Post on 14-Jan-2016
description
Marinus van OersProfessor of Hematology/Head of the Department of Clinical Hematology,
Academic Medical Center, University of Amsterdam, The Netherlands
Chairman of the DutchHematology Society
Chairman of the HOVON CLL Group
Co-authored numerous papers in national and international peer-reviewed scientific journals
Principal investigator of theEORTC 20981 study
Prior Chairman of the Lymphoma Group of the Dutch Cancer Society
Prior board member of the Dutch Hemato-oncology Group
Academic Medical Center
Maintenance treatment in follicular lymphoma (FL): indications
and considerations
Marinus van OersAcademic 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;4:1470–802Weisdorf D, et al. J Clin Oncol 1992;10:942–7
3Montoto S, et al. Ann Oncol 2002;13:523–30
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;85:29–352Kimby E, et al. Cancer Treat Rev 2005;31:456–73
3Berinstein N, et al. Ann Oncol 1998;9:995–1001
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
GLSG51Ghielmini M, et al. Blood 2004;103:4416–23
2Hainsworth JD, et al. J Clin Oncol 2005;23:1088–953Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
4van Oers MHJ, et al. Blood 2006;108:3295–3015Forstpointner R, et al. Blood 2006;108:4003–8
Rituximab 375mg/m² every 2 months x 4
n=151
PD off study
n=202
Prolongedtreatment
Rituximab375mg/m²weekly x 4
Observation
R
SD, PR, CR
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
Ghielmini M, et al. Blood 2004;103:4416–23 R = rituximab SD = stable disease; PD = progressive disease
SAKK 35/98 results 52% response to induction rituximab
No increase in toxicity with rituximab maintenance versus observation
Median EFS (months)* Observation
Rituximabmaintenance p value
All patients 11.8 23.2 0.024
Previously untreated 19.0 36.0 0.009
*Patients randomised
Ghielmini M, et al. Blood 2004;103:4416–23EFS = event-free survival
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
Hochster HS, et al.Blood 2005;106:106a (Abstract 349)
Observation
Rituximab maintenance therapy
• 375mg/m2 weekly x 4• every 6 months x 4
RANDOMISE
PR, CR or stable
CVP 6–8 cycles
ECOG = Eastern Cooperative Oncology GroupCVP = cyclophosphamide/vincristine/prednisone
ECOG 1496: progression-free survival (PFS) in FL
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5 6
Years from maintenance randomisation
MR (120)
Observation (117)
Log-rank one-sided p=0.0000003HR: 0.4 (0.3–0.6)
Pro
bab
ilit
y
HR = hazard ratioMR = rituximab maintenance therapy Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
Median PFS: 61 months vs 15 months
ECOG 1496: PFS at 3 years from randomisation
Characteristic MR Observation p valueHR
(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 – –
Hochster HS, et al. Blood 2005;106:106a (Abstract 349)
CI = confidence interval; FLIPI = Follicular Lymphoma International Prognostic Index
ECOG 1496: OS in FL
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5 6
MR (120)
Observation (117)
Log-rank one-sided p=0.03HR: 0.5 (0.3–1.1)
Pro
bab
ilit
y
Years from maintenance randomisation
OS at 42 months from randomisation: 91% vs 75%
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
CHOP x 6
R-CHOP x 6
Observation
MR 375mg/m2
Every 3 months to relapse or for 2 years
RANDOMISE
van Oers MHJ, et al. Blood 2006;108:3295–301
RANDOMISE
*474 patients randomised; nine excluded due to missing consent forms
CHOP = cyclophosphamide/doxorubicin/vincristine/prednisone
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
Overall log-rank test: p<0.001HR: 0.40
100
80
60
40
20 0
0 1 2 3 4 5Years
MRMedian 51.5 months
ObservationMedian 14.9 months
PF
S (
%)
van Oers MHJ, et al. Blood 2006;108:3295–301
Rituximab maintenance prolongs PFS irrespective of induction therapy
PFS after CHOP (n=145)
Overall log-rank test: p<0.001; HR: 0.30
100
90
80
70
60
50
40
30
20
10
0
Years
0 1 2 3 4 5
Overall log-rank test: p=0.004; HR: 0.54
PFS after R-CHOP (n=189)
Years
MRMedian 42.2 months
ObservationMedian 11.6 months
ObservationMedian 23.0 months
MRMedian 51.8 months
PF
S (
%)
PF
S (
%)
van Oers MHJ, et al. Blood 2006;108:3295–301
100
90
80
70
60
50
40
30
20
10
00 1 2 3 4 5
MR significantly prolongs OS
Overall log-rank test: p=0.011HR: 0.52
100
90
80
70
60
50
40
30
20
10
0
Years0 1 2 3 4 5 6
MR 3 years 85.1%
Observation 3 years 77.1%
OS
(%
)
van Oers MHJ, et al. Blood 2006;108:3295–301
Rituximab maintenance effect on OS: analysis by induction therapy
OS after CHOP100
90
80
70
60
50
40
30
20
10
0
Years0 1 2 3 4 5 6
Overall log-rank test: p=0.073HR: 0.52
OS
(%
)
OS after R-CHOP
Years
Overall log-rank test: p=0.059HR: 0.49
OS
(%
)
van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation
MR
Observation
MR
Observation
100
90
80
70
60
50
40
30
20
10
00 1 2 3 4 5 6
Adverse events during maintenance: events with >2% reported grade 3-4 events
(World Health Organization)
Per
cen
t
Neutropenia PulmonaryInfection Skin
Observation
Rituximab
Cardiacvan Oers MH, et al. Blood 2006;108:3295–301
*
*p=0.009
10
5
0 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4
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;108:3295–301van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation
The cost-effectiveness plane: EORTC 20981 analysis
Incremental drug benefit (QALYs)
Incr
emen
tal
cost
s (£
/$ C
AD
)
£/$
£/$
£/$
£/$
Maturi B, et al. Blood 2006;108:106a (Abstract 343)QALY = quality adjusted life years
Cost-effectiveness
threshold
Area of acceptance
Area of rejection
R-maintenance = 17,136/0.839 = $20,428 CAD/QALY gained
1 1.5 20.50
The German Lymphoma Study Group trial: study design
RANDOMISE
4 x FCM
Rituximabplus
4 x FCM
RANDOMISE
MR*
Observation only
Advanced stage relapsed/refractory FL or MCL
Forstpointner R, et al. Blood 2004;104:3064–71
*4 x rituximab (375 mg/m2) at 3 and 9 months after induction
CR/PR
CR/PR
MCL = mantle cell lymphomaFCM = fludarabine/cyclophosphamide/mitoxantrone
MR after R-FCM improves DR in patients with FL and MCL
MR (32/41)Median: not
reached
Observation (21/40)Median: 26 months MR (11/22)
Median: 14 months
Observation (2/25) Median: 12 monthsp=0.035 p=0.049
1.00
0.75
0.50
0.25
0
Years
0 1 2 3 4 5 6
Pro
bab
ilit
y
Years
0 1 2 3 4 5 6
FL MCL
Forstpointner R, et al. Blood 2006;108:4003–8
Pro
bab
ilit
y
1.00
0.75
0.50
0.25
0
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
Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95
Rituximab retreatment• 375mg/m2 qw x 4• Retreat if responsive disease
for 3 months after each course
Rituximab maintenance• 375mg/m2 qw x 4• 6, 12 and 18 months
PR, CR or stable
Rituximab375mg/m2
weekly x 4
RANDOMISE
MR achieves improved outcomes compared with retreatment
Rituximab
OutcomeMaintenance
(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
Hainsworth JD, et al. J Clin Oncol 2005;23:1088–95
*Subjective primary endpoint
58/106 (55%) still in response at end of
2 years maintenance
19/58 still in remission after
7 years
35/58 progressed 4/58 died while still in remission
Rituximab retreatment after MR
Hainsworth JCO 2002;20:4261
Hainsworth JCO 2005;23:1088
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;23:1088–953Hochster 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