Indolent Lymphoma:
The Case for
Intensifying
Future Treatment
Richard I. Fisher, M.D.
President & CEO
Fox Chase Cancer Center
Chair, SWOG Lymphoma
Committee
Multiple Treatment Options
Exist for Indolent NHL

Watchful waiting

Chemotherapy
– Single agent
– Combination

Monoclonal antibody
therapy

Radioimmunotherapy
(RIT)*

Stem cell
transplantation

External beam
radiation
– Rituximab
*Investigational
Vose. Ann Oncol. 1996;7(suppl 6)S13–S19; Horning. Semin Oncol. 1993;20(suppl 5):75–88.
Follicular Lymphoma: 1970 – 1990’s
Conclusions from Past Trials

Overall Survival (OS) was not impacted by
treatment with alkylating agents, anthracyclines,
or combination chemotherapy

Median OS for all patients = 7 – 10 years

Less than 20% of patients were alive at 20 years

“Watch and wait” therapy did not reduce OS

IMPROVED OS WAS NOT A REASONABLE
ENDPOINT FOR CLINICAL TRIALS!!!
The Natural History of
Indolent NHL Remains Unchanged
Survival (N = 1021), 1960–1991
100
1960–1975
1976–1986
1987–1991
80
Actuarial
survival
(%)
60
40
20
0
0
6
12
18
Years
Horning. Semin Oncol. 1993;20(suppl 5):75–88.
24
30
36
1990’s
WHAT CHANGED??
RITUXIMAB
R-CVP vs. CVP in Untreated Stage III/IV FL
322 untreated patients: 49% FLIPI poor risk, 41%
intermediate

Rituximab
Repeat cycle
375 mg/m2
(8 cycles total)
R
Cyclophosphamide
A
750 mg/m2
N
Vincristine
D
O
M
I
Z
1.4 mg/m2
1 2 3 4 5 6 7
14
Days
21
Prednisolone
40 mg/m2
E
Marcus et al. Blood. 2005;105, 1417.
Primary endpoint:
Time To Treatment Failure
1.0
Event-free probability
0.9
median FU 42 months
0.8
0.7
0.6
R-CVP: median 27 months
0.5
0.4
0.3
0.2
CVP: median 7 months
p < 0.0001
0.1
0
0
6
12
18
24
30
36
42
48
54
60
Study month
86
0
Overall survival
R-CVP: median not reached
1.0
Event-free probability
0.9
0.8
0.7
CVP: median not reached
0.6
0.5
0.4
0.3
median FU 42 months
0.2
p = 0.0553
0.1
0
0
6
12
18
24
30
36
42
48
54
Study month
7
60
CHOP ± Rituximab in Previously Untreated
FL
Pts aged ≥60 years
CR, PR
R
R
A
A
R-CHOP × 6-8
Untreated
N
N
FL
D
D
CHOP × 6-8
O
O
M
M
I
I
Z
Z
E
E
Intensive IFN
maintenance
Standard IFN
maintenance
Pts aged <60 years
PBSCT
IFN
maintenance
Hiddemann et al. Blood. 2005;106:3725.
CHOP ± Rituximab in Previously
Untreated FL: TTF
1.0
0.8
R-CHOP (195/223)
P<0.01
0.6
Probability
CHOP (144/205)
0.4
0.2
0
0
1
2
3
4
Years
Hiddemann et al. Blood. 2005,106:3725.
CHOP ± Rituximab in Previously
Untreated FL: OS
1.0
R-CHOP (217/223)
0.8
CHOP (188/205)
Probability
0.6
P=0.016
0.4
0.2
0.0
0
1
2
3
4
Years
Hiddemann et al. Blood. 2005,106:3725.
Overall survival: Meta-Analysis Total Group
HR [95%-CI)
Study
Weight [%]
Lenz 2005
4.11
Baez 2005
HR [95%-CI)
0.96
6.90
0.96
Forstpointner 2005
15.10
0.42
Marcus 2005
16.10
0.70
Hiddemann 2005
28.86
0.60
Herold 2005
28.92
0.60
Total (95% CI)
100.00
0.62 (0.49 - 0.77)
0.2
Total events:
0.5
1
2
Favors R + Chemo
Favors Chemo
100/760
143/718
Test for heterogeneity: (P = 0.60), I² = 0%
•Schulz, ASH 2005 Abstract #351
Follicular Lymphoma: last decade
HAS OS REALLY
IMPROVED??
Has The Natural History of Follicular NHL
Changed??
OS by Treatment
100%
8 0%
60%
40 %
CHOP + Mab
ProMace
CHOP
20 %
N
179
425
356
4-Year
Estimate
91%
79%
69%
Death
18
189
226
0%
0
2
4
6
8
10
Years Af te r Reg i s t ra t ion
•Fisher, et. al. J. Clin. Oncol. 23: 8447-8452, 2005
Stage IV FL Over 25 Years: OS and FailureFree Survival by Therapy Regimen
•OS
•Failure-Free Survival
•10
0
•FND-R+IFN vs FND->R+IFN
•75
•CHOP-Bleomycin + IFN
•10
0
•ATT->IFN vs FND->IFN
•ATT->IFN
•FND-R+IFN vs FND->R+IFN
•ATT->IFN vs FND->IFN
•ATT->IFN
•75
•CHOP-Bleomycin + IFN
•CHOP-Bleomycin
•50
•Survival (%)
•25
•0
•P < 0.001
•5
•10
•15
•20
•25
•30
•Failure Free (%)
•CHOP-Bleomycin
•50
•25
•0
•P < 0.001
•5
•Time (Years)
•Reproduced with permission from Liu. J Clin Oncol. 2006;24:1582.
•10
•15
•20
•Time (Years)
•25
•30
Indolent Non-Hodgkin‘s Lymphoma:
Antibody Therapy – Change of Paradigms!
Survival probability
Overall Survival – GLSG Trials
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
MCP
CHOP-1
CHOP-2
R-CHOP
p<0.0001
0
12
24
36
48
60
72
84
96
Months since registration
108
120
PRIMA Study Design
INDUCTION
MAINTENANCE
Rituximab maintenance
375 mg/m2
every 8 weeks
Registration
untreated
Immunochemotherapy
8 x rituximab
+
8 x CVP or
follicular
6 x CHOP or
lymphoma
6 x FCM
High
tumor burden
for 2 years
CR/CRu
PR
PD/SD
Random 1:1
Observation
off study
5 YEARS FOLLOW-UP
Primary endpoint (PFS) met at the
planned interim analysis
Rituximab maintenance significantly reduced the risk of lymphoma progression by
50% (stratified by response and induction regimen, HR=0.50, 95% CI 0.39; 0.64)
1.0
Progression-free rate
82%
Rituximab maintenance
0.8
N=505
0.6
HR=0.50
0.4
Observation
66%
N=513
p<0.0001
0.2
0
0
6
12
Patients at risk
18
24
30
36
42
103
82
18
15
0
0
Time (months)
505
472
443
513
469
411
336
289
230
195
Bendamustine-Rituximab (B-R) vs. CHOP-R
• StiL NHL 1-2003
•Bendamustine-Rituximab
•Follicular
•Waldenströms
•Marginal zone
•R
•Small lymphocytic
•Mantle cell
•CHOP-Rituximab
•Bendamustine 90 mg/m2 day 1+2 + R day 1, max 6 cycles, q 4 wks.
•CHOP-R, max 6 cycles, q 3 wks.
Bendamustine/Rituximab vs R-CHOP for
the Frontline Treatment of FL: PFS
•1.0
•0.9
•Survival Probability
•0.8
Regimen
Median
PFS*
ORR
CR
R-CHOP
46.7 mos
91.3%
30.0%
NR
92.7%
39.6%
Bendamustine/Rituximab
•0.7
•0.6
•Bendamustine/Rituximab
•0.5
•(N=260)
•0.4
•R-CHOP
(N=253)
•0.3
•0.2
•*P=0.0281
•0.1
•HR=0.63 (95% CI, 0.42-0.95)
•0.0
•0
•
•12
•24
•36
•48
•60
•72
•Time (Months)
Significantly less adverse events with bendamustine/rituximab: alopecia,
paresthesias, stomatitis, erythema, allergic reactions, and infectious complications
•Rummel. ASH. 2009 (abstr 405).
Overall Survival
•1.0
•0.9
•Probability
•0.8
•0.7
•0.6
•0.5
•0.4
•0.3
•0.2
•0.1
•0.0
•0
•12
•24
•36
•48
•60
•72
•84
months
B-R vs. CHOP-R - Toxicities (all CTCgrades)
•
B-R (n=260)
CHOP-R (n=253)
(no. of pts)
(no. of pts)
P value
-
+++
< 0.0001
•Paresthesias
18
73
< 0.0001
•Stomatitis
16
47
< 0.0001
•Skin (erythema)
42
23
= 0.0122
•Allergic reaction (skin)
40
15
= 0.0003
•Infectious complications
96
127
= 0.0025
•Sepsis
1
8
= 0.0190
•Alopecia
COMPARISON OF
3 YEAR PFS

StiL NHL 1-2003:
– R-CHOP Induction

S0016
– R-CHOP Induction

52%
70%
PRIMA
– R-CHOP + R Maintenance
85%
BCR signaling in NHL:
A rational therapeutic target?
BCR is maintained
on most lymphoma
cells.
Tonic signaling
through BCR
maintains lymphoma
survival in vitro.
Cell 117:787, 2004
Syk (spleen tyrosine
kinase) amplifies
BCR signal and
initiates downstream
events.
Objective Responses of 48 Evaluable
Patients
•Fowler N et al. ASH 2010. abstract 2716
SWOG Lymphoma Committee