Transcript Slide 1

Modern management of
Follicular Lymphoma
Tim Illidge
Professor of Targeted therapy and Oncology
School of Cancer and Enabling Sciences
Manchester University
Christie Hospital
E-mail: [email protected]
Overview of talk
Follicular NHL :
1. Background
2. Treatment approaches
3. Progress and Current standard of care
Frequency of NHL Subtypes in Adults
Composite lymphomas (12%)
Small lymphocytic (6%)
Follicular (22%)
Mantle cell (6%)
Peripheral T-cell (6%)
Marginal zone B-cell,
MALT (5%)
Diffuse large B-cell (31%)
Other subtypes with a
frequency <2% (9%)
Marginal zone B-cell, nodal (1%)
Lymphoplasmacytic (1%)
Armitage et al. J Clin Oncol. 1998;16:2780–2795.
Survival of patients with indolent NHL:
the Stanford experience, 1960–1992
100
1960–1976 (195)
1976–1987 (513)
1987–1992 (314)
Probability
80
60
40
20
0
0
5
10
15
Years
Adapted from Horning. Semin Oncol 1993; 20:75–88
20
25
30
Survival patterns for indolent and
aggressive lymphoma in last century
Probability of Survival (%)
100
Indolent NHL
(e.g. Follicular lymphoma)
75
50
Aggressive NHL
(e.g. Diffuse large B-cell lymphoma)
25
0
0
2
4
6
Years
8
10
12
Advances in follicular NHL
• Development of the FLIPI prognostic model
• Increased understanding of biology - prognostic
groups based on infiltrating immune cells
• Clinical trials :
– Randomised trials of chemotherapy +/rituximab and chemotherapy
– Maintenance therapy with rituximab
– Radioimmunotherapy
– Transplantation : autologous / allogeneic
Follicular Lymphoma International
Prognostic Index (FLIPI)
No
L
A
S
H
Risk Group
Low
Intermediate
High
Nodal regions >4
Elevated LDH
Age >60 years
Stage III/IV
Haemogloblin <12 g/dL
# Factors
% of Patients
5-year OS
10-year OS
0–1
36%
90.6%
70.7%
2
37%
77.6%
50.9%
3–5
27%
52.5%
35.5%
Solal-Celigny P, et al. Blood 2004;104(5):1258-1265
F2 index - Serum ß2 microglobulin
Treatment approaches in Follicular lymphoma




Wait and see policy
Mono- or combination chemotherapy
Radiotherapy
Marrow ablative chemo-radiotherapy followed by
autologous peripheral blood stem cell transplantation
 Immunotherapy:
- interferons
- allogeneic stem cell transplantation
- monoclonal antibodies
- radio-immunotherapy
- vaccination strategies
BNLI Trial of Watchful waiting
309 patients with stages III/IV low grade NHL
without - symptoms
- critical organ failure
- rapid progression
median age - 61 years
Follicular lymphoma – 66%
Randomisation
Chlorambucil
Observation
(local RT permitted)
Watch & wait versus immediate treatment for
asymptomatic advanced stage indolent NHL
Overall survival
Cumulative survival (%)
100
Observation (n = 151)
Chlorambucil (n = 153)
80
60
40
20
0
0
4
8
12
16
20
24
Years
Median
5-year
10-year
15-year
Chlorambucil
5.9 years
57%
35%
21%
Observation
6.7 years
58%
34%
22%
Ardeshna KM, et al. Lancet 2003; 362:516–522
Observation Arm
Of 151 patients in the observation arm:
– 109 (72%) subsequently received systemic Rx
Median time until Rx 2.7 years (range 0-9.5)
– 24 (16%) died without receiving systemic Rx
Median time until death 3.8 years
(range 0.5-7.9)
– 18 (12%) are alive and have still not received
systemic Rx
Conclusions - Watch & wait versus
immediate treatment
• The overall chance of not requiring chemotherapy
or dying of lymphoma is 19% at 10 years
• Chance of not requiring chemotherapy > 70yr =
40%
• Median delay in requiring chemotherapy is 2.6
years
• No improvement in survival in watch and wait arm
• Current trial watch and wait versus rituximab
Ardeshna KM, et al. Lancet 2003; 362:516–522
R-chemo standard of care in
untreated advanced follicular NHL
Study
Treatment, n
Marcus
et al. 20061
CVP, 159
R-CVP, 162
Hiddemann
et al. 20052
CHOP-IFN, 205
R-CHOP-IFN, 223
Herold
et al. 20063
MCP-IFN, 96
R-MCP-IFN, 105
Foussard
et al. 20064
CHVP-IFN, 183
R-CHVP-IFN, 175
Median
FU,
months
Median
TTP/ TTF/
EFS, mo
15
34
P<.0001
OS,
%
77
83
P = .0290
ORR,
%
CR,
%
53
57
81
10
41
18
90
96
17
20
29
NR
P<.001
90
95
P = .016
47
75
92
25
50
26
NR
P<.0001
74
87
P = .0096
73
84
63
79
46
67
P<.0001
84
91
P = .029
42
1. Marcus R, et al. Blood. 2006;108: Abstract 481. 2. Hiddemann W, et al. Blood. 2005;106(12):3725-3732. 3. Herold M,
et al. Blood. 2006;108: Abstract 484. 4. Foussard C, et al. J Clin Oncol. 2006;24(18S): Abstract 7508.
Time to progression, relapse or death: Median
follow-up: 30 months
1.0
Event-free probability
0.9
0.8
0.7
R-CVP: median 32 months
0.6
0.5
0.4
0.3
0.2
CVP: median 15 months
P < 0.0001
0.1
0
0
3
6
9
12
15
18
24
27
30
33
36
39
42
45
Study month
Patients at risk:
CVP
21
159
140
129
109
87
75
64
58
46
28
21
12
5
0
0
0
R–CVP 162
156
144
140
131
119
111
106
95
68
50
32
20
10
2
0
Marcus R, et al. Blood 2005; 105:1417–1423
Overall Survival in
Follicular Lymphoma patients
Rituximab + chemotherapy + IFN :
89% overall survival
1.00
Overall survival
x
x
0.75
Chemotherapy + IFN:
75% overall survival
0.50
0.25
p=0.0162
0.00
0
10
20
30
40
Months
50
60
70
Treatment Algorithms in First-line
Follicular NHL (options 6 and 7)
Induction

Consolidation

* Marrow-ablative
* Rituximab (R)
treatment +
* R-chemo
auto-PBSCT
*Radioimmunotherapy:
Ibritumomab tiuxetan
Maintenance
* Interferon
* Rituximab
FIT Study Schema
Start
of study
Patients with previously
untreated follicular lymphoma
First-line therapy with
chlorambucil, CVP,CHOP,
CHOP-like, fludarabine
combination, or rituximab
combination
6-12 weeks after
last dose of induction
CR/CRu
or PR
INDUCTION
NR
PD
NOT ELIGIBLE
R
A
N
D
O
M
I
Z
A
T
I
O
N
90Y-ibritumomab
(n = 207)
Rituximab 250 mg/m2 IV
on day −7 and day 0 +
90Y-ibritumomab
14.8 MBq/kg
(0.4 mCi/kg) on day 0
CONSOLIDATION
No further
treatment
(n = 202)
CHOP = cyclophosphamide, doxorubicin, vincristine, prednisone; CVP = cyclophosphamide,
vincristine, prednisone; NR = no response; PD = progressive disease.
Morschhauser F, et al. J Clin Oncol. 2008;26(32):5156-5164.
CONTROL
Overall PFS for Treatment Groups
The 4-year overall PFS is
52% in the 90Y-ibritumomab arm compared with 31% in the control arm
Cumulative Percentage
100
75
90Y-ibritumomab
arm
Median PFS: 53.8 months
N = 207
50
25
Control arm
Median PFS: 13.8 months
N = 202
Log-rank P = .0001
HR 0.45 (95% CI: 0.35-0.59)
0
0
90Y-ibritumomab
207
Control 202
12
24
36
48
173
115
132
80
96
53
34
17
Morschhauser F, et al. J Clin Oncol. 2008;26(32):5156-5164.
60 months
9
6
Treatment Algorithms in First-line
Follicular NHL
Induction

Consolidation

* Marrow-ablative
* Rituximab (R)
treatment +
* R-chemo
auto-PBSCT
*Radioimmunotherapy:
Ibritumomab tiuxetan
Maintenance
* Interferon
* Rituximab
Maintenance treatment in follicular lymphoma
Four large prospective Phase III randomised trials have
demonstrated duration of remission with Rituximab
Initial therapy
• CVP
Hochster H et al; Blood 2005;106 abstract 349
• R(4)
Ghielmini M et al; Blood 2004; 103: 4416-23
•
R (12)
Salles et al ASCO 2010
Relapsed
• R-CHOP Van Oers M et al; Blood 2005; 106 abstract # 353
• R-FCM
Hiddemann W et al; Blood 2005; 106 Abstract # 920
Phase II
• R (4)
Hainsworth J et al; J Clin Oncol 2005; 23: 1088-95
PRIMA STUDY
(Primary Rituximab and Maintenance Study) :
CR/PR
Only
Indolent NHL
stages III–IV,
untreated
R-CVP,
R-CHOP,
R-MCP,
or
R-FCM
x 6-8 cycles
Maintenance
1 dose q 8 weeks
for 24 month
R
Observation
PDs/SDs
off study
PRIMA STUDY(Primary Rituximab
and Maintenance Study) :
• 1,217 patients untreated FL and high tumor
burden, stage III or IV, requiring treatment.
• Patients were initially treated with rituximab
plus CHOP (75%), CVP (22%), or FCM (3%).*
Responders to initial therapy (n = 1,018) were
randomized to observation alone or
maintenance rituximab infusions every 2
months for 2 years.
• Median follow-up - 25 months, PFS 82% in
rituximab maintenance therapy arm vs 66% in
observation arm, (P < .0001).
PRIMA STUDY
(Primary Rituximab and Maintenance Study)
:
• Consistent benefit observed for rituximab
maintenance therapy for secondary endpoints.
• Risk of requiring a new round of lymphoma treatment
was reduced by 39% (P < .0003 vs observation).
• Benefits of rituximab maintenance therapy observed
across all subgroups, including age, disease severity,
and type of induction chemotherapy received.
• Rituximab maintenance therapy well tolerated. Grade
3 and 4 events were more frequent in the maintenance
arm (23% vs 16%, respectively) and grade 2 infections
were also more frequent (37% vs 22%, respectively).
• Quality of life was similar in both arms
Summary :
Treatment Algorithms in First-Line
Follicular NHL
Induction

* R-chemo
(Superiority of
containing regimen
and 6 vs 8 cycles
unconfirmed)
Consolidation

Maintenance
Ibritumomab tiuxetan RIT Rituximab
(Role unproven
in first-line)
EORTC Intergoup Phase III Trial:
Study Design
R
A
N
D
O
M
I
S
E
D
Chemotherapy
every 21 days
maximum six
cycles
Rituximab +
chemotherapy
every 21 days
maximum six
cycles
R
A
N
D
O
M
I
S
E
D
Complete
response
Partial
response
2
Observation
Rituximab
maintenance*
*375mg/m every 3 months
for 2 years or until relapse
EORTC Intergroup Phase III Trial:
Progression-Free Survival – Induction Treatment
100
P=0.0007
90
80
70
60
R + CHEMO
median: 30 months
50
40
30
20
CHEMO
median: 20 months
10
0
(years)
0
1
2
3
4
O N
123 231
Number of patients at risk :
126
52
17
5
96 234
157
6
76
27
5
EORTC Intergroup Phase III Trial:
Progression-Free Survival – Maintenance Treatment
100
P < 0.0001
90
80
70
Rituximab maintenance
median: 38 months
60
50
40
30
20
Observation
median: 15 months
10
0
(years)
0
O N
85 159
52 157
1
2
3
Number of patients at risk :
70
25
6
100
35
17
4
1
5
5
Overall survival
100
Rituximab maintenance
90
80
70
60
50
Observation
40
30
20
10
0
(years)
0
O N
25 159
12 157
1
2
3
Number of patients at risk :
113
56
22
119
52
25
4
4
5
5
Observation
Rituximab maint.
Objectives of Marrow-ablative treatment and
Autologous PBSCT in Follicular lymphoma
• To improve progression-free survival by at least 2-3 years?
• To improve overall survival?
• 1980 -2005 : Too many phase II clinical trials without
conclusive evidence of a definitive role for marrow-ablative
treatment followed by autologous PBSCT
Rationale for Non-marrow ablative
Stem cell Transplantation (NST)
• Less toxic immunosuppressive regimen
• limits TRM / expands patient eligibility
• allows allogeneic engraftment
• Cure mediated by GVL effect of donor T
cells
PFS: Reduced Intensity Conditioning
low Grade Lymphoma
100
80
60
N = 100
40
20
1
2002/03/12
2
3
Years
4
5
6
TRM: Reduced Intensity Conditioning
Low
Grade
Lymphoma
100
80
60
40
N = 100
20
1
2002/03/12
2
3
Years
4
5
6
Relapse Rate: Reduced Intensity
Conditioning Low grade Lymphoma
100
80
60
40
N = 100
20
1
2002/03/12
2
3
Years
4
5
6
Conclusions for Follicular
lymphoma
• Understanding of biology has increased greatly and new
insights will impact on clinical practice in coming decade
• Overall survival improved by Rituximab + chemotherapy
• Optimal type of chemotherapy with Rituximab remains
controversial but anthracycline probably optimal
• Maintenance rituximab become standard
• Allograft increasingly used in badly behaving FL