Dr. Luis de la Cruz. Hospital Universitario de Sevilla.

TERAPIA ANTI-CD20
LA PERSPECTIVA DEL ONCÓLOGO
V SIMPOSIO SEAP-SEOM
BIOMARCADORES EN HEMATOPALOGÍA
Luis de la Cruz Merino
Sº Oncología Médica
HUVMacarena (Sevilla)
Índice
1.
2.
3.
4.
5.
6.
Introducción: el antígeno CD20 en linfomas
Mecanismo de acción de AcMo anti-CD20
Impacto clínico de terapia anti-CD20: LBDCG y folicular
Perspectiva del patólogo (Dra Mar García. H del Mar, BCN)
Radioinmunoterapia y Nuevos AcMo anti-CD20 en desarrollo
Conclusiones
Antígeno CD20 como diana
para la inmunoterapia
Stem
Pre-Pre-
Cell
B Cell
Pre-B Cell
Immature
Mature
Activated
B Cell
B Cell
B Cell
sIgM
HCR
HCR
R/D
HCR
µ
sIgM
+D
Plasma
Cell
sIgM
sIgG
sIgA
IgM
IgG
IgA
HCR
R/D
ANTIGEN INDEPENDENT
ANTIGEN DEPENDENT
CD20
expression
Neoplasias: Precursor B-cell leukemias
B-Cell lymphomas/CLL
WM/
Myeloma
Adapted from Longo. Lymphocytic Lymphomas. In: Cancer: Principles and Practice of Oncology. 1993.
Frecuencia de subtipos LNH en adultos y expresión CD20
MCL=mantle-cell lymphoma; FL=follicular lymphoma; SLL=small lymphocytic lymphoma; MZL=marginal zone B-cell lymphoma; MALT=mucosaassociated lymphoid tissue; LL=lymphoplasmacytic lymphoma; DLBCL=diffuse large B-cell lymphoma.
Armitage et al. J Clin Oncol. 1998;16:2780-2795.
El antígeno diana ideal
Expresado SÓLO por las células del tumor
 No expresado por células normales de tejidos esenciales
para el huésped
 No debe producirse toxicidad en el caso de que se eliminen
TODAS las células Ag+
 Expresado por TODAS las células del tumor
 No sometido a mutaciones, variaciones o modulación
 El Ag. tiene una función “crítica” para la célula
 No internalizable ni secretable

 CD20, antígeno asociado a tumor (TAA) tipo antígeno de
diferenciación tisular específica
Epítopos antígeno CD-20
Cang J Hematol&Oncol 2012
MECANISMO DE ACCIÓN AcMo
Brody J Clin Oncol 2011
Rituximab potencia la actividad “in vitro” de
diversos citotóxicos
% Citotoxicidad
Agente citotóxico
DTX
Ricin
TNF alpha
ADR
CDDP
VP16
+ MabThera®
– MabThera®
P Valor
50
40
43
53
27
8.5
36
5
7
28
4
0.6
0.0001
0.004
0.0015
0.0027
0.0456
0.0263
Demidem et al. Cancer Biother Radiopharm. 1997;12:177.
Chemotherapy
Radiotherapy
TLR4
HMGB1
P
H/RS cells
Agents targeting
Immune synapses
Lenalidomide
P
CD 52
CD 30
P
AcMo
antiCD30
CD 20
Dendritic cell
Stimulated
CTL Activity
AcMo
antiCD20
antiCD52
Tumor
microenvironment
cells
Impacto clínico de la terapia anti-CD20:
difuso de células grandes y folicular
Revised IPI (R-IPI): era Rituximab
edad superior a 60 años
estadios avanzados III ó IV
PS > 1
LDH elevada
Más de 1 área extraganglionares afectas
Risk Group
Very good
Good
Poor
Sehn LH, et al. Blood. 2007;109:1857-1861.
IPI Factors, n
0
1-2
3-5
Supervivencia global según IPI revisado (R-IPI)
1.0
Very good
0.9
Percent Survival
0.8
Good
0.7
0.6
Poor
0.5
0.4
0.3
0.2
0.1
0
0
1
* QT BASADA EN R-CHOP
P < .0001
2
3
4
5
Yrs
Sehn LH, et al. Blood. 2007;109:1857-1861.
CHOP ± Rituximab en DLBCL: resultados de SG a 7 años
(GELA LNH-98.5 Study)
OS (N = 399)
Survival Probability
1
CHOP
R-CHOP
0.8
0.6
0.4
0.2
Parameter, %
Low
Risk
High
Risk
Age, < 70 vs ≥ 70 yrs
58.0
49.0
LDH, NI vs > NI
69.0
45.0*
Stage, I/II vs III/IV
67.0
50.0
Bone marrow, yes vs no
60.0
34.5*
Tumor size, < 10 vs ≥ 10 cm
60.0
36.5
β2-microglobulin, NI vs > NI
64.5
39.0*
Serum albumin, ≥ 35 vs < 35 g/L
60.0
40.0
P = .0004
0
*P < .05 (multivariate analysis).
0
1
2
3
4
5
Yrs
Coiffier B, et al. ASCO 2007. Abstract 8009.
6
7
8
R-CVP vs CVP en linfoma folicular
sin tratamiento previo
•Follicular NHL
(IWF B,C, D)
•Stage III-IV
•> 18 yrs.
•No prior Rx
•Measurable Dz
•Central histology
review
R
A
N
D
O
M
I
Z
E
CVP x 4 cycles
(q 3 weeks)
R-CVP x 4 cycles (q
3 weeks)
rituximab 375 mg/m2 IV d1
cyclophosphamide 750 mg/m2 IV d1
vincristine 1.4 mg/m2 IV d1
prednisone 40 mg/m2 PO d1–5
R
e
s
t
a
g
i
n
g
CVP x 4 cycles
(q 3 weeks)
CR, PR
R-CVP x 4 cycles (q
3 weeks)
SD,PD off treatment
Tiempo al fallo del tto. y tiempo hasta la progresión
(mediana de seguimiento 25 meses)
Event-free
probability
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
TTF
Event-free
probability
R-CVP: median 27m
CVP: median 7m
0.2
0.1
0.0
P<0.0001
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Study month
All deaths, n (%)
Death from lymphoma
Marcus R et al. Proc ASH 2003.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
TTP
R-CVP: median 30m
CVP: median 15m
P<0.0001
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Study month
CVP
22 (13.8)
15 (9.4)
R-CVP
15 (9.3)
9 (5.6)
CHOP
rituximab en primera línea de linfoma folicular
Patients < 60 years
R
A
N
D
O
M
I
S
A
T
I
O
N
CHOP x 4–6
+
MabThera
CHOP x 4–6
CR, PR
CR, PR
R
A
N
D
O
M
I
S
A
T
I
O
N
Peripheral blood stem cell
transplant
2 x CHOP +/- MabThera +
standard IFN-maintenance
OR
Patients > 60 years
2 x CHOP +/- MabThera +
intensive IFN-maintenance
2 x CHOP +/- MabThera +
standard IFN-maintenance
Hiddemann W, et al. Blood 2003;102:104a (Abstract 352)
CHOP
rituximab en primera línea de linfoma folicular:
tiempo hasta el fracaso de tratamiento
1.0
MabThera + CHOP (143/159)
Proportion on treatment
0.9
0.8
0.7
0.6
0.5
0.4
CHOP (102/143)
0.3
0.2
0.1
0
0
1
2
Years after start of therapy
3
Hiddemann W, et al. Blood 2003;102:104a (Abstract 352)
# Abst 3. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R)
as first-line treatment in patients with indolent and mantle cell lymphomas (MCL):
Updated results from the StiL NHL1 study. Mathias J. Rummel. ASCO 2012
StiL NHL 1-2003
Bendamustine-Rituximab
Follicular G I-II
Waldenströms
Marginal zone
Small lymphocytic
Mantle cell
R
CHOP-Rituximab
Bendamustine 90 mg/m2 day 1+2 + R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks.
Supervivencia libre de progresión (45 meses seguimiento)
1.0
Median (months)
0.9
0.8
B-R
69.5
CHOP-R
31.2
0.7
0.6
0.5
0.4
0.3
0.2
Hazard ratio, 0.58 (95% CI 0.44 - 0.74)
0.1
p = 0.0000148
0.0
0
12
24
36
48
60
72
84
96
m
Radioinmunoterapia y
Nuevos AcMo anti-CD20
AcMo anti-CD20, además de Rituximab….
Brody J Clin Oncol 2011
Elección del isótopo
Properties
131I
90
Yttrium
131
Iodine
Half-life
64 hours
192 hours
Energy emitter
Beta
(2.3 MeV)
Gamma (0.36 MeV)
Beta (0.6 MeV)
Path length
90 5 mm
90 0.8 mm
Urinary
excretion
Minimal
7% in 7 days
Extensive/variable
46 - 90% in 2 days
Dosing
Based on
Clearance based
weight and dosing using whole
platelet count
body dosimetry
Administration
Outpatient
Inpatient or
restrictions to
protect family/public
Zevalin en linfoma indolente
Cheson BD. Blood 2003; 101: 391-398.
GA101: AcMo anti-CD20 tipo II
•
The first type II, glycoengineered,
humanised anti-CD20 monoclonal
antibody (mAb)
CD20 peptide
Heavy chain
– Designed to provide an
advancement in antibody
technology
•
In preclinical studies comparing it
to rituximab, GA101 showed:
– Increased direct cell death
induction
– Enhanced antibody-dependent cellmediated cytotoxicity (ADCC)
•
Light chain
Glycoengineering
GA101 is being evaluated in an
extensive clinical trial program in
B-cell malignancies
Mössner E, et al. Blood 2010;115:43934402; Niederfellner G, et al. Blood 2011; 118:358−367
GA101: mecanismos de acción
Increased direct cell death
Type II versus Type I antibody
Enhanced ADCC
Glycoengineering for increased
affinity to FcγRIIIa
Effector
cell
B-cell
Lower CDC activity
GA101
Complement
CD20
FcγRIIIa
Type II versus Type I antibody
CDC, complement-dependent cytotoxicity
Mössner E, et al. Blood 2010;115:43934402
GA101 induce muerte celular directa
GA101 induced increased cell death on a panel of B-lymphoma
cell lines compared with rituximab
P<0.03
Raji
Daudi
Granta 519
SU-DHL4
90
Cell death (% annexin V/PI +ve)
80
70
60
50
40
30
20
10
0
Control
GA101
Rituximab
Alduaij W et al. Blood 2009; 114:Abstract 725, taken from oral presentation at ASH 2009
Resumen datos preclínicos GA101:
anti-CD20 AcMo
Compared with rituximab:
Increased direct cell death
induction due to Type II mode of
binding
Increased ADCC due to
glycoengineering (stronger
affinity for FcγRIIIa)
Superior B-cell depletion
compared with rituximab in
whole-blood assay as well as
lymphoid tissue in cynomolgus
monkeys
Complete tumour remissions in various
NHL xenograft models
Induced anti-tumour activity in
combination with chemotherapy
ADCC
ADCC
ADCC
ADCC
Cell
Celldeath/
death/
proliferation
proliferation
Cell
Cell death/
death/
proliferation
proliferation
CDC
CDC
CDC
CDC
Rituximab
Mössner E, et al. Blood 2010;115:43934402
Herting F, et al. Blood 2010;116:Abstract 3915, taken from poster presentation at ASH, Dec. 2010
GA101
GA101 estudios completados y en marcha(Fase I/II)
Note: dark blue shaded studies are ongoing
n
Patient
population
Treatments
Primary
endpoint
GAUGUIN (BO20999)
34
CD20+
• GA101
Safety
GAUSS (BO21003)
22
CD20+
• GA101
Safety
JO21900 (Japan)
24
CD20+
• GA101
Safety
GAUDI (BO21000)
56
R/R fNHL
First-line fNHL
GA101 + CHOP
GA101 + FC
GA101 + CHOP
GA101 + bendamustine
Safety
80
•
•
•
•
40
First-line CLL
• GA101 + FC
• GA101 + bendamustine
Safety
GAUGUIN (BO20999)
100
R/R iNHL, aNHL, CLL
GAUSS (BO21003)
180
Relapsed iNHL
Phase I
GALTON (GAO4779g)
Phase II
Source: www.clinicaltrials.gov
• GA101
ORR
• GA101 vs rituximab
ORR
GA101 estudios completados y en marcha (Fase III)
Note: all studies are ongoing
n
Patient
population
CLL-11 (BO21004)
780
First-line CLL with
comorbidities
GADOLIN (GAO4753g)
360
Rituximab-refractory iNHL
GOYA (BO21005)
1400
First-line DLBCL
GALLIUM (BO21223)
1400
First-line iNHL
Treatments
Primary
endpoint
Phase III
Source: www.clinicaltrials.gov
• GA101 + chlorambucil
• Rituximab + chlorambucil
• Chlorambucil
PFS
• GA101 + bendamustine
• Bendamustine
PFS
• GA101 + CHOP
• Rituximab + CHOP
PFS
• GA101 + chemotherapy
• Rituximab + chemotherapy
PFS
GOYA (BO21005) fase III: diseño
GA101 1000 mg +
CHOP x 6 or 8 (n=700)
Previously
untreated CD20+
DLBCL (n=1400)
Rituximab 375 mg/m2 +
CHOP x 6 or 8 (n=700)
Experimental arm
GA101 1000 mg d1, d8, d15 cycle 1; d1 cycles 2–8 q21d + CHOP
Control arm
Rituximab 375 mg/m2 on d1 q21d cycles 1–8 + CHOP
Primary endpoint
Investigator-assessed PFS
Secondary endpoints
OS, EFS, ORR, DFS, DOR, TTNLT, medical resource utilisation
DFS, disease-free survival; DOR, duration of response; OS, overall survival; TTNLT, time to next lymphoma treatment
www.clinicaltrials.gov; NCT01287741
Conclusiones
Antígeno CD20, cumple criterios de “antígeno ideal”
Mecanismo de acción citotóxico directo e inmunológico
Terapia anti-CD20 ha cambiado la historia natural de la mayor
parte de LNH: incremento en SG, cambios en índices pronósticos
y nuevos estándares de tratamiento
Radioinmunoconjugados y nuevos anti-CD20 en desarrollo
Incertidumbres anti-CD20: forma admon, duración, estrategias
de combinación, resistencias…..