1. Follicular Lymphoma Laurie H. Sehn, MDCM, MPH BC Cancer Agency Vancouver, Canada

2. Pathogenesis of Follicular Lymphoma t(14;18) t(14;18) B cell GC reaction SHM machinery Additional genetic alterations 6q- -1p36.3 +der18 +7, +8 Additional genomic alterations Immune Response 2 Immune Response 1 B cell Adverse Course Favorable Course Ag Host Genetics Host Genetics Bcl-2 N-glycosylation RFH FL

3. Dave, NEJM, 2004;351:2159

4. Reported Molecular Markers in FL FavorableUnfavorable Bcl-6 expression CD-10 expression MUM1 negative PU.1 Cyclin B1 Immune response IR-1 Chromosomal gains (+7, +12q13-14, +18q) Chromosomal losses (del6q, -9p21, -17p13) Bcl-2 expression BCL-6 translocation MDM2 expression Bcl-XL Macrophage content Microvessel density 81-gene predictor (variable) Immune response IR-2

5. Follicular Lymphoma Grades X Grade 1 Grade 2 Grade 3a Grade 3b MIB1

6. WHO Lymphoid Neoplasm Classification Revisions 2008 Maintains Grading Grade 1/2 (low grade)0-15 centroblasts/hpf –Grade 10-5 centroblasts/hpf –Grade 2 6-15 centroblasts/hpf Grade 3 –Grade 3A > 15 centroblasts/hpf –Grade 3Bsolid sheets of centroblasts Any diffuse areas with >15 centroblasts/hpf is now called DLBCL with follicular lymphoma

7. Follicular Lymphoma International Prognostic Index (FLIPI) FactorAdverse Nodal Sites≥5 LDH>Normal Age≥60 StageIII-IV Hemoglobin<12 g/dL Prognosis Number of Factors Patients (%) 5-year OS (%) 10-year OS (%) Good0-1369171 Intermediate2377851 Poor≥3≥3275336 Solal-Celigny et al, Blood 2004

8. Comparison of IPI and FLIPI Indices IPI FLIPI Perea, Annals Oncol 2005 HR IR LR

9. TTF According to FLIPI Following R-CHOP Buske, Blood 2006

11. Indolent Lymphoma Age Adjusted Mortality vs Normal Weisdorf, J Clin Oncol 1992;10:942 Indolent lymphoma > 75

12. Treatment Options for Follicular Lymphoma Interferon Autologous Allogeneic (full or non- myeloablative) Alkylator-based treatment CVP Chlorambucil CHOP SpecificNonspecific Purine analogs Fludarabine Fludarabine-based combination Chemotherapy-based Antibody-based Rituximab alone Chemo-immunotherapy Radioimmunotherapy Tositumomab Ibritumomab tiuxetan Biologic-basedTransplantation

13. Optimal Therapy in FL Should be Individualized Curative therapy has not been identified Treatment decisions must be individualized and should consider: –Goal of therapy –Efficacy of therapy –Toxicity –Patient’s medical condition –Patient preferences –Lifelong management –Appropriate sequencing

14. Watch and Wait No survival advantage to starting therapy early –Young, RC et al. Semin Hematol 1988 –Brice, P et al. J Clin Oncol 1997 –Ardeshna, KM et al. Lancet 2003 Avoids unnecessary toxicity and maintains QOL Allows new information and therapies to emerge Not yet tested in era of immuno-chemotherapy

15. Randomized Trials of Rituximab and Chemotherapy in Untreated Follicular NHL TrialTreatmentCR% ORR % Results Marcus Blood 2005, JCO 2008 CVP vs R-CVP 10 41 57 81 Improved TTP and OS Hiddemann Blood 2006 CHOP vs R-CHOP 17 20 90 96 Improved TTF and OS Herold ASH 2005, ASH 2006 MCP vs R-MCP 25 50 75 92 Improved EFS and OS Salles, Foussard J Clin Oncol 2008 CHVP/IFN vs R-CHVP/IFN 63 79 73 84 Improved EFS

16. Time to Treatment Failure R-CVP versus CVP 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 27 months CVP: median 7 months 6672 159 CVP R–CVP Patients at risk: 162 86 123 51 113 34 98 30 93 21 76 17 69 14 63 10 53 6 37 3 14 10 30 p<0.0001 Median FU: 53 months Marcus et al, ASH 2006

17. Marcus, R et al. J Clin Oncol 2008 Overall survival R­CVP versus CVP

18. Do we need to use an Anthracycline? No survival advantage to using an anthracycline –Dana, et al. J Clin Oncol 1993 –Peterson, et al. J Clin Oncol 2003 Greater Toxicity Variable results reported with R-CHOP –Czuczman, et al. J Clin Oncol 2004 –Hiddemann, et al. Blood 2005 Consider lifelong management (transformation risk)

19. Risk of Transformation by Initial Treatment Al-Tourah et al. J Clin Oncol, 2008

20. Follicular Lymphoma Grading Grade 1 FLGrade 3a FL Grade 2 FL The spectrum of FL is a continuum from grade 1  grade 3a Increasing Proliferation

21. Overall Survival of Grade 3A FL According to Treatment Time (years) Overall SurvivalDisease Specific Survival Anthracycline (n=32) No Anthracycline (n=67) Shustik et al, Lugano 2008

22. MJR PFS : Bendamustine-R vs R-CHOP B-R CHOP-R p = 0,11 0122436 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability 48 months Median observation period 18 months Rummel et al, ASH 2007

23. Randomized Maintenance Rituximab Trials in Indolent NHL TrialPatientsInductionResults Hochster J Clin Oncol 2009 UntreatedCVPImproved EFS Ghielmini Blood 2004 Untreated/ Relapsed RituximabImproved EFS Hainsworth J Clin Oncol 2005 RelapsedRituximabImproved PFS Forstpointner Blood 2006 RelapsedFCM v R-FCM Improved Response Duration van Oers Blood 2006, ASH 2009 RelapsedCHOP v R-CHOP Improved PFS and ?OS

24. RANDOMISERANDOMISE CHOP q21d maximum 6 cycles R-CHOP q21d maximum 6 cycles RANDOMISERANDOMISE Observation Rituximab maintenance therapy* * 375 mg/m 2 every 3 months for 2 years or until relapse CR PR n = 234 n = 231 n = 167 van Oers M, et al. Blood 2006 Rituximab in Induction and Maintenance Treatment of Relapsed Follicular NHL- EORTC Trial

25. Rituximab maintenance prolongs PFS by more than 3 years Rituximab maintenance median: 51.5 months Observation median: 14.9 months p < 0.001 Years 01234 5 0 10 20 30 40 50 60 70 80 90 100 Patients (%) PFS > 3 years PFS after R-CHOP/CHOP induction in EORTC 20981 trial van Oers M, et al. Blood 2006

26. Rituximab maintenance improves PFS irrespective of induction regimen PFS after CHOP inductionPFS after R-CHOP induction Observation Median: 23.0 months Maintenance Median: 51.8 months p = 0.004 Maintenance median: 42.2 months Observation median: 11.6 months p < 0.001 Years 012345 0 20 40 60 80 100 Years 01234 5 0 20 40 60 80 100 van Oers M, et al. Blood 2006

27. Rituximab maintenance significantly improves overall survival Years 01234 6 0 10 20 30 40 50 60 70 80 90 100 Patients (%) p = 0.011 HR: 0.52 5 Rituximab maintenance: 3 years 85.1% Observation: 3 years 77.1% OS after CHOP/R-CHOP induction in EORTC 20981 trial van Oers M, et al. Blood 2006

28. Vidal et al, J Natl Cancer Inst 2009 Meta-Analysis: Overall Survival with Rituximab Maintenance versus Observation

29. Vidal et al, J Natl Cancer Inst 2009 Meta-Analysis: Infection-Related Adverse Events with Rituximab Maintenance

30. FIT Study Design ZEVALIN (n = 208) Rituximab 250 mg/m 2 IV day -7 and day 0 + Zevalin 14.8 MBq/kg (max 1184 MBq/kg) day 0 Advanced Stage FL First-line CVP, CHOP- like, fludarabine combinations, chlorambucil, or rituximab combination INDUCTION CONSOLIDATION No further treatment (n = 206) NR PD CR/CRu or PR No inclusion RANDOMIZATIONRANDOMIZATION CONTROL Start of study

31. Morschhauser et al, J Clin Oncol 2008 Progression-Free Survival 90Y-ibritumomab tiuxetan versus Observation 90 Y-ibritumomab tiuxetan (n=208) Median 36.5 mos P<0.0001 Control (n=206) Median 13.3mos

32. Overall Survival 90Y-ibritumomab tiuxetan versus Observation Morschhauser et al, J Clin Oncol 2008

33. Ladetto et al, Blood 2008 Overall SurvivalEvent-Free Survival Outcome in Untreated FL Following CHOP-R versus Rituximab and ABMT

34. Rezvani, et al. J Clin Oncol 2008 Outcome Following Reduced-Intensity Allogeneic Transplantation - Seattle n=16 n=46

35. Impact of Transformation on Survival of pts with Follicular Lymphoma Al-Tourah et al, J Clin Oncol, 2008

36. Risk of Transformation = 3% per year 10 y Risk = 30% Transformation Risk in FL British Columbia (N= 600) Al-Tourah et al, J Clin Oncol, 2008

37. Transformation is a heterogenous process mutation of P53 P16 alterations rearrangements involving c-myc secondary non-random cytogenetic changes 5’UTR Bcl-6 mutations mutations in Bcl-2 Transformation

38. Impact of Initial Management On Risk of Transformation Al-Tourah et al, J Clin Oncol, 2008

39. Post-Transformation Survival by Treatment: CHOP-R vs CHOP- Like CHOP-R (N= 23) 5yr OS 61% CHOP-Like (N= 85) 5yr OS 33% P= 0.01 Proportion Surviving Post-Transformation Survival (y) Al-Tourah, ASH 2007, Abst # 790

40. 1980-88 n = 367 1998-2006 n = 941 1989-97 n = 710 33 % decrease in 10 y mortality Outcome for Follicular Lymphoma in BC by Era

41. Conclusion Combined chemoimmunotherapy improves survival in patients who need treatment Maintenance rituximab significantly prolongs remission Transformation remains a treatment challenge and greatly impacts survival Challenge  Use biologic insight of key factors at play in individual patients to guide treatment