Optimal use of rituximab in aggressive NHL
Professor Michael Pfreundschuh
International Prognostic Index (IPI)
Patients of all ages Risk factors Age >60 yearsPS 2–4LDH level Elevated Extranodal involvement >1 siteStage (Ann Arbor) III-IV
Patients 60 years (age-adjusted)PS 2–4LDH ElevatedStage III-IV
Shipp N Engl J Med 1993;329:987
DLBCL: overall survival
Year
Adapted from Armitage and Weisenburger. J Clin Oncol. 1998;16:2780.
Pat
ien
ts (
%)
100
60
40
20
0
0 2 5 6 7 83 41
80
IPI 0–1
IPI 2–3
IPI 4–5p<0.001
Rituximab in first-line treatment of aggressive NHL
Rituximab plus CHOP versus CHOP in elderly patients with DLBCL
Cyclophosphamide 750mg/m²Doxorubicin 50mg/m²Vincristine 1.4mg/m²Prednisone 40mg/m²/day x 5 days
3 weeks 8 cycles
R-CHOP 375mg/m²
Coiffier B, et al. N Engl J Med 2002;346:235–43Feugier P, et al. J Clin Oncol 2005 23:4117–26
GELA phase III trial (n=399)
GELA- LNH 98.5 trial planned interim analysis: initial data
R-CHOP CHOP p value (n=169) (n=159)
Median 1-year
EFS (%) 69 49 <0.0005
OS (%) 83 68 <0.01
Coiffier B, et al. Blood 2000;96:223a (Abstract 950)
GELA-LNH 98.5 5-year follow-up: overall survival
p<0.007
Rituximab plus CHOP 58%
CHOP 45%
0 1 2 3 4 5 6 7
100
80
60
40
20
0
Ove
rall
su
rviv
al (
%)
Years
Feugier P, et al. J Clin Oncol 2005;23:4117–26
GELA-LNH 98.5 5-year follow-up: progression-free survival
100
80
60
40
20
00 1 2 3 4 5 6 7
Pro
gre
ssio
n-f
ree
surv
ival
(%
)
Rituximab plus CHOP 54%
CHOP 30%
Years
p<0.00001
PFS excludes late deaths not related to lymphoma or treatment
Feugier P, et al. J Clin Oncol 2005;23:4117–26
GELA-LNH 98.5: 5-year EFS in low-aaIPI patients (aaIPI 0/1)
100
80
60
40
20
0 1 2 3 4 5 6 7
Eve
nt-
free
su
rviv
al (
%)
Rituximab plus CHOP 63%
CHOP 34%
Years
p=0.0008
Feugier P, et al. J Clin Oncol 2005;23:4117–26
GELA-LNH 98.5: 5-year EFS in high-aaIPI patients (aaIPI 2/3)
100
80
60
40
20
00 1 2 3 4 5 67
Eve
nt-
free
su
rviv
al (
%)
Rituximab plus CHOP 41%
CHOP 27%
Years
p=0.004
Feugier P, et al. J Clin Oncol 2005;23:4117–26
RANDOMISED
Stratified by IPI(0–1 vs 2–4)
CHOP
1 2 3Cycle 4 5 6 7 8
Rituximab
RANDOMISED
Stratified by IPICR/PR; induction
MR every6 months x
2 years
Observation
(n=632) (n=415)1 2 3Cycle 4 5 6 7 8
ECOG 4494 phase III trial: study design
Habermann T, et al. Blood 2004;104:40a (Abstract 127)
ECOG 4494: R-CHOP versus CHOP weighted analysis to remove the effect of maintenance
HR=0.64p=0.003
R-CHOP
CHOP
HR=0.72p=0.05
R-CHOP
CHOP
Pro
bab
ilit
yP
rob
abil
ity
1.0
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
Years from induction randomisation
0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
Years from induction randomisation
OS
FFS
Habermann T, et al. Blood 2004;104:40a (Abstract 127)
Rituximab plus CHOP for DLBCL in British Columbia (BC): study aim
March 1, 2001: BC Cancer Agency implemented a new policy recommending R-CHOP for all patients with advanced stage DLBCL in BC
Population-based retrospective analysis over a 3-year interval (1/9/99 – 31/8/02)
Compare outcomes– 18 months prior to rituximab policy (pre-rituximab)
versus– 18 months following rituximab policy
(post-rituximab)
Sehn LH, et al. J Clin Oncol 2005;23:5027–33
CHOP rituximab in British Columbia: overall survival by treatment era and age (≥60 vs <60 years)
1.0
0.8
0.6
0.4
0.2
0
Post-rituximab
Pre-rituximab
p=0.0003
Pro
bab
ilit
y o
f su
rviv
al
0 1 2 3 4 5 Years Years
1.0
0.8
0.6
0.4
0.2
0
Post-rituximab
Pre-rituximab
p=0.02
Pro
bab
ilit
y o
f su
rviv
al
0 1 2 3 4 5
≥60 years (n=170) <60 years (n=122)
Sehn LH, et al. J Clin Oncol 2005;23:5027–33
RICOVER 60: trial design
CD20+ DLBCL61–80 years
IPI I-V
(n=828)
RANDOMISATION2 x 2 factorial design
6 x CHOP-14+ 36 Gy (Bulk, E)
8 x CHOP-14+ 36 Gy (Bulk, E)
6 x CHOP-14+ 36 Gy (Bulk, E)
+ 8 x rituximab
8 x CHOP-14+ 36 Gy (Bulk, E)
+ 8 x rituximab
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
CHOP-14 R-CHOP-14 p
CR/CRu (%) 73 81 0.008
Progressive disease (%) 9 6 0.102
RICOVER 60: response to therapy
6 Cycles 8 Cycles p
CR/CRu (%) 76 78 0.432
Progressive disease (%) 7 7 0.985
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
RICOVER 60 interim analysis: freedom from treatment failure (FFTF)
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
Regimen No. of patients FFTF*
6 x CHOP-14 203 53%
6 x CHOP-14 + 8 x R 211 70%
8 x CHOP-14 210 58%
8 x CHOP-14 + 8 x R 203 70%
*Median 26 months follow-up
CHOP-14 vs R-CHOP-14
Fai
lure
-fre
e su
rviv
al (
%)
8 x (R)-CHOP-14(n=415)
6 x (R)-CHOP-14(n=413)
p=0.000025 -crit* = 0.031
57%
70%64%
62%
p=0.23
Fai
lure
-fre
e su
rviv
al (
%)
100
80
60
40
20
0
100
80
60
40
20
0
6/8 x R-CHOP-14(n=414)
6/8 x CHOP-14(n=414)
0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45
Months Months
6 cycles vs 8 cycles
RICOVER 60: time to treatment failure
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
p=0.088p=0.284
78%
77%
78%
76%
CHOP-14 vs R-CHOP-14
Su
rviv
ing
(%
)
6 x (R)-CHOP-14(n=415)
8 x (R)-CHOP-14(n=413)
100
80
60
40
20
00 5 10 15 20 25 30 35 40 45
Months
Su
rviv
ing
(%
)
100
80
60
40
20
0
6/8 x R-CHOP-14(n=414)
6/8 x CHOP-14(n=414)
0 5 10 15 20 25 30 35 40 45
Months
6 cycles vs 8 cycles
RICOVER 60: survival
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
Historical perspective (I): stages I–IV
78%
72%*
58%*
*Pfreundschuh et al., Blood 2004;104:634–41
Su
rviv
ing
(%
)
100
80
60
40
20
0 0 5 10 15 20 25 30 35 4045 Months
8 x R + 6/8 x CHOP-14 (n=414)6 x CHOP-14* (n=172)6 x CHOP-14* (n=176)
Elderly DLBCL: survival
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
Historical perspective (II): stages II–IV
* Feugier P, et al. J Clin Oncol 2005 23:4117–26
8 x R + 6/8 x CHOP-14n=4148 x R-CHOP-21*n=2028 x CHOP-21*n=197
74%
55%*
64%*
Elderly DLBCL: survival
Su
rviv
ing
(%
)
0 5 10 15 20 25 30 35 40 45 50 55 60
100
90
80
70
60
50
40
30
20
10
0
Months
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
• R-CHOP-14 superior to CHOP-14
• Trend in favour of 8 x CHOP-14 over 6 x CHOP-14
- disappears after rituximab
• 8 x R+ 6/8 x CHOP-14: best results in elderly to date
• 8 x R + 6 x CHOP-14: reference for future trials
RICOVER 60: conclusions
Pfreundschuh et al., Blood 2005;106 (Abstract 13)
CD20+ DLBCL18–60 years
IPI 0,1Stages II–IV,I with bulk
(n=823)
6 x CHOP-like+ 30–40 Gy (Bulk, E)
6 x CHOP-like+ rituximab
+ 30–40 Gy (Bulk, E)
Randomisation
MInT: trial design
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)
Median observation time: 22 months
MInT: time to treatment failure
p=0.00 00 00 00 7
R-Chemo
Chemo
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35 40 45 50
Months
80%
61%
Pro
bab
ilit
y
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)
Lymphoma-associated deaths:Chemo: 42R-Chemo: 13
Median observation time: 23 months
p=0.0002
MInT: overall survival
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35 40 45 50
Months
Pro
bab
ilit
y
R-Chemo
Chemo
95%
86%
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)
R-CHOP vs CHOP R-CHOEP vs CHOEP
Pro
ba
bil
ity
50454035302520151050
Months
R-CHOEP (n = 181)
CHOEP (n = 180)
80.4%
65.1%
P = 0.0006
R-CHOP (n = 197)
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Months
Pro
ba
bil
ity
CHOP (n = 197)
82.9%
55.3%
P < 0.00000005
MInT: time to treatment failure
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)
CHOP vs CHOEP R-CHOP vs R-CHOEP
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
55.3%
65.1%
P = 0.04
Months
Pro
bab
ility
Months
Pro
bab
ility
50454035302520151050
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
R-CHOEP(n = 181)
80.4%
82.9%
P = 0.67
CHOP(n = 187)
CHOEP(n = 180)
R-CHOP(n = 197)
MInT: time to treatment failure
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)
MInT: overall survival for (R)-CHOP versus (R)-CHOEP
1.0
0.8
0.6
0.4
0.2
00 5 10 15 20 25 30 35 40 45 50
Months
Pro
bab
ility
p=0.26
95.1%
100%
R-CHOEP
R-CHOP1.0
0.8
0.6
0.4
0.2
0
Months
Pro
bab
ility
p=0.65
92.8%
95.8% R-CHOP
0 5 10 15 20 25 30 35 40 45 50
R-CHOEP
Very favourable (IPI=0, no bulk)
Less favourable(IPI=1 and/or bulk)
Pfreundschuh M, et al. Proc Am Soc Clin Oncol 2005 (Abstract 6529)
Rituximab in first-line treatment of aggressive NHL: conclusions
8 cycles of rituximab plus chemotherapy is the standard of care for DLBCL patients irrespective of age or risk factors– confirmed in a community-based study
Addition of 8 cycles of rituximab to dose intensified strategies allows a reduction in the number of cycles of CHOP– may reduce toxicity, particularly cardiotoxicity
Rituximab in relapsed/refractory aggressive NHL
Kewalramani T, et al. Blood 2004;103:3684–8
Rituximab plus ICE for relapsed/refractory CD20+ DLBCL
Day
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Rituximab x
Ifosfamide x
Carboplatin x
Etoposide x x x
G-CSF x x x x x x x x
Median days to complete three cycles R-ICE: 45 (35–59) vs 37 with ICE
10/34 (29%) patients completed R-ICE in 35 days
28/34 (83%) sufficient PBPC harvest vs 80/92 (87%) ICE
R-ICE for relapsed/refractory CD20+ DLBCL
Months from ASCT
Pro
po
rtio
n p
rog
ress
ion
-fre
e
p=0.25
ICE (n=92;historical controls)
R-ICE (n=34)
PFS1.0
0.8
0.6
0.4
0.2
0 0 20 40 60 80 100 120
Response rates
R-ICE (%)
ICE (%)
ORR 78 71
Relapsed CR 65 34
Refractory CR 31 19
Kewalramani T, et al. Blood 2004;103:3684–8
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Rituximab + EPOCH in relapsed aggressive NHL: protocol
MabThera 375 mg/m2 i.v. day 1 Doxorubicin 15 mg/m2 c.i.v. days 2–4
Etoposide 65 mg/m2 c.i.v. days 2–4 Vincristine 0.5 mg c.i.v. days 2–4
Cyclophosphamide 750 mg/m2 i.v. day 5 Prednisone 60 mg/m2 p.o. days 1–14
Days
MabThera
Doxorubicin
Vincristine
Etoposide
Cyclophosphamide
Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.
Prednisone
Rituximab + EPOCH in relapsed aggressive NHL: response
Patients (%)
(n=50)
ORR 64
CR 26
PR 38
Stem cell harvest in 18 of 27 patients (67%) under 60 years
Updated from Jost et al. Proc Am Soc Clin Oncol. 2001;21:290a. Abstract 1157.
CORAL trial of R-ICE versus R-DHAP
CD20+ DLBCL
Relapsed/refractory
R-ICE x 3
R-DHAP x 3
R
A
N
D
O
M
I
S
E
R
A
N
D
O
M
I
S
E
SD/PD Off
PR/CR
ASCT
R x 6
Obs
BEAM+
400 patients needed
Stratification:rituximab-naive
versus previousrituximab
Rationale for rituximab in vivo purging and consolidation
Rituximab in vivo purging can eliminate residual lymphoma cells, a major cause of relapse, from stem cell harvests, without adversely affecting the yield or function of stem cells
Rituximab can also be used as consolidation therapy post-transplant to eliminate residual malignant cells and reduce the likelihood of relapse
In vivo purging with rituximab prior to ASCT
B-NHL patients (n=27) received rituximab plus DexaBEAM therapy prior to ASCT
Patients (%)
Remission rate 25 (96)
Complete remission 24 (92)
Partial remission 1 (4)
16 months post HDT: – 95% overall survival– 77% progression-free survival
Flohr T, et al. Bone Marrow Transplant 2002;29:796–75
CY BCNU/VP/CY
Harvest†
Horwitz SM, et al. Blood 2004;103:777–83
Rituximab* Rituximab*
ASCT
*375mg/m2 weekly x 4†CD34-enriched and in-vitro antibody purged
Rituximab after HDT/ASCT
Time6 months
42 days
All patients Recurrent DLBCL
Rituximab after autologous transplantation: event-free survival
120
100
80
60
40
20
00 1 2 3 4 5 0 1 2 3 4 5
Years Years
n=35 n=21
120
100
80
60
40
20
0
Eve
nt-
free
su
rviv
al (
%)
Eve
nt-
free
su
rviv
al (
%)
Horwitz S, et al. Blood 2004;103:777–83
Rituximab for treatment of relapsed/refractory aggressive NHL:
conclusions
Adding rituximab to salvage chemotherapy improves the response to chemotherapy and therefore can improve patient outcome
In vivo purging with rituximab prior to ASCT may impact progression-free and overall survival
Rituximab consolidation post-ASCT may impact event-free survival providing further patient benefit
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