1. 1 Do we really need to transplant young patients with Mantle Cell Lymphoma? Brad Kahl, MD University of Wisconsin

2. Disclosures  Consulting –Genentech, Roche, Gilead, Teva, Millennium  Research Funding –Genentech, Gilead, Millennium, Pharmacyclics, Abbott, Infinity

3. Additional Disclosures  No one really knows the answer to this question  Why not? –Studies addressing this question have not been attempted (with one exception in the pre-rituximab era)  What do we know? –MCL outcomes appeared dismal –Several groups adopted intensive strategies –Out of necessity these trials limited to younger, healthier patients –Result have been impressive  Are results due to treatment intensity, patient selection, both?

4. Take home message  My opinion (will support with data) –Its OK to watch and wait selected MCL patients –Older patients do relatively well with modern treatment strategies that do not include SCT –Younger patients likely derive longer PFS from SCT based strategies but impact on OS is unclear  More upfront toxicity with intensive approach  Hence, there is a trade-off  Worthwhile engaging patient and family in decision making –I am willing to treat a younger patient with a non-intensive strategy if that is their preference and they understand the potential trade-off

5. Mantle Cell Lymphoma: 6% of NHL Cases

6. 6 Diagnosis of Mantle Cell Lymphoma Morphology Small-medium lymphoid cells with irregular to occasionally cleaved nuclei Blastic variant Cell of origin Pre germinal center lymphocyte Mantle zone of the follicle Immuno- phenotyping CD5 +, CD20 bright, CD23 -, cyclin D 1 +, FMC7+ t(11;14) detectable by FISH Nodal Architecture Nodular Diffuse Mantle Zone growth Skarin AT, Dorfman DM. CA Cancer J Clin. 1997;47:351-372. Harris NL et al. Hematology. 2001:194-220.

7. 7 Mantle Cell Lymphoma Clinical Features M:F ratio 4:1 Median age 64 Advanced stage Leukemic phase 30% B symptoms 30% extranodal sites common GI tract 80% –lymphomatous polyposis Elevated LDH 25% Elevated B2M 60% Moderately aggressive course Relatively poor prognosis Fisher et al. Hematology. 2004;221.

8. 8 European MCL Intergroup Survey Overall Survival (n = 365)

9. The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in MCL Median OS varies from 0.7-8.0 yrs! Reprinted from Rosenwald A, et al. Cancer Cell. 2003;3:185-197. Copyright 2003, with permission from Elsevier. 0 0.2 0.4 0.6 0.8 1.0 01214 Probability OS (Yrs) All Cases P = 5.07 x 10 -9 108642 Prognostic Factors: Molecular Signature

10. 10 Clinical Prognostic Features: MIPI Factors independently associated with OS –PS –LDH –WBC –Age Risk distribution –Low 44% ( score < 5.7) –Int 35% (score 5.7-6.1) –High 21% (score > 6.1) Formula for calculating MIPI: [0.03535 x age (years)] + 0.6978 (if ECOG > 1) + [1.367 x log10(LDH/ULN)] + [log10(WBC count)]

11. Frontline Treatment Considerations  There is no “standard of care” for MCL in 2013 –MCL not yet shown to be reliably curable with currently available frontline treatments –Intensive strategies appear to prolong remission duration in younger patients –More upfront toxicity –Unclear impact on OS –Hence several “reasonable” options (there are tradeoffs)  Optimal frontline standard of care not yet defined

12. Its OK to watch and wait in MCL  Martin et al, JCO 2009

13. Approach to a newly diagnosed patient R-CHOP + MR R-Bendamustine + MR R-CHOP/RIT Modified HyperCVAD vs R-CHOP/ASCT R-CHOP/R-DHAP/ASCT R-HyperCVAD/MTX/Ara-C Nordic Less intensive More intensive

14. Estimate ORR 95%, CR 60-70%, median EFS 4-5 years What does an intensive approach get you in MCL? 1 Hermine O, et al. ASH 2011. abstract #110. 2 Damon LE, et al. J Clin Oncol 2009;36:6101-6108 3 Geisler CH, et al. Blood 2008;112:2687-2693. 4 Romeguera JE, et al. J Clin Oncol 2005;23:7013-7023. TrialNAge3 yr EFS5 yr EFSComments R-CHOP- ASCT 1 2495560%40%Unpublished. Short follow up R-CHOP/R- DHAP ASCT 1 2485675%65%No OS difference. CALGB 59909 2 785759%46%Median follow up 4.7 years. Nordic 3 1605670%60%Updated 2012. MD Anderson 4 996165%50%Single inst. updated 2010

15. Comparison of transplant vs. non transplant strategies 1 Delarue R, et al, Blood 2013,121:48-53. 2 Damon LE, et al. J Clin Oncol 2009;36:6101-6108 3 Geisler CH, et al. Blood 2008;112:2687-2693. 4 Kahl B, et al, ASH meeting 2013. 5 Martin P, et al, Ann Oncol 2008, 19:1327-1330. TrialNAge5 yr PFS5 yr OSFollow up R-CHOP/R- DHAP ASCT 1 605760%75%5.5 years. CALGB 59909 2 785756%64%4.7 years. Nordic 3 1605665%75%6.5 years. E1405 4 756246%80%4.5 years Cornell 5 11163n/a66%3.5 years

16. 16 UW approach 3 sequential trials in MCL (no SCT)  Modified R-hyperCVAD with MR x 2 yrs (n = 22) –HO00401 (UW and WON)  VcR-CVAD with MR x 5 yrs (n = 30) –HO05401 (UW and WON)  VcR-CVAD with MR x 2 yrs (n = 76) –E1405 (ECOG)

17. 17 Trial Comparisons Modified (n = 22) VcR-CVAD (n = 30) E1405 (n = 75) ORR77%90%97% CRR64%77%68% (80%) 3 yr PFS50%63%73% 5 yr OS64%80%84%

18. Novel approaches for MCL (relapse) AgentNResponse RatemPFS Bortezomib15533%6 months Bendamustine-rituximab2875%12-18 months Y 90 ibritumomab tiuxetan3431%6 months Temsirolimus5422%5 months Lenalidomide5742%6 months Lenalidomide-rituximab5257%11 months GS1101 (CAL-101)2148%5 months Ibrutinib11168%13.9 months *Keep an eye out for ABT-199

19. StiL: First-line Bendamustine + Rituximab in Patients With FL, Indolent, and MCL Rummel MJ, et al. ASH 2009. Abstract 405. Bendamustine-Rituximab B 90 mg/m 2 on Days 1, 2 + R 375 mg/m 2 day 1 Max 6 cycles, q4w (n = 260) R-CHOP Max 6 cycles, q3w (n = 253) Stage III or IV CD20+ lymphoma (N = 549)

20. PFS: mantle cell (n=93) Median (months) B-R 35.4 CHOP-R 22.1 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0 12 24 36 48 60 72 84 96 months HR, 0.50 (95% CI 0.29 - 0.81) p = 0.0061

21. 8 x R-CHOP IFN-  maintenance (3 x 3 M IU/week) or Peg-IFN (1ug/kg week) CR,CRu,PR 6 x R-FC Rituximab maintenance (every 2 mos to PD) First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010) Newly diagnosed, >60 yr; performance 0-2, Stages II-IV, central PA review

22. Impact of maintenance

23. My current approach to patients for whom non-intensive strategies are appropriate  R-bendamustine followed by MR (for 2 years) –Admittedly an extrapolation of existing data –Bendamustine MOA is alkylator –MR makes sense in non-curative disease where the challenge is keeping patients in remission –UW data supports MR notion –2 studies demonstrated median PFS ~ 3 yrs with MR  R-CHOP followed by MR would be very reasonable –And have more data behind it

24. E1411: Randomized Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma in patients REGISTRATIONREGISTRATION BR x 6 BVR x 6 Lenalidomide + Rituximab 24 BR x 6 Rituximab Lenalidomide + Rituximab BVR x 6

25. What if an intensive approach is an option? R-CHOP + MR R-Bendamustine + MR R-CHOP/RIT Modified HyperCVAD vs R-CHOP/ASCT R-CHOP/R-DHAP/ASCT R-HyperCVAD/MTX/Ara-C Nordic Less intensive More intensive

26. MCL: No standard of care in 2013  NCCN guidelines –Lists 5 intensive options  I think it is OK to treat a younger patient with a non-intensive option  Tell them about the trade-off –Lists 6 non-intensive options  Clinical trial usually the best option  US Cooperative Groups are “cooperating” –Hope to define standards of care upon which future regimens can be compared  Extremely exciting new agents which need to be rapidly worked into frontline treatment paradigms