneic Transplantation - Seattle
n=16n=16
n=46n=46
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Impact of Transformation on Survival of pts with Follicular Lymphoma
Al-Tourah et al, J Clin Oncol, 2008
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Risk of Transformation = 3% per year
10 y Risk = 30%10 y Risk = 30%
Transformation Risk in FLBritish Columbia (N= 600)
Al-Tourah et al, J Clin Oncol, 2008
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Transformation is a heterogenous process
mutation of P53
P16 alterations
rearrangements involving c-myc
secondary non-random cytogenetic
changes
5’UTR Bcl-6 mutations
mutations in
Bcl-2
Transformation
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Impact of Initial Management On Risk of Transformation
Al-Tourah et al, J Clin Oncol, 2008
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14121086420
1.0
.8
.6
.4
.2
0.0
Post-Transformation Survival by Treatment: CHOP-R vs CHOP- Like
CHOP-R (N= 23)
5yr OS 61%
CHOP-Like (N= 85)
5yr OS 33%
P= 0.01
Pro
port
ion
Sur
vivi
ng
Post-Transformation Survival (y)
Al-Tourah, ASH 2007, Abst # 790
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Follicular Lymphoma in BC by Era
80-88 (367) 89-97 (710) 98-06 (941)
Overall survival (y)
2520151050
Cum
Sur
viva
l
1.0
.8
.6
.4
.2
0.01980-88 n = 367
1998-2006 n = 941
1989-97 n = 710
33 % decrease
in 10 y mortality
Outcome for Follicular Lymphoma in BC by Era
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Conclusion
• Combined chemoimmunotherapy improves survival in patients who need treatment
• Maintenance rituximab significantly prolongs remission
• Transformation remains a treatment challenge and greatly impacts survival
• Challenge Use biologic insight of key factors at play in individual patients to guide treatment