1. CORAL: COllaborative trial in Relapsed Aggressive Lymphoma R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by autologous stem cell transplantation: CORAL study. C. Gisselbrecht, B. Glass, N. Mounier, D. Gill, D. C. Linch, M. Trneny, A. Bosly, O. Shpilberg, H. Hagberg, N. Ketterer, D. Ma, P. Gaulard, C. Moskowitz, and N. Schmitz.

2. WHAT TO DO IN RELAPSING DLBLCL  Standard of care in DLBCL, failing first line chemotherapy treatment, is salvage regimen followed in chemosensitive patients with autologous stem cell transplantation (ASCT).  In the Parma study the 7 yr event free survival rate was 41% for ASCT vs 13% for conventional arm.  Before rituximab era: different salvage regimens would provide a response rate between 50% to 68% with mobilization of hematopoetic peripheral stem cell in most situation.  In the rituximab era:  What is the best salvage regimen? No randomized comparison have been made previously  What is the place of rituximab after transplantation?

3. CORAL Trial of RICE v DHAP CD20+ DLBCL Relapsed/Refractory R-ICE x 3 R-DHAP x 3 RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE SD/POD → Off PR/CR → → A BS EC AT MA BS EC AT M R x 6 Obs N=400 Which salvage regimen is the best? Place of immunotherapy post transplantation? Orlando ASCO May 2009 / Coral study C. Gisselbrecht

4. CORAL Study NCT 00137995. Eudract N° 2004-002103-32 Inclusion Criteria Diffuse large B Cell Lymphoma, CD 20+: in 1st relapse, partial response to first line treatment ≤ 65 year old Eligible for transplant Previously treated with chemotherapy regimen containing anthracyclines with or without rituximab PS  2 Informed consent Orlando ASCO May 2009 / Coral study C. Gisselbrecht

5. CORAL Study Primary objective :  Part I: induction therapy : Overall response rate (ORR) adjusted with successful mobilization: MARR  Target difference in Response Rate 15% with 400 pts randomized  Part II: maintenance therapy : Event free survival (EFS) at 2 years post transplantation  Target difference 15% with 240 patients randomized Secondary objectives:  Eligibility for transplant,  toxicities with R-ICE and R-DHAP  Toxicity Rituximab post transplant  Time to progression or relapse  Disease-free survival for complete responders  overall survival. Orlando ASCO May 2009 / Coral study C. Gisselbrecht

6. Patient distribution Australasia 60 Germany 113 Cesz Republic 36 France 128 Belgium 31 Israel 13 US 9 Sweden 13 Switzerland 24 481 patients 30/6/2008 Ireland 4 UK 50 Thank you to all investigators and pathologists CORAL Study Orlando ASCO May 2009 / Coral study C. Gisselbrecht

7. CORAL Study  Report on 400 patients included between July 24, 2003 to September 4, 2007 : First randomization: R-ICE vs R-DHAP  Second randomization : Rituximab vs no further therapy still on going (240 pts) Stratification for subgroup analysis i) Center, group ii) Prior treatment with Rituximab during first line iii) Relapse < 12months and Refractory (non achieving CR 1st line treatment) Orlando ASCO May 2009 / Coral study C. Gisselbrecht

8. Patients randomized N = 400 R-ICE N = 202 R-DHAP N = 194 Received study treatment N = 197 Received study treatment N = 191 Completed induction phase N = 169 Completed induction phase N = 161 Received BEAM+ASCT N = 101 Received BEAM+ASCT N = 105 Randomized in maintenance N = 98 Randomized in maintenance N = 99

9. Arm of treatment All ARM A / R- ICE ARM B / R- DHAP N%N%N% Response after first line 108541015220953 COMPLETE RESPONSE UNCONFIRMED COMPLETE RESPONSE 231124124712 PARTIAL RESPONSE 402037197720 STABLE DISEASE 63105164 PROGRESSIVE DISEASE 241220104411 NOT EVALUATED 001110 122601226324462 RITUXIMAB WHAT TYPE OF PATIENTS HAVE BEEN INCLUDED IN CORAL RESPONSE AT 1ST LINE Tt Orlando ASCO May 2009 / Coral study C. Gisselbrecht

10. CORAL PATIENTS ITTMAIN CHARACTERISTICS AT INCLUSION R-ICE (202) R-DHAP (194) Median age 54 y 55 y Sex M 125 118 F 77 76 Stage I-II 81 66 Stage III-IV 119121 ENS > 1 55 64 LDH > Nl104 94 S-AaIPI 0-1 119 107 S-AaIPI 2-375 74 <12 months 89 87  12 months 112103 P=0.09 Orlando ASCO May 2009 / Coral study C. Gisselbrecht

11. R-ICE R-DHAP N 197% N 191% Response including deaths COMPLETE RESPONSE 48 24 53 28 UNCONFIRMED COMPLETE RESPONSE 24122212 PARTIAL RESPONSE 53274524 STABLE DISEASE 23122212 PROGRESSIVE DISEASE 38193518 DEATH 63 105 PREMATURE WITHDRAWAL / NOT EVALUATED 4242 Total 197100191100 RESPONSE AFTER INDUCTION TREATMENT INCLUDING DEATHS FOR ALL PATIENTS (Intent To Treat) 63.5 % 62.8 % Arm of treatmentNb patients Nb responders with successful mobilizationMARR (%) R-ICE19710352.3 R-DHAP19110454.5 Orlando ASCO May 2009 / Coral study C. Gisselbrecht

12. CORAL TOXICITY R-ICE R-DHAP Infection with neutropenia Grade 3-4 Yes 33 (17%) 31 (16%) Infection without neutropenia Grade 3-4 Yes 11 (6%) 15 (8%) Renal Grade 3-4 Yes 2(1%) 11 (6%) Platelets Transfusions % pts 35% 57% Toxic deaths 1 3 On induction safety population, in R-ICE arm 90 SAEs and in the R- DHAP arm 120 SAEs during the whole study, concerning respectively 58 patients (29%) and 69 patients (36%).

13. Response p Patients CR/Cru/PR All patients 245 63 % CR/CRu 147 38% Prior RituximabNo12283% <0.0001 Yes12451% Relapse> 12 months14088% <0.0001 Refractory< 12 months10646% s IPI< 216071% <0.0002 > 17652% CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS *No difference between GELA DSHNHL ALLG ** More early relapse in prior Rituximab Group Orlando ASCO May 2009 / Coral study C. Gisselbrecht

14. Arm of treatment ARM A / R-ICE ARM B / R-DHAP N%N% Consolidation treatment (BEAM) 1015110555 Yes No 96498645 Total 197100191100 Transplantation CONSOLIDATION – PATIENTS WITH BEAM AND ASCT (INDUCTION ITT) Main Reasons for premature withdrawals: Progressive lymphoma 53% Toxicity 7% Collection failure 10% (CD 34/kg < 2.106) Deaths 4% Orlando ASCO May 2009 / Coral study C. Gisselbrecht

15. OVERALL SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) Orlando ASCO May 2009 / Coral study C. Gisselbrecht 56% 42% 45%

16. PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT) Orlando ASCO May 2009 / Coral study C. Gisselbrecht N=160 N=228 N=147 N=241 31% 64% 30% 62%

17. Failure from diagnosis =>= 12 months EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT Failure from diagnosis > 12 months Standard salvage regimen does not overcome poor prognosis of early relapse Failure from diagnosis =< 12 months N= 106 N= 54 N= 41 N= 187

18. MULTIVARIATE ANALYSIS FOR SURVIVAL p PFS EFS OS  Prior Rituximab0.003 0.00070.01  Relapse < 12 months < 0.0001< 0.0001< 0.0001  sIPI > 1 < 0.0001< 0.0004< 0.0001  Treatment Arm 0.1 0.3 0.07 Prior rituximab exposure will be the rule in future study Relapses after rituximab exposure are more severe. Early relapses and failure are the main adverse prognostic factors. Orlando ASCO May 2009 / Coral study C. Gisselbrecht

19. PROGRESSION-FREE SURVIVAL OF PATIENTS SUBMITTED TO ASCT from date of 1st randomization (INDUCTION ITT) Progression-Free Survival of maintenance ITT population from date of 2nd randomization RANDOMIZERANDOMIZE PR/CR → R x 6 N = 102 Obs N = 95 Randomized in maintenance N = 197 Orlando ASCO May 2009 / Coral study C. Gisselbrecht N=197 pts 58% 140 events are required to conclude. Nowadays: 85 events (43%) Final analysis of maintenance arm 2010

20.  R-ICE and R-DHAP have similar activity and mobilization ability with less adverse events for R ICE.  Prognostic factors affecting response and survival: relapse 1, prior rituximab exposure  A new profile of relapses and refractory patients after rituximab will come out from this trial, and will help the design of future study with new drugs.  A bio CORAL program is on going to better understand this population of poor prognosis patients CORAL CONCLUSION POOR RESULTS : RESPONSE RATE 50% PFS 30% GOOD RESULTS : RESPONSE RATE 80% PFS 60%

21. Many Thanks again investigators pathologists GELA RC M Fournier/N. Mounier statistics C.Pitrou/ G Chartier project leaders L. Gérard, Data management and all the project managers in the different countries Thank you for their continous support: Roche, Baxter, Chugai