Optimal frontline therapy for Follicular lymphoma:
Do we need to start with chemotherapy?
NO!
Jonathan W. Friedberg M.D., M.M.Sc.
University of Rochester Medical Center
Follicular Lymphoma is Heterogeneous
Follicular Lymphoma International Prognostic Index
FL-IPI clinical prognostic scoring system
• Age (>60)
• Ann Arbor stage (III-IV)
• Hemoglobin level (<120 g/L)
• Serum lactate dehydrogenase (>ULN)
• Number of involved nodal sites (>4)
Solal-Céligny et al. Blood. 104:1258
Follicular Lymphoma
Survival Probability
Overall Survival According to FL-IPI
1.0
0.8
Low
0.6
Intermediate
0.4
High
0.2
P<10-4
0.0
0 12 24 36 48 60 72 84 96 108 120
Time (Months)
Risk Group
Factors (#)
Patients (%)
0–1
36
91
71
Intermediate
2
37
78
51
High
≥3
27
53
36
Low
5-Year OS (%) 10-Year OS (%)
Solal-Céligny et al. Blood. 104:1258
Biological heterogeneity of follicular lymphoma:
Impact of nodal microenvironment
“Immune-response 1”
T cells
Macrophages
Favorable
OS: > 10 years
“Immune-response 2”
Macrophages
Dendritic cells
Unfavorable
OS: < 4 years
NEJM 351:2159
What is the aim of therapy in an incurable
disease like follicular lymphoma?
• “Clinical benefit”
– Symptom relief (note most patients are not symptomatic)
– Quality of life
• Physical: decreased transfusions, decreased infections, etc.
• Psychological: “…better to be in remission…..”
– Change the natural history of disease
• Transformation, Overall survival
• Delay need for toxic therapy
Follicular Lymphoma
Common Management Approach
After Staging Evaluation
Early stage
Involved
Field Radiation
Advanced stage
Advanced stage
Low Tumor Burden
High Tumor Burden
Observation
Therapy
TRANSFORMATION
Follicular Lymphoma
Common Management Approach
After Staging Evaluation
Early stage
Involved
Field Radiation
Advanced stage
Advanced stage
Low Tumor Burden
High Tumor Burden
Observation
Therapy
TRANSFORMATION
“Watch and Wait” Strategy for Select
Indolent NHL Patients
• Study of asymptomatic, advanced stage, low-grade
NHL found no difference in OS between immediate
chlorambucil vs delay of therapy until progression1
• Chlorambucil: 5.9 yr
• Observation: 6.7 yr
• Current NCCN Guidelines recommend observation for
select indolent NHL patients particularly if2:
• Advanced Age
• Asymptomatic
• Low Tumor Burden
1Ardeshna
KM, et al. Lancet. 2003;362:516-522.
2NCCN guidelines. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.
Randomized Trial of Rituximab vs W&W in Patients
With Stage II-IV Asymptomatic Non-Bulky FL
Arm A
Arm B
Arm C
Intervention
Observe
R x 4 wk
R x 4 wk
Maintenance
--
--
R q 2 mo x 2 yr
Number
186
84
192
CR/PR (%)
3/6
45/33
49/36
PFS
30%
60%
80%
TNT
33 mo
NR
NR
• Summary
• Improved PFS in R arms (P < 0.001)
• Improved time to initiation of new treatment in the R arms: 33
mo vs. not reached at 4 yr (P < 0.001)
• No difference in OS (P > 0.5)
• Quality of life no worse
Ardeshna et al, ASH 2010 Plenary
Ardeshna K, et al. Blood. 2010;116:5a. Abstract 6.
Watchful waiting (WW) vs active
treatment (AT): Lymphocare
2,727 patients with newly
diagnosed FL enrolled
59 patients excluded*
1,822
Stage
III/IV
WW group
n = 270
AT group
n = 1,462
R-monotherapy
n = 232
R-chemotherapy
n = 1,019
31 patients excluded*
Other†
n = 211
Sinha et al, ASH 2011
Baseline characteristics (WW vs AT)
WW
(n = 270)
61
(34–91)
45
AT
(n = 1,462)
60
(22–97)
49
1–2
79
68
3
10
20
Mixed or unknown
11
12
Good
18
14
Intermediate
48
35
Poor
34
51
0
85
61
≥1
15
39
Characteristic, %
Age, median years (range)
Male
FL grade:
FLIPI risk:
ECOG PS:
p-value
0.9003
0.2601
0.0002
< 0.0001
< 0.0001
Patients receiving AT had higher percentages of stage IV, LDH > ULN, Hgb < 12 g/dL,
and more than one extranodal site
Race, number of nodal sites and bone marrow involvement were not significantly
different between groups (Pearson chi-square test, p > 0.05)
No differences in overall survival
at 5 years of follow-up
Median follow-up
time, months
WW
(n = 270)
R-mono
(n = 232)
R-chemo
(n = 1,019)
Other
(n = 211)
60
57
59
62
Median OS
Deaths, %
Not reached
18
25
20
18
SAKK 35/98 trial design: Standard vs.
Prolonged Rituximab in indolent NHL
n = 202
n = 151
Standard
R
375 mg/m²
weekly x 4
SD,PR,CR
Prolonged
375 mg/m² every 2 months x 4
PD
off
trial
Characteristics of the patients
Included
(n = 202)
Randomised
(n = 151 )
57
57
PS 0-I
94 %
97 %
Stage III-IV
85 %
85 %
Involved BM
52 %
50 %
Bulky (> 5 cm)
53 %
48 %
Elevated LDH
37 %
30 %
Previous chemotherapy
68 %
66%
Median age
Prolonged vs. standard rituximab EFS:
Blood 103:4416 2004
0.8
1.0
Effect of schedule on event free survival:
Update 2009
Event-free survival in randomized follicular lymphoma patients
0.6
Median FU: 9.4 years
0.4
25% still in remission
at 8 years
/
/ /
//
//
0.2
///// /
Prolonged
Standard
/
/
/
0.0
Probability
P = 0.0007
1
2
3
4
5
6
7
Years since start of treatment
8
9
10
///
/
EFS in chemo-naïve responders:
Update 2009
0.8
1.0
Event-free survival in chemo-naive patients with CR/PR at 12 wee
0.6
Pr o lo ng ed
Stan da r d
0.4
/ /
45% of chemo-naive
/
responders
in remission
at 8 years
0.2
/
/
/
0.0
Probability
P<0.0001
P<0.0001
1
2
3
4
5
6
7
Ye ar s s in c e s tar t o f tr e atme nt
8
9
10
///
1.0
Overall Survival:
2009 lymphoma patients
Overall survival inUpdate
randomized follicular
0.8
/ / //
/
0.6
//
/
/
/
/
// /
/
/
/ ////
/
//// / / //// ///// ///// / /
/// // // // //// / // / / / //// /
//
0.4
P = 0.09
0.2
Prolonged
Standard
0.0
Probability
/
/// /
1
2
3
4
5
6
7
Years since start of treatment
8
9
10
Conclusions: Ghielmini et al
•Prolonged rituximab therapy is safe
•With 8 total doses of rituximab, the chance of being still in remission is
~25% at 5 and 8 years.
•Trend toward improved overall survival
•Excellent outcome for selected patients treated with rituximab
alone.
•Would patients do better with chemotherapy?
•Is it worth the risks?
E4402 (RESORT) Schema
Rituximab
375 mg/m2 qw
4
CR or PR
R
A
N
D
O
M
I
Z
E
Rituximab
Maintenance*
375 mg/m2
q 3 months
Rituximab
re-treatment at
progression*
375 mg/m2 qw  4
*Continue until treatment failure
No response to retreatment or PD within 6 months of R
Initiation of cytotoxic therapy or Inability to complete rx
Kahl et al, ASH 2011
E4402 Major Eligibility
 Indolent NHL





Follicular grade 1 or 2
Small Lymphocytic
MALT
Marginal Zone nodal
Marginal Zone splenic
 No prior lymphoma
therapy
 Stage III or IV disease
 Measurable disease
 Low tumor burden as defined
by GELF
 No tumor mass > 7cm
 Fewer than 3 nodal
masses > 3 cm
 No system symptoms or
B symptoms
 No splenomegaly greater
than 16 cm by CT scan
 No risk of organ
compression
 No leukemic phase
 No cytopenias
Primary Endpoint: Time to
Treatment Failure
Time to First Cytotoxic Therapy
90% of patients did not require
cytotoxic therapy for first 5 years of
diagnosis
Conclusions: RESORT
• In this study of previously untreated low
tumor burden FL:
– Rituximab retreatment was as effective as
maintenance rituximab for time to
treatment failure
– No benefit in QOL or anxiety at 12 months
with MR
– Virtually all of these selected patients did
extremely well without chemotherapy
Randomized phase III trial ML16865
Indolent CD20+
lymphoma
Central
pathology
review
R
A
N
D
O
M
I
Z
A
T
I
O
N
Rituximab x 4
Rituximab x 4
+ IFN x 5 weeks
E
Rituximab x 4
V
A
L CR, CRu
U PR MR
A
T
Rituximab x 4
I
+ IFN x 5 weeks)
O
N
SD, PD off protocol therapy
Rituximab 375mg/m2 i.v. day 1
IFN-2a
CHEMOTHERAPY
3.0 MIU/day s.c. daily (Week 1)
4.5 MIU/day s.c. daily (Weeks 2–5)
Kimby et al, ASH 2012
Overall survival:
ITT follicular lymphoma patients
1.0
0.9
Event-free probability
0.8
0.7
% pts
with event
Median
95% CI
Rituximab
13%
NE
NE
Rituximab + IFN
10%
NE
NE
0.6
0.5
p value
0.4289
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
Time (months)
Patients at risk:
Rituximab only
135
134
132
130
129
126
123
109
96
82
74
60
41
30
23
Rituximab + IFN
122
122
120
120
116
115
111
97
86
79
64
53
39
29
17
p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)
Time to treatment failure:
ITT follicular lymphoma patients (n=257)
% pts
with event
Median
95% CI
Rituximab
67%
23.2
18.1–31.3
Rituximab + IFN
66%
31.7
21.9–43.3
1.0
0.9
p value
Event-free probability
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
66
72
78
84
Time (months)
Patients at risk:
Rituximab only
135
108
92
80
66
56
50
43
37
26
23
21
15
12
10
Rituximab + IFN
122
104
92
81
69
62
56
45
40
34
26
21
15
12
6
p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)
0.3627
Many patients with follicular lymphoma do
not require chemotherapy
• Watch and wait
– No overall survival benefit with early
treatment
– No change in transformation with early
treatment
• Rituximab:
– Highly active therapy in a variety of
schedules
– Long responses and outstanding survival
Phase 2 study of lenalidomide and
rituximab for follicular lymphoma
Lenalidomide 20 mg
Rituximab 375 mg
Progression-free
survival
3 year PFS: 81%
PET Imaging Results
Pre-Treatment
Post-Treatment
Positive
Negative
Positive
Negative
N
44
1
3
42*
%
98%
2%
7%
93%
1. Juweid, M. et al. JCO. 2007. 25(5): 571-578.
Fowler et al, ASH 2012
RELEVANCE Study Design
(Rituximab and LEnalidomide versus Any ChEmotherapy)
1st line
FL
N=1000
R2
R2 Maintenance
R + Chemo
Rituximab Maint.
R
• R+Chemo:
•Investigator’s choice of R-CHOP, R-CVP, BR
• Lenalidomide 20mg for 6 cycles, then 10mg if CR
Thank you!
Questions?