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
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
StiL NHL 1-2003
Follicular
Bendamustine-Rituximab
Waldenstroms
Marginal zone
Mantle cell
(B: 90ng/m2 day 1+2, max 6 cycles, q4wks)
R
Small lymphocytic
(n=549)
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, q3 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 1st-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
48.3m
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 uCR 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
StiL NHL 7-2008 MAINTAIN
B-R +
Follicular
(n=611)
2 years Rituximab q2m
R
B-R+
4 years Rituximab q2m
Induction with B-R
If CR or PR then maintenance
Primary endpoint: PFS
Rummel et al. Lancet 2013;381:1203
Hodgkin’s lymphoma
HL is a curable disease
Significant improvement in survival rate between 1970s and 1990s;
However, the survival rate has plateaued in last two decades
BEACOPP
MOPP
Stanford V
1980
GHSG HD9 study
1995
1992
ABVD
5-year survival of HL still is only 85%
2009
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 hematotoxicity
Hematotoxicity, Infertility
How to Increase efficacy ?
How to increasing tolerability?
JCO 2013;31:684
Lancet 2012;379:1791
Different approaches to targeting CD30
Anti-CD30
naked mAb
CD30
Anti-CD30
ADCs
Modified antiCD30 Ab
(improving
receptor affinity)
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
Relapsed or
refractory CD30+
HL
Age ≧ 12 years
Measurable
disease≧ 1.5cm
ECOG 0~1
Prior ASCT
Treatment (n=102)
Follow-up
Brentuximab vedotin
1.8mg/kg IV Q3W
Administered
outpateint over 30
mins
Q3mo for 2 yrs
Min.8 to max. 16
cycles for SD or
better
Annually after 5
years
Q6 mo year 3~5
Restage at cycles
2,4,7,10,13,16
Primary endpoint: ORR by Independent review Facility (IRF)
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
7.8m
4.1m
P<0.001
0.41
JCO 2012;30:2183
Summary: changing therapeutic paradigms?
Standard treatment
Open questions
3rd line
• Brentuximab vedotin
2nd line
• HDCT+ASCT
• DEXA-BEAM, mini-BEAM
• ICE, DHAP, GDP
Improving salvage?
Introducing maintenance?
1st line
• ABVD
• BEACOPP
New combination?
GHSG approach:
“targeted BEACOPP” BrECADD
Medikament
Bleomycin
Etoposide
Adriamycin
BrECADD
Cyclophosphamide
Vincristine
Brentuximab
vedotin
Procarbazine
Prednisolone
Dacarbazine
1250
Dexamethasone
Comment
Pulmonary toxicity
150
40
Neurotoxicity
1.8
Gonadal toxicity
Cushing, infection
2×250
4×40
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 I
Rituximab
Ofatumumab
Type II
Tositumomab
GA 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