Transcript Folie 1

Periphere T-Zell Lymphome
Wien, 13.10.2008
Gerald Wulf
Seite 1
23. Januar 2007
Biologie systemischer T-NHL: Heterogenität und Epidemiologie
1%
2%
2%
5%
11%
6%
14%
23%
18%
7%
PTCL-U
ALK+ ALCL
ETTL
SCPTCL
12%
AILT
NK/T
ALK - ALCL ATLL
Cut ALCL HSTCL
Other/Unclass
Armitage et al. JCO 2008
Expressionsprofil von PTCL: Assoziation mit maturen T-Zelltypen
AILT
Geissinger et al. J Path 2006
Genexpressionsprofil von PTCL
Piccalagua et al. JCI 2007
Martinez-Delgado Hemtol Oncol 2006
Genexpressionprofil von PTCL: Identifikation von Zielstrukturen
Piccalagua et al. JCI 2007
Prognose des anaplastisch großzelligen Lymphoms
Gisselbrecht et al. Blood 1998
Anaplastisch großzelliges Lymphom: Bedeutung von ALK-Positivität
FFS
OS
Savage et al. Blood 2008
Prognose des kutanen anaplastisch großzelligen T-Zell Lymphoms
Bekkenk et al. Blood 2002
Savage et al. Blood 2008
kutanes ALCL versus lymphomatoide Papulose
Bekkenk et al.
Blood 2002
Savage et al. Blood Reviews2007
Prognose systemischer T-NHL: klinische Faktoren
IPI
Age, PS, LDH, ES, stage
PIT
Age, PS, LDH, BM
Gallamini et al. Blood. 2004
PTCL: approaches to improved treatment efficacy
66-8
x CHOP14
x CHO/E/P14
addition of humoral immunotherapy :
consolidation/maintenance
alemtuzumab
addition of humoral immunotherapy:
alemtuzumab
addition of cellular immunotherapy:
allogeneic SC transplantation
DHAP
FBC12
dose escalation:
HD therapy / autologous tx
novel agents:
antibodies
small compounds
Mega
CHOEP
Dexa
BEAM
TBI
Cy
Standard chemotherapy in PTCL: anthracycline-based ?
PTCL NOS
AILT
Armitage et al. JCO 2008
Periphere T-Zell Lymphome (PTCL): CX + Alemtuzumab
Weidmann
(Germany)
Gallamini
(Italy)
Porcu
(USA)
Janik
(USA)
HOVON
(NL)
Furman
(USA)
Trümper
(Germany)
PTCL
excl:
alk+ALCL
PTCL
excl.
alk+ALCL
PTCL
Incl. alk+
ALCL, ATLL,
PTLD, CTCL,
LGL
PTCL
CD52positive,
ATLL
PTCL,
excl: all
ALCL,
hepatospl.
EATLwithout
measurable
disease
PTCL
Probably incl.
alk+ALCL
PTCL
excl. alk+ALCL
FCD
CHOP 21
x8
CHOP-21
x8
EPOCH
CHOP-14
x8
CHOP-21
x6
CHO(E)P-14
x6
INDUCTION
INDUCTION
INDUCTION
INDUCTION
INDUCTION
INDUCTION
CONSOLID.
Dose
esc.
Yes
Yes
Yes
Yes
Yes
No
Yes
Camp
Total
dose
292 mg
180-300 mg
77-293 mg
180-540
mg
673 mg
435-495 mg
180 mg
Cam
route
i.v.
s.c.
s.c.
i.v.
s.c.
s.c.
i.v.
No pts
33
20
8
10
17
2
37
Target
group
CT
regimen
Camp
timing
8x CHOP-21 + Alemtuzumab
OS
PFS
Gallamini et al. Blood 2007
DSHNHL 2003-1: phase II alemtuzumab consolidation in PTCL
DSHNHL Trial 2003-1
peripheral T-NHL
18 – 60 years:
60 – 70 years:
6 x CHOEP-14
+ Peg-F
6 x CHOP-14
+ Peg-F
CR / PR
no infection
Alemtuzumabconsolidation
133 mg in / 4 wks
36 Gy Bulk/E
RTx
DSHNHL 2003-1: treatment outcome (ITT)
DSHNHL Trial 2003-1
EFS
Therapy arm
OS
2 - years rate
95% CI
2 - years rate
95% CI
≤ 60 years
(n=27)
38.1%
[14.0%;
62.2%]
63.5%
[40.8%;
86.2%]
> 60 years
(n=14)
22.9%
[ 0.0%; 48.0%]
55.0%
[28.1%;
81.9%]
total
(n=41)
32.0%
[14.2%;
49.8%]
61.0%
[43.6%;
78.4%]
with
MabCampath
(n=29)
43.9%
[20.8%;
67.0%]
73.6%
[54.6%;
92.6%]
DSHNHL 30.07.07
CHOP + Alemtuzumab phase III: DSHNHL 2006-1B / ACT-2
documentation
forms
BII
:
S
BI
RE
C
PT
T-cell lymphoma
61-80 years
eligible for
chemotherapy
all stages, except
stage I IPI 0 w/o bulk
C
C
C
H
O
P
C
H
O
P
C
H
O
P
A
A
A
C
H
O
P
C
H
O
P
C
H
O
P
progress
:
F
RE
C
C
C
C
H
O
P
C
H
O
P
C
H
O
P
A
A
C
H
O
P
C
H
O
P
R
days
1
15
29
A
C
H
O
P
43
57
71
F
death
:
D
EBV-associated secondary NHL post CHOP w alemtuzumab
case
primary
histology
secondary
histology
interval post
alemtuzumab
m, 41y
PTCL NOS
EBV + (endoth.)
CD2+,3+,5+
recurr. EBV –
10 months
f, 32y
PLTCL
EBV+, CD20+
- cerebral mass
9 months
- cerv. DLBCL
12 months
- cut. ind B-NHL 21 months
RX
RX, rituximab
PLTCL
21 months
alive
EBV+, CD20+
B-lymphoprol.
23 months
early death
m, 59y
AILT
outcome
refractory to CT,
death
AILT
n = 20, HOVON 69 trial, 8x CHOP-21 w 8x 90 mg alemtuzumab
Kluin-Nelemans et al. Blood 2008: 02-138800
EBV associated secondary NHL post CHOP w alemtuzumab
HOVON 69
GITIL-trial
ACT-2
CX
8x CHOP-21
8x CHOP-28
6x CHOP-14 6x CHO(E)P-14
alemtuzumab
720
240 (n=20)
120 (n=4)
360
133
time of cx
[weeks]
24
32
12
12 / 4
observation
24+
11 (5-42)
24+
n
20
24
41 / 29
EBV-associated
sec. NHL
3
0
0
cumulative
DSHNHL 2003-1
[months]
Hochdosistherapie und autologe SZT bei PTCL
Author
(year)
n
Regimen
Response
OS
Histology
Gisselbrecht
(2002)
43
33
BEAM + ASCT
ACVBP
No data
32% (5-year )
39% (5-year)
ALCL : 29 (ALK unknown)
PTCL: 55 (12 LBL)
Corradini
(2006)
62
Mito/Mel or
BEAM
74%
CR/PR
34% (12-year )
ALCL: 19
PTCL-U: 28
Mercadal
(2006)
41
HighCHOP/ES
HAP
60%
CR/PR
39% (4-year )
No ALK+ ALCL
D´Amore
(2006)
129
BEAM
na
67% (3-year )
No ALK+ ALCL
Rodriguez
(2007)
26
MegaCHOP+/IFE
73%
CR/PR
73% (3-year )
No ALK+ ALCL
Reimer
(ASH 2005)
65
Cy/TBI
69%
CR/PR
50% (3-year )
No ALK+ ALCL
HD Therapie bei PTCL phase II: Probleme
sekundär
refraktär
primär
refraktär
stabile
Remission
100%
Dx
65-75%
HDT
35…%
3yEFS
HD Therapie bei PTCL phase II: MegaCHOEP II / III
1
0.9
Event free survival (%)
0.8
n=36
0.7
0.6
total
1.5 year rate
95%CI
31 %
(16%;46%)
3 year rate
0.5
24 %
(9%;38%)
0.4
0.3
0.2
0.1
0
0
1
2
3
Years
DSHNHL 08.03.07
4
5
6
HD Therapie bei PTCL phase II: autologe versus allogene SZT
first-line treatment of mature (peripheral)
T-cell lymphoma (PTCL), patients 60 years
inclusion criteria
• Peripheral T-cell lymphoma, unspec’d (PTCLu)
• Angioimmunoblastic T-cell lymphoma (AIL)
• Anaplastic large cell lymphoma, ALK negative
• Extranodal NK/T-cell lymphoma, nasal type
• Enteropathy type T-cell lymphoma
• Hepatosplenic T-cell lymphoma
• Subcutaneous panniculitis type T-cell lymphoma
C
H
O
P
C
H
O
P
C
H
O
P
CR, PR, NC
D
H
A
P
B
E
A
M
A
S
C
T
C
H
O
P
C
H
O
P
C
H
O
P
C
H
O
P
CR, PR, NC
D
H
A
P
F
B
C
S
C
T
R
• all stages and IPI except stage I with aaIPI 0
days
R
C
H
O
P
1
15
29
43
64
|––-–– 4 - 6 weeks –-–––|
= At diagnosis, patients are randomized to allogeneic or autologous transplantation. Donor search (family or unrelated) will be
initiated only in patients randomized to allogeneic transplantation. Patients randomized to allogeneic tx but without a donor
will receive autologous tx. Peripheral blood stem cells are harvested after DHAP in patients who are to receive autologous tx
(randomized or crossed over from the allogeneic transplant arm because no donor is available).
ASCT = autologous stem cell transplantation, SCT = allogeneic stem cell transplantation
Allogene SZT bei rezidiviertem aggressiven NHL: konv. Konditionierung
n=111
Sung-Won et al. Blood 2006
PTCL im Rezidiv: allogene SCT nach Dosis-reduzierter Konditionierung
n=17
Corradini et al. JCO 2004
allogeneic SCT in relapsed PTCL: Göttingen experience
indication:
relapsed peripheral T-cell lymphoma, chemosensitive
conditioning:
fludarabin/busulfan (12 mg/kg bw)/cyclophosphamide
n:
20
OS:
11/20, median observation 4 months (range 1-47 months)
early death (TRM100):
3 / 20
late death (relapse):
3 / 20
late death (non-relapse): 3 / 20
novel substances
agent
target
indication
ORR
[%]
author
Gemcitabine
AraG 506U78
nucleosid
analoga
PTCL
PTCL
60
14
Sallah 2001
Czucsman 2004 a
Denileukin
Difitox
Il-2R
PTCL
50
Dang 2004 a
Depsipeptide
SAHA
HDAc
PTCL
26
Piekarz 2005a
SGN30
CD30
ALCL
33
Forero-Torres 2004a
Zanolimumab (CD4), Daclizumab (Il-2R), Bevacizumab
Sorafenib (TKI), Thalidomide (IMID), Bortezomib (proteasome)
Zusammenfassung PTCL
heterogene Gruppe von histologisch, immunologisch und nach
Expressionsprofil klassifizierbaren Typen
ALK pos. ALCL: unter Anthracyclin-haltige Chemotherapie gute Prognose,
ansonsten Ergebnisse der konventionellen Therapie unbefriedigend
Primärtherapie
in Studien Evaluation von Alemtuzumab (DSHNHL 20061B, ACT-2)
HD-Therapie mit autologer bzw. allogener Stammzelltransplantation
(DSHNHL 2006-1A)
Sekundärtherapie
allogene SZT (DSHNHL 2003-R4); innovative, zielgerichtete Therapien (Studien)
Vielen Dank
DSHNHL
Kompetenznetz maligne Lymphome
Ihnen für Ihre Aufmerksamkeit