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;115:43934402; 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;115:43934402 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;115:43934402 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…..