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

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

Dave, NEJM, 2004;351:2159

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

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

WHO Lymphoid Neoplasm Classification Revisions 2008 Maintains Grading Grade 1/2 (low grade)0-15 centroblasts/hpf –Grade 10-5 centroblasts/hpf –Grade 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

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 (%) Good Intermediate Poor≥3≥ Solal-Celigny et al, Blood 2004

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

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

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

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

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

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

Randomized Trials of Rituximab and Chemotherapy in Untreated Follicular NHL TrialTreatmentCR% ORR % Results Marcus Blood 2005, JCO 2008 CVP vs R-CVP Improved TTP and OS Hiddemann Blood 2006 CHOP vs R-CHOP Improved TTF and OS Herold ASH 2005, ASH 2006 MCP vs R-MCP Improved EFS and OS Salles, Foussard J Clin Oncol 2008 CHVP/IFN vs R-CHVP/IFN Improved EFS

Time to Treatment Failure R-CVP versus CVP Study month Event-free probability R–CVP: median 27 months CVP: median 7 months CVP R–CVP Patients at risk: p< Median FU: 53 months Marcus et al, ASH 2006

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

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)

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

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

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

MJR PFS : Bendamustine-R vs R-CHOP B-R CHOP-R p = 0, Probability 48 months Median observation period 18 months Rummel et al, ASH 2007

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

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

Rituximab maintenance prolongs PFS by more than 3 years Rituximab maintenance median: 51.5 months Observation median: 14.9 months p < Years Patients (%) PFS > 3 years PFS after R-CHOP/CHOP induction in EORTC trial van Oers M, et al. Blood 2006

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 = Maintenance median: 42.2 months Observation median: 11.6 months p < Years Years van Oers M, et al. Blood 2006

Rituximab maintenance significantly improves overall survival Years Patients (%) p = HR: Rituximab maintenance: 3 years 85.1% Observation: 3 years 77.1% OS after CHOP/R-CHOP induction in EORTC trial van Oers M, et al. Blood 2006

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

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

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

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< Control (n=206) Median 13.3mos

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

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

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

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

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

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

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

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

n = n = n = % decrease in 10 y mortality Outcome for Follicular Lymphoma in BC by Era

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