TERAPIA ANTI-CD20 LA PERSPECTIVA DEL ONCÓLOGO

Transcripción

1 TERAPIA ANTI-CD20 LA PERSPECTIVA DEL ONCÓLOGO V SIMPOSIO SEAP-SEOM BIOMARCADORES EN HEMATOPALOGÍA Luis de la Cruz Merino Sº Oncología Médica HUVMacarena (Sevilla)

2 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

3 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 + D sigm sigg siga IgM IgG IgA HCR HCR µ HCR R/D 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

4 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:

5 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

6 Epítopos antígeno CD-20 Cang J Hematol&Oncol 2012

7 MECANISMO DE ACCIÓN AcMo Brody J Clin Oncol 2011

8 Rituximab potencia la actividad in vitro de diversos citotóxicos % Citotoxicidad Agente citotóxico + MabThera MabThera P Valor DTX Ricin TNF alpha ADR CDDP VP Demidem et al. Cancer Biother Radiopharm. 1997;12:177.

9 Radiotherapy Chemotherapy TLR4 Agents targeting Immune synapses HMGB1 Lenalidomide H/RS cells P P CD 30 CD 52 P Dendritic cell Stimulated CTL Activity AcMo anticd30 CD 20 AcMo anticd20 anticd52 Tumor microenvironment cells

10 Impacto clínico de la terapia anti-cd20: difuso de células grandes y folicular

11 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:

12 Percent Survival Supervivencia global según IPI revisado (R-IPI) P <.0001 Very good Good Poor * QT BASADA EN R-CHOP Yrs Sehn LH, et al. Blood. 2007;109:

13 Survival Probability CHOP ± Rituximab en DLBCL: resultados de SG a 7 años (GELA LNH-98.5 Study) P =.0004 OS (N = 399) Parameter, % Yrs CHOP R-CHOP Low Risk High Risk Age, < 70 vs 70 yrs LDH, NI vs > NI * Stage, I/II vs III/IV Bone marrow, yes vs no * Tumor size, < 10 vs 10 cm β 2 -microglobulin, NI vs > NI * Serum albumin, 35 vs < 35 g/l *P <.05 (multivariate analysis). Coiffier B, et al. ASCO Abstract 8009.

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15 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 e s t a g i n g CR, PR 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 SD,PD off treatment

16 Tiempo al fallo del tto. y tiempo hasta la progresión (mediana de seguimiento 25 meses) Event-free probability P< TTF R-CVP: median 27m CVP: median 7m Study month Event-free probability P< TTP R-CVP: median 30m CVP: median 15m 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.

17 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 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)

18 Proportion on treatment CHOP rituximab en primera línea de linfoma folicular: tiempo hasta el fracaso de tratamiento MabThera + CHOP (143/159) CHOP (102/143) Years after start of therapy Hiddemann W, et al. Blood 2003;102:104a (Abstract 352)

19 # 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 Bendamustine-Rituximab Follicular G I-II Waldenströms Marginal zone Small lymphocytic Mantle cell R CHOP-Rituximab Bendamustine 90 mg/m 2 day R day 1, max 6 cycles, q 4 wks. CHOP-R, max 6 cycles, q 3 wks.

20 Supervivencia libre de progresión (45 meses seguimiento) Median (months) B-R 69.5 CHOP-R Hazard ratio, 0.58 (95% CI ) p = m

21 Radioinmunoterapia y Nuevos AcMo anti-cd20

22 AcMo anti-cd20, además de Rituximab. Brody J Clin Oncol 2011

23 Elección del isótopo Properties 90 Yttrium 131 Iodine Half-life 64 hours 192 hours 131 I Energy emitter Beta (2.3 MeV) Gamma (0.36 MeV) Beta (0.6 MeV) Path length 90 5 mm mm Urinary excretion Dosing Administration Minimal 7% in 7 days Based on weight and platelet count Outpatient Extensive/variable 46-90% in 2 days Clearance based dosing using whole body dosimetry Inpatient or restrictions to protect family/public

24 Cheson BD. Blood 2003; 101: Zevalin en linfoma indolente

25 GA101: AcMo anti-cd20 tipo II 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 cellmediated cytotoxicity (ADCC) GA101 is being evaluated in an extensive clinical trial program in B-cell malignancies CD20 peptide Light chain Glycoengineering Heavy chain Mössner E, et al. Blood 2010;115: ; Niederfellner G, et al. Blood 2011; 118:

26 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 Type II versus Type I antibody GA101 CD20 Complement FcγRIIIa CDC, complement-dependent cytotoxicity Mössner E, et al. Blood 2010;115:

27 Cell death (% annexin V/PI +ve) 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-DHL Control GA101 Rituximab Alduaij W et al. Blood 2009; 114:Abstract 725, taken from oral presentation at ASH 2009

28 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 ADCC Cell death/ proliferation CDC Rituximab Mössner E, et al. Blood 2010;115: Herting F, et al. Blood 2010;116:Abstract 3915, taken from poster presentation at ASH, Dec ADCC Cell death/ proliferation CDC GA101

29 GA101 estudios completados y en marcha(fase I/II) Note: dark blue shaded studies are ongoing Phase I 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) R/R fnhl First-line fnhl GA101 + CHOP GA101 + FC GA101 + CHOP GA101 + bendamustine GALTON (GAO4779g) 40 First-line CLL GA101 + FC GA101 + bendamustine Phase II GAUGUIN (BO20999) 100 R/R inhl, anhl, CLL GA101 ORR GAUSS (BO21003) 180 Relapsed inhl GA101 vs rituximab ORR Safety Safety Source:

30 GA101 estudios completados y en marcha (Fase III) Note: all 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 GADOLIN (GAO4753g) 360 Rituximab-refractory inhl GA101 + bendamustine Bendamustine GOYA (BO21005) 1400 First-line DLBCL GA101 + CHOP Rituximab + CHOP GALLIUM (BO21223) 1400 First-line inhl GA101 + chemotherapy Rituximab + chemotherapy PFS PFS PFS PFS Source:

31 GOYA (BO21005) fase III: diseño Previously untreated CD20+ DLBCL (n=1400) GA mg + CHOP x 6 or 8 (n=700) Rituximab 375 mg/m 2 + CHOP x 6 or 8 (n=700) Experimental arm Control arm Primary endpoint Secondary endpoints GA mg d1, d8, d15 cycle 1; d1 cycles 2 8 q21d + CHOP Rituximab 375 mg/m 2 on d1 q21d cycles CHOP Investigator-assessed PFS 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 NCT

32 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..