1. Hematopoietic Stem Cell Transplantation: High Risk Diffuse Large Cell Lymphoma: Ginna G. Laport, MD Associate Professor of Medicine Division of Blood & Marrow Transplantation Stanford University Medical Center

2. Diffuse Large B-Cell Lymphoma: Stem Cell Transplantation for High Risk Patients Identifying “High Risk” Patients Autologous HSCT in High Risk Patients Phase II Trials Phase III Trials Allogeneic HCT

3. Transplants Transplant Activity Worldwide 1968-2012

4. Indications for Hematopoietic Stem Cell Transplants in the U.S. Number of Transplants

5. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma  Most common NHL: 31% –Peak incidence in 6th decade  Large cells with loss of follicular architecture of node –30% to 40% present with rapidly enlarging, symptomatic mass with B symptoms  Frontline chemotherapy (anthracycline-based + RTX) –CR  50-60% –Long term remission -> 30-35% Diffuse Large B-Cell Lymphoma

6. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma 5 Sehn LH, et al. Blood. 2007;109:1857 LegendRevised IPI Risk Group IPI Factors, n Very good0 Good1, 2 Poor3, 4, 5 Age >60 Perf Status Stage 3-4 LDH Extranodal Overall Survival According to Revised International Prognostic Index

7. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma Yrs OS Diffuse Large B-Cell Lymphoma DLBCL Subgroup5-Yr OS, % Primary Mediastinal64 Germinal Center B cell like (GCB) 59 Activated B cell (ABC)30 1.0 0.8 0.6 0.4 0.2 0 0246810 Rosenwald A, et al. J Exp Med. 2003;198:851-862. Survival by Gene Expression Profiling: DLBCL

8. Prognosis By Interim PET Scanning -Mixed results seen in 4 studies -2 studies confirm predictive value, 2 studies did not Safar et al, J Clin Oncol 2012;30:184 0 20 40 60 80 100 020406080100 Time (months) PET positive (n=12) P=0.02 PET negative (n=73) Progression Free Survival n= 98 0 0.2 0.4 0.6 0.8 1.0 013567 Time (years) PET Positive P=0.146 PET Negative 24 Moskowicz et al. J Clin Oncol 2010;11: 1896 Progression Free Survival n= 112

9. High Risk Diffuse Large Cell Lymphoma Autologous HSCT in First CR/PR

10. High Risk Diffuse Large B Cell NHL: Frontline Autologous HCT Phase II Trials containing rituximab Groupn aaIPI >2 Therapy CR Rate PFS /EFS OS Follow up Tarella 2007 112100Mod R-HDS8073764 yrs Vitolo 2009 97100 R-mega CEOP x BEAM/HCT 8273804 yrs Dilhudy 2010 42100 R CEEP BEAM HCT 55 745 yrs Fitoussi 2011 209100 R-ACVBP + BEAM/HCT 6076784 yrs

11. Cochrane Database Sys Rev 2008;CD004024 Meta-analysis: Autologous HSCT as Front Line Therapy N = 2228 No survival advantage for autologous HSCT in CR1 Haematologica 2003;88:1304 N = 3079 Overall survival advantage for autologous HSCT in CR1 compared to chemotherapy

12. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma Pts with ≥ PR after CHOP ± RTX x 5 (N = 253) CHOP ± Rituximab x 1 + Autologou HSCT* (n = 125) CHOP ± Rituximab x 3 (n = 128) Stiff PJ, et al. ASCO 2011. Abst 8001. R-CHOP x 8 vs R-CHOP x 6 Cycles + Autologous HSCT (SWOG S9704) Eligibility: Bulky stage 2-4 Hi-int/High IPI

13. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma Stiff PJ, et al. ASCO 2011. Abstr 8001. Outcome, %CHOP ± R + AutoSCT (n = 125) CHOP ± R (n = 128) P Value 2-yr PFS (all)69%56%.005  High-interm IPI 60%63 %  High IPI 75%47 %.02 2-yr OS (all)74%71%.16  High-inter IPI pts 70%75%  High IPI pts 82%64%.01  Autologous HSCT prolonged PFS  high-intermediate  high-IPI  Autologous HSCT prolonged OS  high-IPI ASCT After CHOP ± Rtx Improves PFS in Advanced High-Risk Diffuse NHL

14. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma Newly diagnosed DLBCL, aaIPI > 2 n = 399 Newly diagnosed DLBCL, aaIPI > 2 n = 399 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE R-CHOP x 3 R-mega CHOP SD, PD off study PR, CR Ann Oncol 2011; 22 suppl 4: abstr 72. RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE BEAM  AutoHCT Observation only Italian Lymphoma Foundation 2 x 2 Randomized Trial with Autologous HSCT in High Risk Patients

15. Italian Lymphoma Foundation 2 x 2 Randomized Trial with Autologous HCT in High Risk Patients (median followup = 23 mos) PFSOS No BMT5983 BMT7283 P value.008NS - Risk of relapse was 53% lower in BMT patients - No overall survival difference between two arms` 0612182430364248 Months 0.00 0.25 0.50 0.75 1.00 HDT No-HDT Progression Free Survival P=.008

16. High Risk Diffuse Large Cell Lymphoma Is there a role for allogeneic HSCT??

17. Years 026 13 45 Survival after Allogeneic HCT for Diffuse Large B-Cell Lymphoma, 2000-2009 - By Disease Status - 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001 Sensitive (N=383) Resistant (N=124)

18. Reduced Intensity Allogeneic HSCT (after autologous HSCT relapse) nAblat/RICOSPFSNRMF/U EBMT10137%; 64%53%41%28%3 yrs Italian16530%; 70%39%32%28%2 yrs Factors affecting outcomes Dz status at time of allogeneic HCT Time to relapse after autologous HCT ( 12 m) Did not affect outcome Prep regimen Rigacci et al, Ann Heme 2012;91:931 van Kampen et al. JCO 2011;29:1342

19. Need better tools to identify high risk patients Current studies suggest that high-IPI subtype may benefit from autologous HCT early as front line therapy More studies needed to further define role of autologous HSCT as front line therapy –Need study that includes only ABC-subtype Role of allogeneic HSCT in high risk population? Hematopoietic SCT for High Risk DLBCL

20. Stanford University

21. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma Relapsed/ refractory DLBCL n = 396 Relapsed/ refractory DLBCL n = 396 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE R-ICE x 3 R-DHAP x 3 Auto SCT SD, PD off study PR, CR J Clin Oncol 2010; 28:4184–4190. Which salvage regimen is the best? RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE Rituximab q2mos x 6 Rituximab q2mos x 6 Observation only Role of maintenance rituximab Role of maintenance rituximab CORAL Trial: Collaborative Trial in Relapsed Aggressive Lymphoma

22. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma Overall SurvivalEvent Free Survival P =.49 Mos 0123660 1.0 0.8 0.6 0.4 0.2 0 P =.27 Mos 0122436 0.8 0.6 0.4 0.2 0 1.0 R-ICE R-DHAP 60724848244872 CORAL Trial Survival according to Salvage Regimen GCB vs ABC 3 yr PFS: 70% vs 28% R-DHAP vs R-ICE in GCB pts: 3 yr PFS: 100% vs 27%

23. CORAL Trial: EFS by relapse time after initial therapy Relapse > 12 mos from dxRelapse < 12 mos from dx predicted for poor outcome after autologous HCT

24. JCO 2012, In press EFS RTX Obs p=.74 PFS Female Male p=.04 Female pts benefited from RTX maintenance

25. CORAL: Factors affecting survival in relapsed DLCL patients EFSOS Prior rituximab.0007.01 Relapse < 12 mos<.0001 <.0001 sIPI<.0004<.0001 R-DHAP vs R-ICE0.30.7 (Except for GCB pts) p

26. clinicaloptions.com/oncology Evolving Options and Challenges in Mantle Cell Lymphoma Philip T, et al. N Engl J Med. 1995;333:1540 P =.001 0 20 40 60 80 100 EFS (%) 0153045609075 Mos After Randomization P =.038 0 20 40 60 80 100 OS (%) 0153045609075 Mos After Randomization Transplantation Conventional treatment PARMA Study: BMT vs Salvage Chemotx for Relapsed DLBCL Event Free SurvivalOverall Survival