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Symposium des KML * DGHO 2008 * Wien, 13. Oktober 2008
Mantelzell-LymphomAktuelle Standards
und Studienkonzepte
M. Dreyling,
Dept. of Medicine III
Klinikum Grosshadern
LMU/München
Mantle cell lymphoma (MCL)
• Morphology:
small to intermediate size lymphoid
cells with irregular, cleaved nuclei,
cave: round cell, blastoid and
pleomorphic variants
• Immunphenotype:
sIg++, l > k , CD19/20/22+, CD5+,
CD10-, CD23-, CD11c-, HLA-DR++,
CD43+
• molecular/cytogenetics:
t(11;14)(q13;q32);
overexpression of cyclin D1
83%
• clinical outcome:
predominantly elderly, male patients,
extranodal involvement,
late stage, poor outcome
20%
W. Ludwig, Berlin
Clinical risk factors: MIPI clinical
(PALL: PS, age, LDH, leucocyte count)
Hoster, Blood 2008
young patient (<65)
elderly patient (>65)
compromised patient
First line treatment
dose-intensified
immuno-chemotherapy
(either sequential:
e.g. R-CHOP =>PBSCT
or R-Hyper-CVAD)
conventional
immuno-chemotherapy
(e.g. R-CHOP)
Rituximab maintenance ?
radioimmunotherapy ?
watch & wait ?
Rituximab monotherapy
Chlorambucil
Bendamustin
1. relapse
high tumor load:
immuno-chemotherapy
(e.g. R-FC)
allo-transplant ?
radioimmunotherapy ?
Rituximab maintenance ?
immuno-chemotherapy
(e.g. R-FC,
R-Bendamustin)
molecular approaches ?
autologous PBSCT
radioimmunotherapy ?
Rituximab maintenance ?
immunochemotherapy
(e.g.
R-Bendamustin)
molecular approaches
higher relapse
molecular approaches: Bortezomib, CCI-779, Thalidomide/
Lenalidomide, Flavopiridol (preferable in combination)
repeat previous therapy (long remissions)
Dreyling ASCO 2006
Rituximab + HyperCVAD/M-A in MCL
alternate cycles 1 and 2 every 21 days
cycle 1, 3, 5, 7
cycle 2, 4, 6, 8
R-hyperCVAD
R-M-A
day 1
day 21
2
Rituximab 375mg/m (day 1)
2
Methotrexate 200mg/m i.v. 2 hours (day 2)
2
Methotrexate 800mg/m i.v.continuous 22 h (day 2)
2
Cytarabine 1,000/3,000mg/m i.v. 2x 2h (days 3–4)
antifungal, antibacterial, antiviral prophylaxis: G-CSF !!!
Romaguera, JCO 2005
Mantle cell lymphoma
R-Hyper-CVAD
100%
Progression-free survival
80%
60%
40%
Progression
At Risk
or Death
20%
49
1-Year
Estimate
13
89%
4
5
0%
0
1
2
3
Years from Registration
Epner ASH 2007 #387
Mantle cell lymphoma
R-CHOP/High dose Ara-C => ASCT
A: Event-free Survival proportions
80
MCL2 (n=160)
60
40
20
0
0.0
MCL1 (n=41)
P<0.0001
2.5
5.0
7.5
10.0
Years
B: Survival
100
Percent survival
Percent survival
100
80
MCL2 (n=160)
60
40
MCL1 (n=41)
20
P<0.001
0
0.0
2.5
5.0
7.5
10.0
Years
Geisler Blood 2008
European MCL Network
patients <65 years
3 x R-CHOP
PR, CR!
3 x R-CHOP
3 x R-DHAP
alternating
(stem cell
mobilization after
course 4)
3 x R-CHOP
PR, CR!
DexaBEAM
(stem cell mobilization)
Cyclo 120mg/kg
+ TBI 12 Gray
TBI 10 Gray
Ara-C 4 x 1.5 g/m2
Melphalan 140 mg/m2
PBSCT
PBSCT
MCL Younger
Response rate of induction
Documented response
189 55%
Abort without staging
2
CR
59
31%
CRu
40
21%
CR+CRu: 52%
PR
73
39%
CR+CRu+PR: 91%
SD
8
4%
PD
9
5%
ED
0
0%
MCL younger
Time to treatment failure
young patient (<65)
elderly patient (>65)
compromised patient
First line treatment
dose-intensified
immuno-chemotherapy
(either sequential:
e.g. R-CHOP =>PBSCT
or R-Hyper-CVAD)
conventional
immuno-chemotherapy
(e.g. R-CHOP)
Rituximab maintenance ?
radioimmunotherapy ?
watch & wait ?
Rituximab monotherapy
Chlorambucil
Bendamustin
1. relapse
high tumor load:
immuno-chemotherapy
(e.g. R-FC)
allo-transplant ?
radioimmunotherapy ?
Rituximab maintenance ?
immuno-chemotherapy
(e.g. R-FC,
R-Bendamustin)
molecular approaches ?
autologous PBSCT
radioimmunotherapy ?
Rituximab maintenance ?
immunochemotherapy
(e.g.
R-Bendamustin)
molecular approaches
higher relapse
molecular approaches: Bortezomib, CCI-779, Thalidomide/
Lenalidomide, Flavopiridol (preferable in combination)
repeat previous therapy (long remissions)
Dreyling ASCO 2006
European MCL network studies
patients >60 years
4 x R-CHOP
3 x R-FC
PR, CR
4 x R-CHOP
IFN-α maintenance
(3 x 3 M IU/week)
or Peg-IFN
(1mg/kg week)
3 x R-FC
PR, CR
Rituximab
maintenance
(all 2 months)
MCL Elderly
Response rate of induction
Documented Response
Abort without staging
164
50%
6
CR
55
35%
CRu
26
16%
CR+CRu: 51%
PR
51
32%
CR+CRu+PR: 84%
SD
5
3%
PD
19
9%
ED
6
4%
MCL elderly
Time to treatment failure
51 events
MCL elderly
Response duration in CR
4 events
young patient (<65)
elderly patient (>65)
compromised patient
First line treatment
dose-intensified
immuno-chemotherapy
(either sequential:
e.g. R-CHOP =>PBSCT
or R-Hyper-CVAD)
conventional
immuno-chemotherapy
(e.g. R-CHOP)
Rituximab maintenance ?
radioimmunotherapy ?
watch & wait ?
Rituximab monotherapy
Chlorambucil
Bendamustin
1. relapse
high tumor load:
immuno-chemotherapy
(e.g. R-FC)
allo-transplant ?
radioimmunotherapy ?
Rituximab maintenance ?
immuno-chemotherapy
(e.g. R-FC,
R-Bendamustin)
molecular approaches ?
autologous PBSCT
radioimmunotherapy ?
Rituximab maintenance ?
immunochemotherapy
(e.g.
R-Bendamustin)
molecular approaches
higher relapse
molecular approaches: Bortezomib, CCI-779, Thalidomide/
Lenalidomide, Flavopiridol (preferable in combination)
repeat previous therapy (long remissions)
Dreyling ASCO 2006
Bortezomib: Mechanism of action
26S proteasome:
degrades tagged proteins
Bortezomib:
reversible inhibitor
of the proteasome
Inhibition:
prevents proteolysis
of tagged proteins
Clinical studies: bortezomib cytotoxic to a variety of lymphomas !
Bortezomib Ara-C combination in MCL
Efficacy in vitro
Weigert Leukemia 2007
Bortezomib Ara-C combination in MCL
Pilot phase
Weigert, ASH 2006
European MCL network
relapsed MCL (DHAB = R-HAD)
Patients:
n=250, relapsed MCL
after/not appropriate for autologous PBSCT
Therapy:
Dexamethasone 40 mg
Rituximab
375 mg/m2
Ara-C
2 x 1–2 g/m2
+/Bortezomib
1,5 mg/m2
Study aim: - Response rate
- Progression-free/overall survival
- Toxicity/feasability
day 1-4
day 1
day 2
day 1, 4
Mantle cell lymphoma
Lenalidomide
Wiernik ASH 2006
PT
Histology Initi
Best
Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day Day
Response 4
5
20 30 50 51 53 54 58 75 89 91 104 106 108 116 117 122 135 140 170 190 222 229 239 272 373
FCL
SB
CRu
DLC
BS
Cru
DLC
TP
Cru
DLC
KJS
Cru
MCL
SLR
PR
20
MCL
VFG
PR
20
FCL
GO
PR
MCL
BMF
PR
DLC
CD
PR
MCL
JMP
PR
MCL
LMM
PR
TSF
RE
PR
MCL
ERD
PR
15
10
20
20
15
20
20
15
20
20
TSF
KBA
SD
DLC
RA
SD
DLC
BP
SD
DLC
LG
SD
MCL
ET
SD
DLC
GAW
SD
20
MCL
GHM
XPD
20
DLC
OWF
XPD
20
DLC
JET
XPD
DLC
PC
XPD
DLC
RB
XPD
MCL
MR
XPD
MCL
TF
XPD
DLC
JAL
XPD
MCL
JES
XPD
DLC
RF
XPD
DLC
AD
XPD
FCL
RCS
XPD
MCL
FG
XPD
20
10
15
15
15
10
Feasability and efficacy of Lenalidomide maintenance
after prior immuno-chemotherapy induction in relapsed
or refractory mantle cell lymphoma
Inclusion Criteria
•
•
•
Histologically proven MCL
Not eligible / relapse after ASCT
> 1 prior chemotherapy
Recruitment
N=60
Salvage
Therapy
R-FC(M)
R-DHA(P)
R-GemOx
Staging
PR, CR
Response
Endpoints
•
•
•
•
•
Feasability
Duration of Response
TTP and PFS
OS
Safety
Lenalidomide
15mg p.o/d
daily
PD or Toxicity
National centers: Essen, Homburg, Kiel, Mainz, GH-LMU, Tübingen, Ulm
www.european-mcl.net
European MCL Network
clinical intergroup
working party
pathology panel
molecular markers
expression
profiling
pharmaco
genomics
MRD/
cytogenetics
WHO/ Kiel
criteria
phase III studies
(first line)
phase II studies
(relapse)
remission/
survival data
pathological
review
immunostaining of
molecular markers
molecular
analysis
virtual
tumor bank
patient
blood sample
new
molecular
markers
signal
pathway of
resistance
central data base:
analysis of predictive and prognostic risk factors
MRD
European MCL Network: Clinical studies 2008/9
First line
< 65 years
> 65 years
R-CHOP vs. R-CHOP/DHAP
R-CHOP vs. R-FC
PBSCT
anti-CD20 vs. IFN
1. Relapse
> 65 years
R-chemo +/- Bortezomib
2. Relapse
Radio-immuno
consolidation
Rad 001
(mTOR)
< 65 years
„Mini“ transplant
(or not qualifying for R-HAD)
Lenalidomide
consolidation
Bendamustin/
Temsirolimus
www.european-mcl.net