1. Disclosures Geisler:
Advisory boards and IDMC’s:
Roche, Janssen, Celgene, Gilead, Novartis

2. Mantle Cell Lymphoma –a rare lymphoma of the elderly
Median age at diagnosis ~70
Andersen et al 2002, Danish Population Study
And widespread at
diagnosis
Abrahamsson et al 2014: Swedish-Danish Population Study 2

3. Mantle Cell Lymphoma – the course of disease
None %
CLB/P 19%
COP %
Other 18%
CHOP 15%
MCL: 6%
MCP %
CHOP %
R-CHOP 34%
NHL Classification Project 1997
Weisenburger & Armitage 1996
Hermann et al 2008

4. Mantle Cell Lymphoma – the course of disease
None %
CLB/P 19%
COP %
Other 18%
CHOP 15%
We used to say MCL was one of the worst NHL subtypes,
But it is actually heterogeneic
MCL: 6%
MCP %
CHOP %
R-CHOP 34%
NHL Classification Project 1997
Weisenburger & Armitage 1996
Hermann et al 2008

5. Further genomic aberrations of cell cycle & DNA damage patwhay
CCND1
SOX-11
Campo & Jares 2007

6. SOX-11-pos.
CCND1
SOX-11
SOX-11-neg.
Campo & Jares 2007

7. -genetically unstable -spreads to lymph nodes -agressive disease
SOX-11-pos.
-does not enter the GC
IGHV unmutated
-genetically unstable
-spreads to lymph nodes
-agressive disease
CCND1
SOX-11
SOX-11-neg.
SOX-11
SOX-11, a transcription factor,
promotes MCL tumor growth in vivo
and regulates:
- B-cell differentiation,
- cell proliferation,
- apoptosis,
- angiogenesis.
Strong direct target: PAX5,
blocking differentiation into plasma cells.
enters the GC
IGHV mutated
genetically stable
Spreads to blood/spleen
stable disease
Fernandez et al 2010

8. Indolent MCL: Deferred treatment
Martin et al 2009

9. Mantle cell lymphoma International prognostic Index: MIPI
Built on 455 pts from three randomized trials:
CHOP vs MCP
CHOP vs R-CHOP
ASCT vs IFN
MIPI-B: MIPI + Ki67
MIPI: Age
Performance
LDH
WBC
MIPI-B
Google MIPI Rechner
Age at Diagnosis:
Years
ECOG Performance Status:
LDH:
U/l or μkat/l
LDH - Upper Limit of Normal:
Leukocyte Count:
/μl
Hoster et al 2008 9

10. Mantle Cell Lymphoma: How to improve?
MIPI-B: MIPI + Ki67
Rituximab?
Intensify induction?
Targeted therapy?
Maintenance?
-1st-line
Relapsed/refractory 10

11. Mantle Cell Lymphoma: How to improve?
MIPI-B: MIPI + Ki67
Rituximab?
Intensify induction?
Targeted therapy?
Maintenance?
-1st-line
Relapsed/refractory 11

12. Mantle Cell Lymphoma: How to improve?
MIPI-B: MIPI + Ki67
Rituximab?
Intensify induction?
Small molecules?
Maintenance? 12

13. Rituximab PFS TTTF Survival Rule et al 2014
Lenz et al 2005
Rule et al 2014
PFS
TTTF
Survival mo mo
Griffiths et al US SEER Data:
1st-line chemo +/- Ritux
Abrahamsson et al 2014
Nordic Data: +/- Ritux + chemo 13

14. Mantle Cell Lymphoma: How to improve?
MIPI-B: MIPI + Ki67
Rituximab?
Intensify induction?
Small molecules?
Maintenance? 14

15. First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010)
European MCL Network
First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010)
Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review
8 x R-CHOP
6 x R-FC
CR,CRu,PR
Exp. arm
IFN-a maintenance
(3 x 3 M IU/week)
or Peg-IFN
(1ug/kg week)
Rituximab
maintenance
(all 2 months)
JC Kluin-Neelemans et al N Engl J Med 2012;367:520-31

16. European MCL Network
MCL Elderly: Overall survival Induction R-CHOP vs R-FC intention-to-treat analysis
More toxicity in FCR arm
Leading to less treatment* and
More progression
And More R-FC patients than
R-CHOP patients died in CR
(10 vs 4%) due to infection
*23% of FC responders and
12% of CHOP responders
did not complete therapy
JC Kluin-Neelemans et al N Engl J Med 2012;367:520-31

17. MCL Elderly overall survival Interaction of induction and maintenance
European MCL Network
MCL Elderly overall survival Interaction of induction and maintenance
After R-CHOP
After R-FC
Cox analysis: p=0.055 for interaction of induction and maintenance
JC Kluin-Neelemans et al N Engl J Med 2012;367:520-31

18. Mantle Cell Lymphoma: How to improve?
MIPI-B: MIPI + Ki67
After all limited in elderly patients
Rituximab?
Intensify induction?
Small molecules?
Maintenance?  SOC 18

19. CLL Comprehensive Geriatric Assessment (CGA)
Group 1
completely independent
no comorbidity
normal, age-matched life expectance
Group 2
somewhat impaired
Group 3
Severely handicapped
high comorbidity
reduced life expectance
„Go go“
Intensive therapy: FC, FCR, Tx
 long lasting remissions! Cure?
„Slow go“
Mild therapy: CLB, Bendamustine
 control of symptoms
„No go“
Palliative care:
Prednisone
Antibodies
CIRS > 6 0%
20%
40%
60%
80%
100% 70 80 90
Age
„No go“
„Slow go“
„Go go“
Adapted from Michael Hallek 5 19 19

20. Rummel et al.: Blood 114: 168 (abstr #405), 2009
Bendamustine: StiL NHL : 1st-line treatment
Progression free survival
MCL (88)
Follicular
Waldenströms
Marginal zone
Small lymphocytic
Mantle cell
R-Bendamustine R
R-CHOP
R-Bendamustine 90 mg/m2 D 1+2, 6 cycles, q 4 wks.
R-CHOP q3 weeks
All subtypes: BR CHOP-R P
ORR% ns
CR%
Rummel et al.: Blood 114: 168 (abstr #405), 2009 2 2

21. Mantle Cell Lymphoma How to improve further? Intensify induction?
Antibodies?
ASCT?
Targeted therapy?
Maintenance?
Lenalidomide
Proteasome inhibitors
mTor inhibitors
BCR inhibitors
Bcl-2 inhibitors 21

22. Is it still relevant in era of small molecules?
CLL Comprehensive Geriatric Assessment (CGA)
Group 1
completely independent
no comorbidity
normal, age-matched life expectance
Group 2
somewhat impaired
Group 3
Severely handicapped
high comorbidity
reduced life expectance
„Go go“
Intensive therapy: FC, FCR, Tx
 long lasting remissions! Cure?
„Slow go“
Mild therapy: CLB, Bendamustine
 control of symptoms
„No go“
Palliative care:
Prednisone
Antibodies
Is it still relevant in era of small molecules? 0%
20%
40%
60%
80%
100% 70 80 90
Age
„No go“
„Slow go“
„Go go“
Adapted from Michael Hallek 5 22 22

23. Mantle Cell Lymphoma How to improve further? Intensify induction?
Antibodies?
ASCT?
Targeted therapy?
Maintenance?
Lenalidomide
Proteasome inhibitors
mTor inhibitors
BCR inhibitors
Bcl-2 inhibitors 23

24. NLG-MCL4 LENA-BERIT
Nordic Lymphoma Group

25. Nordic-MCL4 (LENA-BERIT)
Phase I-II, 60 elderly/frail patients CT
CT, PET
MRD
CT, PET
MRD
LBR
LBR
LBR
LBR
LBR
LBR L L L L L L L
Weeks
B70R C1-6,
L 10 mg D1-14 C2-6,
Maint 10mg D1-21 C7-13
Jerkeman et al ASH 2011
 Update Lugano 2015

26. NLG-MCL4 (LENA-BERIT) Phase I-II, 60 patients CT CT, PET MRD CT, PET
LBR
LBR
LBR
LBR
LBR
LBR L L L L L L L
Weeks
B70R C1-6,
L 10 mg D1-14 C2-6,
Maint 10mg D1-21 C7-13
Efficacy %
ORR
100
CRR 90
Pet-neg.
10/11 (91%)
MRD-neg
11/18 (61%)
Jerkeman et al ASH 2011

27. NLG-MCL4 (LENA-BERIT) Phase I-II, 60 patients CT CT, PET MRD CT, PET
LBR
LBR
LBR
LBR
LBR
LBR L L L L L L L
Weeks
B70R C1-6,
L 10 mg D1-14 C2-6,
Maint 10mg D1-21 C7-13
Efficacy %
ORR
100
CRR 90
Pet-neg.
10/11 (91%)
MRD-neg
11/18 (61%)
To be updated
Jerkeman et al Lugano 2015:
Stil very high responses, but
maintenance treatment
not well tolerated,
PFS not prolonged comp.
To historic contols.
Jerkeman et al ASH 2011

28. Mantle Cell Lymphoma How to improve further? Intensify induction?
Antibodies?
ASCT?
Targeted therapy?
Maintenance?
Lenalidomide
Proteasome inhibitors
mTor inhibitors
BCR inhibitors
Bcl-2 inhibitors 28

29. R-CHOP vs VR-CAP as First-line Treatment for Newly Diagnosed MCL
Randomized, open-label, multicenter phase III study in newly diagnosed patients with MCL
Primary endpoint: PFS
R-CHOP
Rituximab 375 mg/m2 IV on Day 1
Cyclophosphamide 750 mg/m2 IV on Day 1
Doxorubicin 50 mg/m2 IV on Day 1
Prednisone 100 mg/m2 PO on Days 1-5
Vincristine 1.4 mg/m2 (max 2 mg) IV on Day 1
6-8 cycles, q3w
(n = 244)
Newly diagnosed MCL pts
Stage II-IV, ECOG PS 0-2
Ineligible or not
considered for BMT
(N = 487)
VR-CAP
Rituximab 375 mg/m2 IV on Day 1
Cyclophosphamide 750 mg/m2 IV on Day 1
Doxorubicin 50 mg/m2 IV on Day 1
Prednisone 100 mg/m2 PO on Days 1-5
Bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, 11
6-8 cycles, q3w
(n = 243)
Cavalli F, et al. ASCO Abstract 8500.

30. Superior PFS by IRC With VR-CAP vs R-CHOP: 59% Improvement
100
R-CHOP
VR-CAP
Events, n
165
133
Median PFS, mos
14.4
24.7
95% CI
HR (95% CI)
0.63 ( )
P value
< .001
R-CHOP VR-CAP 80 60
Patients Alive and Progression Free (%) 40 20 6 12 18 24 30 36 42 48 54 60 66
Mos From Randomization
Additional Outcomes
R-CHOP
VR-CAP OR
P Value
CR + CRu, % 42 53
1.69
.007
ORR (CR + CRu + PR), % 90 92
1.43
.275
Median duration of response, mos
15.1
36.5 NA
4-yr OS rate, %
53.9
64.4
Cavalli F, et al. ASCO Abstract 8500.

31. Ibrutinib trials 1.st-line Elderly MCL
UK ENRICH TRIAL (Simon Rule):
R-Chemo vs R-Ibrutinib.

32. Mantle Cell Lymphoma: How to improve?
MIPI-B: MIPI + Ki67
Rituximab?
Intensify induction?
Targeted therapy?
Maintenance?
-1st-line
Relapsed/refractory 32

33. Other trials relapsen/refractory MCL
PFS of:
- R-benda
- Previous regimen
Rummel et al 2005

34. Mantle Cell Lymphoma How to improve further? Intensify induction?
Antibodies?
ASCT?
Targeted therapy?
Maintenance?
Lenalidomide
Proteasome inhibitors
mTor inhibitors
BCR inhibitors
Bcl-2 inhibitors 34

35. Helsinki 2013
Dreyling et al 2014

36. Temsirolimus in relapsed refractory MCL:
Author Dose/week n ORR% PFS Mo
Witzig mg
Ansell mg
Ansell mg + R
Hess mg
175mg
Inv. choice 2
Hess R-Benda + T 50 mg/w feasible and promising

37. SPRINT TRIAL in R/R MCL: Lenalidomide vs investigator-chosen single agent
Efficacy
Lenalidomide
IC* P
Med PFS mo
8.7 ( )
5.2 ( )
0.0044
ORR % 40 9
<0.001
CR/CRu % 5
0.043
Med DOR mo
16.1
10.4
0.4
Med OS
27.9
21.2
0.52
*Inv. Choice
Single drug:
-cytarabine,
-rituximab,
-gemcitabine,
-fludarabine or
-chlorambucil. 
Toxicity Gr 3-4
Lenalidomide
IC*
Neutropenia %
44*
*Inf. Not increased 34
Thrombocytopenia% 18 28
Tumor flare % 10
Invasive 2nd pr mal % 4 5

38. Upstream events in BCR signaling.
”Signalosome”
PI3Kδ
idelalisib
Wiestner A Blood 2012;120:

39. Ibrutinib in R/R MCL: OS by Previous Bortezomib Exposure
100 90 80 70 60
Patients Alive Without Progression (%) 50 40
All Bortezomib exposure No bortezomib exposure 30 20 10 4 8 12 16 20
Mos Since First Documentation of Response
Pts at Risk, n No bortezomib exposure Bortezomib exposure All
3 3 6
0 0 0
Wang ML, et al. N Engl J Med. 2013;369:

40. Nordic Philemon - Chemo-free: R-Lenalidomide-Ibrutinib

41. Maintenance until progression
NLG-MCL6 (PHILEMON)
Phase I-II, 60 patients R R R R R R R R R R R R R R CT
CT, PET
MRD
CT, PET
MRD LI LI LI LI LI LI LI LI LI LI LI LI I I I I I I I I I
Weeks
Maintenance until progression
Weeks

42. Upstream events in BCR signaling.
”Signalosome”
PI3Kδ
Idelalisib
Wiestner A Blood 2012;120:

43. 2014

44. Bcl2-homology (BH) domains
Intrinsic pathway
”Cellular Stress”
BH3-only proteins:
MAC:
Cyt c
Bcl2-homology (BH) domains
”MAC”: Mitochondrial
apoptosis induced channel/
MOMP: Mitochondrial
outer membrane pore
Kang M H , and Reynolds C P Clin Cancer Res 2009;15:

45. Overall Responses in ABT-199 Treated NHL Patients
Matthew S. Davids, et al, ASH 2013
The Single-Agent Bcl-2 Inhibitor ABT-199 (GDC-0199) In Patients With Relapsed/Refractory (R/R) Non-Hodgkin Lymphoma (NHL): Responses Observed In All Mantle Cell Lymphoma (MCL) Patients
Overall Responses in ABT-199 Treated NHL Patients
↵ In DLBCL and FL pts, all responses occurred at doses ≥600 mg.
↵ 2 pts discontinued due to PD prior to first response assessment (1 MZL and 1 DLBCL)
Histology
Overall Response (CR + PR)
Complete Response n (%)
Partial Response n (%)
Stable Disease n (%)
Progressive Disease n (%)
Total (n=32)
53%
2/32 (6)
15/32 (47)
9/32 (28)
6**/32 (19)
DLBCL*
38%
1/8 (13)
2/8 (25)
4/8 (50)
FL*
27% -
3/11 (27)
8/11 (73)
MCL
100%
8/8 (100) MM
1/1 (100)
MZL WM
1/3 (33)
2/3 (67)

46. Adapted from Campo & Rule 2015
MCL treatment algorithm, 1st-line
Young and fit
Elderly
or Bendamustine?
Eg. R-FC-lite
LYMA Trial
Adapted from Campo & Rule 2015

47. Relapsed MCL in elderly
Relapse after R-chemo
DOR > 2 years
DOR < 2 years
Repeat/
Other R-chemo/
Clinical trial
Clinical trial
Or consider:
Ibrutinib
R-Bortezomib
R-Temsirolimus
R-lenalidomide