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