terapia anti-cd20 la perspectiva del oncÓlogo · neoplasias: precursor b-cell leukemias b-cell...
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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. Introducción: el antígeno CD20 en linfomas
2. Mecanismo de acción de AcMo anti-CD20
3. Impacto clínico de terapia anti-CD20: LBDCG y folicular
4. Perspectiva del patólogo (Dra Mar García. H del Mar, BCN)
5. Radioinmunoterapia y Nuevos AcMo anti-CD20 en desarrollo
6. Conclusiones
Antígeno CD20 como diana para la inmunoterapia
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.
Stem
Cell
Pre-Pre-
B Cell Pre-B Cell
Immature
B Cell
Mature
B Cell
Activated
B Cell
Plasma
Cell
IgM
IgG
IgA
sIgM
sIgG
sIgA
sIgM
+ D sIgM
HCR
R/D
HCR
R/D µ HCR HCR
MCL=mantle-cell lymphoma; FL=follicular lymphoma; SLL=small lymphocytic lymphoma; MZL=marginal zone B-cell lymphoma; MALT=mucosa-associated lymphoid tissue; LL=lymphoplasmacytic lymphoma; DLBCL=diffuse large B-cell lymphoma. Armitage et al. J Clin Oncol. 1998;16:2780-2795.
Frecuencia de subtipos LNH en adultos y expresión CD20
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
Cang J Hematol&Oncol 2012
Epítopos antígeno CD-20
MECANISMO DE ACCIÓN AcMo Brody J Clin Oncol 2011
Rituximab potencia la actividad “in vitro” de diversos citotóxicos
DTX 50 36 0.0001 Ricin 40 5 0.004 TNF alpha 43 7 0.0015 ADR 53 28 0.0027 CDDP 27 4 0.0456 VP16 8.5 0.6 0.0263
Agente citotóxico + MabThera® – MabThera® P Valor
% Citotoxicidad
Demidem et al. Cancer Biother Radiopharm. 1997;12:177.
H/RS cells
Radiotherapy Chemotherapy
P
PP
Dendritic cell
HMGB1
TLR4
Stimulated
CTL ActivityTumor
microenvironmentcells
CD 20
CD 52
CD 30
AcMo
antiCD20antiCD52
Agents targeting
Immune synapses
AcMo
antiCD30
Lenalidomide
Impacto clínico de la terapia anti-CD20:
difuso de células grandes y folicular
Revised IPI (R-IPI): era Rituximab
Sehn LH, et al. Blood. 2007;109:1857-1861.
Risk Group IPI Factors, n
Very good 0
Good 1-2
Poor 3-5
edad superior a 60 años estadios avanzados III ó IV
PS > 1 LDH elevada
Más de 1 área extraganglionares afectas
Yrs
Perc
ent
Surv
ival
Very good
Good
Poor
P < .0001
Supervivencia global según IPI revisado (R-IPI)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 1 2 3 4 5
Sehn LH, et al. Blood. 2007;109:1857-1861.
* QT BASADA EN R-CHOP
CHOP ± Rituximab en DLBCL: resultados de SG a 7 años (GELA LNH-98.5 Study)
Coiffier B, et al. ASCO 2007. Abstract 8009.
OS (N = 399) 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 < .05 (multivariate analysis).
Surv
ival
Pro
bab
ility
Yrs
0
0.2
0.4
0.6
0.8
1
0 1 3 5 7 8 2 4 6
CHOP
R-CHOP
P = .0004
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)
R estaging
CVP x 4 cycles (q 3 weeks)
R-CVP x 4 cycles (q 3 weeks)
SD,PD off treatment
CR, PR
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
Tiempo al fallo del tto. y tiempo hasta la progresión (mediana de seguimiento 25 meses)
Event-free probability
0.0 3 6 9 12 15 18 21 24 27 30 42
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
Study month
33 36 39 0.0
3 6 9 12 15 18 21 24 27 30 42
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0
Study month
Event-free probability
33 36 39
TTF TTP
R-CVP: median 30m R-CVP: median 27m
CVP: median 7m CVP: median 15m
P<0.0001 P<0.0001
All deaths, n (%) 22 (13.8) 15 (9.3) Death from lymphoma 15 (9.4) 9 (5.6)
CVP R-CVP
Marcus R et al. Proc ASH 2003.
CHOP
rituximab en primera línea de linfoma folicular
R A N D O M I S A T I O N
CHOP x 4–6
CHOP x 4–6 +
MabThera
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
2 x CHOP +/- MabThera + intensive IFN-maintenance
2 x CHOP +/- MabThera + standard IFN-maintenance
CR, PR
Hiddemann W, et al. Blood 2003;102:104a (Abstract 352)
Patients > 60 years
Patients < 60 years
OR
CHOP
rituximab en primera línea de linfoma folicular: tiempo hasta el fracaso de tratamiento
Years after start of therapy
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0 0 1 2 3
Pro
po
rtio
n o
n t
reat
me
nt
MabThera + CHOP (143/159)
CHOP (102/143)
Hiddemann W, et al. Blood 2003;102:104a (Abstract 352)
Bendamustine-Rituximab
CHOP-Rituximab
Follicular G I-II
Waldenströms
Marginal zone
Small lymphocytic
Mantle cell
R
StiL NHL 1-2003
Bendamustine 90 mg/m2 day 1+2 + R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks.
# 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
Supervivencia libre de progresión (45 meses seguimiento)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 12 24 36 48 60 72 84 96 m
Hazard ratio, 0.58 (95% CI 0.44 - 0.74)
p = 0.0000148
Median (months)
B-R 69.5
CHOP-R 31.2
Radioinmunoterapia y Nuevos AcMo anti-CD20
AcMo anti-CD20, además de Rituximab….
Brody J Clin Oncol 2011
Elección del isótopo
Properties 90Yttrium 131Iodine
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
weight and
platelet count
Clearance based
dosing using whole
body dosimetry
Administration Outpatient
Inpatient or
restrictions to
protect family/public
131I
Zevalin en linfoma indolente
Cheson BD. Blood 2003; 101: 391-398.
• The first type II, glycoengineered,
humanised anti-CD20 monoclonal
antibody (mAb)
– 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 cell-
mediated cytotoxicity (ADCC)
• GA101 is being evaluated in an
extensive clinical trial program in
B-cell malignancies
GA101: AcMo anti-CD20 tipo II
Mössner E, et al. Blood 2010;115:43934402; Niederfellner G, et al. Blood 2011; 118:358−367
Heavy chain CD20 peptide
Glycoengineering
Light chain
GA101: mecanismos de acción
Mössner E, et al. Blood 2010;115:43934402
Lower CDC activity Type II versus Type I antibody
B-cell
Effector
cell
Increased direct cell death Type II versus Type I antibody
Enhanced ADCC Glycoengineering for increased
affinity to FcγRIIIa
CD20 FcγRIIIa
Complement GA101
CDC, complement-dependent cytotoxicity
90
80
70
60
50
40
30
20
10
0
GA101 induce muerte celular directa
Alduaij W et al. Blood 2009; 114:Abstract 725, taken from oral presentation at ASH 2009
GA101 induced increased cell death on a panel of B-lymphoma cell lines compared with rituximab
Raji Daudi Granta 519 SU-DHL4
Ce
ll d
eat
h (
% a
nn
exin
V/P
I +ve
)
Control GA101 Rituximab
P<0.03
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
Resumen datos preclínicos GA101:
anti-CD20 AcMo
Mössner E, et al. Blood 2010;115:43934402 Herting F, et al. Blood 2010;116:Abstract 3915, taken from poster presentation at ASH, Dec. 2010
GA101
CDC
Cell death/ proliferation
ADCC
Cell death/ proliferation
CDC
ADCC
CDC
Cell death/ proliferation
ADCC
CDC
Cell death/ proliferation
ADCC
Rituximab
Cell death/ proliferation
CDC
ADCC
Rituximab
Cell death/ proliferation
CDC
ADCC
n Patient
population
Treatments Primary
endpoint
Phase I
GAUGUIN (BO20999) 34 CD20+ • GA101 Safety
GAUSS (BO21003) 22 CD20+ • GA101 Safety
JO21900 (Japan) 24 CD20+ • GA101 Safety
GAUDI (BO21000) 56
80
R/R fNHL
First-line fNHL
• GA101 + CHOP
• GA101 + FC
• GA101 + CHOP
• GA101 + bendamustine
Safety
GALTON (GAO4779g) 40 First-line CLL • GA101 + FC
• GA101 + bendamustine
Safety
Phase II
GAUGUIN (BO20999) 100 R/R iNHL, aNHL, CLL • GA101 ORR
GAUSS (BO21003) 180 Relapsed iNHL • GA101 vs rituximab ORR
Source: www.clinicaltrials.gov
GA101 estudios completados y en marcha(Fase I/II)
Note: dark blue shaded studies are ongoing
n Patient
population
Treatments Primary
endpoint
Phase III
CLL-11 (BO21004) 780 First-line CLL with
comorbidities
• GA101 + chlorambucil
• Rituximab + chlorambucil
• Chlorambucil
PFS
GADOLIN (GAO4753g) 360 Rituximab-refractory iNHL • GA101 + bendamustine
• Bendamustine
PFS
GOYA (BO21005) 1400 First-line DLBCL • GA101 + CHOP
• Rituximab + CHOP
PFS
GALLIUM (BO21223) 1400 First-line iNHL • GA101 + chemotherapy
• Rituximab + chemotherapy
PFS
Source: www.clinicaltrials.gov
GA101 estudios completados y en marcha (Fase III)
Note: all studies are ongoing
Rituximab 375 mg/m2 + CHOP x 6 or 8 (n=700)
GA101 1000 mg + CHOP x 6 or 8 (n=700)
Previously untreated CD20+ DLBCL (n=1400)
GOYA (BO21005) fase III: diseño
DFS, disease-free survival; DOR, duration of response; OS, overall survival; TTNLT, time to next lymphoma treatment www.clinicaltrials.gov; NCT01287741
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
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…..
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