Optimal use of rituximab in aggressive NHL Professor Michael Pfreundschuh.
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Transcript of Optimal use of rituximab in aggressive NHL Professor Michael Pfreundschuh.
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