1. Pr. Christian Gisselbrecht, Hôpital Saint Louis, Paris, France Relapsed & Refractory Non-Hodgkin’s Lymphoma: Summary of GELA Trials Tel Aviv, February 12, 2009 Groupe d’Etude des Lymphomes de l’Adulte

2. Management of aggressive NHL Primary refractory Relapse Second-line therapy Investigational or BSC HDT/ASCT Investigational or BSC CR/PR NR (R)-CHOP or (R)-CHOP-like CR Cure

3. EVENT FREE SURVIVAL ACCORDING TO TREATMENT PARMA STUDY - MEDIAN FOLLOW-UP : 8.3 yrs 100 90 80 70 60 50 40 30 20 10 0 0306090120150 Conventional treatment (N = 54) Transplantation (N = 55) Months after randomization % Event-free survival p = 0.002 41% 13% Philip T, et al. N Engl J Med 1995;333:1540–5

4. Improving salvage regimen with the use of immunotherapy Improving post transplant outcome with the use of immunotherapy Improving conditioning regimen before ASCT with RIT

5. RegimenDisease statusnORR/CRASCT performed Survival in ASCT patients R-ICEDLBCL3678%/53%70%67% OS at 2 years R-ICEAggressive B NHL875%/ 50%100% R-various (mostly ICE) DLBCL59Not given100%81% OS at 2 years R-ICEAggressive B NHL1189%/67%27% R-DHAPAggressive B NHL5362%/32%38%Median 20.4 months OS DHAP/VIM/DHAP ± R Aggressive B NHL22575%/46% versus 54%/35% ± R, respectively 63% versus 46% ± R, respectively At 2 years FFS 50%versus 24% in favour of R (p<.001) R-ESHAPDLBCL/MCL/HD24 (15 = DLBCL) Not given79%DFS = 53% R-ESHAPDLBCL/MCL6100%/67%Not done R-ESHAPAggressive B NHL26 92 %/46%88% R-ESHAPAggressive B NHL1856%/28%38% R-ICE or R-DHAPDLBCL1060%/10%Not done R-ASHAPAggressive B NHL2075%/45%25% R-DHAOXNHL33 (10 were HIV+) 70%/27%Not stated R-ICE or R-DHAP followed by HDT (BEAM) and ASCT ± R maintenance Relapsed DLBCL39663%/38%52% (n= 204)49% OS at 3 years Gisselbrecht C. B J H:2008 143, 607–621

6. Vellenga E et al (Blood. 2008;111: 537-543)

7. RITUXIMAB IMPROVES DHAP-VIM-DHAP, ASCT IN CD20+ NHL Response rate 75% vs 54% Failure free survival Patients with CR/PR and BEAM.SCT Vellenga E et al (Blood. 2008;111: 537-543)

8. The standard of care in relapsing diffuse large B cell lymphoma is salvage chemotherapy followed in responding patients with autologous stem cell transplantation. Questions in 2002 for relapsed/refractory diffuse large B cell lymphoma CD 20+ ?: Does rituximab improve salvage treatment?: patients naïve of rituximab exposure patients prior exposure to rituximab Which salvage regimen is the best? Place of immunotherapy post transplantation? CORAL : COllaborative trial in Relapsed Aggressive Lymphoma

9. 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 → → ASCTASCT R x 6 Obs N=400 Which salvage regimen is the best? Place of immunotherapy post transplantation?

10. CORAL Study 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 C. Gisselbrecht, 2008

11. CORAL Study: Diffuse large B Cell Lymphoma, CD 20+ in 1st relapse, less than PR or partial response to first line treatment First randomization:R-ICE vs R-DHAP Stratification a) Center, group: upfront treatment intensive or not b) Treatment with Rituximab during first line: evaluation of response according to prior treatment c) Refractory : non achieving CR after first line of treatment ( PR, Stable, PD) and relapse < 12months ( Parma study)  Second randomization : Rituximab vs no further therapy San Francisco December, 2008 / Coral study

12. 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 TOTAL 201100193100394100 WHAT TYPE OF PATIENTS HAVE BEEN INCLUDED IN CORAL RESPONSE AT 1ST LINE San Francisco December, 2008 / Coral study C. Gisselbrecht

13. Coral patients main characteristics at inclusion R-ICE (202) R-DHAP (194) Median age 54y 55y Sex 125 118 77 76 Stage I-II 81 66 Stage III-IV 119121 ENS > 1 55 64 LDH > Nl 104 94 S-AaIPI 0-1 119 107 S-AaIPI 2-3 75 74 P=0.09 San Francisco December, 2008 / Coral study C. Gisselbrecht

14. R-ICE R-DHAP N% N% 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 (INDUCTION ITT) 63.5 % 62.8 % Arm of treatmentNb patients Nb responders with successful mobilizationMARR (%)95% CI lower95% CI upper ARM A / R-ICE19710352.340.654.9 ARM B / R-DHAP19110454.538.352.9 San Francisco December, 2008 / Coral study C. Gisselbrecht

15. CORAL TOXICITY (Median + range) R-ICE R-DHAP HB(g/dl) day 10 10.6 (15-6) 11.1(16-7) day 14 10.3 (15-5) 10.1 (15-7) WBC(/µl) day 10 3.8 (30-0) 6 (86-0) day 14 6.3 (71-0) 6 (68-0) Platelets(/µl)day 10 190 (1088-9) 101(2940-2) day 14 58 (616-2) 47 (2360-1) Transfusions % pts 35% 57% Nb pts with 3 cycles 169 (86%) 161(84%) San Francisco December, 2008 / Coral study C. Gisselbrecht

16. 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%) Toxic deaths 1 3 San Francisco December, 2008 / Coral study C. Gisselbrecht On induction safety population, a total of 90 SAEs in R-ICE arm and 120 in the R-DHAP arm were reported during the whole study, concerning respectively 58 patients (29%) and 69 patients (36%).

17. Response p Patients CR/Cru/PR All patients 246 63 % CR/CRu 148 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 San Francisco December, 2008 / Coral study C. Gisselbrecht

18. RESPONSE RATE PROGNOSTIC FACTORS CR/CRu/PR and for CR Logistic Model p value ORR CR  Prior Rituximab 0.01 0.6  Relapse < 12 months 0.0001 0.0001  sIPI > 1 0.003 0.05  Treatment Arm 0.8 0.6 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. San Francisco December, 2008 / Coral study C. Gisselbrecht

19. 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% Deaths 4% San Francisco December, 2008 / Coral study C. Gisselbrecht

20. Figure 4.5 ‑ 6 Secondary criteria – Overall Survival (induction ITT) FIGURE 4.5 ‑ 6 SECONDARY CRITERIA – OVERALL SURVIVAL (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht FIGURE 4.5 ‑ 4 SECONDARY CRITERIA – PROGRESSION-FREE SURVIVAL (INDUCTION ITT)

21. Progression-Free Survival according to Response after Induction including deaths for all patients (CR/CRu Vs PR) - induction ITT San Francisco December, 2008 / Coral study C. Gisselbrecht

22. FIGURE 4.5 ‑ 7 OVERALL SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht FIGURE 4.5 ‑ 5 PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT)

23. FIGURE 4.5 ‑ 23 EXPLORATORY ANALYSES – PROGRESSION-FREE SURVIVAL ACCORDING TO AGE ADJUSTED IPI (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht

24. PROGRESSION-FREE SURVIVAL ACCORDING TO PRIOR RITUXIMAB (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht PROGRESSION-FREE SURVIVAL ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT)

25. Failure from diagnosis =>= 12 months Event-Free Survival by Prior Rituximab - induction ITT Failure from diagnosis =< 12 months

26. MULTIVARIATE ANALYSIS FOR SURVIVAL p value PFS EFS OS  Prior Rituximab 0.003 0.0007 0.01  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. San Francisco December, 2008 / Coral study C. Gisselbrecht

27. Improving salvage regimen with the use of immunotherapy Improving post transplant outcome with the use of immunotherapy Improving conditioning regimen before ASCT with RIT

28. PROGRESSION-FREE SURVIVAL OF PATIENTS SUBMITTED TO ASCT from date of 1st randomization (INDUCTION ITT) San Francisco December, 2008 / Coral study C. Gisselbrecht Progression-Free Survival of maintenance ITT population measured from date of 2nd randomization to date of progression/relapse or death from any cause. RANDOMIZERANDOMIZE PR/CR → R x 6 Obs

29. 140 events will be required to conclude. According to the definition of events nowadays: 85 patients (43%) presented with an event: 2 (1%) with a new treatment out of progression, 77 (39%) with progression/relapse and 6 (3%) with death without progression. PART II MAINTENANCE: EVENT-FREE SURVIVAL San Francisco December, 2008 / Coral study C. Gisselbrecht RANDOMIZERANDOMIZE PR/CR → R x 6 Obs

30. Main Conclusions from the CORAL study In relapsing patients > 12 months, not previously treated with rituximab, rituximab associated salvage chemotherapy provides a high response rate: 82% and 2 yr EFS 66% In refractory patients ( <12months) to upfront rituximab associated chemotherapy, results of salvage with R Chemo remain poor: response rate: 54% and 2 yr EFS 34%. After transplantation the number of events to analyse the post transplant immunotherapy is not reached until now, and preclude subgroups analysis. No safety concerns. However we will have to wait two more years for the second part. Last patient will finish treatment next fall. A new profile of relapses and refractory patients will come out from the study. (« Genomic » profile to be studied, GELA P) From CORAL to Bio CORAL first meeting with pathologists in February.

31. What is the standard for second-line therapy in NHL in older patients?

32. LNH98-5 patients in the CHOP arm : overall survival after progression p= 0.00043 Salvage with rituximab (n=22) Salvage without rituximab (n=87) Feugier et al, JCO 2005 n=109 0123456 Years 0.0 0.2 0.4 0.6 0.8 1.0 Cumulative Proportion Surviving A

33. p= 0.076 LNH98-5 patients in the R-CHOP arm : overall survival after progression Salvage with rituximab (n=9) Salvage without rituximab (n=64) Feugier et al, JCO 2005 n=73 012345 Years 0.0 0.2 0.4 0.6 0.8 1.0 Cumulative Proportion Surviving

34. RegimenDisease statusnORR/CRSurvivalReference R-GEMHigh grade B-NHL (64–78 years) 771%/29%median PFS and OS, 10 and 11 months, (Wenger et al, 2005) R- GEMOX Aggressive NHL4674%/72%2-year EFS 43%, 2-year OS 66% (El Gnaoui et al, 2007) R-GIFOXAggressive NHL1377%/54%median FFS 80%(Corazzelli et al, 2006) GaRDAggressive NHL1979%/42%(Cabanillas et al, 2006) GaRDAggressive B-NHL2255%/27% (CR/CRu) (Smith et al, 2006) R + EDLBCL667%/50%(Leonard et al, 2005) R + EDLBCL1547%/33% (CR/CRu) median PFS 6 months (Strauss et al, 2006) R-CMDDLBCL (65–79 years) 3074%/57% (CR/CRu) 2-year OS 45%, PFS 37% (Niitsu et al, 2006) R-TTPAggressive NHL71 (32 primary refractory) 70% 25%primary refractory median DR 21 months (Younes et al, 2005) R-TTPB-cell lymphoma1060%/30%(Canales et al, 2005) R-ADOXDLBCL (heavily pre-treated) 2070%/25%Median OS 11 mos(Woehrer et al, 2005) Rituximab and other salvage regimens CMD: irinotecan, mitoxantrone, dexamethasoneTTP: paclitaxel, topotecan E: epratuzumab Gisselbrecht C. B J H:2008 143, 607–621

35. Rituximab: 375 mg/m² d1 Gemcitabine: 1000 mg/m² d2 followed by Oxaliplatin: 100 mg/m² d2 Toxicity: d1 = d15 Rituximab, Gemcitabine and Oxaliplatin (R-GEMOX) grade 3-4 % of cycles neutropenia 42 thrombocytopenia 22 infection 3 neurologic, renal 0 46 PTS ORR 83% CR 50% Median TTP 20 m El Gnaoui et al ann oncol 2007 18:1363-8

36. R-GEMOX pilot study: progression-free survival Median follow-up: 27 months (n=46) 1.00 0.75 0.50 0.25 0.00 Survival distribution function 0102030 40 50 DELPFS Product-limit estimate curve Censored observations 43% + 8 at 2 years El Gnaoui et al ann oncol 2007 18:1363-8

37. Improving conditioning regimen before ASCT

38. HIGH DOSE CONDITIONING REGIMEN  Conditioning regimens are designed to overcome drug resistance and stem cell autologous transplant to overcome toxicity  Combination of drugs without TBI: BEAM and others…… BEAM and others……  Combination of drugs with TBI: Cyc + Etoposide, Cytarabine+melphalan. Cyc + Etoposide, Cytarabine+melphalan.  Combination of drugs with involved field radiotherapy:  Pre transplant Parma study, MSKCC  Pre transplant Parma study, MSKCC  Post transplant residual mass, routine  Post transplant residual mass, routinepractice

39. HIGH DOSE CONDITIONING REGIMEN Conditioning regimens are designed to overcome drug resistance and stem cell autologous transplant to overcome toxicity Conditioning regimens are designed to overcome drug resistance and stem cell autologous transplant to overcome toxicity Combination of drugs without TBI: Combination of drugs without TBI: BEAM and others…… BEAM and others…… Combination of drugs with TBI: Combination of drugs with TBI: Cyc + Etoposide, Cytarabine+melphalan. Cyc + Etoposide, Cytarabine+melphalan. Combination of drugs with involved field radiotherapy: Combination of drugs with involved field radiotherapy:  Incorporation of Radioimmunotherapy in may improve conditioning regimen by targeting the residual disease. Is it Safe?  Incorporation of Radioimmunotherapy by targeting the residual disease. may improve conditioning regimen

40. Comparable biological effect? IFRTTBI (transplant procedure) RIT 20–40 Gy12 Gy 15–30 Gy 90 Y-ibritumomab tiuxetan (0.4 mCi/kg) 131 I-tositumomab (0.75 Gy TBD) 20–30 fractions 4–6 weeks 6 fractions 3 days Continuous exposure T 1/2 – 64 h  Incorporation of radioimmunotherapy by targeting the residual disease may improve conditioning regimen

41. Use of radiolabeled immunotherapy in myeloablative concepts + ASCT Principles: 90 Y-ibritumomab tiuxetan dose escalation (escalation Z) 90 Y-ibritumomab tiuxetan + high-dose chemotherapy (eg Z-BEAM) 90 Y-ibritumomab tiuxetan dose escalation instead of TBI (eg escalation Z-Etoposide/Cy) 90 Y-ibritumomab tiuxetan dose escalation + high-dose chemotherapy (eg escalation Z-BEAM) ZBEAM Etoposide/Cy BEAM Z Z Z

42. Inpatient Outpatient Day -14-7-4-2-21 Indium- In2B8 Imaging Zevalin therapy 0.4 mCi/Kg VP/AraC Mel TRANSPLANT Close observation, discharge upon blood count recovery Close observation Biodistribution study BCNU -5-3-60 (Z-BEAM) Patients: 12 age: Median 61yr. 20-78 yr. Histology:DLCL, MCL 90 Y Zevalin 32 mCi (20.7-40)BEAM Time to recovery: WBC 11 days, platelets 11 jours Fung H et al ASH 2003 TRIALS COMBINING CONVENTIONAL-DOSE RIT AND BEAM AS A CONDITIONING REGIMEN

43. IBRITUMOMAB TIUTEXAN WITH HIGH-DOSE BEAM Progression Free Survival by histology Time after transplantation (months ) 1.0 0.8 0.6 0.4 0.2 0 0 1218 243036424854660 Diffuse large B-cell lymphoma (n = 20) Mantle cell lymphoma (n = 13) P =.54 Proportion of patients ( A. krishnan et al., JCO, 2008)

44. IBRITUMOMAB TIUXETAN ( 90 Y-Ibritumomab Tiuxetan) COMBINED BEAM AND ASCT IN 23 AGGRESSIVE NON-HODGKIN’S LYMPHOMAS PET + BEFORE ASCT (A. Shimoni et al., Experimental hematology 2007 OVERALL SURVIVAL Median FU 17 m 1.000 0.750 0.500 0.250 0.000 05 1015202530 Months after Transplantation Overall Survival OS : 67% PFS: 52% Months after Transplantation 1.000 0.750 0.500 0.250 0.000 relapse 05 1015202530 Relapse rate : 31% RELAPSE Induction failure : 12pts Refractory relapse: 11 pts CR post transplant 70%

45. Ibritumomab Tiuxetan BEAM CONSOLIDATION IN 1st LINE DIFFUSE LARGE B CELL LYMPHOMA WITH POOR PROGNOSIS : Z BEAM 2 Diffuse Large B cell Lymphoma IPI >1 Upfront treatment No more than 1 initial chemotherapy CHOP like Treatment with Rituximab – Mobilization PBPC CR or PR / PET + or - Z-BEAM - Autograft Day 100 evaluation Follow up Inclusion – Informed consent Completed 12 2008 With 75 patients

46. Is there a place for allotransplantation in diffuse large B cell lymphoma

49. Zevalin RIC allo in refractory NHL Z fluda/bu =6 Z fluda/mel= 6 SLL transf: 4 DLBCL:3 FL: 3 MCL:2 Refractory relapse : 11 PET + pre transplant: 12 1.000 0.750 0.500 0.250 0.000 0.0 10.020.030.040.0 Months after transplantation Relapse rate 1.000 0.750 0.500 0.250 0.000 10.020.030.040.0 Months after transplantation Overall survival 0.0 (A. Shimoni, et al., Bone Marrow Transplantation 2008, 41:355-61 )

50. Conclusions The use of rituximab in DLBCL patients in relapsing patients improves the outcome –in younger patients –in older patients These combinations are well tolerated and do not hamper the ability to harvest stem cells Evaluation of treatment requires PET scan Questions –when rituximab is used in first-line therapy, what is the optimal salvage combination? New drugs mandatory –What is the place of rituximab post transplant? –can we improve consolidation with radioimmunotherapy conditioning regimen or high dose RIT with stem cell support? –RIC allo can be proposed in selected patients

51. Pr. Christian Gisselbrecht Hôpital Saint Louis Paris, France VII U728 VII