Radioimmunothérapie du lymphome: Routine clinique et perspectives

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1 Radioimmunothérapie du lymphome: Routine clinique et perspectives Françoise Kraeber-Bodéré, Nantes Apramen

2 Principe de la RIT Effets radiobiologiques Effets immunologiques (ADCC, CDC, Apoptose) Feu croisé 90 Y RIT 90 Y 90 Y Dose absorbée Radiosensibilité tumorale Masse tumorale Apramen

3 LNH: indication intéressante de la RIT CD19 Radiosensibilité élevée Antigènes bien caractérisés Efficacité de l immunothérapie CD20 CD22 CD22 HLA-DR Apramen

4 AMM Zevalin LF CD20+ traité par chimio-immunothérapie First pre-dose Pre-dose + Zevalin Cold anti-cd20 antibody* (Rituximab 250 mg/m 2 ) Cold anti-cd20 antibody* (Rituximab 250 mg/m 2 ) Followed by 90 Y-Zevalin (15 or 11 MBq/kg; max dose 1200 MBq) Day *Dose of cold anti-cd20 monoclonal antibody to optimize biodistribution of Zevalin Apramen Wagner et al. J Nucl Med 2002;43:

5 Zevalin Versus Rituximab in Low-Grade Lymphoma: Responses Patients (%) Zevalin International Workshop for NHL Response Criteria (IWRC) At Week 13 after beginning treatment 80% 30% P=0.002 P= % 16% n=73 Rituximab n=70 Partial response Complete response Witzig et al. J Clin Oncol 2002;20: Apramen

6 Zevalin Versus Rituximab in Low-Grade Lymphoma: Time to Progression Progression free (%) All patients CR or CRu P=0.182 Zevalin (n=73) P= Months Rituximab (n=70) Apramen 2008 Witzig et al. J Clin Oncol 2002;20:

7 Pre-RIT 6 w post-rit Apramen

8 Updated Response Rates in Zevalin Trials % 85% 83% Overall response Complete response 80% Response (%) % Phase I/II (all patients) 33% Follicular Phase I/II 47% n=51 n=33 n=30 n=73 Phase II (mild thrombocytopenia) 34% Phase III Witzig et al. Presented at Am Soc Clin Oncol 2003 Apramen

9 Développements actuels Consolidation (Maladie résiduelle) Avant autogreffe Après chimiothérapie conventionnelle Première ligne Fractionnement, Injections répétées Autres AcM (autres cibles, AcM humanisés) Apramen

10 Maladie résiduelle: situation idéale Biodistribution et dose tumorales favorables Sensibilité aux RI supérieure Effets des AcM froids Brown, Cancer Res (1998) 58: Apramen

11 Schéma général du traitement du lymphome B Induction Consolidation maintenance Immuno-chemotherapy => tumor reduction SCT RIT => MRD Apramen

12 Avant autogreffe: chimio-rit vs chimio-ict O Press, Blood 2000; 96: patients, tout grade, non randomisée Apramen

13 Apramen

14 FIT Study First-line therapy with CVP, CHOP/-like, fludarabine combinations, chlorambucil, or rituximab combination INDUCTION NR PD No inclusion CR/CRu or PR Start of study R AN D O MI ZA T I O N ZEVALIN (n = 208) Rituximab 250 mg/m 2 IV day - 7 and day 0 + Zevalin 14.8 MBq/kg (max 1184 MBq/kg) day 0 CONSOLIDATION No further treatment (n = 206) CONTROL Apramen

15 FIT Study First-line regimen Control, % Zevalin, % CR/CRu CR/CRu All patients Chlorambucil CVP / COP CHOP CHOP-like Fludarabine comb Rituximab comb Apramen

16 Fig 3. Kaplan-Meier plots for progression-free survival (PFS) in all patients and PFS stratified by response to first-line induction treatment Morschhauser, F. et al. J Clin Oncol; 26: Apramen

17 Consolidation: Zevalin en consolidation en première ligne R R-C(H)OP PR, CR, SD Zevalin n=40 n=39 Shipley et al. Proc ASCO 2005;24:579s(6577) Apramen

18 Consolidation: Zevalin en consolidation en première ligne Response rates (%) PR 0 After chemoimmunotherapy CR/CRu After Zevalin Progression free survival (%) Progression-free survival Months Shipley et al. Proc ASCO 2005; 23(16S):579s, abstr 6577 Apramen

19 A Phase II trial of fractionated 90 Y-hLL2, as consolidation after R-chemotherapy induction therapy, in patients with DLBCL Sponsor: GOELAMS, Start in 2008 One advantage of 90Y-hLL2 is to be specific for a different antigen than rituximab with the possibility of targeting populations of lymphoma cells not expressing CD20 or having lost its expression as a result of treatment. Apramen

20 Anti-CD22 hll2-90y (epratuzumab) Developed by Immunomedics (Morris Plains, New Jersey) Humanized mab Internalized by target cells Stable labeled using DOTA Administered without loading dose of cold antibody, at variance with Zevalin and Bexxar Apramen

21 90 Y-Epratuzumab Fractionated Study, ASCO Y Total Dose (mci/m 2 ) 5-10 OR 41% (7/17) CR/CRu 29% (5/17) % (7/12) 45% (6/12) % (9/16) 44% (7/16) % (16/16) 75% (12/16) Apramen

22 90 Y-Epratuzumab Fractionated Study, ASCO 2008 Pt with CR Small para-aortic LN Involvement Baseline CT 111 In-hLL2 targeting Tumor Ureter Ureter Ureter Apramen Baseline PET PET 6 wks post RIT PET 24 mo post RIT

23 Patient with FL recurrence (mediastinal LN) Treated with 2 injection of 15 mci/m2 (on going level) Good tumor targeting 90 Y-Epratuzumab Fractionated Study, ASCO 2008 Apramen

24 90 Y-Epratuzumab Fractionated Study, ASCO weeks after RIT 6 wks after RIT Before RIT Apramen

25 Essai Goelams: hll2-90y en consolidation en 1ère ligne dans le LBDGC LNH B diffus à grandes cellules > 60 ans non candidat à une autogreffe I-II grosse masses III-IV 3 cures de CHOP-R Evaluation par CT et TEP FDG NR, Progression (selon Cheson CT) Sortie d'étude CR, CRi, PR (selon Cheson CT) 3 CHOP-R Evaluation par CT et TEP FDG 2 cures de 90Y-hLL2 Apramen

26 Conclusion AMM du Zevalin: Réponses objectives chez des patients réfractaires aux autres traitements Effet supérieur en premières lignes thérapeutiques Bonne tolérance en consolidation avec des résultats thérapeutiques intéressants à confirmer chez des patients traités par chimio-immunothérapie Autres cibles, humanisation, fractionnement Apramen