1. Mantle Cell Lymphoma: How are novel agents changing the therapeutic platform?
Michael E. Williams, MD, ScM
Byrd S. Leavell Professor of Medicine
Chief, Hematology/Oncology Division
Director, Hematologic Malignancies Program
University of Virginia Cancer Center
Charlottesville

2. Challenges in MCL Improve understanding of pathogenesis
Genetics, epigenetics, microenvironment
Risk-adapted therapies
Address clinical and biologic heterogeneity
Role for MIPI, Ki-67, MRD?
Timing and type of therapy
Induction therapy for younger/fit vs older/less fit
Role of dose-intensive regimens and SCT
Therapeutic sequencing
Targeting relevant molecular pathways
Rare disease, limiting patients for clinical trials

3. Treatment Approach in MCL
Modified From: Dreyling and Williams, in Lymphoma: Pathology, Diagnosis and Treatment; Marcus, Sweetenham & Williams, Eds. Cambridge Univ. Press, 2nd ed, 2013

4. CHOP ± Rituximab in MCL: Progression-Free Survival
1.00
0.75
R-CHOP (35/58)
P=0.31
Probability
0.50
CHOP (23/44)
0.25 1 2 3 4
Years
Lenz et al. J Clin Oncol

5. Intensive Treatment Options The role of high-dose cytarabine and ASCT

6. R-HyperCVAD Alternating With R-M/A as Initial Therapy in MCL: FFS
Romaguera et al. Blood 2008; 112 (11): abstract #833

7. R-HyperCVAD Alternating With R-M/A as Initial Therapy in MCL
Italian multicenter Phase II MCL trial (n=60) Merli et al, Brit J Haem 2011
ORR = 83%, CR = 72%
Estimated 5-year OS = 73% and PFS = 61%
Only 37% completed all Rx, 3 deaths on study
US Multicenter Phase II Trial, SWOG 0213 (n=49)
Bernstein et al. Annals Oncol 2013
ORR = 86%, CR/CRu = 55%
Median PFS 4.8 yr, Median OS 6.8 yr
39% did not complete Rx due to toxicity
1 Rx-related death, 2 MDS

8. * Due to decreased ability to collect stem cells in HyperCVAD arm
SWOG 1106  CLOSED* A RANDOMIZED PHASE II TRIAL OF INDUCTION FOLLOWED BY CONSOLIDATION WITH AUTOLOGOUS STEM CELL TRANSPLANT FOR PATIENTS ≤ 65 YEARS OF AGE WITH PREVIOUSLY UNTREATED MANTLE CELL LYMPHOMA
Induction #1
Induction #2 R
≥ PR
R-HCVAD Cycle 3 Collect stem cells
R-MTX/Ara-C Cycle 4
≥ PR
R-HCVAD Cycle 1 R-MTX/Ara-C Cycle 2
Auto SCT A N D O M I
≥ PR
≥ PR
R-Bendamustine Cycles 1-4
R-Bendamustine x 2 Cycles 5-6
Mobilization/
Auto SCT Z E
* Due to decreased ability to collect stem cells in HyperCVAD arm

9. R-maxi-CHOP alternating with R-HiDAC  ASCT in MCL: The Nordic Study
100
5-year Outcomes
MCL-2 Survival (n = 160)
75% 80
MCL-2 EFS (n = 160)
MCL-1 EFS (n = 41) 60
63%
Percentage of Patients 40
15%
Maxi-CHOP, No Hi-Dac, Rituximab or SCT 20
EFS, MCL 1 vs MCL 2: P < .0001
0.0
2.5
5.0
7.5
10.0
Years
Geisler CH, et al. ASH Abstract LB1; Andersen et al, JCO 2009; 27

10. European MCL Younger Phase III Trial: R-CHOP vs R-CHOP/R-DHAP  ASCT
(2+1) x R-CHOP/R-DHAP
alternating
4 x R-CHOP
2 x R-CHOP
PR, CR
Stem cell mobilization after course 6
DexaBEAM
(stem cell mobilization)
PR, CR
TBI 10 Gray
Ara-C 4x1.5 g/m2
Melphalan 140 mg/m2
Cyclo 120mg/kg
+ TBI 12 Gray
PBSCT
PBSCT
Update November 19, 2010, European MCL Network, V ; O.Hermine, ASH 2010, Blood 116; Abstract 110 10

11. European MCL Network “Younger” Trial: Is High-dose AraC Important?
Pts < 65 years,n = 497
83% of R-CHOP and 80% R-DHAP  ASCT
Results: R-CHOP versus R-CHOP/R-DHAP
Post-Induc: ORR 90% v 95%, CR 25% v 36%
Post-ASCT: ORR 98% v 97%, CR 62% v 61%
MRD tested by PCR
Timepoints: mid-induction, post-induction, post-ASCT, during follow-up
O.Hermine, ASH 2012, abstract 151; Pott et al, Blood 2010

12. MCL Younger: Time to treatment failure
Hazard Ratio 0.68
(one sided sequential test)
Hermine et al, ASH Update September 26, 2012, European MCL Network, V 12

13. MCL Younger: Overall Survival
ARM 24 36 48
R-DHAP
88%
83%
80%
R-CHOP
76%
74%
Hermine et al, ASH Update September 26, 2012, European MCL Network, V 13 13

14. Should molecular remission be a goal of therapy?
Also see Fulton et al, ASH 2013, #3002, Sunday poster session

15. Impact of ASCT on MRD Status
MCL Younger:
Impact of ASCT on MRD Status
100
R-CHOP
R-DHAP ns ns
p = 0.04 *
p = 0.01 * 75 * *
82%
87%
82%
73%
% MRD negative 50
70%
60% 25
54%
36% PB BM PB BM
Hermine et al, ASH Update September 26, 2012, European MCL Network, V

16. MCL Younger: Remission Duration by MRD Status
after Induction (pooled Arms; n = 142)
Hermine et al, ASH Update September 26, 2012, European MCL Network, V

17. MCL Younger: Conclusions
R-CHOP/R-DHAP is superior to R-CHOP
Significantly improves TTF in all MIPI groups
Faster response kinetics
Higher efficacy to MRD negativity
Trend for improved OS
ASCT contributes to molecular remission in both treatment arms, moreso after R-CHOP
MRD is the strongest prognostic factor for outcome after induction and ASCT
Hermine et al, ASH 2012, abstract 151; C. Pott et al, Blood 2010

18. Bendamustine

19. Bendamustine: Chemical Structure
Cheson B D , Rummel M J JCO 2009;27:1492

20. Recommended Bendamustine Dosing
Initial therapy:
90 mg/m2 d 1-2, q 3-4 wk
Prior cytotoxic therapy:
60-70 mg/m2 d 1-2, q 4 wk
Dosing in renal or hepatic dysfunction not fully defined
Precautions:
Myelosuppression, infections
Infusion reactions, tumor lysis syndrome
Rash, esp. with concomitant allopurinol
Cheson BD et al. Clinical Lymphoma, Myeloma & Leukemia 2010; 10:21-7

21. Bendamustine-Rituximab (BR) vs CHOP-R
StiL NHL
Bendamustine-Rituximab
- Bendamustine 90 mg/m2 day 1+2
- Rituximab 375 mg/m2 day 1
Follicular
Waldenström’s
Marginal zone
Small lymphocytic
Mantle cell (elderly) R
CHOP-Rituximab
- Cyclophosphamide 750 mg/m2 day 1
- Doxorubicin 50 mg/m2 day 1
- Vincristine 1.4 mg/m2 day 1
Prednisone 100 mg days 1-5
Rituximab 375 mg/m2 day 1
Rummel et al. ASCO Plenary 2012, abstract # 3

22. Progression free survival Subentities
1.0
Follicular
p = 0,0072
1.0
Mantle cell
p = 0,0061
0.9
0.9
0.8
0.8
0.7
0.7
0.6
B-R
0.6
0.5
0.5
0.4
0.4
0.3
CHOP-R
0.3
B-R
0.2
0.2
CHOP-R
0.1
0.1
0.0
0.0
1.0
Marginal zone
p = 0,3249
1.0
Waldenström
p = 0,0033
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5
B-R
0.5
0.4
0.4
0.3
0.3
B-R
0.2
CHOP-R
0.2
0.1
0.1
CHOP-R
0.0
0.0 . 2 2

23. StiL NHL1: MCL Findings M Rummel et al, Lancet 2013; 381:1203-10
Median PFS: MCL
BR 35 mo vs R-CHOP 22 mo
Lower toxicity with BR
To date, no difference in rates of secondary malignancies or impaired stem cell collection
Supports BR as a front-line regimen for indolent B cell-NHL and MCL

24. BR x 6 Rituximab BVR x 6 Rituximab BR x 6 BVR x 6
E Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma
Randomized phase II, N ~ 328; 82 eligible per arm
BR x 6
Rituximab R E G I S T A O N
BVR x 6
Rituximab
BR x 6
Lenalidomide
+ Rituximab
Lenalidomide
+ Rituximab
BVR x 6
BR = Bendamustine, Rituximab
V= Bortezomib

25. What’s the Role for Maintenance Immunotherapy in MCL?

26. 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
PR, CR
IFN-a maintenance
(3 x 3 M IU/week)
or Peg-IFN
(1mg/kg week)
Rituximab
maintenance
(q 2 months)
to progression

27. MCL Elderly: Response to induction therapy
ORR CR
4 yr OS
R-CHOP
86%
34%
62%
R-FC
78% (p = NS)
40% (p = NS)
47% (p = .005
More toxicity and deaths from infection with R-FC
More patients with disease progression in R-FC arm
Kluin-Nelemans et al, NEJM 2012; 367:520-31

28. MCL Elderly: overall survival related to induction regimen
Kluin-Nelemans et al, NEJM 2012; 367:520-31

29. MCL Elderly study: Remission duration on maintenance after R-CHOP induction; Intention-to-treat analysis
Kluin-Nelemans et al, NEJM 2012; 367:520-31

30. European MCL Network Elderly Study: Conclusions
Induction therapy favors R-CHOP over R-FC
Higher overall responses, less toxicity
Rituximab maintenance doubles the remission duration in patients responding to initial therapy
87% 4 year OS for R-CHOP  R maintenance
Low toxicity of long-term rituximab
Kluin-Nelemans et al, NEJM 2012; 367:520-31

31. Novel Targeted Therapeutics
Changing the MCL Treatment Paradigm

32. Selected Agents and Targets in Clinical Trial for MCL
Lenalidomide Microenvironment
Palbociclib (PD ) CDK4/CDK6
Everolimus,Temsirolimus mTOR
Idelalisib, TGR-1202 PI3Kδ
Ibrutinib, AVL BTK
Obatoclax, ABT BCL2, BH3/apoptosis
Vorinostat, Romidepsin HDAC
Antibody/drug conj. CD79b, CD22
Weniger, Wiestner. Semin Hematol 2011; 48:214-26; Perez-Galan, Dreyling, Wiestner. Blood 2011; 117:26-38

33. Lenalidomide

34. Rationale for Lenalidomide Therapy in MCL and Other Lymphomas
Disrupts cytokine-mediated interactions between tumor and stromal cells
Immunomodulatory stimulation of T- and NK-cell activity
Enhances immunologic synapse formation between rituximab-labeled lymphoma cells and T/NK effector cells
Direct anti-proliferative effects
Ramsay et al, Blood 2009; 114:4713; Witzig et al, JCO 2009; 27:

35. Lenalidomide in Relapsed/Refractory Aggressive NHL: Results
Histology n
ORR
PFS (mo.)
DLBCL
108
28%
2.3
Mantle 57
42%
5.7
Follicular (grade 3) 19
6.3
T-cell 33
45%
4.6
ORR in patients with prior SCT = 37% (27/73)
Gr 3-4 neutropenia 41%, thrombocytopenia 19%
Witzig et al. Blood 2009; 114: ASH Abstract #1676

36. MCL-001: Study Design (Goy et al, JCO 2013)
Phase II global, multicenter, single-arm, open-label study (NCT ; data cut-off July 2, 2012)1
MCL patients relapsed, progressed, or refractory to bortezomib (N = 134)
Follow-up
CT every 90 days
Treatment phase*:
Lenalidomide 25 mg days 1-21, q28d; CT every 2 cycles
PD or toxicity
Primary endpoints†: ORR and DOR
Secondary endpoints: CR, PFS, TTP, OS, and safety
*Aspirin or low molecular weight heparin prophylaxis for TEE provided for high-risk patients.
†Based on independent central review per modified International Working Group criteria.2-4
1. Goy et al. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract Cheson et al. J Clin Oncol. 1999;17: Kane et al. Clin Cancer Res. 2007;13: Fisher et al. J Clin Oncol. 2006;24:

37. MCL-001: Efficacy of Lenalidomide (Goy et al, JCO 2013)
Efficacy Parameter
(N = 134)
Central Review,
n (%)
Investigator Review,
ORR*
37 (28)
43 (32)
CR/CRu
10 (7.5)
22 (16) PR
27 (20)
21 (16) SD
39 (29)
36 (27) PD
35 (26)
Median DOR, months (95% CI)
16.6 ( )
18.5 ( )
Median DOR for CR/CRu, months (95% CI)
16.6 (16.6-NR)
26.7 (16.8-NR)
ASH 2013, Goy et al, #3057: Updated safety and efficacy plus correlation of response with Ki-67 expression
ASH 2013, Ruan et al, #247: Lenalidomide + R as front-line in MCL
NR, not reached.
*No response assessments were available for 23 patients (central) and 12 patients (investigator).
Goy et al. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 905.

38. Lenalidomide FDA-approved for relapsed MCL, 2013
Duration of response, progression-free survival and overall survival after lenalidomide in relapsed/refractory mantle-cell lymphoma (by central review)
DOR
Lenalidomide FDA-approved for relapsed MCL, 2013
PFS OS
Goy A et al. JCO 2013;31:

39. ASH 2013, abstract # 247
Combination Biologic Therapy Without Chemotherapy As Initial Treatment For Mantle Cell Lymphoma (MCL): Multi-Center Phase II Study Of Lenalidomide Plus Rituximab
Jia Ruan, Peter Martin, Bijal Shah, Stephen J Schuster, Sonali Smith, Richard R Furman, Paul Christos, Amelyn Rodriguez, Jakub Svoboda, Jessica Lewis, Morton Coleman, John P Leonard
Weill Cornell Medical College; Moffitt Cancer Center; U Penn Abramson Cancer Center; U Chicago Medical Center

40. Maintenance (week 49 - POD)
Study Design
Treatment Schedule
Induction (week )
Lenalidomide: 20 mg/day for days 1-21 of a 28-day cycle for 12 cycles. Dose escalation to 25 mg/day allowed if no excess toxicity.
Rituximab: 375 mg/m2 per dose for 9 doses (weeks 1-4, 12, 20, 28, 36 and 44).
Maintenance (week 49 - POD)
Lenalidomide: 15 mg/day for days 1-21 of a 28-day cycle.
Rituximab: 375 mg/m2 one dose every 8 weeks, starting at week 52.
Objectives
1st - Response rates
2nd – Survival & Safety
Eligibility (N=32)
Untreated MCL: CD20+CD5+CD23-cyclinD1+
Tumor mass ≥ 1.5 cm
Low – int risk MIPI
High risk MIPI if non-chemo candidate
Adequate organ function
Abstract #247 40

41. Efficacy: Clinical Response
No. of patients
ITT (n=32)
Evaluable (n=30)
Overall response (CR + PR) 26
81%
87% CR 16
50%
53% PR 10
31%
33% SD 2 6% 7% PD
Inevaluable#
Median time to PR
3 months (range 3-13)
Median time to CR
11 months (range 3-22)
ITT: Intent-to-treat
#: Treatment was discontinued in 2 patients due to tumor flare without progression before tumor response evaluation.
Abstract #247 41

42. Efficacy: Progression-Free Survival
0.00
0.25
0.50
0.75
1.00 30 28 21 13 6
Number at risk 5 10 15 20 25
Months from Treatment
Progression-Free Survival
Probability of progression free survival
12-month PFS = 93.2% (95% CI = 75.5%, 98.3%)
Median Follow-up = 16 months (range 7-26)
Abstract #247 42

43. Targeting the B-cell Receptor Pathway

44. BCR, NF-kB, and PI3K/AKT/mTOR signaling pathways are dysregulated in MCL
Overexpressed
Down-regulated
P. Perez-Galan et al. Blood. 2011

45. BCR, NF-kB, and PI3K/AKT/mTOR signaling pathways: Selected Inhibitors
Fostamatinib
Idelalisib
IPI-145
Ibrutinib
AVL-292
Perifosine
Enzastaurin
Everolimus
Temsirolimus
Rapamycin
OSI-027
(dual mTOR inh)
Bortezomib
Carfilzomib
ABT-737
ABT-199
Obatoclax
Modified from P. Perez-Galan et al. Blood. 2011

46. Idelalisib: pI3Kδ Inhibitor

47. Published on-line: Kahl et al. Blood 2014, March 10.
Final results of a phase 1 study of idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase P110 (PI3K) in patients with relapsed or refractory mantle cell lymphoma (MCL)
Stephen E Spurgeon1, Nina D Wagner-Johnston2, Richard R Furman3, Ian Flinn4, Steven E Coutre5, Jennifer R Brown6, Don M Benson Jr7, John C Byrd7, John Leonard3, Sissy Peterman8, David M Johnson8, Jessie Gu8, Roger D Dansey8, Wayne R Godfrey8, Brad S Kahl9
1Oregon Health & Science University, Portland, OR; 2Washington University School of Medicine, St. Louis, MO; 3Weill Cornell Medical College, New York, NY; 4Sarah Cannon Research Institute, Nashville, TN; 5Stanford Cancer Center, Stanford, CA; 6Dana-Farber Cancer Institute, Boston, MA; 7The Ohio State University, Columbus, OH; 8Gilead Sciences, Seattle, WA; 9University of Wisconsin Carbone Cancer Center, Madison, WI
Published on-line: Kahl et al. Blood 2014, March 10.

48. Overall Response Rates Idelalisib Monotherapy Has Substantial Activity in heavily pretreated MCL (median 4 prior regimens)
Category
n, %
ORR
16 (40) CR
3 (7.5) PR
13 (32.5) SD
19 (47.5) PD
4 (10) NE
1(2.5)
ORR for patients with ≥ 150 mg BID was 67% (8/12)
ORR for patients with < 150 mg BID was 29% (8/28)
Presented by: Stephen E Spurgeon, Oregon Health & Science University

49. Best Nodal Response (N=39)b
aCriterion for lymphadenopathy response [Cheson 2007]
b1 patient without a follow-up tumor assessment
Presented by: Stephen E Spurgeon, Oregon Health & Science University
b1 patient without a follow-up tumor assessment

50. Study 101-02+99 (MCL Cohort): 2° Endpoint: PFS and DOR
Median PFS 3.7 months
1 year PFS is 22%
At 18 months 13% PF
Median DOR 2.7 months
At 18 months 25% PF
ASH 2013, Gopal et al, abstract #85: Mature data for phase II Idelalisib in refractory indolent NHL
Presented by: Stephen E Spurgeon, Oregon Health & Science University
Confidential 50

51. Serious Adverse Events, and Adverse Events leading to Discontinuation
Serious Adverse Event*, n (%)
Pneumonia
4 (10)
Diarrhea
3 (7.5)
Acute Renal Failure
2 (5)
Pulmonary Embolism
Pyrexia
*In more than one subject
Discontinuations due to AE, n (%)
Diarrhea
2 (5)
Acute Renal Failure
1 (2.5)
Malignant Pleural Effusion
Muscle Cramps
Pneumonia
Rash/Mucositis
Transaminase Elevation
Presented by: Stephen E Spurgeon, Oregon Health & Science University

52. Ibrutinib: Bruton Tyrosine Kinase Inhibitor

53. Ibrutinib (PCI-32765): BTK inhibitor
PCI (ibrutinib) forms a bond with cysteine-481 in BTK
Highly potent BTK inhibition at IC50 = nM
High degree of B-cell specificity
Orally administered once daily dosing
EHA 2013, PCYC-1104 Rule et al.
14/11/ :31

54. Targeting BTK with Ibrutinib in Relapsed or Refractory MCL
Phase II study, n = 111
Stratified for prior bortezomib treatment
Primary endpoint = ORR
Oral ibrutinib 560 mg/d continuous
Median age 68y, median 3 prior therapies
86% with high- or intermediate-risk MIPI
Wang ML, et al. NEJM 2013

55. Ibrutinib in R/R MCL: Results by prior bortezomib treatment
No prior B (n = 63)
Prior B
(n = 48)
All patients (n = 111)
ORR
43 (68%)
32 (67%)
75 (68%) CR
12 (19)
11 (23)
23 (21)
Median DOR
15.8 mo NR
17.5 mo
Median PFS
7.4 mo
16.6 mo
13.9 mo
Median f/u = 15.3 months
Wang ML, et al. NEJM 2013

56. Ibrutinib in R/R MCL: DOR
Wang ML, et al. NEJM 2013

57. Ibrutinib in R/R MCL: PFS
Wang ML, et al. NEJM 2013

58. Ibrutinib in R/R MCL: OS
Wang ML, et al. NEJM 2013

59. Treatment Emergent AEs in > 10% of Patients Regardless of Relationship to Study Therapy
Hematological AE 0%
10%
20%
30%
40%
50%
60%
Neutropenia
Thrombocytopenia
Anemia
Bleeding events ≥ grade 3 occurred in 5% of patients
Non-Hematological AE 0%
10%
20%
30%
40%
50%
60%
Diarrhea
Fatigue
Nausea
Oedemaperipheral
Dyspnea
Constipation
Upper respiratory tract infection
Vomiting
Decreased appetite
Cough
Pyrexia
Abdominal pain
Contusion
Rash
Dizziness
Muscle spasms
Urinary tract infection
Hyperuricemia
Back pain
Myalgia
Sinusitis
Dehydration
Pneumonia
Stomatitis
Arthralgia
Asthenia
Dyspepsia
Epistaxis
Headache
Pain in extremity
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
EHA 2013, PCYC-1104 Rule et al.

60. Ibrutinib in R/R MCL: Conclusions
Highest single-agent responses observed to date
CR rates increased over time with continued ibrutinib therapy
Favorable toxicity profile
Only 7% of patients d/c Rx due to toxicity
Combination regimens now under investigation, including previously untreated MCL

61. My approach to initial therapy of MCL: 2014
Younger, fit patients
R-CHOP/R-DHAP  ASCT consolidation
Older, non-SCT-eligible
ECOG 1411: R-benda +/- Bortezomib  R vs R2 maintenance
R-benda or R-CHOP  R Maintenance
Frail and/or significant co-morbid illness
Single-agent R, consider adding lenalidomide or using ibrutinib

62. My approach to relapsed MCL: 2014
Younger, fit patients
Consider allogeneic SCT
Older, non-SCT-eligible
Clinical trial
Ibrutinib, lenalidomide +/- R
Frail and/or significant co-morbid illness
Single-agent R, lenalidomide or ibrutinib
Many clinical trials of novel agents +/- immuno-chemotherapy are in progress for front-line and relapsed MCL  Enroll patients whenever possible!