2013 Lymphoma Update 2013 08 05 Outline Follicular

2013 Lymphoma Update 2013. 08. 05

Outline • Follicular lymphoma • Hodgkin’s lymphoma • Chronic lymphocytic leukemia

Follicular Lymphoma

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

1 st line treatment in FL R-CHOP vs CHOP R-CVP vs CVP 2 -yr OS 95% vs 90% (P=0. 016) 4 -yr OS 83% vs 77% (P=0. 0290) Blood 2005; 106: 3725 Lancet 2013; 381: 1203

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 New perspectives • Which chemotherapy should be best combined with Rituximab?

B-R vs R-CHOP Sti. L NHL 1 -2003 Follicular Waldenstroms Marginal zone Mantle cell Small lymphocytic (n=549) Bendamustine-Rituximab (B: 90 ng/m 2 day 1+2, max 6 cycles, q 4 wks) R 81 centers in Germany Enrolled between Sep 2003~Aug 2008 Stage III/IV IL or MCL Median f/u 45 mos Non-inferiority study R-CHOP (max 6 cycles, q 3 wks) Primary endpoint: PFS Rummel et al. Lancet 2013; 381: 1203

Grade 3+4 hematotoxicity B-R (n=261) (%) R-CHOP (n=253)(%) P value Leukocytopenia 37 72 <0. 0001 Neutropenia 29 69 <0. 0001 Thrombocytopenia 5 6 Anemia 3 5 Non-hematological toxicity B-R (n=261) (%) R-CHOP (n=253)(%) P value Alopecia 0 100 <0. 0001 Paresthesia 7 29 <0. 0001 Somatitis 6 19 <0. 0001 Skin allergy 15 6 0. 0006 Rummel et al. Lancet 2013; 381: 1203

Response rates B-R (n=261) R-CHOP (n=253) ORR 92. 7% 91. 3% CR 39. 8% 30. 0% SD 2. 7% 3. 6% PD 3. 5% 2. 8% P value 0. 021 Rummel et al. Lancet 2013; 381: 1203

PFS B-R R-CHOP P value PFS 69. 5 mos 31. 2 mos P<0. 0001 OS NR NR Rummel et al. Lancet 2013; 381: 1203

FL Marginal zone MCL Waldenstrom Rummel et al. Lancet 2013; 381: 1203

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

Treatment strategies in IL Induction Immunochemotherapy Tumor reduction Consolidation Maintenance Eradication?

PRIMA: study design

PFS R maintenance (n=505) Observation (n=513) P value HR (95% CI) NR 48. 3 m P<0. 0001 0. 50 (0. 39~0. 64) Lancet 2010; 377: 42

OS R maintenance (n=505) Observation (n=513) P value HR (95% CI) NR NR P=0. 60 HR 0. 87 (0. 51~1. 47) CR or u. CR after maintenance R maintenance (n=505) Observation P value (n=513) HR (95% CI) 71. 5% 51. 5% P=0. 0001 Lancet 2010; 377: 42

Lancet 2010; 377: 42

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

Hodgkin’s lymphoma

HL is a curable disease Significant improvement in survival rate between 1970 s and 1990 s; However, the survival rate has plateaued in last two decades BEACOPP MOPP Stanford V 1980 GHSG HD 9 study 1995 1992 ABVD 5 -year survival of HL still is only 85% 2009

ABVD or BEACOPP? ABVD Most recent E 2496 study BEACOPP Most recent GHSG HD 15 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 hematotoxicity Hematotoxicity, Infertility How to Increase efficacy ? How to increasing tolerability? JCO 2013; 31: 684 Lancet 2012; 379: 1791

Different approaches to targeting CD 30 Anti-CD 30 naked m. Ab CD 30 Anti-CD 30 ADCs Modified anti. CD 30 Ab (improving receptor affinity)

CD 30 -directed immunotherapy Date Antibody Authors 1992 BER-H 2(saponin-conjugated) Falini et al. 2005 Ki-4 -131 I(radio-conjugate) Schnell et al. 2007 MDX-060 (naked) Ansell et al. 2008 SGN-30 (naked) Bartlett et al. 2009 MDX-1401 (engineered) Cardarelli et al. 2010 SGN-35 (drug-conjugated) Younes et al.

Brentuximab vedotin antibody-drug conjugate (ADC)

Mechanism of Brentuximab vedotin

Phase II trial of brentuximab vendotin in R/R HL Eligilibilty Relapsed or refractory CD 30+ HL Age ≧ 12 years Measurable disease≧ 1. 5 cm ECOG 0~1 Prior ASCT Treatment (n=102) Follow-up Brentuximab vedotin 1. 8 mg/kg IV Q 3 W Administered outpateint over 30 mins Min. 8 to max. 16 cycles for SD or better Restage at cycles 2, 4, 7, 10, 13, 16 Q 3 mo for 2 yrs Q 6 mo year 3~5 Annually after 5 Primary endpoint: ORR by Independent review Facility (IRF) years JCO 2012; 30: 2183

IRF (n=102) ORR, % (95% CI) CR, % (95% CI) 75 (65, 83) 34 (25, 44) PR, % 40 SD, % 22 PD, % 3 Not evaluable, % 1 JCO 2012; 30: 2183

Brentuximab (n=57) Prior therapy (n=57) P value HR 7. 8 m 4. 1 m P<0. 001 0. 41 JCO 2012; 30: 2183

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

GHSG approach: “targeted BEACOPP” Br. ECADD Medikament Bleomycin Etoposide Adriamycin Br. ECADD 150 40 Comment Pulmonary toxicity 1 1 Cyclophosphamide 1250 / 2 1 0 2 Vincristine ce Neurotoxicity n i s g Brentuximab 1. 8 uitin r c e r vedotin s i y d u Procarbazine. St Gonadal toxicity Prednisolone Cushing, infection Dacarbazine 2× 250 Dexamethasone 4× 40

Chronic lymphocytic leukemia

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

History of anti-CD 20 m. Abs

GA 101: type II, glycoenginered anti-CD 20 m. Ab • First type II, glycoengineered , humanized Ig. G 1 anti-CD 20 m. Ab • In preclinical studies comparing against rituximab, GA 101 provided: ü Enhanced ADCC, oligosaccharides that enhance the interaction with FcγR, particularly FcγRIIIa, even in effector cells bearing the low affinity polymorphic variant of FcγRIIIa ü Increased direct cell death induction ü Decreased complement-dependent cytotoxicity

Type I and type II anti-CD 20 m. Abs Type I Rituximab Ofatumumab Type II Tositumomab GA 101 CDC ++ - ADCC ++ ++ Move CD 20 into lipid rafts ++ - Homotypic adhesion - ++ Induced cell death - ++

Summary of direct cell death with type II m. Abs (GA 101) • Most anti-CD 20 m. Abs in development are type I. Non of type I m. Abs had proven to be superior to rituximab. • The type II anti-CD 20 m. Ab GA 101 exhibit increased PCD, enhanced ADCC and lower CDC compared with type I m. Abs • GA 101 induced PCD via non-apoptotic pathways involving lysosomes nad ROS • Loss of cell surface CD 20 by ”shaving” involving phagocytosis and modulation on tumor surface may affect anti-CD 20 efficacy of m. Abs.

Thanks for your attention comments and questions