1. Mantelzell-Lymphom- Aktuelle Standards und Studienkonzepte
internet: •
Symposium des KML * DGHO 2008 * Wien, 13. Oktober 2008
Mantelzell-Lymphom-
Aktuelle Standards und Studienkonzepte
M. Dreyling,
Dept. of Medicine III
Klinikum Grosshadern LMU/München

2. 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
clinical outcome:
predominantly elderly, male patients, extranodal involvement, late stage, poor outcome
83%
20%
W. Ludwig, Berlin

3. Clinical risk factors: MIPI clinical
(PALL: PS, age, LDH, leucocyte count)
Hoster, Blood 2008

4. elderly patient (>65) compromised patient
young patient (<65)
elderly patient (>65)
compromised patient
First line treatment
conventional
immuno-chemotherapy
(e.g. R-CHOP)
Rituximab maintenance ?
radioimmunotherapy ?
dose-intensified immuno-chemotherapy
(either sequential: e.g. R-CHOP =>PBSCT
or R-Hyper-CVAD)
watch & wait ?
Rituximab monotherapy
Chlorambucil
Bendamustin
1. relapse
immuno-chemotherapy
(e.g. R-FC, R-Bendamustin)
molecular approaches ? autologous PBSCT
radioimmunotherapy ? Rituximab maintenance ?
high tumor load:
immuno-chemotherapy
(e.g. R-FC)
allo-transplant ?
radioimmunotherapy ? Rituximab maintenance ?
immuno-chemotherapy
(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

5. Rituximab + HyperCVAD/M-A in MCL
alternate cycles 1 and 2 every 21 days
cycle 1, 3, 5, 7 R-hyperCVAD
cycle 2, 4, 6, 8 R-M-A
day 1
day 21
Rituximab 375mg/m2 (day 1)
Methotrexate 200mg/m2 i.v. 2 hours (day 2)
Methotrexate 800mg/m2 i.v.continuous 22 h (day 2)
Cytarabine 1,000/3,000mg/m2 i.v. 2x 2h (days 3–4)
antifungal, antibacterial, antiviral prophylaxis: G-CSF !!!
Romaguera, JCO 2005

6. R-Hyper-CVAD Mantle cell lymphoma 100% 80% 60% 40% 20% 0% 1 2 3 4 5
Progression-free survival
80%
60%
40%
Progression
1-Year
At Risk
or Death
Estimate
20% 49 13
89% 0% 1 2 3 4 5
Years from Registration
Epner ASH 2007 #387

7. R-CHOP/High dose Ara-C => ASCT
Mantle cell lymphoma
R-CHOP/High dose Ara-C => ASCT
Geisler Blood 2008

8. (stem cell mobilization after course 4) (stem cell mobilization)
European MCL Network
patients <65 years
3 x R-CHOP
3 x R-DHAP
alternating
3 x R-CHOP
PR, CR!
(stem cell mobilization after course 4)
3 x R-CHOP
PR, CR!
DexaBEAM
(stem cell mobilization)
TBI 10 Gray
Ara-C 4 x 1.5 g/m2
Melphalan 140 mg/m2
Cyclo 120mg/kg
+ TBI 12 Gray
PBSCT
PBSCT

9. 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%

10. MCL younger Time to treatment failure

11. elderly patient (>65) compromised patient
young patient (<65)
elderly patient (>65)
compromised patient
First line treatment
conventional
immuno-chemotherapy
(e.g. R-CHOP)
Rituximab maintenance ?
radioimmunotherapy ?
dose-intensified immuno-chemotherapy
(either sequential: e.g. R-CHOP =>PBSCT
or R-Hyper-CVAD)
watch & wait ?
Rituximab monotherapy
Chlorambucil
Bendamustin
1. relapse
immuno-chemotherapy
(e.g. R-FC, R-Bendamustin)
molecular approaches ? autologous PBSCT
radioimmunotherapy ? Rituximab maintenance ?
high tumor load:
immuno-chemotherapy
(e.g. R-FC)
allo-transplant ?
radioimmunotherapy ? Rituximab maintenance ?
immuno-chemotherapy
(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

12. European MCL network studies
patients >60 years
4 x R-CHOP
3 x R-FC
PR, CR
4 x R-CHOP
3 x R-FC
PR, CR
IFN-α maintenance
(3 x 3 M IU/week)
or Peg-IFN
(1mg/kg week)
Rituximab
maintenance
(all 2 months)

13. MCL Elderly Response rate of induction
Documented Response
164
50%
Abort without staging 6 CR 55
35%
CRu 26
16%
CR+CRu: 51% PR 51
32%
CR+CRu+PR: 84% SD 5 3% PD 19 9% ED 4%

14. MCL elderly Time to treatment failure
51 events

15. MCL elderly Response duration in CR
4 events

16. elderly patient (>65) compromised patient
young patient (<65)
elderly patient (>65)
compromised patient
First line treatment
conventional
immuno-chemotherapy
(e.g. R-CHOP)
Rituximab maintenance ?
radioimmunotherapy ?
dose-intensified immuno-chemotherapy
(either sequential: e.g. R-CHOP =>PBSCT
or R-Hyper-CVAD)
watch & wait ?
Rituximab monotherapy
Chlorambucil
Bendamustin
1. relapse
immuno-chemotherapy
(e.g. R-FC, R-Bendamustin)
molecular approaches ? autologous PBSCT
radioimmunotherapy ? Rituximab maintenance ?
high tumor load:
immuno-chemotherapy
(e.g. R-FC)
allo-transplant ?
radioimmunotherapy ? Rituximab maintenance ?
immuno-chemotherapy
(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

17. 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 !

18. Bortezomib Ara-C combination in MCL Efficacy in vitro
Weigert Leukemia 2007

19. Bortezomib Ara-C combination in MCL Pilot phase
Weigert, ASH 2006

20. relapsed MCL (DHAB = R-HAD)
European MCL network
relapsed MCL (DHAB = R-HAD)
Patients: n=250, relapsed MCL
after/not appropriate for autologous PBSCT
Therapy: Dexamethasone 40 mg day 1-4
Rituximab mg/m2 day 1
Ara-C x 1–2 g/m2 day 2
+/-
Bortezomib 1,5 mg/m2 day 1, 4
Study aim: - Response rate
- Progression-free/overall survival
- Toxicity/feasability

21. Mantle cell lymphoma
Lenalidomide
Wiernik ASH 2006

22. Salvage Therapy R-FC(M) R-DHA(P) R-GemOx Lenalidomide 15mg p.o/d daily
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
Response
Staging PR, CR
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

23. clinical intergroup working party
European MCL Network
clinical intergroup working party
pathology panel
molecular markers
expression profiling
pharmacogenomics
MRD/
cytogenetics
WHO/ Kiel criteria
molecular
analysis
phase III studies (first line)
pathological review
virtual
tumor bank
patient
blood sample
phase II studies (relapse)
new
molecular markers
signal pathway of resistance
MRD
remission/
survival data
immunostaining of
molecular markers
central data base:
analysis of predictive and prognostic risk factors

24. European MCL Network: Clinical studies 2008/9
First line
< 65 years
> 65 years
R-CHOP vs. R-CHOP/DHAP
PBSCT
R-CHOP vs. R-FC
anti-CD20 vs. IFN
1. Relapse
> 65 years
< 65 years
R-chemo +/- Bortezomib
„Mini“ transplant
2. Relapse (or not qualifying for R-HAD)
Radio-immuno consolidation
Rad 001
(mTOR)
Lenalidomide consolidation
Bendamustin/ Temsirolimus