Transcript Slide 1
Marinus van Oers
Professor of Hematology/Head of the Department of Clinical Hematology,
Academic Medical Center, University of Amsterdam, The Netherlands
Chairman of the Dutch
Hematology Society
Chairman of the HOVON
CLL Group
Co-authored numerous papers in
national and international
peer-reviewed scientific journals
Academic Medical Center
Principal investigator of the
EORTC 20981 study
Prior Chairman of the Lymphoma
Group of the Dutch Cancer Society
Prior board member of the Dutch
Hemato-oncology Group
Maintenance treatment in follicular
lymphoma (FL): indications
and considerations
Marinus van Oers
Academic Medical Center,
University of Amsterdam, The Netherlands
Rituximab maintenance therapy
in FL: objectives
Natural history of FL
Relapsing/remitting course
Duration of response (DR) to subsequent therapy
diminishes
Rituximab maintenance therapy
in FL: objectives
Natural history of FL
Relapsing/remitting course
Duration of response (DR) to subsequent therapy
diminishes
Objectives of rituximab maintenance therapy
Maintain remission, because prolonged remission predicts
for improved overall survival (OS)1–3
Improve response quality over time (partial response [PR]
complete response [CR])
Eradicate minimal residual disease (MRD), thereby
potentially increasing OS
1Gallagher
C, et al. J Clin Oncol 1986;4:1470–80
D, et al. J Clin Oncol 1992;10:942–7
3Montoto S, et al. Ann Oncol 2002;13:523–30
2Weisdorf
Rituximab maintenance in follicular
non-Hodgkin’s lymphoma (NHL): rationale
Maintenance treatment with cytotoxic agents or
interferon alpha does not improve OS, but has
considerable side effects and long term toxicity1
Rituximab has minimal acute toxicity2
There is no known cumulative toxicity2
The CD20 persists on residual or recurrent lymphoma3
Long half-life allows infrequent therapy while
maintaining long-term exposure (in contrast
to chemotherapy)3
1Rohatiner
A, et al. Br J Cancer 2001;85:29–35
E, et al. Cancer Treat Rev 2005;31:456–73
3Berinstein N, et al. Ann Oncol 1998;9:995–1001
2Kimby
Rituximab maintenance studies in FL
Maintenance after induction with single agent rituximab
SAKK 35/981
Minnie Pearl2
Maintenance after induction with chemotherapy
ECOG 14963
Maintenance after induction with rituximab +
chemotherapy
EORTC 209814
Ghielmini M, et al. Blood 2004;103:4416–23
GLSG5
1
2Hainsworth
JD, et al. J Clin Oncol 2005;23:1088–95
HS, et al. Blood 2005;106:106a (Abstract 349)
4van Oers MHJ, et al. Blood 2006;108:3295–301
5Forstpointner R, et al. Blood 2006;108:4003–8
3Hochster
SAKK 35/98: study design
Phase III trial of rituximab maintenance therapy
202 patients with previously untreated (n=64) or relapsed/refractory FL;
151 (51 previously untreated) patients randomised
n=202
n=151
Observation
R
Rituximab
375mg/m²
weekly x 4
SD, PR, CR
Prolonged
treatment
Rituximab 375mg/m²
every 2 months x 4
PD off study
R = rituximab
SD = stable disease; PD = progressive disease
Ghielmini M, et al. Blood 2004;103:4416–23
SAKK 35/98 results
52% response to induction rituximab
No increase in toxicity with rituximab maintenance
versus observation
Median EFS
(months)*
Observation
Rituximab
maintenance
p value
All patients
11.8
23.2
0.024
Previously untreated
19.0
36.0
0.009
*Patients randomised
EFS = event-free survival
Ghielmini M, et al. Blood 2004;103:4416–23
ECOG 1496 study: rituximab maintenance
after first line treatment of indolent NHL
Phase III trial of CVP ± rituximab maintenance therapy
401 patients with previously untreated indolent NHL
– 322 randomised
– 237 (78%) with follicular histology
CVP
6–8 cycles
PR, CR or
stable
ECOG = Eastern Cooperative Oncology Group
CVP = cyclophosphamide/vincristine/prednisone
R
A
N
D
O
M
I
S
E
Rituximab maintenance
therapy
• 375mg/m2 weekly x 4
• every 6 months x 4
Observation
Hochster HS, et al.
Blood 2005;106:106a (Abstract 349)
ECOG 1496: progression-free
survival (PFS) in FL
1.0
Median PFS: 61 months vs 15 months
Probability
0.8
0.6
MR (120)
0.4
Observation (117)
0.2
Log-rank one-sided p=0.0000003
HR: 0.4 (0.3–0.6)
0
0
1
2
3
4
5
Years from maintenance randomisation
HR = hazard ratio
MR = rituximab maintenance therapy
6
Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
ECOG 1496: PFS at 3 years
from randomisation
Characteristic
MR
Observation
p value
HR
(95% CI)
All patients (n=237) (%)
62
36
0.0000003
0.4 (0.3–0.6)
FLIPI score (%)
0–2 (n=118)
3–5 (n=68)
59
58
36
35
0.002
0.004
0.5 (0.3–0.8)
0.4 (0.2–0.8)
Tumour burden (%)
Low (n=85)
High (n=152)
65
59
51
28
0.025
<0.0001
0.5 (0.3–1.0)
0.4 (0.2–0.6)
Residual disease (%)
MRD (n=170)
Gross (n=134)
73
48
41
30
<0.001
0.005
0.3 (0.2–0.5)
0.5 (0.3–0.9)
Total events
42
74
–
–
CI = confidence interval; FLIPI = Follicular Lymphoma
International Prognostic Index
Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
ECOG 1496: OS in FL
OS at 42 months from randomisation: 91% vs 75%
1.0
MR (120)
Probability
0.8
Observation (117)
0.6
0.4
0.2
Log-rank one-sided p=0.03
HR: 0.5 (0.3–1.1)
0
0
1
2
3
4
5
Years from maintenance randomisation
6
Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
ECOG 1496: conclusions
After successful induction, MR
– delays disease progression, with more than half of
patients remaining disease-free more than 4 years
after completion of CVP
– shows a strong trend towards improved OS for
rituximab maintenance over observation at a
median 3-year follow-up after randomisation
Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
EORTC 20981: trial design
Phase III trial of CHOP ± rituximab, with or without MR
465* patients with relapsed or refractory FL
334 randomised to maintenance versus observation
R
A
N
D
O
M
I
S
E
R-CHOP x 6
CHOP x 6
R
A
N
D
O
M
I
S
E
MR
375mg/m2
Every 3 months to relapse or for
2 years
Observation
*474 patients randomised; nine excluded due to missing
consent forms
CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone
van Oers MHJ, et al. Blood 2006;108:3295–301
EORTC 20981: patient characteristics
at second randomisation (n=334)
Observation
(n=167)
MR
(n=167)
Induction (%)
CHOP
R-CHOP
41
59
45
55
Induction response (%)
CR
PR
29
71
29
71
FLIPI 2 (%)
70
66
van Oers MHJ, et al. Blood 2006;108:3295–301
EORTC 20981: rituximab maintenance
prolongs PFS by more than 3 years
100
PFS (%)
80
MR
Median 51.5 months
60
40
20
Observation
Median 14.9 months
Overall log-rank test: p<0.001
HR: 0.40
0
0
1
2
3
4
5
Years
van Oers MHJ, et al. Blood 2006;108:3295–301
Rituximab maintenance prolongs PFS
irrespective of induction therapy
PFS after CHOP (n=145)
100
100
90
90
80
70
PFS (%)
60
50
40
Observation
Median 11.6 months
30
MR
Median 51.8 months
80
MR
Median 42.2 months
70
PFS (%)
PFS after R-CHOP (n=189)
60
50
40
Observation
Median 23.0 months
30
20
20
10
Overall log-rank test: p<0.001; HR: 0.30
0
10
Overall log-rank test: p=0.004; HR: 0.54
0
0
1
2
3
Years
4
5
0
1
2
3
4
5
Years
van Oers MHJ, et al. Blood 2006;108:3295–301
OS (%)
MR significantly prolongs OS
100
90
80
70
60
50
40
30
20
10
0
MR
3 years 85.1%
Observation
3 years 77.1%
Overall log-rank test: p=0.011
HR: 0.52
0
1
2
3
Years
4
5
6
van Oers MHJ, et al. Blood 2006;108:3295–301
Rituximab maintenance effect on OS:
analysis by induction therapy
OS after CHOP
OS after R-CHOP
100
100
90
90
80
70
70
60
Observation
OS (%)
OS (%)
MR
80
MR
50
40
30
60
50
Observation
40
30
20
20
Overall log-rank test: p=0.073
HR: 0.52
10
Overall log-rank test: p=0.059
HR: 0.49
10
0
0
0
1
2
3
Years
4
5
6
0
1
2
3
Years
4
5
6
van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation
Adverse events during maintenance: events
with >2% reported grade 3-4 events
(World Health Organization)
10
Observation
Rituximab
Percent
*
5
0
Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
Neutropenia
*p=0.009
Infection
Cardiac
Pulmonary
Skin
van Oers MH, et al. Blood 2006;108:3295–301
EORTC 20981: conclusions
Rituximab maintenance therapy superior to
observation for PFS
– in the overall population
– in subgroups (after R-CHOP/CHOP, after CR/PR)
Rituximab maintenance therapy improves OS
– in the overall population
– in subgroups longer follow-up required
van Oers MHJ, et al. Blood 2006;108:3295–301
van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation
Incremental costs (£/$ CAD)
The cost-effectiveness plane:
EORTC 20981 analysis
£/$
Area of rejection
£/$
£/$
Costeffectiveness
threshold
Area of acceptance
R-maintenance = 17,136/0.839 =
$20,428 CAD/QALY gained
£/$
0
0.5
1
1.5
Incremental drug benefit (QALYs)
QALY = quality adjusted life years
2
Maturi B, et al. Blood 2006;108:106a (Abstract 343)
The German Lymphoma Study Group
trial: study design
Advanced
stage
relapsed/
refractory
FL or MCL
R
A
N
D
O
M
I
S
E
Rituximab
plus
4 x FCM
4 x FCM
R
CR/PR A
N
D
O
M
I
CR/PR S
E
MR*
Observation
only
*4 x rituximab (375 mg/m2) at 3 and 9 months after induction
MCL = mantle cell lymphoma
FCM = fludarabine/cyclophosphamide/mitoxantrone
Forstpointner R, et al. Blood 2004;104:3064–71
MR after R-FCM improves DR
in patients with FL and MCL
FL
1.00
1.00
MR (32/41)
Median: not
reached
0.75
Observation (21/40)
Median: 26 months
0.50
0.25
Probability
0.75
Probability
MCL
0.50
MR (11/22)
Median: 14 months
0.25
p=0.035
Observation (2/25)
Median: 12 months
p=0.049
0
0
0
1
2
3
Years
4
5
6
0
1
2
3
4
5
6
Years
Forstpointner R, et al. Blood 2006;108:4003–8
Rituximab maintenance
versus retreatment upon relapse
Minnie Pearl Cancer Research Network:
rituximab maintenance versus retreatment
Phase II randomised trial of MR versus retreatment at
disease progression
114 patients with relapsed/refractory indolent NHL following
prior chemotherapy, 90 randomised
Rituximab
375mg/m2
weekly x 4
PR, CR or
stable
R
A
N
D
O
M
I
S
E
Rituximab maintenance
• 375mg/m2 qw x 4
• 6, 12 and 18 months
Rituximab retreatment
• 375mg/m2 qw x 4
• Retreat if responsive disease
for 3 months after each course
Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95
MR achieves improved outcomes
compared with retreatment
Rituximab
Outcome
Maintenance
(n=44)
Retreatment
(n=46)
p
Overall response rate (%)
52
35
0.14
CR (%)
27
4
0.007
Continuous remission (%)
45
24
0.05
Remaining in CR (%)
23
2
0.03
Median PFS (months)
31.3
7.4
0.007
Median duration of benefit (months)*
31.3
27.4
0.94
*Subjective primary endpoint
Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95
Rituximab retreatment after MR
Hainsworth JCO
2002;20:4261
19/58 still in
remission after
7 years
58/106 (55%) still in
response at end of
2 years maintenance
35/58 progressed
Hainsworth JCO
2005;23:1088
4/58 died while
still in remission
MR versus retreatment: conclusions
The majority of patients who relapse after 2 years of
MR remain sensitive to rituximab – can even be given
MR again
Retreatment with rituximab, as a single agent, or in
combination with chemotherapy, is a reasonable
therapeutic option at the time of progression
A ongoing prospective phase III study (RESORT) also
addresses quality of life and pharmacoeconomics
Hainsworth JD, et al. Blood 2006;108:263b (Abstract 4723)
MR schedules: all demonstrate
significantly improved outcome
Study
Schedule
Outcomes
Maintenance after induction with single agent rituximab
SAKK 35/981
One dose every
2 months x 4
EFS (median)
23.2 vs 11.8 months
Minnie Pearl2
Four doses every
6 months for 2 years
PFS (median)
31.3 vs 7.4 months
Maintenance after induction with chemotherapy
ECOG 14963
Four doses every
6 months for 2 years
PFS (median)
61.0 vs 15.0 months; OS
Maintenance after induction with rituximab + chemotherapy
EORTC 209814
One dose every
3 months for 2 years
PFS (median)
51.5 vs 14.9 months: OS
GLSG5
Four doses at 3 and
9 months
DR (median)
NR vs 17.0 months
1Ghielmini
M, et al. Blood 2004;103:4416–23; 2Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95
3Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
4van Oers MHJ, et al. Blood 2006;108:3295–301; 5Forstpointner R, et al. Blood 2006;108:4003–8
MR in FL: open questions
Role of rituximab maintenance after R-chemotherapy
in first line (PRIMA study)
MR in FL: open questions
Role of rituximab maintenance after R-chemotherapy
in first line (PRIMA study)
Optimal rituximab maintenance regimen
– schedule
– duration
MR in FL: open questions
Role of rituximab maintenance after R-chemotherapy
in first line (PRIMA study)
Optimal rituximab maintenance regimen
– schedule
– duration
• 2 years?
• until relapse?
– long term toxicity?
– Ig levels/infections
– CD20-negative relapse
Ongoing trials of rituximab maintenance
Study
Description
PRIMA*
Maintenance versus observation after first-line
R-chemotherapy
BNLI*
Watch and wait versus rituximab monotherapy versus
monotherapy plus maintenance
SAKK*
Maintenance (8 months) versus maintenance until
progression (maximum 5 years) after first-line rituximab
ECOG
(RESORT)†
Rituximab extended schedule or retreatment after first-line
R-monotherapy
*One infusion every 2 months
†One infusion every 3 months or four infusions at relapse
Rituximab maintenance therapy:
conclusions
Rituximab + chemotherapy induction and rituximab maintenance
therapy is the standard in relapsed/refractory indolent NHL, where it
confers a PFS and OS benefit
Rituximab maintenance therapy:
conclusions
Rituximab + chemotherapy induction and rituximab maintenance
therapy is the standard in relapsed/refractory indolent NHL, where it
confers a PFS and OS benefit
The benefit of rituximab maintenance is observed
– after rituximab monotherapy, chemotherapy and rituximab
immunochemotherapy
– in previously untreated and relapsed/refractory patients
– in MCL as well as FL
– in patients with low-, intermediate- and high-risk FL
Rituximab maintenance therapy:
conclusions
Rituximab + chemotherapy induction and rituximab maintenance
therapy is the standard in relapsed/refractory indolent NHL, where it
confers a PFS and OS benefit
The benefit of rituximab maintenance is observed
– after rituximab monotherapy, chemotherapy and rituximab
immunochemotherapy
– in previously untreated and relapsed/refractory patients
– in MCL as well as FL
– in patients with low-, intermediate- and high-risk FL
Rituximab maintenance appears to be safe, despite prolonged
B-cell depletion
Rituximab maintenance therapy:
conclusions
Rituximab + chemotherapy induction and rituximab maintenance
therapy is the standard in relapsed/refractory indolent NHL, where it
confers a PFS and OS benefit
The benefit of rituximab maintenance is observed
– after rituximab monotherapy, chemotherapy and rituximab
immunochemotherapy
– in previously untreated and relapsed/refractory patients
– in MCL as well as FL
– in patients with low-, intermediate- and high-risk FL
Rituximab maintenance appears to be safe, despite prolonged
B-cell depletion
Rituximab maintenance therapy is a cost-effective treatment strategy for
patients with FL