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
Stem Pre-Pre- Immature Mature Activated Plasma
Cell B Cell Pre-B Cell B Cell B Cell B Cell Cell
sIgM
sIgM sIgG IgM
sIgM
+D sIgA IgG
IgA
HCR HCR HCR
HCR
µ R/D 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=mucosa-
associated 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

 Brody J Clin Oncol 2011
MECANISMO DE ACCIÓN AcMo
 Rituximab potencia la actividad “in vitro” de
diversos citotóxicos
% Citotoxicidad

Agente citotóxico + MabThera® – MabThera® P Valor

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

Demidem et al. Cancer Biother Radiopharm. 1997;12:177.

 Radiotherapy Chemotherapy
TLR4 Agents targeting
Immune synapses

HMGB1 Lenalidomide

P P
H/RS cells
CD 52
CD 30

P AcMo
antiCD30 AcMo
antiCD20
antiCD52
CD 20
Stimulated Tumor
Dendritic cell CTL Activity 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 IPI Factors, n

Very good 0
Good 1-2
Poor 3-5

Sehn LH, et al. Blood. 2007;109:1857-1861.

 Supervivencia global según IPI revisado (R-IPI)

1.0
Very good
0.9
0.8 Good
0.7
Percent Survival

0.6
Poor
0.5
0.4
0.3
0.2
0.1 P < .0001
0
0 1 2 3 4 5
* QT BASADA EN R-CHOP 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)

Low High
OS (N = 399) Parameter, %
Risk Risk
1
CHOP Age, < 70 vs ≥ 70 yrs 58.0 49.0
0.8 R-CHOP LDH, NI vs > NI 69.0 45.0*
Survival Probability

Stage, I/II vs III/IV 67.0 50.0

0.6
Bone marrow, yes vs no 60.0 34.5*
0.4 Tumor size, < 10 vs ≥ 10 cm 60.0 36.5
β2-microglobulin, NI vs > NI 64.5 39.0*
0.2
Serum albumin, ≥ 35 vs < 35 g/L 60.0 40.0
P = .0004
0 *P < .05 (multivariate analysis).
0 1 2 3 4 5 6 7 8
Yrs

Coiffier B, et al. ASCO 2007. Abstract 8009.

 R-CVP vs CVP en linfoma folicular
sin tratamiento previo

•Follicular NHL R CVP x 4 cycles R CVP x 4 cycles

(IWF B,C, D) A (q 3 weeks) e (q 3 weeks)
•Stage III-IV N s
•> 18 yrs. D t
•No prior Rx O CR, PR
a
•Measurable Dz M g
•Central histology I R-CVP x 4 cycles (q R-CVP x 4 cycles (q
i
review Z 3 weeks) 3 weeks)
n
E g

rituximab 375 mg/m2 IV d1

cyclophosphamide 750 mg/m2 IV d1 SD,PD off treatment
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
TTF TTP
Event-free
probability
1.0
0.9 1.0
0.8 0.9
0.8
0.7
R-CVP: median 27m 0.7
0.6 R-CVP: median 30m
0.6
0.5
0.5
0.4
0.4
0.3 CVP: median 7m 0.3 CVP: median 15m
0.2 0.2
0.1 P<0.0001 P<0.0001
0.1
0.0 0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Study month Study month
CVP R-CVP
All deaths, n (%) 22 (13.8) 15 (9.3)
Death from lymphoma 15 (9.4) 9 (5.6)
Marcus R et al. Proc ASH 2003.
CHOP rituximab en primera línea de linfoma folicular

Patients < 60 years

R R Peripheral blood stem cell

A A transplant
CHOP x 4–6
N CR, PR N
+ 2 x CHOP +/- MabThera +
D D
MabThera standard IFN-maintenance
O O
M M
I I OR
S S
A A Patients > 60 years
T CR, PR T
CHOP x 4–6 2 x CHOP +/- MabThera +
I I
O O intensive IFN-maintenance
N N
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)
0.9
0.8
Proportion on treatment

0.7
0.6
0.5
0.4 CHOP (102/143)
0.3
0.2
0.1
0
0 1 2 3
Years after start of therapy
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
R
Mantle cell
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
B-R 69.5
0.8 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

90 131
Properties Yttrium Iodine

Half-life 64 hours 192 hours

131I Beta Gamma (0.36 MeV)

Energy emitter
(2.3 MeV) Beta (0.6 MeV)
Path length 90 5 mm 90 0.8 mm
Urinary Minimal Extensive/variable
excretion 7% in 7 days 46 - 90% in 2 days
Based on Clearance based
Dosing weight and dosing using whole
platelet count body dosimetry
Inpatient or
Administration Outpatient 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, CD20 peptide

Heavy chain
humanised anti-CD20 monoclonal
antibody (mAb)
– Designed to provide an
advancement in antibody
technology
• In preclinical studies comparing it Light chain

to rituximab, GA101 showed:

– Increased direct cell death
induction Glycoengineering
– Enhanced antibody-dependent cell-
mediated cytotoxicity (ADCC)
• 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

Enhanced ADCC
Increased direct cell death
Glycoengineering for increased
Type II versus Type I antibody affinity to FcγRIIIa

Effector
cell

B-cell

Lower CDC activity GA101 Complement

Type II versus Type I antibody
CD20 FcγRIIIa

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
90 Daudi
80
Granta 519
SU-DHL4
Cell death (% annexin V/PI +ve)

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:
Compared with rituximab: anti-CD20 AcMo
Increased direct cell death
induction due to Type II mode of
binding
Increased ADCC due to
ADCC
ADCC
glycoengineering (stronger
affinity for FcγRIIIa)
Superior B-cell depletion
compared with rituximab in ADCC
ADCC
whole-blood assay as well as
lymphoid tissue in cynomolgus Cell
Cell death/
death/
monkeys Cell
Celldeath/
death/ proliferation
proliferation
proliferation
proliferation
Complete tumour remissions in various
NHL xenograft models CDC
CDC
Induced anti-tumour activity in CDC
CDC
combination with chemotherapy Rituximab GA101
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 estudios completados y en marcha(Fase I/II)
Note: dark blue shaded studies are ongoing

n Patient Treatments Primary

population endpoint
Phase I
GAUGUIN (BO20999) 34 CD20+ • GA101 Safety
GAUSS (BO21003) 22 CD20+ • GA101 Safety
JO21900 (Japan) 24 CD20+ • GA101 Safety
GAUDI (BO21000) 56 R/R fNHL • GA101 + CHOP Safety
• GA101 + FC
80 First-line fNHL • GA101 + CHOP
• GA101 + bendamustine
GALTON (GAO4779g) 40 First-line CLL • GA101 + FC Safety
• GA101 + bendamustine
Phase II
GAUGUIN (BO20999) 100 R/R iNHL, aNHL, CLL • GA101 ORR
GAUSS (BO21003) 180 Relapsed iNHL • GA101 vs rituximab ORR

Source: [Link]
 GA101 estudios completados y en marcha (Fase III)
Note: all studies are ongoing

n Patient Treatments Primary

population endpoint
Phase III

CLL-11 (BO21004) 780 First-line CLL with • GA101 + chlorambucil PFS

comorbidities • Rituximab + chlorambucil
• Chlorambucil
GADOLIN (GAO4753g) 360 Rituximab-refractory iNHL • GA101 + bendamustine PFS
• Bendamustine
GOYA (BO21005) 1400 First-line DLBCL • GA101 + CHOP PFS
• Rituximab + CHOP
GALLIUM (BO21223) 1400 First-line iNHL • GA101 + chemotherapy PFS
• Rituximab + chemotherapy

Source: [Link]
 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
[Link]; 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…..