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Jonathan W. Friedberg M.D., M.M.Sc.

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

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Jonathan W. Friedberg M.D., M.M.Sc.

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

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

  3. 1.0 0.8 Low 0.6 Intermediate Survival Probability 0.4 High 0.2 P<10-4 0.0 36 120 12 48 84 108 24 60 0 72 96 Time (Months) Follicular LymphomaOverall Survival According to FL-IPI Solal-Céligny et al. Blood. 104:1258

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

  5. 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

  6. Follicular LymphomaCommon Management Approach TRANSFORMATION

  7. Follicular LymphomaCommon Management Approach TRANSFORMATION

  8. “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 progression1 • Chlorambucil: 5.9 yr • Observation: 6.7 yr • Current NCCN Guidelines recommend observation for select indolent NHL patients particularly if2: • Advanced Age • Asymptomatic • Low Tumor Burden 1Ardeshna KM, et al. Lancet. 2003;362:516-522. 2NCCN guidelines. http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.

  9. Randomized Trial of Rituximab vs W&W in Patients With Stage II-IV Asymptomatic Non-Bulky FL • Summary • Improved PFS in R arms (P < 0.001) • Improved time to initiation of new treatment in the R arms: 33 movs. not reached at 4 yr (P < 0.001) • No difference in OS (P > 0.5) • Quality of life no worse Ardeshna et al, ASH 2010 Plenary Ardeshna K, et al. Blood. 2010;116:5a. Abstract 6.

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

  11. Baseline characteristics (WW vs AT) 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)

  12. No differences in overall survivalat 5 years of follow-up

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

  14. Characteristics of the patients Included Randomised (n = 202) (n = 151 ) Median age 57 57 PS 0-I 94 % 97 % Stage III-IV 85 % 85 % Involved BM 52 % 50 % Bulky (> 5 cm) 53 % 48 % Elevated LDH 37 % 30 % Previous chemotherapy 68 % 66%

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

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

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

  18. Overall Survival: Update 2009 P = 0.09

  19. 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?

  20. E4402 (RESORT) Schema R A N D O M I Z E Rituximab Maintenance* 375 mg/m2q 3 months Rituximab 375 mg/m2 qw  4 CR or PR Rituximabre-treatment atprogression* 375 mg/m2 qw  4 *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

  21. 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

  22. Primary Endpoint: Time to Treatment Failure

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

  24. 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

  25. Randomized phase III trial ML16865 RANDOMIZATION EVALUATION Rituximab x 4 Rituximab x 4 Indolent CD20+ lymphoma Central pathology review CR, CRu PR MR Rituximab x 4 + IFN x 5 weeks Rituximab x 4 + IFN x 5 weeks) SD, PD off protocol therapy • Rituximab 375mg/m2i.v. day 1 • IFN-2a • 3.0 MIU/day s.c. daily (Week 1) • 4.5 MIU/day s.c. daily (Weeks 2–5) CHEMOTHERAPY Kimby et al, ASH 2012

  26. Overall survival: ITT follicular lymphoma patients 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Event-free probability 0.3 0.2 0.1 0.0 0 54 60 36 84 78 66 72 42 48 30 24 6 18 12 130 120 132 120 23 17 30 29 129 116 134 122 135 122 82 79 74 64 126 115 123 111 60 53 41 39 109 97 96 86 Patients at risk: Rituximab only Rituximab + IFN Time (months) p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)

  27. Time to treatment failure: ITT follicular lymphoma patients (n=257) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 Event-free probability 0.3 0.2 0.1 0.0 24 66 72 6 18 12 0 54 60 30 36 84 78 42 48 66 69 21 21 15 15 43 45 37 40 80 81 108 104 92 92 135 122 26 34 23 26 56 62 50 56 12 12 10 6 Time (months) Patients at risk: Rituximab only Rituximab + IFN p-value obtained from stratified log-rank test (stratification: previous treatment for lymphoma)

  28. 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

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

  30. RELEVANCE Study Design(Rituximab and LEnalidomide versus Any ChEmotherapy) R2 R2 Maintenance 1st line FL N=1000 R R+ Chemo RituximabMaint. • R+Chemo: • Investigator’s choice of R-CHOP, R-CVP, BR • Lenalidomide 20mg for 6 cycles, then 10mg if CR

  31. Thank you! Questions?

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