1. 2013 Lymphoma Update 2013.08.05

2. Outline Follicular lymphoma Hodgkin’s lymphoma Chronic lymphocytic leukemia

3. Follicular Lymphoma

4. Epidemiology of FL Account 22% of NHL Chronic relapsing and remitting pattern Most patients aged > 50 Median survival 12~14 years

5. 1st line treatment in FL Blood 2005;106:3725 Lancet 2013;381:1203 R-CVP vs CVP 4-yr OS 83% vs 77% (P=0.0290) R-CHOP vs CHOP 2-yr OS 95% vs 90% (P=0.016)

6. Standard care with indolent lymphoma There’s still a role for watch& wait, despite new therapy modalities Combined immuno-chemotherapy is standard of care Rituximab maintenance as consolidation Which chemotherapy should be best combined with Rituximab? New perspectives

7. B-R vs R-CHOP Follicular Waldenstroms Marginal zone Mantle cell Small lymphocytic (n=549) Bendamustine-Rituximab (B: 90ng/m2 day 1+2, max 6 cycles, q4wks) R-CHOP ( max 6 cycles, q3 wks) StiL NHL 1-2003 R Rummel et al. Lancet 2013;381:1203 Primary endpoint: PFS 81 centers in Germany Enrolled between Sep 2003~Aug 2008 Stage III/IV IL or MCL Median f/u 45 mos Non-inferiority study

8. Grade 3+4 hematotoxicity B-R (n=261) (%)R-CHOP (n=253)(%) P value Leukocytopenia3772<0.0001 Neutropenia2969<0.0001 Thrombocytopenia56 Anemia35 B-R (n=261) (%)R-CHOP (n=253)(%) P value Alopecia0100<0.0001 Paresthesia729<0.0001 Somatitis619<0.0001 Skin allergy1560.0006 Non-hematological toxicity Rummel et al. Lancet 2013;381:1203

9. Response rates B-R (n=261)R-CHOP (n=253) P value ORR92.7%91.3% CR39.8%30.0%0.021 SD2.7%3.6% PD3.5%2.8% Rummel et al. Lancet 2013;381:1203

10. PFS Rummel et al. Lancet 2013;381:1203 B-RR-CHOPP value PFS69.5 mos31.2 mosP<0.0001 OSNR

11. FL MCL Marginal zoneWaldenstrom Rummel et al. Lancet 2013;381:1203

12. Conclusion B-R is not only less toxic but also more effective than R-CHOP B-R could be considered as a preferred 1 st -line treatment for patients with FL, indolent and MCL Rummel et al. Lancet 2013;381:1203

13. Treatment strategies in IL InductionConsolidation ImmunochemotherapyMaintenance Tumor reduction Eradication?

14. PRIMA: study design

15. PFS R maintenance (n=505) Observation (n=513) P value HR (95% CI) NR48.3mP<0.0001 0.50 (0.39~0.64) Lancet 2010;377:42

16. R maintenance (n=505) Observation (n=513) P value HR (95% CI) NR P=0.60 HR 0.87 (0.51~1.47) Lancet 2010;377:42 R maintenance (n=505) Observation (n=513) P value HR (95% CI) CR or uCR after maintenance 71.5%51.5%P=0.0001 OS

17. Lancet 2010;377:42

18. B-R with maintenance Follicular (n=611) B-R + 2 years Rituximab q2m B-R+ 4 years Rituximab q2m StiL NHL 7-2008 MAINTAIN R Rummel et al. Lancet 2013;381:1203 Primary endpoint: PFS Induction with B-R If CR or PR then maintenance

19. Hodgkin’s lymphoma

20. HL is a curable disease 19802009 GHSG HD9 study 1992 MOPP BEACOPP ABVD Stanford V 1995 Significant improvement in survival rate between 1970s and 1990s; However, the survival rate has plateaued in last two decades 5-year survival of HL still is only 85%

21. ABVD or BEACOPP? ABVD Most recent E2496 study BEACOPP Most recent GHSG HD15 study 3-yr PFS for advanced stage (Ann Arbor III/IV): 71% 5-yr PFS for advanced stage (Ann Arbor III/IV): 91.1% 3-yr OS: 84%5-yr OS: 95.6% Less hematotoxicityHematotoxicity, Infertility How to Increase efficacy ?How to increasing tolerability? JCO 2013;31:684 Lancet 2012;379:1791

22. Different approaches to targeting CD30 CD30 Anti-CD30 naked mAb Modified anti- CD30 Ab (improving receptor affinity) Anti-CD30 ADCs

23. CD30-directed immunotherapy DateAntibodyAuthors 1992BER-H2(saponin-conjugated)Falini et al. 2005Ki-4- 131 I(radio-conjugate)Schnell et al. 2007MDX-060 (naked)Ansell et al. 2008SGN-30 (naked)Bartlett et al. 2009MDX-1401 (engineered)Cardarelli et al. 2010SGN-35 (drug-conjugated)Younes et al.

24. Brentuximab vedotin antibody-drug conjugate (ADC)

25. Mechanism of Brentuximab vedotin

26. Phase II trial of brentuximab vendotin in R/R HL Relapsed or refractory CD30+ HL Age ≧ 12 years Measurable disease ≧ 1.5cm ECOG 0~1 Prior ASCT Brentuximab vedotin 1.8mg/kg IV Q3W Administered outpateint over 30 mins Min.8 to max. 16 cycles for SD or better Restage at cycles 2,4,7,10,13,16 Q3mo for 2 yrs Q6 mo year 3~5 Annually after 5 years EligilibiltyTreatment (n=102)Follow-up Primary endpoint: ORR by Independent review Facility (IRF) JCO 2012;30:2183

27. IRF (n=102) ORR, % (95% CI) CR, % (95% CI) 75 (65,83) 34 (25,44) PR, %40 SD, %22 PD, %3 Not evaluable, %1

28. JCO 2012;30:2183 Brentuximab (n=57) Prior therapy (n=57) P value HR 7.8m4.1mP<0.001 0.41

29. Summary: changing therapeutic paradigms? 3 rd line Brentuximab vedotin 2 nd line HDCT+ASCT DEXA-BEAM, mini-BEAM ICE, DHAP, GDP 1 st line Standard treatmentOpen questions ABVD BEACOPP Improving salvage? Introducing maintenance? New combination?

30. GHSG approach: “targeted BEACOPP” BrECADD MedikamentBrECADDComment BleomycinPulmonary toxicity Etoposide150 Adriamycin40 Cyclophosphamide1250 VincristineNeurotoxicity Brentuximab vedotin 1.8 ProcarbazineGonadal toxicity PrednisoloneCushing, infection Dacarbazine2×250 Dexamethasone4×40 Study is recruiting since 2012/11

31. Chronic lymphocytic leukemia

32. Classification of CLL patients according to their fitness Blood 2009;114:3359

34. History of anti-CD20 mAbs

35. GA 101: type II, glycoenginered anti-CD20 mAb First type II, glycoengineered, humanized IgG1 anti-CD 20 mAb In preclinical studies comparing against rituximab, GA 101 provided: Enhanced ADCC, oligosaccharides that enhance the interaction with FcγR, particularly FcγRIIIa, even in effector cells bearing the low affinity polymorphic variant of FcγRIIIa Increased direct cell death induction Decreased complement-dependent cytotoxicity

37. Type I and type II anti-CD20 mAbs Type I Rituximab Ofatumumab Type II Tositumomab GA 101 CDC++- ADCC++ Move CD20 into lipid rafts ++- Homotypic adhesion-++ Induced cell death-++

38. Summary of direct cell death with type II mAbs (GA 101) Most anti-CD20 mAbs in development are type I. Non of type I mAbs had proven to be superior to rituximab. The type II anti-CD20 mAb GA101 exhibit increased PCD, enhanced ADCC and lower CDC compared with type I mAbs GA 101 induced PCD via non-apoptotic pathways involving lysosomes nad ROS Loss of cell surface CD20 by ”shaving” involving phagocytosis and modulation on tumor surface may affect anti-CD20 efficacy of mAbs.

51. Thanks for your attention comments and questions