Transcript Overall survival in relapsed/refractory FL patients

Management of Follicular
Lymphoma
F Morschhauser
Centre Hospitalier Universitaire de Lille, France
When are we going to start
a cytotoxic treatment ?
GELA criteria
 High tumor bulk defined by either:
- a tumor > 7 cm
- 3 nodes in 3 distinct areas
each > 3 cm
- symptomatic splenic enlargement
- organ compression
- ascites or pleural effusion
BNLI criteria
 Rapid disease progression in
the preceding 3 months
 Life threatening organ
involvement
 Renal or liver infiltration
 Bone lesions
 Presence of systemic symptoms
 Serum LDH or β2-microglobulin
above normal values
 Systemic symptoms or pruritus
 Hb<10 g/dL or WBC< 3.0×109/L
or Plat.<100×109/L ; related to
marrow involvement
Management of Follicular lymphoma
Low tumor burden
RWW Study(Ardeshna et al, ASH 2010)
ARM A
R
A Watch and Wait
N  cc
D
ARM B
O
M Rituximab Induction
I
S
ARM C
A Rituximab Induction
T
& maintenance
I
O Progressive disease
requiring therapy
N
stops protocol
treatment
Clinic visits
Continued
follow up
Compulsory
CT scan
CT scan
only if
clinical CR
Compulsory
CT scan
Bone marrow for histology and MRD only if CT shows cCR
Time to Initiation of New Therapy
1.0
0.9
0.8
Proportion
of patients
with
no new
treatment
initiated
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Events
Totals
W+W
83
187
R4
19
84
R4 + M
19
192
% not requiring Rx at 3yr
W+W=48%
R4=80%
R4+RM=91%
0.0
0
1
2
3
4
5
Years from randomisation
HR (Rituximab vs W+W) = 0.37, 95%CI = 0.25, 0.56, p<0.001
HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p<0.001
HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p=0.10
Progression-free survival
3yr PFS
W+W=33%
R4=60%
R4+RM=81%
1.0
0.9
0.8
Proportion
of
patients
progressionfree
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Events
Totals
W+W
108
181
R4
33
83
R4 + M
33
189
0.0
0
1
2
3
4
5
Years from randomisation
HR (Rituximab vs W+W) = 0.46, 95%CI = 0.33, 0.65, p<0.001
HR (Rituximab + M vs W+W) = 0.21, 95%CI = 0.15, 0.29, p<0.001
HR (Rituximab + M vs Rituximab) = 0.43, 95%CI = 0.24, 0.72, p=0.001
Overall survival
1.0
0.9
0.8
% of
patients
alive
0.7
3yr OS=95%
0.6
0.5
0.4
0.3
Events
Totals
0.2
W+W
9
187
0.1
R4
4
84
R4 + M
8
192
0.0
0
1
2
3
4
5
Years from randomisation
HR (Rituximab vs W+W) = 0.63, 95%CI = 0.21, 1.92, p=0.42
HR (Rituximab + M vs W+W) = 0.84, 95%CI = 0.32, 2.18, p=0.72
HR (Rituximab + M vs Rituximab) = 1.21, 95%CI = 0.37, 3.97, p=0.75
SAKK 35/98 trial design
FL n = 202
n = 151
Standard
R
375 mg/m²
weekly x 4
SD,PR,CR
Prolonged
375 mg/m² every 2 months x 4
PD
off
trial
SAKK 35/98 (Ghielmini et al, ASCO 2011)
Effect of schedule on event free survival
1.0
Event-free survival in randomized follicular lymphoma patients
Median FU: 9.4 years
0.6
0.4
25% still in remission
at 8 years
/
/ /
//
//
0.2
///// /
Prolonged
Standard
/
/
/
0.0
Probability
0.8
P=0.0007
1
2
3
4
5
6
7
Years since start of treatment
8
9
10
///
/
EFS in chemo-naïve responders (n=38)
1.0
Event-free survival in chemo-naive patients with CR/PR at 12 weeks
0.6
45% of chemo-naive
responders in remission
at 8 years
Prolonged
Standard
/
0.4
/ /
0.2
/
/
/
0.0
Probability
0.8
(p = 0.03)
P<0.0001
P<0.0001
1
2
3
4
5
6
7
Years since start of treatment
8
9
10
///
E4402 (RESORT) Schema
Rituximab
375 mg/m2 qw
4
CR or PR
R
A
N
D
O
M
I
Z
E
Rituximab
Maintenance*
375 mg/m2
q 3 months
Rituximab
re-treatment at
progression*
375 mg/m2 qw  4
*Continue until treatment failure
No response to retreatment or PD within 6 months of R
Initiation of cytotoxic therapy or Inability to complete rx
13
Primary Endpoint: Time to Treatment
Failure
Time to First Cytotoxic Therapy
LF faible masse tumorale
 W&W still valid
 Rituximab is an option but optimal duration of
maintenance or retreatment to be discussed?
 Room for SC rituximab sub? PK?
 Redefine Treatment criteria in the post
rituximab era?
Management of Follicular
Lymphoma
High Tumor Burden
Rituximab + chemotherapy has
improved overall survival in FL
Overall survival (%)
Study name and author
Follow-up
P
Control
Rituximab
M3902; Marcus et al.1
4 years
77
83
GLSG; Hiddemann et al.2
5 years
84
90


M39023; Herold et al.3
4 years
75
89

FL2000; Salles et al.4
8 years
79
84

Cochrane analysis:
HR = 0.63 [0.51–0.79]
Schulz H et al. Cochrane Database Syst Rev. 2007 Oct
17;(4):CD003805.
1. Marcus R, et al. J Clin Oncol 2008; 26:4579–4586.
2. Buske C, et al. Blood 2008; 112:abstract 2599.
3. Herold M, J Clin Oncol 2007; 25:1986–1992.
4. Bachy et al, Lugano 2011
R-Bendamustine versus R-CHOP
Progression free survival follicular lymphoma
B-R: not reached vs CHOP-R: 46,7 months (median)
HR = 0.63 (95% CI: 0.42 - 0.95)
100
p = 0.0281
Probability
80
B-R
60
40
CHOP-R
20
0
0
12
24
36
48
60
72
Time (months)
Rummel et al.: Blood 114: 168 (abstr #405), 2009
How to consolidate the results
after rituximab plus chemotherapy ?
Consolidate with
ASCT ?
6–8x
R-CVP or R-CHOP
(or R-BENDA)
Maintenance with
rituximab ?
PRIMA study
Consolidate with
RIT ?
FIT, SWOG study
FIT: OVERALL PFS FOR TREATMENT GROUPS
Cumulative Percentage
The 7-year overall PFS was
23% in the control arm compared with 47% in the 90Y-ibritumomab arm
HR = 2.09 (95% CI: 1.63 – 2.67); P < 0.001
100
Median follow-up: 75.7 months
75
90Y-ibritumomab:
n = 207
Median PFS: 49.3 mo
50
25
Control: n = 202
Median PFS: 12.6 mo
N
F
207 110
Control 202 149
90Y-ibritumomab
0
0
21
42
63
84
PFS From Time of Randomization (months)
At risk:
90Y-ibritumomab
Control
207
202
143
86
102
63
89
48
25
14
Update May 2011
FIT: TIME TO NEXT TREATMENT (TTNT)
Patients in the 90Y-ibritumomab arm had a greater than
5-year advantage in TTNT compared with patients in the control arm
HR = 2.03 (95% CI: 1.53 – 2.69); P < 0.0001
Cumulative Percentage
100
90Y-ibritumomab:
n = 207
Median TTNT: > 99 mo
75
50
Control: n = 202
Median TTNT: 35 mo
25
N F
206 82
Control 202 122
90Y-ibritumomab
0
0
At risk:
90Y-ibritumomab
Control
12
24
36
48
60
TTNT From Time of Randomization (months)
206
202
192
154
165
116
138
92
119
78
99
60
PRIMA: study design
Induction
Maintenance
Rituximab maintenance
375 mg/m2
every 8 weeks
for 2 years‡
Registration
High
tumor burden
untreated
follicular
lymphoma
Immunochemotherapy
8 x Rituximab
+
8 x CVP or
6 x CHOP or
6 x FCM
CR/CRu
PR
PD/SD
off study
Random 1:1*
Observation‡
* Stratified by response after induction, regimen of chemo, and geographic region
‡ Frequency of clinical, biological and CT-scan assessments identical in both arms
Five additional years of follow-up
PRIMA additional follow-up:
>2/3 of patients are free of progression
1.0
4 years = 68%
0.8
Rituximab maintenance
PFS
0.6
0.4
Observation
Stratified HR = 0.55
(95% CI: 0.44–0.68)
p < 0.0001
0.2
4 years = 50%
0.0
0
6
12
18
24
30
36
42
48
54
60
Time from randomization (months)
Observation
513
Event
n (%)
254 (50)
Rituximab
506
160 (32)
Subjects (n)
Censored
n (%)
259 (50)
Median survival
(95% CL)
48.36 (41.17–54.21)
346 (68)
NA (NA –NA)
Salles G, et al. unpublished data
Consistent benefit
in pre-defined subgroups
Category
All
Subgroup
Hazard ratio (HR)
N
HR*
95% CIs
All
1,018
0.55
0.44–0.68
Age
< 60
≥ 60
624
394
0.49
0.67
0.37–0.65
0.47–0.94
Sex
Female
Male
485
533
0.63
0.48
0.45–0.87
0.36–0.64
FLIPl ≤ 1
FLIPl = 2
FLIPl ≥ 3
216
370
431
0.39
0.44
0.68
0.21–0.72
0.30–0.64
0.51–0.92
R-CHOP
Induction
R-CVP
Chemotherapy
R-FCM
768
222
28
0.51
0.68
0.54
0.39–0.65
0.45–1.02
0.13–2.24
Response to
Induction
CR/CRu
PR
720
291
0.57
0.48
0.44–0.74
0.32–0.72
FLIPl Index
2
3
0
1
Favours maintenance
Favours observation
* Non-stratified analysis.
PFS from registration
by induction regimen
100
R-CHOP 66.5% (63.1–69.6%)
80
Patients (%)
R-FCM 58.9% (43.0–71.8%)
60
40
R-CVP 48.9% (42.4–55.0%)
20
42 months
p < 0.0001
0
0
1
R-CHOP n = 881
R-CVP n = 268
R-FCM n = 44
2
3
Time (years)
4
5
PFS by induction regimen
R-CHOP
R-CVP
100
100
Rituximab maintenance
67.2% (57.3–75.2%)
Rituximab maintenance
81.9% (77.6–85.5%)
80
60
40
Observation
61.8% (56.7–66.6%)
Maintenance n = 382
Observation n = 386
20
p = 0.0001
Patients (%)
Patients (%)
80
60
40
Observation
54.3% (44.5–63.1%)
20
Maintenance n = 109
Observation n = 113
p = 0.0589
36 months
36 months
0
0
0
1
2
3
Time (years)
4
5
0
1
2
3
Time (years)
4
5
Predictive effect of PET-CT in the
two study arms
Observation
Rituximab maintenance
Probability of PFS
PET negative
PET positive
PET negative
PET positive
1.0
1.0
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
p = 0.0032
0
p = 0.1687
0
0
6 12 18 24 30 36 42 48 54 60
0
6 12 18 24 30 36 42 48 54 60
Time (months)
No. of subjects
44
PET Negative
PET Positive
15
Event
34% (15)
Censored
66% (29)
73% (11)
27% (4)
Median PFS (95% Cl)
51.81 (43.40–NR)
29.01 (13.17–35.09)
Time (months)
No. of subjects
38
9
Event
26% (10)
Censored
74% (28)
44% (4)
56% (5)
Median PFS (95% Cl)
NR (51.75 NR)
NR (8.74 NR)
Trotman J et al., JCO 2
Rituximab maintenance is safe
100
Patients (%)
80
Observation (n = 508)
Rituximab maintenance (n = 501)
60
40
52
20
37
35
22
16
<1
23
<1
4
<1
4
0
Any adverse
event
Grade ≥2
infections
Grade 3/4
Grade 3/4
adverse events neutropenia
Grade 3/4
infections
Salles et al., Lancet 2011
Future Strategies and Next
Generation Trials
In Follicular Lymphoma
How to improve on current results in FL?
Optimizing the mAb itself
↑ Affinity
↑ PCD
Target
↑ ADCC
↑ CDC
FcRn
Conjugates
Optimization of
Rituximab’s
efficacy
Stimulating immune effector cells
Mφ
NK
T
Possible effects of anti-CD20 mAb on B- cells
ADCC
Complement
Fixation
CDC
CR3
FcgR
Type I
(Rituximab)
Both Type I and
Type II
Programmed
cell death (PCD)
CD20
on B-cell
surface
Type II
(Tositumomab)
GA101: A glycoengineered anti-CD20
antibody
Type II antibody
Low CDC
Low fucose
content
Elbow hinge
substitution
↑ ADCC
↑ Cell death
Clone B-Ly1
ADCC = antibody-dependent cellular cytotoxicity
CDC = complement-dependent cytotoxicity
Umaña P, et al. Ann Oncol 2008; 19:Abstract 098.
Umaña P, et al. Blood 2006; 108:Abstract 229.
GAUGUIN aNHL Phase II: Study design
400 mg
18 patients
Low-dose GA101* (400 mg) x 8 cycles
R/R iNHL
(n = 40)
R
1600 mg
800 mg
22 patients
High-dose GA101* (1600/800 mg) x 8 cycles
*GA101 was given on d1, d8 and every 21 days (9 infusions)
†ORR
GAUGUIN iNHL Phase II: End-oftreatment response by dose cohort
CR
PR
SD
PD
UNK
ORR†
High dose
(n=22)
2
10
6
4
0
55%
Low dose
(n=18)
0
3
6
9
0
17%
Cohort
End of treatment response is defined as 28 days from the last GA101 infusion using Cheson 1999
response criteria
based on evaluable patients
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UNK, unknown
Salles G, et al. Blood 2010;116:Abstract 2868, taken from poster presentation at ASH, Dec. 2010
49
GAUGUIN iNHL Phase II: End-of-treatment response
in rituximab-refractory patients (n=24)
†ORR
CR
PR
SD
PD
UNK
ORR†
High dose
(n=11)
1
4
3
2
0
50%
Low dose
(n=13)
0
1
4
7
0
8%
Cohort
End of treatment response is defined as 28 days from the last GA101 infusion using Cheson 1999
response criteria
Rituximab refractory defined as patients who had a response of <6 months or who failed to
respond to a rituximab-containing regimen (rituximab monotherapy or in combination with
chemotherapy)
based on evaluable patients
CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; UNK, unknown
Salles G, et al. Blood 2010;116:Abstract 2868, taken from poster presentation at ASH, Dec. 2010
50
GALLIUM (BO21223) Phase III: Study
design
GA101 1000 mg
+ chemotherapy* (n=700)
Previously untreated
advanced indolent
NHL (n=1400)
Maintenance GA101
q2m  2 years
CR/PR
Rituximab 375 mg/m2
+ chemotherapy* (n=700)
Maintenance
rituximab
q2m  2 years
*FL: Each site to choose 1 of 3 chemotherapy regimens (CHOP, CVP, or
bendamustine) which will; then be administered to all patients
Non-FL: CHOP, CVP, or bendamustine selected on a patient-by-patient basis
Experimental arm
GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 2-8 q21d + CHOP, CVP or
cycles 2–6 q28d + bendamustine
Control arm
Rituximab 375 mg/m2 on d1 cycles 1-8 q21d + CHOP, CVP or cycles 1-6 q28d
+ bendamustine
Primary endpoint
Investigator-assessed PFS
Extended treatment
Patients achieving CR, PR or SD, may continue induction therapy every
2 months for up to 2 years
www.clinicaltrials.gov; NCT01332968
How to improve in FL?
Optimizing the mAb itself
↑ Affinity
↑ Apoptosis
Target
↑ ADCC
↑ CDC
FcRn
Conjugates
Optimization of
Rituximab’s
efficacy
Stimulating immune effector cells
Mφ
NK
T
Follicular Lymphoma is a Disease of
Immune Suppression
FL cells Directly Immune Suppress the
Patient
─ By inducing T-cell immunologic synapse dysfunction in CTLs
which render them impotent
Ramsay A G , et. al. Blood 2009;114:4713-4720
Follicular Lymphoma is a Disease of
Immune Suppression
Expression of the T-cell Synapse
Cytolytic Effector Molecule in the
Tumor Microenvironment Predicts
Long Term Survival in FL
Ramsay A G , et. al. Blood 2009;114:4713-4720
“The challenge now is, can CTL activity be enhanced or reengineered by immunomodulatory strategies to tilt the
balance away from immunosuppression in the
microenvironment and toward potent anti-tumor activity
and maximizing the kiss of death in FL.”
Ramsay A G , Gribben J G Blood 2011;118:5365-5366
63
Lenalidomide repairs FL T-cell immunologic synapse
dysfunction with autologous tumor cells.
Ramsay A G et al. Blood 2009;114:4713-4720
R2 Study Design
1
2
3
4
5
7
6
8
9
10
11
12
Lenalidomide 20mg Days 1-21 Cycles 1-6*
Lenalidomide 20mg Days 1-21 Cycles 7-12*
Rituximab 375mg/M2 Day 1 of Cycles 1-6
Rituximab 375mg/M2 Day 1 of Cycles 7-12
R= RESTAGING
R
R
If clinical benefit,
can proceed to 12
cycles
R
R
*SLL patients: Dose escalation of lenalidomide
starting with cycle 1: (10mg, 15mg, 20mg)
•Phase II, single institution
•Planned Enrollment
•N= 50 Follicular lymphoma (grade I/II)
•N=30 Small lymphocytic lymphoma
•N=30 Marginal zone lymphoma
•Groups analyzed independently for response and toxicity
Fowler, N. et al. ICML 2011. Abst#137.
R2 as Frontline Combination for Follicular
Lymphoma: Clinical Response
BY GELF CRITERIA N=45
GELF (+) N=22 (49%)
GELF (-) N=23 (51%)
SD
PR
CR/CRu
ORR
SD
PR
CR/CRu
ORR
0
1 (5%)
21(95%)
100%
1(5%)
4(17%)
18 (78%)
95%
BY BULK OF DISEASE N=45
BULKY N=13 (29%)
NON-BULKY N=32 (71%)
SD
PR
CR/CRu
ORR
SD
PR
CR/CRu
ORR
0
1(8%)
12(92%)
100%
1(3%)
4 (13%)
27 (84%)
97%
Fowler, N. et al. ICML 2011. Abst#137.
Grade 3/4 AEs* FL (N=49) – R2
Combination therapy in untreated FL
AE
N
G3/G4
20
%
G3&G4
27%
Rash
7
9%
Pain (Muscle) Fatigue
7
9%
Thrombocytopenia
4
5%
Thrombosis
3
4%
Infection
3
4%
Neutropenia
Fowler, N. et al. ICML 2011. Abst#137.
Progression Free Survival
All Evaluable Patients
Percent survival
100
80
60
40
N=93
24 mo PFS: 86%
20
0
0
10
20
30
PFS (months)
Fowler, N. et al. ICML 2011. Abst#137.
RELEVANCE – Study Design
CR, CRu, PR
R2
R2 maintenance
(lenalidomide 1 yr + rituximab 2 yrs)
1st line
FL
N=1000
R
CR, CRu, PR
R-Chemo
Rituximab
maintenance
(2 yrs)
6 mos.
24 mos.
• Stratification: FLIPI (0-1 v 2 v 3-5), Age (>60 v ≤ 60), diameter of
largest node (> 6 v ≤ 6 cm)
• R-Chemo arm: Investigator choice of R-CHOP, R-CVP, R-B
81
RELEVANCE - Results Expected
 Two futility analyses
• 1st Futility analysis to evaluate the complete
response rate at 6 months of treatment for the
first 200 patients Nov 2013
• 2nd Futility analysis to evaluate the complete
response rate at 120 weeks for the first 200
patients – July 2015
 Surrogate Endpoint Results - 2016
 PFS Endpoint Results - 2024
Microenvironment in FL
Immune cells
TCD8
Stromal cells
MSC
NK
Treg
FDC
Tgd
FRC
MRC
1 cancer
2 niches
TFH
TAM
Pre-FL
Normal B cell
FL
Tumor niche
Shaffer et al Annu Rev Immunol 2012; 30:565
Nouvelles stratégies dans le traitement
du LF
 Target TFH (PD-1/PD-L1)
 Target Treg (CCR4 inhibitors)
 Target cytotoxic cells (anti-CD137, anti-KIR, Ac
optimisés pour ADCC, agonists Tgd)
 Target macrophages (anti-CD47 antagonists, inh
CSF1-R)
 Target stromal cells (AMD3100, pepducins, PCI32765)
Conclusions
 Next generation trials all include some kind of
maintenance and further investigate:
─ Stimulating immune effector cells
─ Optimizing the antibodies
─ Chemosparing strategies compared to Rchemotherapy
Thank You
LNH folliculaire: options en rechute
At relapse
 Many strategies are applicable:
─ Rituximab alone
─ Radiolabelled antibody
─ Other chemotherapy agents (FCM, DHAP,
Bendamustine…)
─ Autologous transplant
─ Allogeneic transplant
─ New agents …
 New antibodies
 Proteasome inhibitors (bortezomib), IMiDs
 BH3 mimetics, BTK inhibitors, PI3K inhibitors??
Monoclonal antibodies
 Naked Mab
─ GA101
─ Epratuzumab
─ Galiximab
anti-CD20
anti-CD22
anti-CD80
 MAb + radionucleide
─
─
─
90Y
ibritumomab tiuxetan
131I tositumomab
90Y epratuzumab tetraxetan
anti-CD20
anti-CD20
anti-CD22
 MAb + toxin
─ CMC-544 (calicheamicin)
─ SAR3419
anti-CD22
anti-CD19
Progression-free survival depends
on first-line treatment
Median PFS in patients with FL
PFS (months)
80
60
40
20
0
R + MR1
R-CVP2
CVP+MR3
R-CHVP4
R-CHOP5
1. Hainsworth JD, et al. J Clin Oncol 2005; 23:1088–1095.
2. Marcus R, et al. J Clin Oncol 2008; 26:4579–4586.
3. Hochster H, et al. J Clin Oncol 2009; 27:1540–1542.
4. Salles G, et al. Blood 2008; 112:4824–4831.
5. Buske C, et al. Blood 2008; 112:Abstract 2599.
Treatment of first relapse in FL
Two philosophies
 Avoid chemotherapy as long as possible
Rituximab
Tositumomab
Rituximab 90Y ibritumomab
Other
biologics Combinations Chemotherapy
0
2
4.5
3.5
5.5
7
yrs
 Try to reach a CR and have a long duration of CR
R-CHOP
0
Biologics
6–8
12–15
yrs
Treatment of relapse/progression in FL
 Treatment depends
─ Line of relapse: 1st, 2nd, >2nd
─ Time to relapse (from last dose of treatment): cut-off
at 12months? 6 months for refractory disease
─ Previous treatment(s)
─ Histological transformation
─ Patient’s age, comorbidities
─ Patient wishes
─ ….
Histological transformation
at 1st relapse
Bachy E, et al. J Clin Oncol 2009; in press.
Treatment of first relapse
 Objectives
─ To achieve the longest survival
─ To reach the longest PFS
 Try to have a 2nd CR
─ To preserve quality of life
 Use less toxic regimens even if less CRs ?
 Obtain a new CR with long PFS ?
─ Try not to use agents with long term toxicity
Chemotherapy
 If the patient had already received R-CHOP
 Salvage regimen
─ With rituximab
─ DHAP, ESHAP, ICE, VIM
─ Followed by high-dose therapy and autologous
transplant
(Z-BEAM or BEAM)
─ R-FC, R-FM, R-FCM, R-bendamustine
 No study comparing the different regimens
Phase II prospective
R-FM study in relapsing FL patients
Progression-free survival
(median = 33 months)
Overall survival
ORR 84%; CR/CRu 68%
Morschhauser F, et al., submitted.
Survival probability
Rituximab plus HDT offers improved
survival after relapse in patients with FL
1.0
No HDT – no rituximab
0.8
No HDT – with rituximab
With HDT – no rituximab
With HDT – with rituximab
0.6
0.4
0.2
Log-rank p < 0.0001
0
0
5
10
15
Survival after first relapse/progression (years)
20
Sebban C, et al. J Clin Oncol 2008; 26:3614–20.
Event-free survival
Overall survival
Arm A (R–)
60.4 % [45.5% ; 72%] vs 92 % [72% ; 98%]
Arm B (R+)
65 % [46% ; 79%] vs 92 % [56.5% ; 99%]
Rituximab maintenance in relapse:
Meta-analysis of randomised studies
Pool estimates of overall survival
HR (95% CI)
Study
Forstpointner 2006
Ghielmini 2004
Hainsworth 2005
Hochster 2005
Hochster 2007
van Oers 2006
Subtotal (95% CI)
Weight (%)
8.1
20.7
25.3
15.2
1.5
29.1
100
HR (95% CI)
0.49 (0.18–1.30)
0.50 (0.27–0.92)
0.86 (0.49–1.49)
0.51 (0.25–1.04)
4.51 (0.47–43.4)
0.51 (0.31–0.86)
0.60 (0.45–0.79)
p < 0.0003
0.001
0.1
1
10
1000
Favours rituximab Favours observation
Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.