1. Mantle Cell Lymphoma: The Inevitable Relapse Peter Martin, MD Assistant Professor of Medicine Division of Hematology/Oncology Weill Cornell Medical College New York, New York

2. Johnson PWM et al. J Clin Oncol. 1995;13(1):140-147. Patterns of survival in FL T = 20 years

3. Adapted from Johnson PWM et al. J Clin Oncol. 1995;13(1):140-147. Probable pattern of survival in MCL T = 5 years

4. Goy A et al. Ann Oncol 2008;20:520-525 Bortezomib in Relapsed or Refractory MCL (Phase II PINNACLE Study): Progression-free survival

5. Haberman TM, et al. Br H Haematol. 2009; Zinzani PL, ASH 2008. Reeder CB, et al. ASH 2008. Wang et al. ICML 2011 STUDYDesignResults/Comments NHL-002 N=15 Median of 4 prior rx Prior ASCT Prior Bort ORR: 53% (CR-20%) Median DOR: 13.7 mos Median PFS : 5.6 mon Dose reductions in 53% NHL-003 N= 39 Median age 66, 3 prior Rx Bort-23% ORR: 41% (CR or CRu-13%) Median DOR: 13.7 mos Grade 3-4 : Neutropenia (51%), thrombocytopenia (25%), anemia (13%), fatugue (10%) and Febrile Neutropenia (10%) Prior BORT- POOLED NHL- 002 and 003 N=14, median prior Rx-4, 50% Bort refractory ORR-57%, CR or CRu-21%. Similar AEs Rev+ Ritux N=46 Phase II O ORR 57%, CR 33% RD 19 mo. Lenalidomide

6. Mammalian target of rapamycin (mTOR) Witzig T E et al. JCO 2005;23:5347-5356

7. DoseNRRTTPGrade 3-4 heme tox. Witzig250 mg3538%6.5 mo.84% Ansell25 mg2941%6 mo.54% Phase 2 studies of temsirolimus in relapsed MCL Witzig et al. JCO 2005;23:5347 Ansell et al. Cancer 2008;113:508

8. Hess G et al. JCO 2009;27:3822-3829 Phase 3 trial of temsirolimus compared to investigator’s choice in MCL

9. Renner et al. Haematol 2012 Epub Phase 2 trial of everolimus in MCL RR = 20% Median PFS 5.5 mo.

10. BCR, NF-κB, and PI3K/AKT/mTOR deregulation in MCL Pérez-Galán P et al. Blood 2011;117:26-38

11. Phase 2 trial of fostamatinib (oral Syk inhibitor) in relapsed NHL Friedberg J W et al. Blood 2010;115:2578-2585 MCL patients N=9 1 PR 4 SD 4 PD

12. CAL-101 (GS-1101) Is an Orally Bioavailable Small Molecule That Inhibits PI3K Delta Potently and Selectively Class I PI3K Isoform Cell-based Activity PDGF-induced pAKT LPA-induced pAKT fMLP-induced CD63+ Fc  R1-induced CD63+ EC 50 (nM) >20,00019003000 8 Alpha Beta Gamma Delta Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions No off-target activity against Class II or III PI3K, mTOR, or DNA-PK No off-target activity seen in screen of >350 protein kinases Lannutti. Blood. 2011. CAL-101

13. Cal-101 in B-cell Lymphoma Best Response -50* -75 % Change in Lymph Node Area -25 -100 +25 +50 +75 +100 0 MCL (n = 21) iNHL (n = 30) Best on-treatment change in tumor size (ITT analysis) Inevaluable (patients without a follow-up tumour assessment; includes two patients with LPL with no adenopathy) *Criterion for response [Cheson 2007, Hallek 2008] Kahl B et al. Blood (ASH Annual Meeting Abstracts). 2010;116:1777.

14. PCI-32765 Novel Small-molecule Btk Inhibitor Forms a specific and irreversible bond with cysteine-481 in Btk Potent Btk inhibition – IC 50 = 0.5 nM Orally available Once-daily dosing results in 24-hour sustained target inhibition N N N N NH 2 O N O

15. Best Response BTZ-naïve (n = 31) BTZ-exposed (n = 20) Total (n = 51) CR PR SD PD 71% 16% 13% 65% 69% 20% 15% 18% 15% 50% 16% 55% 16% 53% BTZ= Bortezomib *Wang et al. ASH 2011; Abstract 442

16. n/NORR % All Patients35/5169 Bulky Disease4/757 Refractory Yes No 14/21 21/30 67 70 Prior cancer treatments < 3 regimens ≥ 3 regimens 23/30 12/21 77 57 Prior high intensity therapy Yes No 22/31 13/20 71 65 MIPI Score: Low Risk Intermediate Risk High Risk 6/8 13/20 15/20 75 65 75 Best Response by Patient Characteristics 16

17. The Cell Cycle G1 S G2 M p21 p27 p57 Negative Go Positive Cyclin D + CDK4/6 pS-Rb-E2F Cyclin E + CDK2 pST-Rb E2F release p16 p15 p18 p19 CDK: Cyclin-Dependent Kinase p18 INK4c (CDKN2C ) mid-G1 checkpoint Slide courtesy of Dr Selina Chen-Kiang

18. PD0332991-induced changes in Rb phosphorylation and Ki-67 expression in pre- and on-treatment lymph node biopsies. Leonard J P et al. Blood 2012;119:4597-4607

19. Quantification of FDG- and FLT-PET changes on PD0332991 and correlation with each other and time to progression. Leonard J P et al. Blood 2012;119:4597-4607

20. The anti-apoptotic phenotype and alterations in BCL-2 family members in MCL Pérez-Galán P et al. Blood 2011;117:26-38

21. Low-dose metronomic oral chemotherapy Prednisone 20 mg at breakfast Etoposide 50 mg at lunch Cyclophosphamide 50 mg at supper Procarbazine 50 mg at bedtime Start daily, then titrate frequency based on ANC RegimenDesignNRROutcome PEPCretrospective2282%TTP 17 mo. RT-PEPCprospective2573%PFS 10 mo. Coleman et al. Leuk Lymphoma 2008;49:447-450 Ruan et al. Cancer 2010;116:2655-2664

22. Conclusion All MCL patients eventually acquire resistance to intermittent chemotherapy Treatment with novel agents/continuous therapy is required to maintain remissions

23. Future challenges Is there a role for early detection/treatment of subclinical relapse? Should novel treatments be used as single agents in relapse or combined with upfront induction/consolidation/maintenance regimens? Mechanisms of response/resistance of novel agents need to be clarified to justify rational combinations.