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

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

Mantle Cell Lymphoma – the course of disease 1975-82 None 9% CLB/P 19% COP 39% Other 18% CHOP 15% MCL: 6% 1996-2000 MCP 13% CHOP 52% R-CHOP 34% NHL Classification Project 1997 Weisenburger & Armitage 1996 Hermann et al 2008

Mantle Cell Lymphoma – the course of disease 1975-82 None 9% CLB/P 19% COP 39% Other 18% CHOP 15% We used to say MCL was one of the worst NHL subtypes, But it is actually heterogeneic MCL: 6% 1996-2000 MCP 13% CHOP 52% R-CHOP 34% NHL Classification Project 1997 Weisenburger & Armitage 1996 Hermann et al 2008

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

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

-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

Indolent MCL: Deferred treatment Martin et al 2009

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

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

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

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

Rituximab PFS TTTF Survival Rule et al 2014 Lenz et al 2005 Rule et al 2014 PFS TTTF Survival 22 44 mo 27 66 mo Griffiths et al US SEER Data: 1st-line chemo +/- Ritux Abrahamsson et al 2014 Nordic Data: +/- Ritux + chemo 13

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

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

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

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

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

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

Rummel et al.: Blood 114: 168 (abstr #405), 2009 Bendamustine: StiL NHL 1-2003: 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% 93 91 ns CR% 40 30 0.02 Rummel et al.: Blood 114: 168 (abstr #405), 2009 2 2

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

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

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

NLG-MCL4 LENA-BERIT Nordic Lymphoma Group

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 1 5 9 13 17 21 25 29 33 37 41 45 49 1 5 9 13 17 21 25 29 33 37 41 45 49 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

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 1 5 9 13 17 21 25 29 33 37 41 45 49 1 5 9 13 17 21 25 29 33 37 41 45 49 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

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 1 5 9 13 17 21 25 29 33 37 41 45 49 1 5 9 13 17 21 25 29 33 37 41 45 49 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

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

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 2014. Abstract 8500.

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 12.0-16.9 19.8-31.8 HR (95% CI) 0.63 (0.50-0.79) 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 2014. Abstract 8500.

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

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

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

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

Helsinki 2013 Dreyling et al 2014

Temsirolimus in relapsed refractory MCL: Author Dose/week n ORR% PFS Mo Witzig 2005 250 mg 34 38 6 Ansell 2008 25 mg 27 41 6 Ansell 2011 25mg + R 69 59 11 Hess 2009 175mg75 54 22 5 175mg25 54 6 4 Inv. choice 2 Hess 2011 R-Benda + T 50 mg/w feasible and promising

SPRINT TRIAL in R/R MCL: Lenalidomide vs investigator-chosen single agent Efficacy Lenalidomide IC* P Med PFS mo 8.7 (5.5-12.1) 5.2 (3.7-7.0) 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

Upstream events in BCR signaling. ”Signalosome” PI3Kδ idelalisib Wiestner A Blood 2012;120:4684-4691

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 43 32 75 30 26 56 23 17 40 15 9 24 3 3 6 0 0 0 Wang ML, et al. N Engl J Med. 2013;369:507-516.

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

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 1 5 9 13 17 21 25 29 33 37 41 45 49 53 57 61 65 69 73 77 81 Weeks Maintenance until progression Weeks

Upstream events in BCR signaling. ”Signalosome” PI3Kδ Idelalisib Wiestner A Blood 2012;120:4684-4691

2014

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;15:1126-1132

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)

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

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