1. email@med.uni-muenchen.de Neue Perspektiven in der Therapie Follikulärer Lymphome

2. CVP 57 %15 mo 85 % R-CVP81 % (p<0.001) 32 mo (p<0.001) 89 % (p=0.22) Marcus et al. 2005 CHOP 90 % 31 mo 90 % R-CHOP 96 % (p=0.011) n.r. (p=0.0006) 95 % (p=0.016) Hiddemann et al. 2005 MCP 75 % 26 mo 74 % R-MCP 92 % (p=0.0009) n.r. (p<0.0001) 87 % (p=0.0096) Herold et al. 2007 CHVP+IFN 72 % 35 mo 79 % R-CHVP+IFN 81 % (p<0.0001) n.r. (p<0.0001) 84 % (p=0.029) Salles et al. 2008 OR PFSOS Rituximab – Chemotherapy Combinations

3. CHOP versus R-CHOP for First-Line Therapy Time to Treatment Failure Randomised R-CHOP (216/283) Randomised CHOP (145/276) Years after start of therapy R-CHOP (120/135) 1.0 0.8 0.6 0.4 0.2 0 01234560123456 p<0.0001

4. Randomised R-CHOP (270/283) Randomised CHOP (248/276) p=0.0101 R-CHOP (131/135) Years after start of therapy 1.0 0.8 0.6 0.4 0.2 0 01234560123456 CHOP versus R-CHOP for First-Line Therapy Overall Survival

5. email@med.uni-muenchen.de Palliation of Symptomes Prolongation of Life Cure Key Steps in Improving Treatment for Follicular Lymphoma

6. Comparison of Two Consecutive Study Generations of the GLSG RandomizationRandomization RandomizationRandomization 6 - 8 x CHOP + Ritux 6 - 8 x CHOP CHOP MCP RandomizationRandomization PBSCT IFN-maintenance pts. < 60 yrs pts. > 60 yrs GLSG 1996 GLSG 2000

7. Comparison of Two Consecutive Study Generations of the GLSG Time to Treatment Failure

8. Comparison of Two Consecutive Study Generations of the GLSG Overall Survival

9. email@med.uni-muenchen.de Future Strategies in Follicular Lymphomas Induction Therapy in Remission Maintenance ASCT => Lymphoma Control => Lymphoma Reduction Chemotherapy plus Rituximab No further Therapy

10. FLIPI and Time to Treatment Failure low intermediatehigh

11. Follicular Lymphomas Questions for the Next Steps of Therapy Value of R maintenance after R chemo in first line therapy Best chemotherapy to be combined with Rituximab Value of radio-immuno therapy Value of stem cell transplantation after R chemo

12. PDs/SDs off study follicular NHL stages III–IV, untreated Maintenance (SAKK) 1 dose q 2 months for 24 months Observation R CR/PR 6 x CHOP 6 x FCM 6 x COP plus 8 x R PRIMA Study 2005 Follicular Lymphomas

13. PDs/SDs off study follicular NHL stages III–IV, untreated Maintenance (SAKK) 1 dose q 2 months for 24 months Observation R CR/PR 6 x CHOP 6 x FCM 6 x MCP plus 8 x R R OSHO/GLSG Study 2007 Follicular Lymphomas Not eligible for PBCT or Age > 65 Yrs.

14. 90 Y-ibritumomab tiuxetan (n=208) Induction chemotherapy* Newly diagnosed follicular lymphoma stage III/IV CR PR NR PD off study watch & wait (n=206) ** R FIT: 90 Y-ibritumomab tiuxetan as first-line consolidation FIT: First-line Indolent lymphoma Trial * CVP, CHOP, Fludarabin (combination), etc. ** n = 414 R Randomisierung Hagenbeek, ASH 2007;110: abstr 643

15. Log rank p < 0.0001 HR 0.463 90 Y-ibritumomab tiuxetan: median 37 mo (n=208) Control: median 13.5 mo (n=206) Progression-free survival FIT: 90 Y-ibritumomab tiuxetan as first-line consolidation Hagenbeek, ASH 2007;110: abstr 643

16. RandomizationRandomization 6 - 8 x CHOP 6 - 8 x MCP CR,PR RandomizationRandomization PBSCT standard IFN-maintenance intensive IFN-maintenance standard IFN-maintenance pts. < 60 yrs. (<65yrs.) pts. > 60 yrs. (>65 yrs.) Hiddemann et al., Blood 2005 GLSG Study `96

17. Lenz et al., Blood 2004 GLSG – Progression free Survival

18. ASCT in 1st Remission: Analysis from two Consecutive Study Generations of the GLSG RandomizationRandomization RandomizationRandomization 6 - 8 x CHOP + Ritux 6 - 8 x CHOP 6 – 8 x CHOP 6 – 8 x MCP RandomizationRandomization ASCT IFN-maintenance pts. < 60 yrs pts. > 60 yrs GLSG 1996 GLSG 2000

19. ASCT in 1st Remission: Analysis from two Consecutive Study Generations of the GLSG RandomizationRandomization RandomizationRandomization 6 - 8 x CHOP + Ritux 6 - 8 x CHOP 6 – 8 x CHOP 6 – 8 x MCP RandomizationRandomization ASCT IFN-maintenance pts. < 60 yrs pts. > 60 yrs GLSG 1996 GLSG 2000

20. GLSG Studies 1996 and 2000 Response Duration 12-03 Years after end of induction therapy 1.0 0.8 0.6 0.4 0.2 0 0123456701234567 CHOP + IFN ’00 CHOP + IFN ’96 CHOP + PBSCT ’96 CHOP + PBSCT ’00 R-CHOP + PBSCT ’00 R-CHOP + IFN ’00 December 2003 Probability

21. Years after end of induction therapy 1.0 0.8 0.6 0.4 0.2 0 012345678910 R-CHOP + PBSCT (81/94) CHOP + IFN (48/160) R-CHOP + IFN (105/126) CHOP + PBSCT (95/137) Probability GLSG Studies 1996 and 2000 Response Duration 12-06

22. 1.0 0.8 0.6 0.4 0.2 0 Probability No. of patients at risk R/ASCT116 97 76 523926 7 0 ASCT145132118107876954382212 R/IFN152120 86 623217 5 0 IFN167114 85 6244362817 9 2 Month after end of induction 01224364860728496108120 R/ASCT ASCT R/IFN IFN p<0.0001 GLSG Studies 1996 and 2000 Response Duration 08-08

23. 100 MRD data 98 CHOP 2 no treatment documented 553 assigned to R- CHOP 418 treated R-CHOP 436 treated R-CHOP 145 MRD data 142 R-CHOP 3 treated with CHOP 224 MRD data 172 R-CHOP 52 no treatment documented 490 MRD data 327 R-CHOP 108 CHOP 54 no treatment documented 433 randomized R- CHOP 428 randomized to CHOP 861 first randomization 411 treated CHOP 156 not randomized 13 MRD data CHOP vs. R-CHOP +/-PBSCT 1524 patients randomized

24. Quantitative t(14;18) Analysis MRD levels at induction 10 -5 10 -4 10 -3 10 -2 10 10 0 MRD level neg R-CHOP Induction p<0,0001 CHOP Induction p=0,0021 Diagnosis p=0,0134 Induction 2 28% Induction 4 Induction 6 74% 28% 72% 15%

25. Remission Duration according to Consolidation (n=30, MRD negative after induction)

26. UK SH Remission Duration according to Consolidation MRD neg. MRD pos.

27. 6 x CHOP + 8 x R CR,PR RANDOMISATIONRANDOMISATION ASCT Rituximab maintenance Rituximab maintenance RiCHOP study 2009 for First-Line Therapy of FL Patients aged <65 Years

28. Ultimate Goal : Cure by combining all proven effective treatment modalities R-chemo for initial therapy ASCT R maintenance The Concept of „Total Therapy“ RiCHOP study 2009 for First-Line Therapy of FL Patients aged <65 Years

29. email@med.uni-muenchen.de Palliation of Symptomes Prolongation of Life Cure Key Steps in Improving Treatment for Follicular Lymphoma

30. Supported by Deutsche Krebshilfe GLSG Study Group