Gemeinsame Jahrestagung 2009
der Deutschen, Österreichischen und Schweizerischen
Gesellschaften für Hämatologie und Onkologie
2. bis 6. Oktober 2009 in Heidelberg / Mannheim
Kompetenznetz Maligne Lymphome
Aggressive Non-Hodgkin-Lymphome:
Aktuelle Ergebnisse der DSHNHL
Norbert Schmitz
Abteilung Hämatologie und Stammzelltransplantation
Asklepios Klinik St. Georg, Hamburg
B-NHL
Derzeitige DSHNHL-Protokolle zur Primärtherapie
aggressiver B-Zell-Lymphome
IPI = 0
kein Bulk


IPI = 1 /
Bulk
IPI ≥ 2
FLYER
RICOVER
UNFOLDER
MegaCHOEP
Nachfolgestudie
(in Vorbereitung)
Phase III
≤60 Jahre

>60 Jahre
FLYER (6-6/6-4) STUDY DESIGN
Stage I/II
aaIPI=0
no Bulk
18-60 years
R
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
R
R
R
R
R
R
d1
d 64
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
R
R
R
R
d 106
R
R
UNFOLDER (21/14) STUDY DESIGN
+ / - Radiatio
Bulk / E
IPI = 1
and/or
Bulk
R
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
d1
C
H
O
P
14
+ / - Radiatio
Bulk / E
R
d 75
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
R
R
R
d 105
DSHNHL 2002-1 „Mega-CHOEP“
study design after amendment 1 for CD20+ B-NHL
PBSC
mCHOEP I
mCHOEP II
mCHOEP III
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
CYC 1500
ADR 70
VCR 2
ETO 600
PRD 500
1
PBSC
22
43
PBSC
mCHOEP IV
CYC 6000
ADR 70
VCR 2
ETO 1480
PRD 500
64
R
: Rituximab
77
98
days
Mega-CHOEP study (phase III)
Patients 18 - 60 years, aaIPI 2,3, B-cell (CD20+), ITT (n=185)
Event Free Survival (EFS) -- all patients
1
0.9
0.8
Proportion
0.7
0.6
0.5
0.4
0.3
0.2
Median observation time: 29 months
0.1
0
0
5
10
20
30
40
Months
DSHNHL 23.03.09
50
60
70
Mega-CHOEP study (phase III)
Patients 18 - 60 years, aaIPI 2,3, B-cell (CD20+), ITT (n=216)
EFS* according to Rituximab
1
0.9
0.8
Proportion
0.7
0.6
0.5
0.4
0.3
without Rituximab
(n=31)
with Rituximab
(n=185)
0.2
0.1
p=0.003
0
0
DSHNHL 23.03.09
5
10
20
30
40
Months
50
60
70
*event „additional R“ not counted
one patient changed treatment arm to Mega-CHOEP+R after study meeting and is censored
DSHNHL 2002-1 „Mega-CHOEP“
study design after amendment 1 for CD20+ B-NHL
PBSC
mCHOEP I
mCHOEP II
mCHOEP III
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
CYC 1500
ADR 70
VCR 2
ETO 600
PRD 500
1
PBSC
22
43
PBSC
mCHOEP IV
CYC 6000
ADR 70
VCR 2
ETO 1480
PRD 500
64
R
: Rituximab
77
98
days
DSHNHL 2002-1 „Mega-CHOEP“
study design after the MegaCHOEP arm is closed
1
15
29
43
71
: Rituximab
99
days
RICOVER-60
Study Design
6 x CHOP-14
+ 30-40 Gy (Bulk, E)
CD20+ DLBCL
Stages I-IV
61 to 80 years
Random
2x2
Factorial
Design
8 x CHOP-14
+ 30-40 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
III. Elderly Patients
Is further
Improvement
possible ?
Study Design
DENSE-R-CHOP-14
C
H
O
P
CD20+ DLBCL
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
Stages I-IV
61 to 80 years
0
2
4
6
Weeks
8
10
12
14
DENSE-R-CHOP-14
RICOVER-60 (6xCHOP+8R)
Progression-free Survival*
IPI 1, 2
IPI 3 - 5
1
0.9
84%
0.9
0.8
83%
0.8
p=0.584
0.7
% patients
% patients
1
0.6
0.5
0.4
0.3
RICOVER-60
(6xCHOP-14+8xR; n=183)
0.2
DENSE-R-CHOP-14
(6xCHOP-14+12xR; n=52)
0.1
77%
0.7
p=0.064
0.6
64%
0.5
0.4
0.3
RICOVER-60
(6xCHOP14+8xR; n=123)
0.2
DENSE-R-CHOP-14
(6xCHOP-14+12xR; n=72)
0.1
0
0
0
2
4
6
8 10 12 14 16 18 20 22 24
Months
0
2
4
6
8 10 12 14 16 18 20 22 24
Months
DENSE-R-CHO/MP-60
UNFAVORABLE
Study Design
R-CHOP-14
+ 36 Gy IN-RT*
CD20+ DLBCL
IPI 2-4
IPI 1 Bulky
61 to 80 years
Random
2x2
Factorial
Design
DENSE-R-CHOP-14
+36 Gy IN-RT*
R-CHMP-14
+ 36 Gy IN-RT*
* Except Interim-PET-neg.
DENSE-R-CHMP-14
+ 36 Gy IN-RT*
Involvement of CNS in aggressive NHL
 risk factors and prophylaxis 
Norbert Schmitz, Volkmar Boehme, Samira Zeynalova,
Markus Loeffler and Michael Pfreundschuh
GERMAN HIGH-GRADE NHL STUDY GROUP (DSHNHL)
Risk-factors for CNS events in the RICOVER-60 trial
multivariate analysis
all patients
risk factor
RR
95% CI
p - value
> 1 extranodal sites
3.4
(2.0; 5.8)
< 0.001
B-symptoms
1.9
(1.1; 3.3)
0.025
LDH > UNV
1.5
(0.9; 2.7)
0.146
risk factor
RR
95% CI
p - value
> 1 extranodal sites
2.0
(0.8; 4.9)
0.134
ECOG > 1
2.8
(1.1; 7.0)
0.025
LDH > UNV
3.9
(1.3; 11.9)
0.018
R-treated patients only
CNS events in the RICOVER-60 trial
"high-risk" patients with LDH > N, >1 E-lesion, B-symptoms / ECOG >1
all patients (
) / only patients with R-CHOP-14 (
)
0.40
0.35
proportion of patients
0.30
"high-risk" patients
0.25
0.20
0.15
0.10
p<0.001
all other patients
0.05
0.00
0
10
20
30
40
months
50
60
70
80
CNS prophylaxis
In the RICOVER-60 trial
MTX 15mg i.th.
1
d1
5
15
d15
20
d29
d43
d57
d71
d85
d99
d43
d57
d71
d85
d99
In future trials
MTX 15mg i.th.
d1
d15
d29
2 weeks after last chemo
2
MTX 1.5mg/m² i.v.
T-NHL
DSHNHL 2006-1B
Primärtherapie für PTCL bei älteren Patienten (>60 J.)
A C
30 H
mg O
A C
30 H
mg O
A C
30 H
mg O
A C
30 H
mg O
A C
30 H
mg O
A C
30 H
mg O
P
P
P
P
P
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
n=150
R
A = Alemtuzumab
n=150
T-cell lymphomas in DSHNHL trials
Results from the NHL-B1 trial (≤ 60 years, LDH ≤ N, n=98)
Event-free survival: role of etoposide
1
0.9
0.8
6x CHOEP-14/21 (n=52)
0.7
Proportion
0.6
0.5
0.4
0.3
6x CHOP-14/21 (n=46)
0.2
p=0.010
0.1
0
0
10
20
30
40
50 60
Months
3-years EFS-rate:
DSHNHL
70
80
90
100 110
with Etoposide:
without Etoposide:
70.6% (95% CI: 58.1-83.1%)
49.8% (95% CI: 35.3-64.3%)
HDT / ASCT in T cell lymphoma as part of primary treatment
Prospective Phase II Trials
n
Median age
Regimen
ASCT (%)
CR / PR pre Tx
TRM
OS
EFS /FFS/ PFS
Follow-up
Corradini
Lopez-Guillermo
Reimer
D`Amore
(Leukemia 2006)
(ASH 2006, #3070)
(JCO 2009)
(EHA 2009 #1082)
62
41
83
166
(incl.19 ALK+ ALCL)
(no ALK+ ALCL)
(no ALK+ ALCL)
(no ALK+ ALCL)
43y
47y
47y
57y
1) 2xAPO>2xDHAP
HD Mito./Mel
2) MACOP-B>HD AraC/Mito
BEAM
3xmaxiCHOP +
3xESHAP altern.
4-6xCHOP-21 +
DexaBEAM
HD Cy + TBI
6xCHOEP-14
BEAM
74%
41%
66%
70%
56% / 16%
49% / 10%
39% / 40%
50% / 35%
4.8%
3%
3.6%
(4%)
34% (12y) [21%*]
39% (4y)
48%+ (3y)
57% (3y)
30% (12y) 18%*
30% (4y)
PFS: 36%
PFS: 48%
76mo
3.9yrs (survivors)
33 mos
med. 3.75 yrs
[* Non ALK+ ALCL]
[+ CR patients only]
allo SCT in pTCL HLA-id donors (n=74)
Overall Survival and Progression free survival
0,80
0,80
0,60
0,60
PFS
1,00
OS
1,00
43%
0,40
0,40
0,20
0,20
0,00
0
12
24
36
48
60
72
Months after SCT
84
96
108
39%
0,00
0
12
24
36
48
60
72
84
96
108
Months after SCT
The European Group for Blood and Marrow Transplantation
The European Group for Blood and Marrow Transplantation
The European Group for Blood and Marrow Transplantation
DSHNHL 2006-1A: Studiendesign
B-NHL
Rezidivtherapie
CORAL Trial of RICE v DHAP

Which salvage regimen is the best?
R
A
N
→
D
CD20+ DLBCL
O
Relapsed/Refractory
M
I
Z
E
SD/POD → Off
R-ICE x 3
AB
SE
CA
TM
R-DHAP x 3
R
A
Rx6
N
D
PR/CR →
O
M
I
Z
Obs
E
N=400

Place of immunotherapy post transplantation?
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
64%
N=160
31%
N=228
PROGRESSION-FREE
SURVIVAL
ACCORDING TO FAILURE
FROM DIAGNOSIS
(INDUCTION ITT)
62%
N=147
30%
N=241
PROGRESSION-FREE
SURVIVAL ACCORDING TO
PRIOR RITUXIMAB
(INDUCTION ITT)
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
Aggressive B-NHL – Rezidive
Ergebnisse der allogenen SCT – DSHNHL R3
aNHL, 18-65 y, refractory disease, early relapse HR, relapse after ASCT
alloPBSC
MRD
MUD
MMF
Tacrolimus
F F F F F
25 25 25 25 25
R-ICE
R-ICE
C C
60 60
R
B
4
B
4
B
4
MMF
R
R
R
R Tacrolimus
375 375 375 375
w-8
w-5
d-9 d-8 d-7 d-6 d-5 d-4 d-3
w3
w4
w5
w6
R
R
R
R
375 375 375 375
w25
w26
w27
B. Glass
Glass et al , Blood 110: ASH abstract #3043
w28
Aggressive B-NHL - Rezidive
Ergebnisse der allogenen SCT – DSHNHL R3
Progression Free Survival, n=81
DSHNHL
1.0
Probability of PFS
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
Time after Transplant (Years)
Glass et al.
4.5
5.0
5.5
6.0
Future developments
• The addition of Rituximab to conventional
chemotherapy (and high-dose chemotherapy?)
has significantly improved first-line treatment
results of young, high-risk patients with DLBCL.
• Increasingly less patients will show
chemo-sensitive disease after relapse
from R-chemotherapy.
 Results of autografting will deteriorate.
Allogeneic transplantation needs further study.
BACKUP
RICOVER-60
- Event-free Survival 1
0.9
0.8
6x R-CHOP 14
Proportion
0.7
8x R-CHOP 14
3-year rates:
0.6
8x CHOP 14
0.5
66.5%
63.1%
1: 6 x CHOP 14
(n=307)
2: 8 x CHOP 14
(n=305)
3: 6 x R-CHOP 14
(n=306)
4: 8 x R-CHOP 14
(n=304)
0.4
0.3
0.2
0.1
53.0%
47.2%
1, 2: p=0.037
1, 3: p<0.001
1, 4: p<0.001
3, 4: p=0.561
6x CHOP 14
50
70
0
0
10
20
30
40
60
80
Months
Pfreundschuh et al., Lancet Oncol. (2008)
Perspectives of anti-B Cell Antibodies
• Optimization of rituximab
• Dose-dense rituximab
• Combination with IL-21
• 2nd- / 3rd-generation anti-CD20 antibodies
• Ofatumomoab
• GA 101
• anti-CD19
• anti-CD40 (SGN-40)
• anti-CD80
• Radioimmunotherapy
• CD20: 90Y-ibritumomab tiuxetan (#8565)
• CD22: 90Y-epratumomab (#8502)
• Bispecific anti-CD19 antibodies
Rituximab Schedules for
Elderly Patients with DLBCL
GELA
(8 x R)
ECOG
(5 x R)
DSHNHL
(8 x R)
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
24
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
24
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
DLBCL at ASH 2008
Novel therapies for (relapsed DLBCL):
- Lenalidomide :
- ORR 29% (21/73); CR 4%
- mTor Inhibitors (Temsirolimus, Everolimus)
- ORR 35% ; CR 5%
- Fostamatinib (oral Syk-Inhibitor; # 3):
- ORR 23% (5/23), CR 5%
- preclinical:
- IL-21 (# 601)
- PU-H71 (purine-scaffold Hsp 90 inhibitor; # 602)
- LBH589 (HDAC inhibitor; # 603)
- Obatoclax (BH3-mimetic; #605)
- MLN4924 (s.-molec. Inhibitor of Nedd8; #606)
RICOVER-60 Trial
61- 80 years, CD20+ B-cell, with Rituximab (n=610)
by IPI score
PFS
OS
1
1
11
0.9
0.9
0.9
0.9
0.9
0.9
0.8
0.8
0.8
0.8
0.8
0.8
0.7
0.7
0.7
0.7
0.6
0.6
p=0.032
0.5
0.5
p=0.219
0.4
0.4
0.4
0.4
0.3
0.3
0.2
0.2
0.1
0.1
0.3
0.3
0.2
0.2
p<0.001
0.2
0.2
p<0.001
0.1
0.1
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
p<0.001
0.1
0.1
0
0
0
p=0.161
0.5
0.5
p=0.249
0.4
0.4
0.3
0.3
p=0.021
0.6
0.6
p=0.036
0.5
0.5
p=0.005
0.7
0.7
Proportion
0.6
0.6
p<0.001
Proportion
p=0.002
Proportion
Proportion
EFS
00
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
0
0
10
10
20
20
30
30
40
40
Months
Months
Months
Months
Months
Months
IPI 1: 184 (30%); IPI 2: 172 (28%);
IPI 3: 155 (26%);
50
50
60
60
70
70
IPI 4, 5: 99 (16%)
80
80