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Treatment of
Diffuse Large B-Cell Lymphoma
M. Pfreundschuh
German High Grade Non-Hodgkin´s Lymphoma
Study Group (DSHNHL)
M...
Groups contacted:
Australia ALLG +
France Gela +
Europe EORTC +
Germany DSHNHL +
Netherlands HOVON +
Scandinavia Nordic Gr...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulk
and /or IPI=1
...
CALGB:50303 Phase III Randomized Study of
R-CHOP v. DA-EPOCH-R with Microarray
Randomization
ARM A: R-CHOP
ARM B: DA-EPOCH...
NCRI trial: R-CHOP 14 vs 21
Eligible
patients
R
A
N
D
O
M
I
S
A
T
I
O
N
R-CHOP 21
CHOP 21 × 8 cycles
Rituximab × 8 cycles
...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulk
and /or IPI=1
...
CD20+
DLBCL
18–60 years
IPI 0,1
Stages II-IV,
I with bulk
6 x CHOP-like
+ 30–40 Gy (Bulk, E)
6 x CHOP-like
+ rituximab
+ 3...
Time to Treatment
Failure
M o n t h s
Probability
0 10 20 30 40 50 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
59%
CHEM...
Time to Treatment
Failure
M o n t h s
Probability
0 10 20 30 40 50 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
79%
59%
...
Overall Survival
Overall Survival
0 10 20 30 40 50 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
M o n t h s
Probability
84% CHEMO (n=410)...
Overall Survival
0 10 20 30 40 50 60
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
M o n t h s
Probability
93%
84%
p = 0.000...
0
20
40
0 1 2 3 4
CHOP-21
(1975-2001)
CHOEP
(2001-2003)
R-CHO(E)P
(2004)
%Surviving
M O N T H S
Progress in the treatment ...
0
20
40
0 1 2 3 4
CHOP-21
(1975-2001)
CHOEP
(2001-2003)
R-CHOP
(2005)
%Surviving
M O N T H S
Progress in the treatment of
...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulk
and /or IPI=1
...
SWOG Approach for „Limited Stage“
SWOG
C
H
O
P
C
H
O
P
C
H
O
P
24
12

An alternative for good-prognosis?
SWOG Approach for „Limited Stage“
SWOG
C
H
O
P
C
H
O
P
C
H
O
P
24
12

An alternative for good-prognosis?
• encouraging ...
SWOG Approach for „Limited Stage“
SWOG
C
H
O
P
C
H
O
P
C
H
O
P
24
12

An alternative for good-prognosis?
• encouraging ...
SWOG Approach for „Limited Stage“
SWOG
C
H
O
P
C
H
O
P
C
H
O
P
24
12

An alternative for good-prognosis?
• encouraging ...
SWOG Approach for „Limited Stage“
SWOG
C
H
O
P
C
H
O
P
C
H
O
P
24
12

An alternative for good-prognosis?
• encouraging ...
DSHNHL 09/2000
Current Randomized Trials
IPI=0IPI=0
IPI=1IPI=1
aaIPI=2,3aaIPI=2,3
France (GELA)
U
N
F
I
T
U
N
F
I
T
Elderl...
LNH 03-1BLNH 03-1B
<65 years, aaIPI = 0<65 years, aaIPI = 0
N. Ketterer, F ReyesN. Ketterer, F Reyes
RR
ACVBP 14ACVBP 14
M...
DSHNHL 09/2000
Current Randomized Trials
IPI=0IPI=0
IPI=1IPI=1
aaIPI=2,3aaIPI=2,3
France (GELA)
U
N
F
I
T
U
N
F
I
T
Elderl...
Treatment arm 0.4 p=0.000000003
(0.3;0.6)
Bulky disease 1.7 p=0.0003
(1.3;2.2)
IPI 1.6 p=0.0008
(1.2;2.2)
SignificanceHaza...
CHEMO R-CHEMO p
IPI = 0 and no Bulk (n=108/101) 78% 89% 0.054
IPI = 0 and Bulk (n=70/73) 61% 78% 0.064
IPI = 1 and no Bulk...
TTF of Prognostic
Subgroups
Less Favorable
(IPI=1 and/or bulk)
Very Favorable
(IPI=0, no bulk)
0 10 20 30 40 50 60
0.0
0.1...
Overall Survival
Less Favorable
(IPI=1 and/or bulk)
Very Favorable
(IPI=0, no bulk)
R-CHOP (n=39)
R-CHOEP (n=51)
0 10 20 3...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulky disease
and /...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulky disease
and /...
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
RR R R R R
C
H
O
P
R
C
H
O
P
C
H
O
P
R R R
R
FLYER (6-6/6-4) STUDY DESIGN
...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulky disease
and /...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulky disease
and /...
LNH 03-2BLNH 03-2B
<60 years, aaIPI = 1<60 years, aaIPI = 1
C. Recher, H. TillyC. Recher, H. Tilly
RR
60 3 12 15 189 21
R-...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulky disease
and /...
C
H
O
P
21
C
H
O
P
21
C
H
O
P
21
C
H
O
P
21
C
H
O
P
21
C
H
O
P
21
R R R R R R
C
H
O
P
14
R R R R
Rando
C
H
O
P
14
C
H
O
P
...
DSHNHL 09/2000
Current Randomized Trials
aaIPI=2,3aaIPI=2,3
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulk
and /or IPI=1
...
DSHNHL 09/2000
Current Randomized Trials
Cure ∼60%Cure ∼60%
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulk
and /or IPI=1
...
HD-Chemotherapy in Primary Aggressive NHLHD-Chemotherapy in Primary Aggressive NHL
A „foggy“ situation ….
Author Population Rando EFS OS
Haioun et al., 1994 ≥1 RF, Bulk CR n.s. n.s.
2000 ≥ 2 RF CR 0.02* 0.04*
Verdonck et al., 19...
HD-Chemotherapy in Primary Aggressive NHLHD-Chemotherapy in Primary Aggressive NHL
Verdonck et al., 1994
Gianni et al., 19...
Author Population Rando EFS OS
Haioun et al., 1994 ≥1 RF, Bulk CR n.s. n.s.
2000 ≥ 2 RF CR 0.02* 0.04*
Verdonck et al., 19...
The NEW ENGLAND JOURNAL of MEDICINE:
A misleading title …
GOELAMS Trial
CHOP vs. High-Dose in Young
IPI=2,3
GOELAMS Trial Design
Suggestive Time S c a l e
GOELAMS Trial Design
R e a l t i m e s c a l e
C
H
O
P
21
C
E
E
P
15
Rando
HD-
MTX
+
AraC
C
E
E
P
15
B
E
A
M
d 99
20 40 60...
 CHOP-21 = formal standard
 CHOP-21 = hard to justify
 Conventional high-dose debated
 Novel approaches needed
YOUNG H...
DSHNHL 09/2000
Therapeutic Groups
1. DSHNHL: Mega-CHOEP III
2. IIL: DLCL-04 III
3. SWOG: S9704 III
4. Roma-Bologna II
5. G...
mCHOEP IV
CYC 6000
ADR 70
VCR 2
ETO 1480
PRD 500
PBS
C
R
64
PBS
C
PBS
C
mCHOEP III
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
4...
mCHOEP IV
CYC 6000
ADR 70
VCR 2
ETO 1480
PRD 500
PBS
C
R
64
PBS
C
PBS
C
mCHOEP III
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
4...
80706050403020100
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
observation time
55 months
TTF (2y) : 75.0%
302520151050
.7
.6
.5
.4
...
Optimal use of
rituximab
Optimal use of rituximab
Rituximab in Young
Poor-Prognosis DLBCL :
Optimal use of
rituximab
Optimal use of rituximab
Rituximab in Young
Poor-Prognosis DLBCL :
In combination with rituximab
...
Optimal use of
rituximab
Optimal use of rituximab
Consequence :
Optimal use of
rituximab
Optimal use of rituximab
Consequence :
Rituximab should not be combined
with chemotherapy regimen...
DSHNHL 09/2000
Therapeutic Groups
1. DSHNHL: Mega-CHOEP III
2. IIL: DLCL-04 III
3. SWOG: S9704 III
4. Roma-Bologna II
5. G...
RC/RP
RC/RP
RC/RP
RC/RP
NR
Off study
R-MAD x 2*
BEAM + ASCT
R-MegaCHOP x 2
NR
Off study
R-MAD x 2*
BEAM + ASCT
R-CHOP14 x ...
DSHNHL 09/2000
Therapeutic Groups
1. DSHNHL: Mega-CHOEP III
2. IIL: DLCL-04 III
3. SWOG: S9704 III
4. Roma-Bologna II
5. G...
DSHNHL 09/2000
SWOG/ECOG/CALGB/NCI S9704
PR,CR⇒ASCT
ICE Salvage
Evaluation
CHOP x 1
ASCT
CHOP x 3
Evaluation
Cure Relapse
...
DSHNHL 09/2000
Therapeutic Groups
1. DSHNHL: Mega-CHOEP III
2. IIL: DLCL-04 III
3. SWOG: S9704 III
4. Roma-Bologna II
5. G...
First line treatment according to
immunohistochemical panel
GC-like NC-like ABC-like
CD10+, Bcl-6+,
Bcl-2-;
CD10-,Bcl-6+,
...
DSHNHL 09/2000
Therapeutic Groups
1. DSHNHL: Mega-CHOEP III
2. IIL: DLCL-04 III
3. SWOG: S9704 III
4. Roma-Bologna II
5. G...
LNH 03-3BLNH 03-3B
< 60 years, IPIaa = 2-3< 60 years, IPIaa = 2-3
O. Fitoussi, C. GisselbrechtO. Fitoussi, C. Gisselbrecht...
DSHNHL 09/2000
Therapeutic Groups
1. DSHNHL: Mega-CHOEP III
2. IIL: DLCL-04 III
3. SWOG: S9704 III
4. Roma-Bologna II
5. G...
Re-staging 2
PET optional
CR/CRu
PET negative or
no PET done
CR/CRu
PET positive
PR regardless
of PET
SD/PD regardless
of ...
A „foggy“ situation ….
Treatment of Young Poor-Prognosis DLBCLTreatment of Young Poor-Prognosis DLBCL
…. to a bright perspective
Treatment of Young Poor-Prognosis DLBCLTreatment of Young Poor-Prognosis DLBCL
DSHNHL 09/2000
Current Randomized Trials
Cure ∼90%Cure ∼90%
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulk
and /or IPI=1
...
DSHNHL 09/2000
Therapeutic Groups
1. GELA 98-5: 8 x CHOP-21 vs. 8 x R-CHOP-21
2. ECOG 4494: CHOP-21 vs. R-CHOP-21
3. DSHNH...
9080706050403020100
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
CHOEP-14 (n=169)
CHOEP-21 (n=170)
CHOP-21 (n=178)
CHOP-14 (n=172)
M...
0
10
20
30
40
50
60
70
Leukocytopenia
Infection
Cardiotoxicity
Nervous system
Death
CHOP-21
CHOP-14
%patients
72% 70%
7%
1...
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
10
20
30
40
Infection
Cardiotoxicity
Nervous system
Death
CHOP-21
R-CHOP-21
%patients
12%
20%
8% 8% 9%
5%
GELA-98.5: WHO...
Aggressive Lymphomas:
Progress in Elderly Patients
0
20
40
0 1 2 3 4
R-CHO(E)P
(2004)
R-CHOP-21
(2000)
CHOP-14
(2000)
CHOP...
Treatment of Aggressive NHL in the Elderly
Paris‘ Judgement
Therapeutic Groups
1. HOVON: 8 x CHOP-14 vs. 6R-8CHOP-14
2. DSHNHL: 6 vs. 8 (R-)CHOP-14
3. GELA: 8xR-CHOP-21 vs. 8xR-CHOP-...
6 x CHOP-14
+ 30-40 Gy (Bulk, E)
Random
2x2
Factorial
Design
8 x CHOP-14
+ 30-40 Gy (Bulk, E)
8 x CHOP-14
+ 36 Gy (Bulk, E...
Time to Treatment
Failure
RICOVER-60
0 5 10 15 20 25 30 35 40 45
0
10
20
30
40
50
60
70
80
90
100
6 Cycles vs. 8 Cycles CH...
Time to Treatment
Failure
RICOVER-60
Time to Treatment
Failure
RICOVER-60%failure-free
M o n t h s
0 5 10 15 20 25 30 35 40 45
0
10
20
30
40
50
60
70
80
90
100...
Optimal use of
rituximab
Optimal use of rituximab
Conclusion :
Optimal use of
rituximab
Optimal use of rituximab
Conclusion :
In combination with rituximab
6 cycles of R-CHOP-14 are as
...
A randomized phase III study of chimeric anti-
CD20 monoclonal antibody (Rituximab) with 2-
weekly CHOP chemotherapy (CHOP...
Event free survival
Allocated treatment arm
Cumulativepercentage
0 30
0
25
50
75
100
CHOP14
CHOP14+R
months
At risk:
CHOP1...
Cumulativepercentage
0 30
0
25
50
75
100
8 x CHOP-14
(n=100)
0 5 10 15 20 25 30
0
10
20
30
40
50
60
70
80
90
8 x CHOP-14
(...
Cycles given (#)
CHOP14 R-CHOP14
#
0 1 -
1 4 3
2 1 3
3 7 7
4 8 1
5 7 4
6 11 9
7 5 8
8 50 56
Adherence to ProtocolRICOVER-60
1.21.11.0.9.8.7.6.5.4.3.2.10.0
1.
0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
6 x CHOP-14 99%
6 x R-C...
Adherence to ProtocolRICOVER-60
Relative Dose Intensity Cyclophosphamide (median)
6 x CHOP-14 99%
6 x R-CHOP-14 99%
8 x CH...
Time to Treatment
Failure
RICOVER-60%failure-free
M o n t h s
0 5 10 15 20 25 30 35 40 45
0
10
20
30
40
50
60
70
80
90
100...
DSHNHL 09/2000
Current Randomized Trials
Cure ∼90%Cure ∼90%
IPI=0
No bulk
IPI=0
No bulk
ElderlyElderly
Bulk
and /or IPI=1
...
LNH 03-6BLNH 03-6B
66-80 years, aaIPI = 1,2,366-80 years, aaIPI = 1,2,3
R. Delarue, A. BoslyR. Delarue, A. Bosly
4 IT MTXR...
Courbes de Recrutement LNH 03-6B
1
9 12
19
30
41
55
64
73 76
85
94
108
118
129 129
149
158 165
176
185 187 187 187
201
210...
M o n t h s
%surviving
ELDERLY DLBCL : Survival
Historical Perspective (II): Stages II-IV
8 x CHOP-21*
n=197
55%*
* Feugie...
M o n t h s
%surviving
ELDERLY DLBCL : Survival
Historical Perspective (II): Stages II-IV
8 x CHOP-21*
n=197
8 x R-CHOP-21...
M o n t h s
%surviving
ELDERLY DLBCL : Survival
Historical Perspective (II): Stages II-IV
* Feugier et al., JCO 2005
8 x C...
Zeit in Monaten
0 5 10 15 20 25 30 35 40 45
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
IPI1
(n=135)
IPI2
(n=117)
IPI3
(n=...
Optimal use of
rituximab
Optimal use of rituximab
Conclusion :
R-CHOP-14 appears to be
superior to R-CHOP-21,
particularly...
Standard for Eldery DLBCL
Further improvement possible ?
Standard for Eldery DLBCL
Further improvement possible ?
• Chemotherapy ?
Standard for Eldery DLBCL
Further improvement possible ?
• Chemotherapy ?
• New biologicals
Standard for Eldery DLBCL
Further improvement possible ?
• Chemotherapy ?
• New biologicals
• Smarter use of rituximab
1.Inf
2.Inf
3.Inf
4.Inf
5.Inf
6.Inf
7.Inf
8.Inf
1
M
o
2
M
o
3
M
o
6
M
o
9
M
o
0
50
100
150
200
µg/ml
Courtesy of M. Reiser...
Optimal use of rituximab
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
DENSE-R-CHOP-14
12 14
C
H
O
P
C
H
O
P
C
H
O
P
C
H...
R-CHOP-14 (n=21)
1.Inf
2.Inf
3.Inf
4.Inf
5.Inf
6.Inf
7.Inf
8.Inf
1Mo
2M
o
3Mo
6M
o
9M
o
0
50
100
150
200
250
Zeitpunkt
µg/...
DENSE-R-CHOP-14: First Results
Efficacy:
Patients recruited 57
Chemotherapy complete CR/CRu 33/33
Interim restaging CR/CRu...
DENSE-R-CHOP-14: Phase-III
Study Design
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
...
„ πάντα ρεϊ “
(everything is in flux)
Towards the Cure of DLBCL
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  1. 1. Treatment of Diffuse Large B-Cell Lymphoma M. Pfreundschuh German High Grade Non-Hodgkin´s Lymphoma Study Group (DSHNHL) Med. Klinik I, Saarland University Medical School Homburg / Saar, Germany DSHNHL 09-19-00
  2. 2. Groups contacted: Australia ALLG + France Gela + Europe EORTC + Germany DSHNHL + Netherlands HOVON + Scandinavia Nordic Group + Spain GEATANO + United Kigdom NCRI + USA CALGB + ECOG + SWOG + Update on Clinical Trials
  3. 3. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulk and /or IPI=1 Bulk and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 Elderly II-IV Elderly II-IV Elderly 0/IElderly 0/I LimitedLimited aaIPI=2,3aaIPI=2,3 Elderly II-IV Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T U N F I T I,noBulkI,noBulkU N F I T U N F I T Ov er 70 Ov er 70 Japan (JCOG) Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0 LimitedLimited
  4. 4. CALGB:50303 Phase III Randomized Study of R-CHOP v. DA-EPOCH-R with Microarray Randomization ARM A: R-CHOP ARM B: DA-EPOCH-R C1 C2 C3 C4 C5 C6 C7 C8 C1 C2 C3 C4 C5 C6 C7 C8 Stage Stage Stage Treatment completed Treatment completed if no change C5 to C7 staging Treatment completed if change C5 to C7 staging 0 3 6 9 12 15 18 21 25 Time Line (weeks) Tumor Biopsy Blood Samples Repeat Blood Samples at Staging Proteomics/Pharmacogenomics
  5. 5. NCRI trial: R-CHOP 14 vs 21 Eligible patients R A N D O M I S A T I O N R-CHOP 21 CHOP 21 × 8 cycles Rituximab × 8 cycles R-CHOP 14 CHOP 14 × 6 cycles Rituximab × 8 cycles N=540 N=540 Stratified by IPI (0 or 1 vs. 2 vs. 3 vs. 4 or 5) Age <60 vs. ≥60 Treatment centre
  6. 6. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulk and /or IPI=1 Bulk and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 Elderly II-IV Elderly II-IV Elderly 0/IElderly 0/I LimitedLimited aaIPI=2,3aaIPI=2,3 Elderly II-IV Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T U N F I T Stage I Non-BulkStage I Non-BulkU N F I T U N F I T Ov er 70 Ov er 70 Japan (JCOG) Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0 LimitedLimitedI,noBulkI,noBulk
  7. 7. CD20+ DLBCL 18–60 years IPI 0,1 Stages II-IV, I with bulk 6 x CHOP-like + 30–40 Gy (Bulk, E) 6 x CHOP-like + rituximab + 30–40 Gy (Bulk, E) Random. Trial Design
  8. 8. Time to Treatment Failure M o n t h s Probability 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 59% CHEMO (n=410) median observation time: 34 months Pfreundschuh et al., Lancet Oncology 2006
  9. 9. Time to Treatment Failure M o n t h s Probability 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 79% 59% p = 0.000 000 02 R-CHEMO (n=413) CHEMO (n=410) Pfreundschuh et al., Lancet Oncology 2006
  10. 10. Overall Survival
  11. 11. Overall Survival 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 M o n t h s Probability 84% CHEMO (n=410) Pfreundschuh et al., Lancet Oncology 2006
  12. 12. Overall Survival 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 M o n t h s Probability 93% 84% p = 0.0001 R-CHEMO (n=413) CHEMO (n=410) Pfreundschuh et al., Lancet Oncology 2006
  13. 13. 0 20 40 0 1 2 3 4 CHOP-21 (1975-2001) CHOEP (2001-2003) R-CHO(E)P (2004) %Surviving M O N T H S Progress in the treatment of Young good-prognosis DLBCL
  14. 14. 0 20 40 0 1 2 3 4 CHOP-21 (1975-2001) CHOEP (2001-2003) R-CHOP (2005) %Surviving M O N T H S Progress in the treatment of Young good-prognosis DLBCL
  15. 15. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulk and /or IPI=1 Bulk and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 Elderly II-IV Elderly II-IV Elderly 0/IElderly 0/I LimitedLimited aaIPI=2,3aaIPI=2,3 Elderly II-IV Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T U N F I T Stage I Non-BulkStage I Non-BulkU N F I T U N F I T Ov er 70 Ov er 70 Japan (JCOG) Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0 LimitedLimitedI,noBulkI,noBulk
  16. 16. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12  An alternative for good-prognosis?
  17. 17. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12  An alternative for good-prognosis? • encouraging (short-term) results • published in abstract form only • small number of patients (62) • uncommon population - >60 years, stage I / non-bulk - <60 years: stage I / bulky (or LDH or ECOG >1) - <60 years: stage II / non-bolky („very favorable“)
  18. 18. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12  An alternative for good-prognosis? • encouraging (short-term) results • published in abstract form only • small number of patients (62) • uncommon population - >60 years, stage I / non-bulk - <60 years: stage I / bulky (or LDH or ECOG >1) - <60 years: stage II / non-bolky („very favorable“)
  19. 19. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12  An alternative for good-prognosis? • encouraging (short-term) results • published in abstract form only • small number of patients (62) • uncommon population - >60 years, stage I / non-bulk - <60 years: stage I / bulky (or LDH or ECOG >1) - <60 years: stage II / non-bolky („very favorable“)
  20. 20. SWOG Approach for „Limited Stage“ SWOG C H O P C H O P C H O P 24 12  An alternative for good-prognosis? • encouraging (short-term) results • published in abstract form only • small number of patients (62) • uncommon population - >60 years, stage I / non-bulk - <60 years: stage I / bulky (or LDH or ECOG >1) - <60 years: stage II / non-bolky („very favorable“)
  21. 21. DSHNHL 09/2000 Current Randomized Trials IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 France (GELA) U N F I T U N F I T Elderly II-IV Elderly II-IV Elderly 0/I Elderly 0/I Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0
  22. 22. LNH 03-1BLNH 03-1B <65 years, aaIPI = 0<65 years, aaIPI = 0 N. Ketterer, F ReyesN. Ketterer, F Reyes RR ACVBP 14ACVBP 14 MTX IFM - VP16 ARA-C R-ACVBP 14R-ACVBP 14 MTX IFM - VP16 ARA-C No CNS prophylaxis 0 2 4 8 12 Wks22 0 2 4 8 12 22 Wks Primary endpoint: EFS Expected improvement: 10% at 2 years with R-ACVBP (83 to 93%) 400 patients required (in 4 years)
  23. 23. DSHNHL 09/2000 Current Randomized Trials IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 France (GELA) U N F I T U N F I T Elderly II-IV Elderly II-IV Elderly 0/I Elderly 0/I aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulky disease and /or IPI=1 Bulky disease and /or IPI=1 Germany Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0
  24. 24. Treatment arm 0.4 p=0.000000003 (0.3;0.6) Bulky disease 1.7 p=0.0003 (1.3;2.2) IPI 1.6 p=0.0008 (1.2;2.2) SignificanceHazard Ratio (95%-CI) Parameter Cox Regression Analysis* * for primary endpoint TTF
  25. 25. CHEMO R-CHEMO p IPI = 0 and no Bulk (n=108/101) 78% 89% 0.054 IPI = 0 and Bulk (n=70/73) 61% 78% 0.064 IPI = 1 and no Bulk (n=105/107) 57% 76% 0.034 IPI = 1 and Bulk (n=127/132) 44% 74% 0.000 000 3 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability Months 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability Months 89% 76% very favorable less favorable C H E M O: T T F R-C H E M O: T T F
  26. 26. TTF of Prognostic Subgroups Less Favorable (IPI=1 and/or bulk) Very Favorable (IPI=0, no bulk) 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 97% 87% R-CHOP R-CHOEP Months Probability p = 0.142 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 78% 76% Months Probability R-CHOP R-CHOEP p = 0.637 Pfreundschuh et al., Lancet Oncology 2006
  27. 27. Overall Survival Less Favorable (IPI=1 and/or bulk) Very Favorable (IPI=0, no bulk) R-CHOP (n=39) R-CHOEP (n=51) 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 100% 96% Months Probability p = 0.173 Probability 0 10 20 30 40 50 60 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 90% 93% Months R-CHOP (n=160) R-CHOEP (n=130) p = 0.891 Pfreundschuh et al., Lancet Oncology 2006
  28. 28. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulky disease and /or IPI=1 Bulky disease and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 GermanyFrance (GELA) U N F I T U N F I T Elderly II-IV Elderly II-IV Elderly 0/IElderly 0/I Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0
  29. 29. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulky disease and /or IPI=1 Bulky disease and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 GermanyFrance (GELA) U N F I T U N F I T Elderly II-IV Elderly II-IV Elderly 0/IElderly 0/I Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0 Cure∼ 95% Cure∼100%
  30. 30. C H O P C H O P C H O P C H O P C H O P C H O P RR R R R R C H O P R C H O P C H O P R R R R FLYER (6-6/6-4) STUDY DESIGN C H O P R R Stage I/II aaIPI=0 No Bulk 18-60 years d 1 d 64 d 106
  31. 31. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulky disease and /or IPI=1 Bulky disease and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 GermanyFrance (GELA) U N F I T U N F I T Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0
  32. 32. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulky disease and /or IPI=1 Bulky disease and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 GermanyFrance (GELA) U N F I T U N F I T Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0 Cure∼ 90% Cure∼ 90%
  33. 33. LNH 03-2BLNH 03-2B <60 years, aaIPI = 1<60 years, aaIPI = 1 C. Recher, H. TillyC. Recher, H. Tilly RR 60 3 12 15 189 21 R-ACVBP 14R-ACVBP 14 R-CHOP 21R-CHOP 21 Wks MTX IFM - VP16 ARA-C 0 2 4 6 10 14 24 Wks 4 IT MTX Primary endpoint: EFS Expected improvement: 10% at 2 years with R-ACVBP (75 to 85%) 380 patients required (in 4 years)
  34. 34. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulky disease and /or IPI=1 Bulky disease and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 GermanyFrance (GELA) U N F I T U N F I T Elderly IPI=1,2 ,3 Elderly IPI=1,2 ,3 Elderly aaIPI=0 Elderly aaIPI=0 Cure∼ 90% Cure∼ 90%
  35. 35. C H O P 21 C H O P 21 C H O P 21 C H O P 21 C H O P 21 C H O P 21 R R R R R R C H O P 14 R R R R Rando C H O P 14 C H O P 14 C H O P 14 C H O P 14 C H O P 14 R R d 1 d 105d 1 d 75 Treatment for IPI=1 and/or „Bulk“ + / - Radiatio Bulk / E UNFOLDER (21/14) STUDY DESIGN + / - Radiatio Bulk / E
  36. 36. DSHNHL 09/2000 Current Randomized Trials aaIPI=2,3aaIPI=2,3 IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulk and /or IPI=1 Bulk and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 aaIPI=2,3aaIPI=2,3 Elderly aaIPI 1,2,3 Elderly aaIPI 1,2,3 Elderly aaIPI=0 Elderly aaIPI=0 LimitedLimited aaIPI=2,3aaIPI=2,3 Elderly II-IV Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T U N F I T Stage I Non-BulkStage I Non-BulkU N F I T U N F I T Ov er 70 Ov er 70 Japan (JCOG) I,noBulkI,noBulk LimitedLimited
  37. 37. DSHNHL 09/2000 Current Randomized Trials Cure ∼60%Cure ∼60% IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulk and /or IPI=1 Bulk and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 Cure ∼60%Cure ∼60% LimitedLimited Cure ∼60%Cure ∼60% Elderly II-IV Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T U N F I T Stage I Non-BulkStage I Non-BulkU N F I T U N F I T Ov er 70 Ov er 70 Elderly aaIPI 1,2,3 Elderly aaIPI 1,2,3 Elderly IPI=0 Elderly IPI=0 LimitedLimitedI,noBulkI,noBulk LimitedLimited
  38. 38. HD-Chemotherapy in Primary Aggressive NHLHD-Chemotherapy in Primary Aggressive NHL A „foggy“ situation ….
  39. 39. Author Population Rando EFS OS Haioun et al., 1994 ≥1 RF, Bulk CR n.s. n.s. 2000 ≥ 2 RF CR 0.02* 0.04* Verdonck et al., 1994 II-IV <CR n.s. n.s. Gianni et al., 1997 I/IIbulky,III/IV all 0.004 n.s. Santini et al., 1998 IIbulky,III/IV all n.s. n.s. ≥2 RF* 0.008* n.s. Kluin-N. et al., 2001 all CR n.s. n.s. Kaiser et al., 2002 LDH >UNV CR, PR n.s. n.s. Gisselbrecht et al., 2002 ≥RF all -0.01 -0.009 Martelli et al., 2003 ≥2 RF CR, PR n.s. n.s. Sertoli et al., 2003 IIbulky,III/IV all n.s. n.s. MISTRAL 2005 IPI >2RD all n.s. n.s. HD-Chemotherapy in Primary Aggressive NHLHD-Chemotherapy in Primary Aggressive NHL * retrospective subset analysis Milpied et al., 2004 <3RF all 0.03 n.s
  40. 40. HD-Chemotherapy in Primary Aggressive NHLHD-Chemotherapy in Primary Aggressive NHL Verdonck et al., 1994 Gianni et al., 1997 Santini et al., 1998 Haioun et al., 1996 / 2000 Kluin-N. et al., 2001 Kaiser et al., 2002 Gisselbrecht et al., 2002 Martelli et al., 2003 Sertoli et al., 2003 Milpied et al., 2002 ?
  41. 41. Author Population Rando EFS OS Haioun et al., 1994 ≥1 RF, Bulk CR n.s. n.s. 2000 ≥ 2 RF CR 0.02* 0.04* Verdonck et al., 1994 II-IV <CR n.s. n.s. Gianni et al., 1997 I/IIbulky,III/IV all 0.004 n.s. Santini et al., 1998 IIbulky,III/IV all n.s. n.s. ≥2 RF* 0.008* n.s. Kluin-N. et al., 2001 all CR n.s. n.s. Kaiser et al., 2002 LDH >UNV CR, PR n.s. n.s. Gisselbrecht et al., 2002 ≥RF all -0.01 -0.009 Martelli et al., 2003 ≥2 RF CR, PR n.s. n.s. Sertoli et al., 2003 IIbulky,III/IV all n.s. n.s. HD-Chemotherapy in Primary Aggressive NHLHD-Chemotherapy in Primary Aggressive NHL * retrospective subset analysis Milpied et al., 2004 <3RF all 0.03 n.s
  42. 42. The NEW ENGLAND JOURNAL of MEDICINE: A misleading title …
  43. 43. GOELAMS Trial CHOP vs. High-Dose in Young IPI=2,3
  44. 44. GOELAMS Trial Design Suggestive Time S c a l e
  45. 45. GOELAMS Trial Design R e a l t i m e s c a l e C H O P 21 C E E P 15 Rando HD- MTX + AraC C E E P 15 B E A M d 99 20 40 60 80 100 120 140 days C H O P 21 C H O P 21 C H O P 21 C H O P 21 C H O P 21 C H O P 21 C H O P 21 0
  46. 46.  CHOP-21 = formal standard  CHOP-21 = hard to justify  Conventional high-dose debated  Novel approaches needed YOUNG HIGH-RISK PATIENTS: SUMMARY/PERSPECTIVES
  47. 47. DSHNHL 09/2000 Therapeutic Groups 1. DSHNHL: Mega-CHOEP III 2. IIL: DLCL-04 III 3. SWOG: S9704 III 4. Roma-Bologna II 5. G E L A: LNH 03-3B II 6. Nordic Group:LBC-04 II Young Poor-Prognosis
  48. 48. mCHOEP IV CYC 6000 ADR 70 VCR 2 ETO 1480 PRD 500 PBS C R 64 PBS C PBS C mCHOEP III CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 43 mCHOEP II CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP I CYC 1500 ADR 70 VCR 2 ETO 600 PRD 500 221 77 98 days = rando: + / - Rituximab CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14: CYC 750 VCR 2 ADR 50 PRED 500 ETO 300 G-CSF DSHNHL 2002-1 („Mega-CHOEP“): TRIAL DESIGN (≤60 YRS., AGE-ADJUSTED IPI ≥)2 n=230 n=230
  49. 49. mCHOEP IV CYC 6000 ADR 70 VCR 2 ETO 1480 PRD 500 PBS C R 64 PBS C PBS C mCHOEP III CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 43 mCHOEP II CYC 4500 ADR 70 VCR 2 ETO 960 PRD 500 mCHOEP I CYC 1500 ADR 70 VCR 2 ETO 600 PRD 500 221 77 98 days = rando: + / - Rituximab CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14 CHOEP-14: CYC 750 VCR 2 ADR 50 PRED 500 ETO 300 G-CSF DSHNHL 2002-1 („Mega-CHOEP“): TRIAL DESIGN (≤60 YRS., AGE-ADJUSTED IPI ≥)2 n=230 n=230
  50. 50. 80706050403020100 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 observation time 55 months TTF (2y) : 75.0% 302520151050 .7 .6 .5 .4 .3 .2 .1 0.0 TTF (1y): 73.5% 1.0 .9 .8 observation time 19 months Mega-CHOEP Phase II Trials TTF without and with Rituximab Mega-CHOEP (n=92) R-Mega-CHOEP (n=124)
  51. 51. Optimal use of rituximab Optimal use of rituximab Rituximab in Young Poor-Prognosis DLBCL :
  52. 52. Optimal use of rituximab Optimal use of rituximab Rituximab in Young Poor-Prognosis DLBCL : In combination with rituximab myelosuppressive chemotherapy might interfere with rituximab effector mechanisms
  53. 53. Optimal use of rituximab Optimal use of rituximab Consequence :
  54. 54. Optimal use of rituximab Optimal use of rituximab Consequence : Rituximab should not be combined with chemotherapy regimens other than CHOP outside clinical trials
  55. 55. DSHNHL 09/2000 Therapeutic Groups 1. DSHNHL: Mega-CHOEP III 2. IIL: DLCL-04 III 3. SWOG: S9704 III 4. Roma-Bologna II 5. G E L A: LNH 03-3B II 6. Nordic Group:LBC-04 II Young Poor-Prognosis
  56. 56. RC/RP RC/RP RC/RP RC/RP NR Off study R-MAD x 2* BEAM + ASCT R-MegaCHOP x 2 NR Off study R-MAD x 2* BEAM + ASCT R-CHOP14 x 4 R E S T A G I N G ARM 1: 94 pts R-MegaCHOP14 x 4 RARA NDND OMOM II ZAZA TT II ONON ARM 1b: 94 pts R-CHOP14 x 4 ARM 2: 94 pts R-MegaCHOP14 x 4 ARM 2b: 94 pts R-CHOP14 x 4 CR/PR CR/PR CR/PR CR/PR IIL-DLCL4: Study Design
  57. 57. DSHNHL 09/2000 Therapeutic Groups 1. DSHNHL: Mega-CHOEP III 2. IIL: DLCL-04 III 3. SWOG: S9704 III 4. Roma-Bologna II 5. G E L A: LNH 03-3B II 6. Nordic Group:LBC-04 II Young Poor-Prognosis
  58. 58. DSHNHL 09/2000 SWOG/ECOG/CALGB/NCI S9704 PR,CR⇒ASCT ICE Salvage Evaluation CHOP x 1 ASCT CHOP x 3 Evaluation Cure Relapse ASCT CHOP x 5 Evaluation CR, PR< PR
  59. 59. DSHNHL 09/2000 Therapeutic Groups 1. DSHNHL: Mega-CHOEP III 2. IIL: DLCL-04 III 3. SWOG: S9704 III 4. Roma-Bologna II 5. G E L A: LNH 03-3B II 6. Nordic Group:LBC-04 II Young Poor-Prognosis
  60. 60. First line treatment according to immunohistochemical panel GC-like NC-like ABC-like CD10+, Bcl-6+, Bcl-2-; CD10-,Bcl-6+, IRF4+,Bcl-2-; CD10+, Bcl-6+, Bcl-2+; CD10-,Bcl-6+, IRF4+,Bcl-2+; CD10-, Bcl-6-, Bcl-2+, IRF4+; CD10-,Bcl-6-, IRF4-,Bcl-2+; R-CHOP x 6 +/- IFRT R-CHOP x 6 + IEV x 1+ ASCT R-CHOP x 6 + IEV x 1+ ASCT Seràgnoli Institute
  61. 61. DSHNHL 09/2000 Therapeutic Groups 1. DSHNHL: Mega-CHOEP III 2. IIL: DLCL-04 III 3. SWOG: S9704 III 4. Roma-Bologna II 5. G E L A: LNH 03-3B II 6. Nordic Group:LBC-04 II Young Poor-Prognosis
  62. 62. LNH 03-3BLNH 03-3B < 60 years, IPIaa = 2-3< 60 years, IPIaa = 2-3 O. Fitoussi, C. GisselbrechtO. Fitoussi, C. Gisselbrecht 0 2 4 6 R-ACVBP 14R-ACVBP 14 10 14 MTX Wks BEAM PBSC 4 IT MTX Primary endpoint: CR rate after 4 R-ACVBP Expected improvement: 10% = 75% RC 120 patients required (in 2 years)
  63. 63. DSHNHL 09/2000 Therapeutic Groups 1. DSHNHL: Mega-CHOEP III 2. IIL: DLCL-04 III 3. SWOG: S9704 III 4. Roma-Bologna II 5. G E L A: LNH 03-3B II 6. Nordic Group:LBC-04 II Young Poor-Prognosis
  64. 64. Re-staging 2 PET optional CR/CRu PET negative or no PET done CR/CRu PET positive PR regardless of PET SD/PD regardless of PET Follow-up Biopsy if possible Biopsy not possible Normal Lymphoma HD cytarabine x 1 HD Metotrexate x 1 No biopsy Biopsy inconclusive Salvage Therapy [CHOEP-14 + rituximab] x 6 Nordic LCB 04
  65. 65. A „foggy“ situation …. Treatment of Young Poor-Prognosis DLBCLTreatment of Young Poor-Prognosis DLBCL
  66. 66. …. to a bright perspective Treatment of Young Poor-Prognosis DLBCLTreatment of Young Poor-Prognosis DLBCL
  67. 67. DSHNHL 09/2000 Current Randomized Trials Cure ∼90%Cure ∼90% IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulk and /or IPI=1 Bulk and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 Cure ∼90%Cure ∼90% Elderly II-IV Elderly II-IV Elderly aaIPI=0 Elderly aaIPI=0 LimitedLimited Cure ∼90%Cure ∼90% Elderly II-IV Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T U N F I T Stage I Non-BulkStage I Non-BulkU N F I T U N F I T Ov er 70 Ov er 70 I,noBulkI,noBulk LimitedLimited
  68. 68. DSHNHL 09/2000 Therapeutic Groups 1. GELA 98-5: 8 x CHOP-21 vs. 8 x R-CHOP-21 2. ECOG 4494: CHOP-21 vs. R-CHOP-21 3. DSHNHL: 6xCHO(E)P-21 vs. 6xCHO(E)P-14 Elderly Patients (Basic):
  69. 69. 9080706050403020100 1.0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 CHOEP-14 (n=169) CHOEP-21 (n=170) CHOP-21 (n=178) CHOP-14 (n=172) MonthsDSHNHL 15.09.03 56 % 42 % 69 % 49 % Survival after dose-dense CHOP-14 (NHL-B2) CHOP-14 vs. CHOP-21 p < 0.001
  70. 70. 0 10 20 30 40 50 60 70 Leukocytopenia Infection Cardiotoxicity Nervous system Death CHOP-21 CHOP-14 %patients 72% 70% 7% 10% 3% 4% 3% 3% NHL-B2: WHO° 3&4 Toxicity 3% 2.5%
  71. 71. 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 Overallsurvival(%) Years Feugier P, et al. J Clin Oncol 2005;23:4117–26
  72. 72. 0 10 20 30 40 Infection Cardiotoxicity Nervous system Death CHOP-21 R-CHOP-21 %patients 12% 20% 8% 8% 9% 5% GELA-98.5: WHO° 3&4 Toxicity 6% 6%
  73. 73. Aggressive Lymphomas: Progress in Elderly Patients 0 20 40 0 1 2 3 4 R-CHO(E)P (2004) R-CHOP-21 (2000) CHOP-14 (2000) CHOP-21 (1975-2000)
  74. 74. Treatment of Aggressive NHL in the Elderly Paris‘ Judgement
  75. 75. Therapeutic Groups 1. HOVON: 8 x CHOP-14 vs. 6R-8CHOP-14 2. DSHNHL: 6 vs. 8 (R-)CHOP-14 3. GELA: 8xR-CHOP-21 vs. 8xR-CHOP-14 Elderly Patients (Advanced):
  76. 76. 6 x CHOP-14 + 30-40 Gy (Bulk, E) Random 2x2 Factorial Design 8 x CHOP-14 + 30-40 Gy (Bulk, E) 8 x CHOP-14 + 36 Gy (Bulk, E) + 8 x Rituximab 6 x CHOP-14 + 36 Gy (Bulk, E) + 8 x Rituximab Study DesignRICOVER-60 CD20+ DLBCL Stages I-IV 61 to 80 years
  77. 77. Time to Treatment Failure RICOVER-60 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100 6 Cycles vs. 8 Cycles CHOP-14 vs. R-CHOP-14 M o n t h s M o n t h s %failure-free %failure-free 6/8 x CHOP-14 (n=414) 6/8 x R-CHOP-14 (n=414) 6 x (R)-CHOP-14 (n=413) 8 x (R)-CHOP-14 (n=415) p=0.000025 α-crit* = 0.031 57% 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100 70% 64% 62% p=0.23
  78. 78. Time to Treatment Failure RICOVER-60
  79. 79. Time to Treatment Failure RICOVER-60%failure-free M o n t h s 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100 8 x R-CHOP-14 (n=203) 6 x R-CHOP-14 (n=211) 8 x CHOP-14 (n=210) 6 x CHOP-14 (n=204) Median time of observation: 26 months
  80. 80. Optimal use of rituximab Optimal use of rituximab Conclusion :
  81. 81. Optimal use of rituximab Optimal use of rituximab Conclusion : In combination with rituximab 6 cycles of R-CHOP-14 are as good as 8 cycles
  82. 82. A randomized phase III study of chimeric anti- CD20 monoclonal antibody (Rituximab) with 2- weekly CHOP chemotherapy (CHOP 14) in elderly patients with intermediate- or high-risk non-Hodgkin's lymphoma. Results of an interim analysis P. Sonneveld, W.L.J. van Putten, P.C. Huijgens, H. Holte, M. Eriksson Dutch-Belgian HOVON group Nordic Lymphoma Group NLG
  83. 83. Event free survival Allocated treatment arm Cumulativepercentage 0 30 0 25 50 75 100 CHOP14 CHOP14+R months At risk: CHOP14 100 55 25 7 2 CHOP14+R 99 69 39 17 5 Logrank P=.004 CHOP14 100 55 CHOP14+R 99 37 N F Event-free survival
  84. 84. Cumulativepercentage 0 30 0 25 50 75 100 8 x CHOP-14 (n=100) 0 5 10 15 20 25 30 0 10 20 30 40 50 60 70 80 90 8 x CHOP-14 (n=204) EVENT-FREE SURVIVAL CHOP-14 HOVON DSHNHL 100 25% 65%
  85. 85. Cycles given (#) CHOP14 R-CHOP14 # 0 1 - 1 4 3 2 1 3 3 7 7 4 8 1 5 7 4 6 11 9 7 5 8 8 50 56
  86. 86. Adherence to ProtocolRICOVER-60 1.21.11.0.9.8.7.6.5.4.3.2.10.0 1. 0 .9 .8 .7 .6 .5 .4 .3 .2 .1 0.0 6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96% Relative Dose Intensity Cyclophosphamide (median)
  87. 87. Adherence to ProtocolRICOVER-60 Relative Dose Intensity Cyclophosphamide (median) 6 x CHOP-14 99% 6 x R-CHOP-14 99% 8 x CHOP-14 96% 8 x R-CHOP-14 96% • „Prephase“ treatment obligatory: • 1 mg vincristine d-7 • 100 mg prednisone d-7 to d-1 • No dose reduction unless delay >7 days • Strict adherence to G-CSF schedule
  88. 88. Time to Treatment Failure RICOVER-60%failure-free M o n t h s 0 5 10 15 20 25 30 35 40 45 0 10 20 30 40 50 60 70 80 90 100 8 x R-CHOP-14 (n=203) 6 x R-CHOP-14 (n=211) 8 x CHOP-14 (n=210) 6 x CHOP-14 (n=204) Median time of observation: 26 months
  89. 89. DSHNHL 09/2000 Current Randomized Trials Cure ∼90%Cure ∼90% IPI=0 No bulk IPI=0 No bulk ElderlyElderly Bulk and /or IPI=1 Bulk and /or IPI=1 IPI=0IPI=0 IPI=1IPI=1 Cure ∼90%Cure ∼90% LimitedLimited Cure ∼90%Cure ∼90% Elderly II-IV Elderly II-IV Germany France (GELA) U S A (SWOG) U S A (CALBG) U K (NCRI) U N F I T U N F I T Stage I Non-BulkStage I Non-BulkU N F I T U N F I T Ov er 70 Ov er 70 Elderly aaIPI 1,2,3 Elderly aaIPI 1,2,3 Elderly IPI=0 Elderly IPI=0 LimitedLimitedI,noBulkI,noBulk
  90. 90. LNH 03-6BLNH 03-6B 66-80 years, aaIPI = 1,2,366-80 years, aaIPI = 1,2,3 R. Delarue, A. BoslyR. Delarue, A. Bosly 4 IT MTXRR R-CHOP 21R-CHOP 21 0 3 6 9 Wks12 15 18 21 0 2 4 6 10 14 Wks8 12 Prophylactic Darbepoietin alfa Supportive care R-CHOP 14R-CHOP 14 Primary endpoint: EFS Expected improvement: 10% at 3 years with R-CHOP 14 (55 to 65%) 600 patients required (over 4 years)
  91. 91. Courbes de Recrutement LNH 03-6B 1 9 12 19 30 41 55 64 73 76 85 94 108 118 129 129 149 158 165 176 185 187 187 187 201 210 223 0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460 480 500 déc.-03 févr.-04 avr.-04 juin-04 août-04 oct.-04 déc.-04 févr.-05 avr.-05 juin-05 août-05 oct.-05 déc.-05 févr.-06 avr.-06 juin-06 août-06 oct.-06 déc.-06 NombredePatients Recrutement réel Recrutement prévisionnel LNH03-6B
  92. 92. M o n t h s %surviving ELDERLY DLBCL : Survival Historical Perspective (II): Stages II-IV 8 x CHOP-21* n=197 55%* * Feugier et al., JCO 2005
  93. 93. M o n t h s %surviving ELDERLY DLBCL : Survival Historical Perspective (II): Stages II-IV 8 x CHOP-21* n=197 8 x R-CHOP-21* n=202 55%* 64%* * Feugier et al., JCO 2005
  94. 94. M o n t h s %surviving ELDERLY DLBCL : Survival Historical Perspective (II): Stages II-IV * Feugier et al., JCO 2005 8 x CHOP-21* n=197 8 x R-CHOP-21* n=202 6/8 x R-CHOP-14 n=414 74% 55%* 64%*
  95. 95. Zeit in Monaten 0 5 10 15 20 25 30 35 40 45 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 IPI1 (n=135) IPI2 (n=117) IPI3 (n=96) IPI4/ 5 (n=65) Zeit in Monaten 0 5 10 15 20 25 30 35 40 45 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 IPI1 (n=129) IPI2 (n=122) IPI3 (n=97) IPI4/ 5 (n=66) DSHNHL 01.07.05 RICOVER-60 TTF according to IPI without Rituximab with Rituximab M o n t h s M o n t h s
  96. 96. Optimal use of rituximab Optimal use of rituximab Conclusion : R-CHOP-14 appears to be superior to R-CHOP-21, particularly in high-risk patients
  97. 97. Standard for Eldery DLBCL Further improvement possible ?
  98. 98. Standard for Eldery DLBCL Further improvement possible ? • Chemotherapy ?
  99. 99. Standard for Eldery DLBCL Further improvement possible ? • Chemotherapy ? • New biologicals
  100. 100. Standard for Eldery DLBCL Further improvement possible ? • Chemotherapy ? • New biologicals • Smarter use of rituximab
  101. 101. 1.Inf 2.Inf 3.Inf 4.Inf 5.Inf 6.Inf 7.Inf 8.Inf 1 M o 2 M o 3 M o 6 M o 9 M o 0 50 100 150 200 µg/ml Courtesy of M. Reiser, Cologne Median Rituximab Serum Level Nadirs before next Rituximab Application •
  102. 102. Optimal use of rituximab C H O P C H O P C H O P C H O P C H O P C H O P DENSE-R-CHOP-14 12 14 C H O P C H O P C H O P C H O P C H O P C H O P 12 14 R-CHOP-14
  103. 103. R-CHOP-14 (n=21) 1.Inf 2.Inf 3.Inf 4.Inf 5.Inf 6.Inf 7.Inf 8.Inf 1Mo 2M o 3Mo 6M o 9M o 0 50 100 150 200 250 Zeitpunkt µg/ml CHOP-R esk (n=18) 1.Inf. 2.Inf. 3.Inf. 4.Inf. 5.Inf. 6.Inf. 7.Inf. 8.Inf. 1 M o 2 M o 3 M o 6 M o 9 M o 0 50 100 150 200 250 Zeitpunkt µg/ml Median Rituximab Serum Level Nadirs before next Rituximab Application Courtesy of M. Reiser, Cologne • • ? ?
  104. 104. DENSE-R-CHOP-14: First Results Efficacy: Patients recruited 57 Chemotherapy complete CR/CRu 33/33 Interim restaging CR/CRu/PR 40/40 Therapy-assoc. deaths 3 Interstitial pneumonias 7
  105. 105. DENSE-R-CHOP-14: Phase-III Study Design C H O P C H O P C H O P C H O P C H O P C H O P C H O P C H O P C H O P C H O P C H O P C H O P Rando- mization CD20+ DLBCL Stages I-IV 61 to 80 years n = 2 x 400 Start: 01/07
  106. 106. „ πάντα ρεϊ “ (everything is in flux) Towards the Cure of DLBCL

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