1 / 37

MEDITERRANEAN SCHOOL OF ONCOLOGY

MEDITERRANEAN SCHOOL OF ONCOLOGY Diagnostic and therapeutic burning questions on lymphoproliferative diseases Rieti 27-29 Ottobre 2006. Ruolo dell’autotrapianto nell’era dell’immunoterapia con anticorpi monoclonali nei Linfomi Diffusi a grandi cellule B. Umberto Vitolo

newton
Download Presentation

MEDITERRANEAN SCHOOL OF ONCOLOGY

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. MEDITERRANEAN SCHOOL OF ONCOLOGY Diagnostic and therapeutic burning questions on lymphoproliferative diseases Rieti 27-29 Ottobre 2006 Ruolo dell’autotrapianto nell’era dell’immunoterapia con anticorpi monoclonali nei Linfomi Diffusi a grandi cellule B. Umberto Vitolo SSCVD Chemioimmunoterapia dei disordini Linfoproliferativi Dipartimento di Oncoematologia ASO San Giovanni Battista Torino

  2. Young low-risk R-CHOP IPI 0,1  IPI 2,3 Elderly Young high-risk ≤60 years  >60 years Treatment of Diffuse Large B Lymphomas

  3. Revised International Prognostic Factors (R-IPI) vs Standard IPI ( Sehn et al 2005) Sehn et al ASH 2005

  4. Random Random CHOP x 3 DHAP x 4 CHOP x 3 HDC + ASCT DHAP x 2 + BEAC – ASCT EFS OS HDC and ASCT is effective in chemosensitive relapsed indolent and aggressive lymphomas EFS 140 relapsed Follicular Lymhoma patients 109 relapsed DLCL patients OS Schouten HC. JCO, 2003 Philip T et al. NEJM 1995

  5. HDC and ASCT may be effective as first line treatment in indolent and aggressive lymphomas Event-free survival DLCL IPI 1-2 EFS DLCL GOELAMS study Milpied et al NEJM 2004 Gianni et al, NEJM 1997 Event-free survival DLCL IPI 2-3 Event-free survival DLCL IPI 2-3 Intergruppo Italiano Linfomi study Vitolo et al Haematologica 2005 Martelli et al. J Clin Oncol 2003 P = 0.2

  6. 0.1 0.2 0.5 1 2 5 10 Cochrane Meta-analysis of the HR for OS for patients receiving conventional or HDC with ASCT: 14 randomized studies Overall Survival Study Hazard Ratio (fixed) Hazard Ratio (fixed) 95% CI 95% CI Gianni 0.52 [0.24, 1.11] Milpied 0.64 [0.40, 1.05] Intragumtornchai 0.64 [0.30, 1.36] Martelli 1996 0.69 [0.29, 1.65] Santini 1998 0.81 [0.48, 1.37] De Souza 0.92 [0.45, 1.89] Haioun 0.96 [0.71, 1.30] Martelli 2003 1.01 [0.59, 1.73] Kaiser 0.08 [0.75, 1.55] Kluin-Nelemans 1.33 [0.75, 2.37] Rodriguez 2003 1.34 [0.68, 2.65] Verdonck 1.40 [0.73, 2.67] Vitolo 1.41 [0.82, 2.41] Gisselbrecht 1.45 [1.08, 1.93] Total (95% CI) 1.05 [0.92, 1.19] Engert A et al. Submitted to J Clin Oncol 2006 Favours HDCT Favours control

  7. BUT . . . 40–55% of patients relapse after ASCT • Possible explanations for relapse • contamination of stem cell product • residual tumour cells remaining after high-dose chemotherapy (HDT) • Improving outcomes in ASCT • in vivo purging agent • improving response rate before transplantation • post-transplant maintenance immunotherapy

  8. Rituximab improves efficacy of standard chemotherapy in indolent and aggressive lymphomas EFS FL EFS DLBCL elderly R-CVP: median 32 m 321 pts: R-CVP x 8 vs CVP x 8 Marcus et al: Blood 2005 399 pts: R-CHOP x 8 vs CHOP x 8 Feugier et al: JCO 2005 CVP: median 15 m EFS FL R-CHOP 428 pts: R-CHOP x 6-8 vs CHOP x 6-8 Hiddemann et al: Blood 2005 823 pts: R-CHOP x 6 vs CHOP x 6 Pfreundschuh et al: ASH 2004 EFS DLBCL young IPI 0-1 CHOP

  9. CHOP + RITUXIMAB is always the best treatment? HDC with Rituximab + ASCT may improve the outcome of the patients? Poor Prognosis DLBCL (IPI2-3) Refractory/early relapsed patients R-CHOP ?

  10. High Dose Chemotherapy with Rituximab and ASCT: Key issues Reducing lymphoma cell contamination in PBSC Increasing outcome in IPI2-3 DLBCL Dose of Rituximab Toxicity and delayed engraftment after ASCT as in vivo purging Possible Standard or High dose Perhaps ?

  11. Modified HDS with Rituximab (R-HDS)given prior to PBC collections for MCL CTX7 g/sqm HD-ARAC A P O 2nd PBPCautograft 1st PBPCautograft 2nd PBPCharvest 1st PBPCharvest G - C S F G - C S F Rituximab Gianni AM et al. Blood 2003; 102 (2): 749-755

  12. Rituximab and HDC as in vivo purging in PBSC harvest 28 MCL patients 57% 93% Gianni AM et al. Blood 2003; 102 (2): 749-755

  13. High Dose Chemotherapy with Rituximab and ASCT: Key issues Reducing lymphoma cell contamination in PBSC Increasing outcome in IPI2-3 DLBCL Dose of Rituximab Toxicity and delayed engraftment after ASCT as in vivo purging Possible Standard or High dose Perhaps ?

  14. R-ICE + ASCT: aumento risposta pre-ASCTII linea in pz con B-DLCL in recidiva o refrattari R-ICE vs ICE: confronto storico ORR% CR % Kewalramani T et al. Blood 2004; 103 (10): 3684-88

  15. Preautografting treatment with Rituximab in relapsed aggressive Lymhomaa:R-ICE + ASCT vs ICE+ASCT x 3 courses Rituximab Ifosfamide Carboplatino Etoposide CR 53% R-ICE 78 patients p = .01 PBSC CR 27% ICE 71 patients BEAM + ASCT OS PFS 36 pts R-ICE 147 pts ICE Kewalramani T et al. Blood 2004; 103 (10): 3684-88

  16. Study Group R-HDC January 2001-December 2004 77 pts 118 pts Control Group HDC August 1991-August 1995 41 pts R-HDC+ASCT as firts line therapy in poor prognosis (IPI 2-3) DLBCL, age 18-60 • A non randomized comparison between two groups of patients enrolled into two consecutive phase II trial with up-front HDC and ASCT with or without Rituximab with identical inclusion criteria: stage III/IV, IPI 2-3, < 60 yrs, EF > 45% Vitolo U, Cabras MG, Rossi G, Liberati M et al ASH 2006

  17. R-HDC MAD MAD BEAM MegaCEOP14 x 4 PBSC ASCT R R R R R R months 0 0 1 1 2 2 3 3 4 4 5 5 R = Rituximab MAD MAD BEAM MACOPB x 8 weeks PBSC ASCT HDC months Induction chemotherapy Months 1 and 2 Intensified chemotherapy MAD (HD-ARAC + Mitoxantrone x 3 days) Months 3 and 4 High dose chemotherapy BEAM + ASCT Month 5 R-MEGACEOP14 R 375 mg/m2 d 1 Epi 110 mg/m2 d 3 Ctx 1200 mg/m2 d 3 Vcr 1.4 mg/m2 d 3 Pdn 40 mg/m2 dd 1 5 G-CSF 5 mcg/kg dd 5 12 R-MAD Mito 8 mg/m2 dd 1 3 ARA-C 2 g/m2/12h dd 1 3 Dex 4 mg/m2/12h dd 1 3 R 375 mg/m2 d 4 and d -1PBSC G-CSF 5 µg/Kg d 4

  18. 3-yrs FFS 3-yrs OS 80% R-HDC 64% R-HDC 54% HDC 46% HDC p = .016 p = .004 3-yr Failure-free and overall survival Median Follow-up time: R-HDC 36 months; HDC 72 months CR 78% R-HDC 77 patients NO ASCT: 17 (22%) p = .25 CR 68% HDC 41 patients NO ASCT: 10 (24%) Vitolo et al ASH 2005

  19. Maintenance Rituximab after HDC in poor risk DLBCL: LNH98-B3 GELA Study ACVBP Random Maintenance Rituximab Random HDC (ACE) Observation 3-yrs EFS maintenance vs observation: 80% vs 72% p=.10 Haioun C. et al, ASH 2005 abs 677

  20. High Dose Chemotherapy with Rituximab and ASCT: Key issues Reducing lymphoma cell contamination in PBSC Increasing outcome in FL, MCL, IPI2-3 DLBCL Dose of Rituximab Toxicity and delayed engraftment after ASCT as in vivo purging Possible Standard or High dose Perhaps ?

  21. Day – 1 Rituximab 375 mg/mq Day + 7 Rituximab 1000 mg/mq Day + 1 and + 8 Rituximab 1000 mg/mq HARVEST Day 0 ASCT Day 0 GM-CSF 250 mcg/mq G-CSF 10 mcg/kg GM-CSF 250 mcg/mq Edx OR Ifo+VP16 BEAM High or standard dose of Rituximab with ASCT? DFS OS Khoury IF et al. J.Clin.Oncol. 2005; 23: 2240-47

  22. High Dose Chemotherapy with Rituximab and ASCT: Key issues Reducing lymphoma cell contamination in PBSC Increasing outcome in FL, MCL, IPI2-3 DLBCL Dose of Rituximab Toxicity and delayed engraftment after ASCT as in vivo purging Possible Standard or High dose Perhaps ?

  23. Engraftment impairment in patients treated with Rituximab? Neutrophils engraftment R vs no-R: 13 (9-28) vs 12 (8-28) Platelets engraftment R vs no-R: 39 (33-46) vs 27 (22-29) P < .04 P < .01 Hoerr AL et al. J.Clin.Oncol. 2004 Benekli M et al. B. Marrow Transpl. 2003

  24. Post-tranplantation toxicity in patients treated with preautografting Rituximab

  25. Rituximab as adjuvant to HDT and ASCT for aggressive lymphoma: delayed B cell ricovery Horwitz SM et al. Blood 2004

  26. R-CHOP Do we need to stay on CHOP + RITUXIMAB or explore new treatments in aggressive lymphomas? ?

  27. DSHNHL trial < 60yrs aa-IPI 2-3 R-MegaCHOEP x 4 vs R-CHOEP14 x 8 GOELAMS trial < 60yrs aa-IPI 2-3 R-CHOP14 x 8 vs R-CEEP15 + HD-ARAC/MTX + BEAM-ASCT

  28. Study ID: IIL-DLCL04 Phase III randomized, multicenter study in poor-prognosis (IPI2-3) DLBCL young patients. Dose-dense chemotherapy + Rituximab +/- intensified and high dose chemoimmunotherapy with ASCT. Comitato di stesura: Umberto Vitolo (Torino), Emanuele Angelucci (Cagliari), Monica Balzarotti (Rozzano), Ercole Brusamolino (Pavia), Nicola Di Renzo (Lecce), Maurizio Martelli (Roma), Luigi Rigacci (Firenze), Gino Santini (Genova) Disegno statistico e analisi dati: Revisione Istologica e studi biologici: Responsabile Stefano Pileri (Bologna) Responsabile Gianni Ciccone (Torino)

  29. B-DLCL giovani (18-60) IPI 2-3 R-MAD x 2 BEAM+ASCT R-MegaCHOP14 x 4 RC/RP R E S T A G I N G RANDOMIZATION 188 PZ Off study NR R-MAD x 2 BEAM+ASCT R-CHOP14 x 4 RC/RP R-MegaCHOP14 x 2 R-MegaCHOP14 x 4 RC/RP 188 PZ Off study NR R-CHOP14 x 4 RC/RP R-CHOP14 x 4

  30. CRITERI DI INCLUSIONE • Età 18-60 • Istologia: Linfoma diffuso a grandi cellule B CD 20 + (de novo o shift da NHL a basso grado se non pretrattati), Linfoma follicolare grado 3b • Age-adjusted IPI 2 o 3 (intermedio-alto o alto rischio) • Stadio II avanzato, III, IV con almeno 2 fattori di rischio sec. aa-IPI • PS < 3 se non dovuto al linfoma • Frazione di eiezione cardiaca > 45% • Normale funzionalità epatica, renale, polmonare • Markers virali HIV, HBV e HCV negativi • HCV+ senza segni di replicazione in atto confermata istologicamente • AntiHBc+, HbsAg-, AntiHBs+/- (portatori occulti) • Aspettativa di vita > 3 mesi • Assenza di gravidanza in atto al momento dell’inizio della chemioterapia • Consenso informato scritto

  31. RESTAGING MAD MAD BEAM MC MC MC MC PBSC ASCT 0 +14 +28 +42 +70 +98 +126 R R R R R R R R R R R R R R R R R R R R R R R R R R RESTAGING MAD MAD BEAM C C C C PBSC ASCT 0 +14 +28 +42 +70 +98 +126 RESTAGING MC MC MC MC MC MC 0 +14 +28 +42 +56 +70 RESTAGING C C C C C C C C 0 +14 +28 +42 +56 +70 +86 +100 R-MegaCHOP14 Rituximab* 375 mg/m2 g 1 Ciclofosfamide 1200 mg/m2 g 1 Doxorubicina 75 mg/m2 g 1 Vincristina 1,4 mg/m2 (max 2 mg) g 1 Prednisone 100 mg gg 1-5 Pegfilgrastim 6 mg 24 ore dopo la chemioterapia in unica somministrazione *Rituximab g 8 nel ciclo 1 Schema 1: R= Rituximab MC = MegaCHOP14 R-MAD Mitoxantrone 8 mg/m2/die gg 1-3 ARA-C 2000 mg/m2/12 h gg 1-3 Desametazone 4 mg/m2/12 h gg 1-3 Rituximab* 375 mg/m2 g 4 e prima di raccolta PBSC Lenograstim 5 µg/Kg/die a partire da 48 h dopo la chemioterapia e fino a raccolta di PBSC (tra il giorno +13 e +15) *solo nel I ciclo R-MAD Schema 1 bis: R= Rituximab C = CHOP14 Schema 2: R= Rituximab MC = MegaCHOP14 Schema 2 bis: R= Rituximab C = CHOP14

  32. Revisione Istologica centralizzata e studi biologici Revisione istologica centralizzata e caratterizzazione immunoistochimica del profilo di espressione genica (Germinal Center Cell e non-Germinal Center Cell) in tutti i pazienti arruolati nello studio. Per tale revisione i centri dovranno inviare entro 30 giorni dalla diagnosi il materiale diagnostico (blocchetto in paraffina) al patologo di riferimento. Responsabile: Stefano Pileri (Bologna) Antonino Carbone (Aviano) Simonetta Di Lollo (Firenze) Fabio Facchetti (Brescia) Brunagelo Falini (Perugia) Vito Franco (Palermo) Marcello Gambarotta (Milano) Lorenzo Leoncini (Siena) Domenico Novero (Torino) Marco Paulli (Pavia) Edorado Pescarmona (Roma) Mauro Truini (Genova) Alessandro Vitali (Genova) Abbonamento dedicato DHL 105310796

  33. Piemonte 11 Friuli 2 Marche 1 Abruzzo 1 Veneto 4 Lombardia 14 Emilia Romagna 10 Sardegna 2 Liguria 3 Toscana 3 Umbria 2 Lazio 7 Molise 1 Puglia 5 Campania 5 Basilicata 2 Calabria 4 Sicilia 2 IIL-DLCL04 Participating Italian Centers: 79 Planned sample size: 376 patients

  34. STATO ARRUOLAMENTO SETTEMBRE 2006 IIL-DLCL04: 39/79 centri attivi

  35. DLBCL cure R-HDC R-CHOP14 IIL-DLCL04

  36. ConclusionsAddition of Rituximab to HDC • It is feasible without additional acute toxicity. • It allows to collect lymphoma-free PBSC. • The empairment of engraftment, if any, is not clinically relevant. • Preliminary results in DLBCL are encouraging. • Many schedules have been used so far: pre ASCT chemotherapy, immediately before and after ASCT, maintenance  prevent definite conclusions • Immune reconstitution and late toxicities after ASCT need to be monitored and properly studied • Randomized studies are ongoing to compare the efficacy of R-HDC vs R-CHOP.

  37. Ringraziamenti SSCVD Chemioimmunoterapia dei Linfomi EMATOLOGIA ASO S.Giovanni Torino ANATOMIA PATOLOGICA Università Torino Prof G. Inghirami • G. Benevolo • B. Botto • A. Chiappella • L. Orsucci • P. Pregno • P. Francia di Celle • L. Godio • D. Novero • A.Stacchini EPIDEMIOLOGIA DEI TUMORI Università di Torino Prof F. Merletti • G. Ciccone • M. Ceccarelli • F. Saccona

More Related