1. Jonathan W. Friedberg M.D., M.M.Sc. University of Rochester Medical Center Optimal frontline therapy for Follicular lymphoma: Do we need to start with chemotherapy? NO!

3. Follicular Lymphoma is Heterogeneous Solal-C é ligny et al. Blood. 104:1258 Age (>60) Age (>60) Ann Arbor stage (III-IV) Ann Arbor stage (III-IV) Hemoglobin level (<120 g/L) Hemoglobin level (<120 g/L) Serum lactate dehydrogenase (>ULN) Serum lactate dehydrogenase (>ULN) Number of involved nodal sites (>4) Number of involved nodal sites (>4) Follicular Lymphoma International Prognostic Index FL-IPI clinical prognostic scoring system

4. Follicular Lymphoma Overall Survival According to FL-IPI Risk GroupFactors (#)Patients (%)5-Year OS (%)10-Year OS (%) Low 0–1369171 Intermediate2377851 High≥3≥3275336 Solal-Céligny et al. Blood. 104:1258

5. NEJM 351:2159 T cells Macrophages Dendritic cells “Immune-response 1” “Immune-response 2” Favorable OS: > 10 years Unfavorable OS: < 4 years Biological heterogeneity of follicular lymphoma: Impact of nodal microenvironment

6. What is the aim of therapy in an incurable disease like follicular lymphoma? “Clinical benefit” –Symptom relief (note most patients are not symptomatic) –Quality of life Physical: decreased transfusions, decreased infections, etc. Psychological: “…better to be in remission…..” –Change the natural history of disease Transformation, Overall survival Delay need for toxic therapy

7. Follicular Lymphoma Common Management Approach After Staging Evaluation Early stage Involved Field Radiation Advanced stage Low Tumor Burden Observation Advanced stage High Tumor Burden Therapy TRANSFORMATION

8. Follicular Lymphoma Common Management Approach After Staging Evaluation Early stage Involved Field Radiation Advanced stage Low Tumor Burden Observation Advanced stage High Tumor Burden Therapy TRANSFORMATION

9. “Watch and Wait” Strategy for Select Indolent NHL Patients Study of asymptomatic, advanced stage, low-grade NHL found no difference in OS between immediate chlorambucil vs delay of therapy until progression 1 Chlorambucil: 5.9 yr Observation: 6.7 yr Current NCCN Guidelines recommend observation for select indolent NHL patients particularly if 2 : Advanced Age Asymptomatic Low Tumor Burden 1 Ardeshna KM, et al. Lancet. 2003;362:516-522. 2 NCCN guidelines. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

10. Randomized Trial of Rituximab vs W&W in Patients With Stage II-IV Asymptomatic Non-Bulky FL Ardeshna K, et al. Blood. 2010;116:5a. Abstract 6. Summary Improved PFS in R arms (P < 0.001) Improved time to initiation of new treatment in the R arms: 33 mo vs. not reached at 4 yr (P < 0.001) No difference in OS (P > 0.5) Quality of life no worse Arm A Arm B Arm C InterventionObserveR x 4 wk Maintenance-- R q 2 mo x 2 yr Number18684192 CR/PR (%)3/645/3349/36 PFS30%60%80% TNT33 moNR Ardeshna et al, ASH 2010 Plenary

11. Watchful waiting (WW) vs active treatment (AT): Lymphocare 2,727 patients with newly diagnosed FL enrolled 1,822 Stage III/IV AT group n = 1,462 WW group n = 270 R-monotherapy n = 232 R-chemotherapy n = 1,019 Other † n = 211 31 patients excluded*59 patients excluded* Sinha et al, ASH 2011

12. Baseline characteristics (WW vs AT) Characteristic, % WW (n = 270) AT (n = 1,462)p-value Age, median years (range) 61 (34–91) 60 (22–97) 0.9003 Male45490.2601 FL grade: 1–27968 0.0002 31020 Mixed or unknown1112 FLIPI risk: Good1814 < 0.0001 Intermediate4835 Poor3451 ECOG PS: 08561 < 0.0001 ≥ 11539 Patients receiving AT had higher percentages of stage IV, LDH > ULN, Hgb < 12 g/dL, and more than one extranodal site Race, number of nodal sites and bone marrow involvement were not significantly different between groups (Pearson chi-square test, p > 0.05)

13. No differences in overall survival at 5 years of follow-up WW (n = 270) R-mono (n = 232) R-chemo (n = 1,019) Other (n = 211) Median follow-up time, months 60575962 Median OSNot reached Deaths, %18252018

14. SAKK 35/98 trial design: Standard vs. Prolonged Rituximab in indolent NHL 375 mg/m² every 2 months x 4 n = 151 PDofftrial n = 202 Prolonged 375 mg/m² weekly x 4 Standard R SD,PR,CR

15. Characteristics of the patients IncludedRandomised (n = 202)(n = 151 ) Median age5757 PS 0-I94 %97 % Stage III-IV85 %85 % Involved BM52 %50 % Bulky (> 5 cm)53 %48 % Elevated LDH37 %30 % Previous chemotherapy68 %66%

16. Prolonged vs. standard rituximab EFS: Blood 103:4416 2004

17. Effect of schedule on event free survival: Update 2009 P = 0.0007 Median FU: 9.4 years 25% still in remission at 8 years

18. EFS in chemo-naïve responders: Update 2009 P<0.0001 45% of chemo-naive responders in remission at 8 years

19. Overall Survival: Update 2009 P = 0.09

20. Conclusions: Ghielmini et al Prolonged rituximab therapy is safe With 8 total doses of rituximab, the chance of being still in remission is ~25% at 5 and 8 years. Trend toward improved overall survival Excellent outcome for selected patients treated with rituximab alone. Would patients do better with chemotherapy? Is it worth the risks?

21. E4402 (RESORT) Schema Rituximab re-treatment at progression* 375 mg/m 2 qw  4 RANDOMIZERANDOMIZE Rituximab 375 mg/m 2 qw  4 CR or PR Rituximab Maintenance* 375 mg/m 2 q 3 months *Continue until treatment failure No response to retreatment or PD within 6 months of R Initiation of cytotoxic therapy or Inability to complete rx Kahl et al, ASH 2011

22. E4402 Major Eligibility  Indolent NHL  Follicular grade 1 or 2  Small Lymphocytic  MALT  Marginal Zone nodal  Marginal Zone splenic  No prior lymphoma therapy  Stage III or IV disease  Measurable disease  Low tumor burden as defined by GELF  No tumor mass > 7cm  Fewer than 3 nodal masses > 3 cm  No system symptoms or B symptoms  No splenomegaly greater than 16 cm by CT scan  No risk of organ compression  No leukemic phase  No cytopenias

23. Primary Endpoint: Time to Treatment Failure

24. Time to First Cytotoxic Therapy 90% of patients did not require cytotoxic therapy for first 5 years of diagnosis

25. Conclusions: RESORT In this study of previously untreated low tumor burden FL: –Rituximab retreatment was as effective as maintenance rituximab for time to treatment failure –No benefit in QOL or anxiety at 12 months with MR –Virtually all of these selected patients did extremely well without chemotherapy

26. Indolent CD20+ lymphoma Central pathology review RANDOMIZATIONRANDOMIZATION Rituximab x 4 + IFN x 5 weeks EVALUATIONEVALUATION Rituximab x 4 + IFN x 5 weeks) SD, PD off protocol therapy CR, CRu PR MR Rituximab 375mg/m 2 i.v. day 1 IFN-  2a 3.0 MIU/day s.c. daily (Week 1) 4.5 MIU/day s.c. daily (Weeks 2–5) Rituximab x 4 Randomized phase III trial ML16865 CHEMOTHERAPY Kimby et al, ASH 2012

27. Overall survival: ITT follicular lymphoma patients 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Event-free probability 618 30 36 4248 0 12 24 5460 66 72 7884 134 122 130 120 126 115 123 111 109 97 96 86 135 122 132 120 129 116 82 79 74 64 60 53 41 39 30 29 23 17 Patients at risk: Rituximab only Rituximab + IFN Time (months) % pts with eventMedian95% CIp value Rituximab13%NE Rituximab + IFN10%NE 0.4289 p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)

28. 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Event-free probability 618 3036 4248 0 12 24 5460 6672 78 84 108 104 80 81 56 62 50 56 43 45 37 40 135 122 92 66 69 26 34 23 26 21 15 12 10 6 Patients at risk: Rituximab only Rituximab + IFN Time to treatment failure: ITT follicular lymphoma patients (n=257) Time (months) % pts with eventMedian95% CIp value Rituximab67%23.218.1–31.3 Rituximab + IFN66%31.721.9–43.30.3627 p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)

29. Many patients with follicular lymphoma do not require chemotherapy Watch and wait –No overall survival benefit with early treatment –No change in transformation with early treatment Rituximab: –Highly active therapy in a variety of schedules –Long responses and outstanding survival

30. Phase 2 study of lenalidomide and rituximab for follicular lymphoma Pre-TreatmentPost-Treatment PositiveNegativePositiveNegative N441342 * %98%2%7%93% 1. Juweid, M. et al. JCO. 2007. 25(5): 571-578. Lenalidomide 20 mg Rituximab 375 mg 3 year PFS: 81% PET Imaging Results Progression-free survival Fowler et al, ASH 2012

31. RELEVANCE Study Design (Rituximab and LEnalidomide versus Any ChEmotherapy) 1 st line FL N=1000 R R2R2 R + Chemo R 2 Maintenance Rituximab Maint. R+Chemo: Investigator’s choice of R-CHOP, R-CVP, BR Lenalidomide 20mg for 6 cycles, then 10mg if CR

32. Thank you! Questions?