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

1st line treatment in FL

Blood 2005;106:3725Lancet 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)

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

B-R vs R-CHOP

StiL NHL 1-2003

R

Rummel et al. Lancet 2013;381:1203

Primary endpoint: PFS81 centers in GermanyEnrolled between Sep 2003~Aug 2008Stage III/IV IL or MCLMedian f/u 45 mosNon-inferiority study

Grade 3+4 hematotoxicityB-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

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

Non-hematological toxicity

Rummel et al. Lancet 2013;381:1203

Response rates

B-R (n=261) R-CHOP (n=253) P value

ORR 92.7% 91.3%

CR 39.8% 30.0% 0.021

SD 2.7% 3.6%

PD 3.5% 2.8%

Rummel et al. Lancet 2013;381:1203

PFS

Rummel et al. Lancet 2013;381:1203

B-R R-CHOP P value

PFS 69.5 mos 31.2 mos P<0.0001

OS NR NR

FL MCL

Marginal zone 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 1st-line treatment for patients with FL, indolent and MCL

Rummel et al. Lancet 2013;381:1203

Treatment strategies in IL

Immunochemotherapy Maintenance

Tumor reduction Eradication?

PRIMA: study design

PFSR maintenance (n=505)

Observation(n=513)

P valueHR (95% CI)

NR 48.3m P<0.00010.50 (0.39~0.64)

Lancet 2010;377:42

R maintenance (n=505)

Observation(n=513)

P valueHR (95% CI)

NR NR P=0.60HR 0.87 (0.51~1.47)

Lancet 2010;377:42

R maintenance (n=505)

Observation(n=513)

P valueHR (95% CI)

CR or uCR after maintenance

71.5% 51.5% P=0.0001

OS

Lancet 2010;377:42

B-R with maintenance

StiL NHL 7-2008 MAINTAIN

R

Rummel et al. Lancet 2013;381:1203

Primary endpoint: PFSInduction with B-R If CR or PR then maintenance

Hodgkin’s lymphoma

HL is a curable disease

1980 2009

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%

ABVD or BEACOPP?ABVDMost recent E2496 study

BEACOPPMost 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 hematotoxicity Hematotoxicity, Infertility

How to Increase efficacy ? How to increasing tolerability?

JCO 2013;31:684Lancet 2012;379:1791

Different approaches to targeting CD30

CD30-directed immunotherapy

Date Antibody Authors

1992 BER-H2(saponin-conjugated) Falini et al.

2005 Ki-4-131I(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 Treatment (n=102) Follow-up

Primary endpoint: ORR by Independent review Facility (IRF)

JCO 2012;30:2183

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 valueHR

7.8m 4.1m P<0.0010.41

Summary: changing therapeutic paradigms?

1st line

Standard treatment Open questions

• ABVD• BEACOPP

Improving salvage?Introducing maintenance?

New combination?

GHSG approach:

“targeted BEACOPP” BrECADD Medikament BrECADD Comment Bleomycin Pulmonary toxicityEtoposide 150Adriamycin 40Cyclophosphamide 1250Vincristine NeurotoxicityBrentuximab vedotin

1.8

Procarbazine Gonadal toxicityPrednisolone Cushing, infectionDacarbazine 2×250Dexamethasone 4×40

Study is recruiting since 2012/11

Chronic lymphocytic leukemia

Classification of CLL patients according to their fitness

Blood 2009;114:3359

History of anti-CD20 mAbs

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

Type I and type II anti-CD20 mAbs

Type IRituximabOfatumumab

Type IITositumomabGA 101

CDC ++ -

ADCC ++ ++

Move CD20 into lipid rafts

++ -

Homotypic adhesion - ++

Induced cell death - ++

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.

Thanks for your attention

comments and questions