1. Follicular lymphoma Optimal primary therapy and consolidation ? Seminars in Hematological Oncology * Israel, April 26 2007 M. Dreyling, Dept. of Medicine III University Hospital LMU Grosshadern/Munich

2. Follicular lymphoma clinical risk factors conventional chemotherapy antibody monotherapy and combination new concepts: maintenance radioimmunotherapy autologous transplantation

3. Follicular lymphoma grade I/II: Clinical characteristics median age 60 years indolent course (OS 5-10 years) 80% in advanced stage palliative treatment (in relapse) chemosensitive

4. Follicular Lymphoma grade III: Histology grading according to number of blasts/HPF  grade IIIa clinically/ biologically similar to grade I/II  grade IIIb treated according to aggressive lymphoma FLIII a with centrocytesFLIII b without centrocytes Ott, Blood 2003

5. FLIPI in follicular lymphoma (n=1795) 36% 37% 27% Solal-Celigny, Blood 2004 Survival probability

6. R-CHOP in follicular lymphoma Prognostic factor FLIPI Buske, Blood 2006

7. Therapy in localized stages (I/II) Curative approach with radiation (30-40 Gray) ! - involved field ? - extended field ? - total nodal radiation ? - 2x2 Gray (EORTC) ? - plus 2 Gray TBI ? Wilder et al., 2001

8. Therapy in advanced stages (III/IV) watch & wait („to live with the disease “) non-curative chemotherapy only in symptomatic cases : B-symptoms hematopoietic insufficiency hyperviscosity syndrome local LN compression rapid progress

9. Prospective randomised study (follow-up 16 years) : n=309; 65% follicular lymphoma Overall survival Disease-free survival Long term effect watch & wait vs. chlorambucil for asymptomatic advanced stage (low grade) lymphoma Ardeshna, Lancet 2003

10. Indolent lymphoma: overall survival % s 0 0 5 5 10 15 20 25 30 100 80 60 40 20 0 0 1987-1992 (n=668) 1976-1987 (n=513) 1960-1976 (n=195) Horning. Semin Oncol 1993

11. Palliative therapy in follicular lymphoma: What are the critical aims ? event-free survival overall survival ? ? ? quality of life initial response (CR, PR)

12. Anti CD20 antibody in B-cell lymphocytes Mechanism of action 4 x 375 mg/m2 Rituximab response rate48% (166 patients) time to progression 13 months (responder) toxicityFever, rigors, chills (12% grade III, 3% grade IV) Mc Laughlin, JCO 1998

13. First line in asymptomatic advanced stage FL Overall response rates % * according to Cheson criteria Colombat, ASH 2006

14. CR/Cru: med PFS 50.9 months PR: med PFS 23 months SD-PD: med PFS 6.4 months First line in asymptomatic advanced stage FL Progression-free survival Colombat, ASH 2006 median follow-up 84 months

15. Time to progression, relapse or death Study month Event-free probability 0 61218243036424854060 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 R–CVP: median 34 months CVP: median 15 months 6672 159 CVP R–CVP Patients at risk: 162 130 145 88 133 65 113 52 106 40 85 31 78 27 69 23 58 15 42 7 15 10 30 p<0.0001 (median FU: 53 months) Marcus, ASH 2006

16. CVP ± Rituximab in previously untreated FL Summary of results Time to Treatment Failure7 mo27 mo Time to Progression15 mo34 mo Time to new antilymphoma treatment 12 mo49 mo Duration of Response 14 mo 38 mo CVP (n =159) R-CVP (n=162) Overall Response 57 % 81 % p-value <0.0001 CHOP 92% 26 mo (median FU: 53 months) Marcus, ASH 2006

17. Follicular lymphoma CHOP vs. R-CHOP CHOP R-CHOP complete induction: 272284 CR: 17% 20% PR: 74% 77% MR/SD: 6% 2% PD: 3% 1% ED: 1% 1% OR: 90% 96% p=0.0055 Hiddemann, Blood 2005

18. Follicular lymphoma (elderly patients) Progression-free survival (R-CHOP) Buske, ASH 2006 Probability years CHOP (37/109) R-CHOP (78/112) median 2.1 y p<0.0001

19. P<0.0001Not reached Median event free survival P< 0.000194% (76%)85% (49%)Response rate (CR/Cru) 184175Patients evaluable p-value 6x R-CHVP/IFN-  12x CHVP/IFN-  Foussard, ASCO 2006 P< 0.0001Not reached29 monthsMedian event free survival P = 0.000992%75%Response rate 10596Patients evaluable p-valueR-MCPMCPHerold, ASH 2006 P< 0.000127 months7 monthsMedian time to treatment failure P< 0.000181%57%Response rate 162159Patients evaluable p-valueR-CVPCVPMarcus, ASH 2006 P< 0.0001Not reached25/31 monthsMedian time to treatment failure P=0.01196%90%Response rate 112/223109/205Patients evaluable p-valueR – CHOPCHOPBuske, ASH 2006 First Line Treatment: Immuno-chemotherapy

20. Overall survival Study month Event-free probability 0 61218243036424854060 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 R–CVP: median not reached CVP: median not reached 6672 159 CVP R–CVP Patients at risk: 162 155 162 151 160 141 155 136 150 132 144 125 142 120 132 111 124 67 81 30 40 80 70 p=0.0290 (median FU: 53 months) 4-years OS estimates: 83% vs 77% Marcus, ASH 2006

21. M 39023: Overall Survival FL patients (median follow-up 47 months) P = 0.0096 Censored 15 events vs 25 events 4-year OS 87% 4-year OS 74% R-MCP: median nr MCP: median nr 0 0.25 0.50 0.75 1.00 0102030405060 Survival Distribution Function time (months) Herold, ASH 2006

22. years Probability CHOP (89/109) R-CHOP (102/112) 4-y OS: CHOP: 81 % R-CHOP: 90% p=0.039 Buske, ASH 2006 Follicular lymphoma (elderly patients) Overall survival (R-CHOP)

23. Induction Consolidation maintenance SCT => MRD eradication => lymphoma remission Immuno-chemotherapy ! Therapeutic strategies in follicular lymphoma Cure of disease ?

24. Therapeutic strategies in follicular lymphoma Cure of disease ? Options Consolidation maintenance SCT => MRD eradication 1. Rituximab, IFN-  2. radio-immunotherapy 3. autologous SCT 4. allogeneic

25. Hainsworth JCO 2005 Rituximab Maintenance vs. Retreatment Follicular lymphoma

26. Hainsworth JCO 2005 p=0.0066 Rituximab Maintenance vs. Retreatment Progression-free survival Observation

27. IFN versus Beobachtung progessionsfreies Überleben nach initialer Therapie 0123456789 years 0 0,25 0,5 0,75 1 p IFN observation p=0.012 32/84 30/94 IFN maintenance vs. watch & wait follicular lymphoma

28. GLSG: FCM vs. R-FCM Relapsed indolent lymphoma PR, CR F ludarabine C yclophosphamide M itoxantrone F ludarabine C yclophosphamide M itoxantrone + Rituximab 4 x Rituximab (month 3 & 9) watch & wait Forstpointner Blood 2006

29. Maintenance vs. Observation Duration of response (only FL after R-FCM) Observation (21/40) Rituximab (32/41) years after end of initial therapy p=0.0346 Forstpointner, Blood 2006

30. Maintenance vs. Observation Overall survival (after R-FCM) Observation (49/71) Rituximab (56/67) years after end of initial therapy p=0.0562 Forstpointner, Blood 2006

31. RANDOMISATIONRANDOMISATION CHOP every 21 days (maximum six cycles) Rituximab + CHOP every 21 days (maximum six cycles) EORTC 20981 phase III trial Observation Rituximab maintenance* CR PR *375mg/m 2 every 3 months for 2 years or until relapse van Oers, Blood 2006 RANDOMISATIONRANDOMISATION

32. med. 23.1 months median: 51.9 months EORTC 20981 phase III trial

33. OSHO/GLSG study Follicular lymphoma R-CHOP R-FCM R-MCP Rituximab maintenance watch & wait CR/PR R R

34. Radioimmunotherapy: 90 Y vs. 131 I 90 Y 131 I Gamma emission No Yes Beta emission energy (MeV) 2.30.6 Half-life (days) 2.7 8.0 Path length (mm) χ 90 5.30.8 Maximum11.02.9 Mean2.50.4 Beta radiation path length 90 Yttrium 131 Iodine

35. Low risk !!- age 49 years - 58% IPI 1 - 57% no bulk 131 I Tositumomab (Bexxar) in follicular lymphoma Kaminski, NEJM 2005

36. Y-labeled anti-CD20-antibody vs. Rituximab Time to progression 0 10 20 30 40 50 60 70 80 90 100 # C % C # % % % % C # # C % % # # # % % # # # CC C C # # # C CC C C Months Zevalin Rituximab 0246810121416182022242628303234 # # # # # # # # # # # # # # # # # # # # # # # # # # # # # C C C C CCCCCC CCC C CC C % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % C C C C C CCCC CCCCC CC % C p = 0.173

37. Y-labeled anti-CD20-antibody vs. Rituximab Time to Progression Progression free (%) 243018612036 0 20 40 60 80 100 Zevalin ® (n=73) Rituximab (n=70) All patients CR or CRu Months p=0.182 p=0.173