1. Future directions: Can we improve outcomes in relapsed/refractory DLBCL or aggressive NHL? Bertrand Coiffier Service d’Hématologie Hospices Civils de Lyon Equipe « Pathologie des Cellules Lymphoïdes » UMR 5239 CNRS – UCB – ENS - HCL The Lymphoma Study Association

2. One question, lot of possibilities Outcome different according to settings, so treatment objectives are different –Relapse or refractory –First or later progression –Young or old When is it palliative treatment? When the objective is CR?

3. Refractory patients Patients who progress during chemotherapy (first line or later) Patients who progress a few months after responding to chemotherapy –6, 9, or 12 months? Always associated with poor outcome –But not true for 20% to 30% of the “refractory” patients

4. Studies with/without rituximab Without rituximab With rituximab

5. 12 m 9 m15 m Effect of modifying the threshold between early and late relapse

6. Same observation in Italy Tarella et al. ASH 2012 Abst. 305 - 2543 patients - All subtypes of lymphoma - 46% DLBCL

7. N=160 N=228 31% 64% N=147 N=241 30% 62% Gisselbrecht C et al. JCO 2010;28:4184-4190 PFS according to major prognostic factors Time from primary diagnosis to failure Rituximab use at first line

8. GAUGUIN aNHL Phase II: End-of-treatment response in rituximab-refractory patients Rituximab refractory defined as patients who had a response of < 6 months or who failed to respond to a rituximab- containing regimen (rituximab monotherapy or in combination with chemotherapy) 0 20 40 60 80 100 All1,600/800 mg400/400 mg Patients (%) n = 25n = 13n = 12 ORR, n (%)4 (16)1 (8)3 (25) CR000 CRu000 PR413 63% of patients were previously refractory to a rituximab- containing regimen CR CRu PR 16% 8% 25%

9. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma A Younes et al. JCO 2012;30:2183

10. 10 IRC Responses by Type of Prior Therapy *denileukin diftitox, interferon. Other

11. Relapsed patients Patients who responded to prior line of therapy (CR or PR) Some can be salvaged in 2 nd line –45-50% in young patients 1 –Around 20% 2-year OS in elderly patients No good data for 3 rd line 1 Gisselbrecht et al. JCO 2012

12. 98-5 study: OS of relapsing patients Median: 6 months 5-y OS: 15 & 20%

13. First take home message Poor survival after progression in DLBCL However, 20% to 50% of the patients can be salvage, depending on age –Even in primary refractory patients Except for unfit patients, a second line therapy is mandatory –With the objective of cure or long term survival

14. Which therapy (young patients)? Objective in first progression: CR before transplant CORAL: R-DHAP seems a little better than ICE –Other regimens? RIT? –No proven benefit of maintenance/consolidation Other progressions: try allogeneic transplant if good response to salvage

15. Which therapy (older patients)? Older = Not fit for transplant A few regimens: R-GemOx –Phases II of #50 patients –ORR 60%-80% –CR 30%-40% –Median PFS #9 months –Median OS # 12-18 months Rituximab improves response

16. Blood 2008;111:537 225 patients

17. 46 patients ORR 83% CR 50% R-GemOx

18. 48 DLBCL patients, ORR 60%, CR 44% R-GemOx Phase II from GELA PFSOS

19. Eur J Haematol 2008;80:127 32 patients, ORR 43%, CR 34%

20. Other regimens Numerous new “targeted” drugs in phase II

21. Other multidrug regimens Lenalidomide & rituximab 1 Bendamustine & rituximab 2 ADC & rituximab 3 … Usually no efficacy in refractory patients 1 Zinzani et al. Clin Lymph Myel Leuk 2011;11:462; 2 Horn et al. Ann Hematol 2012;91:1579; 3 Fayad et al. J Clin Oncol 2013;on line

22. Regimens for refractory patients No studies directed specifically these patients, –particularly in first line Even if it is the big challenge in DLBCL Always mixed with relapsed patients –Rending interpretation very difficult

24. Conclusion for relapsed patients Incidence decreases with new regimens Try to cure young ones at time of relapse with salvage and autotransplant –Not really a place for allogeneic transplant in first relapse Best regimen for salvage to be defined –R-CT + new agent(s) No demonstrated role for maintenance

25. Conclusion for refractory patients In first line, try to recognize them early on Same problem for truly refractory or early progression Design specific studies addressing this problem Introduce new agents