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

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

Revised International Prognostic Factors (R-IPI) vs Standard IPI ( Sehn et al 2005) Group Factors 2y OS 5y-OS IPI (Shipp1993) Low 0-1 79% 83% Low-int 2 66% 69% High-int 3 59% 46% High 4-5 58% 32% R-IPI 2y-OS 4y-OS Very-good 92% Good 1-2 86% Poor 3-5 56% Sehn et al ASH 2005

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

HDC and ASCT may be effective as first line treatment in indolent and aggressive lymphomas EFS DLCL Event-free survival DLCL IPI 1-2 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

Submitted to J Clin Oncol 2006 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 1 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 0.1 0.2 0.5 2 5 10 Favours HDCT Favours control

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

Pfreundschuh et al : ASH 2004 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 CHOP EFS DLBCL young IPI 0-1

R-CHOP ? 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 ?

? 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 ?

Modified HDS with Rituximab (R-HDS) given prior to PBC collections for MCL CTX 7 g/sqm HD- ARAC A P O 1st PBPC autograft 2nd PBPC autograft 2nd PBPC harvest 1st PBPC harvest G - C S F G - C S F Rituximab Gianni AM et al. Blood 2003; 102 (2): 749-755

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

? 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 ?

R-ICE + ASCT: aumento risposta pre-ASCT II linea in pz con B-DLCL in recidiva o refrattari R-ICE vs ICE: confronto storico ORR% CR % R-ICE ICE p Paz totali 78 71 0.53 53 27 0.01 Recidive 96 79 0.07 65 34 Refrattari 46 63 0.36 31 19 0.46 aaIPI L/LI 86 0.47 39 0.42 aaIPI HI/H 76 61 0.28 Kewalramani T et al. Blood 2004; 103 (10): 3684-88

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

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% Study Group R-HDC January 2001-December 2004 77 pts 118 pts Control Group HDC August 1991-August 1995 41 pts Vitolo U, Cabras MG, Rossi G, Liberati M et al ASH 2006

R-HDC HDC R MegaCEOP14 x 4 MAD BEAM PBSC ASCT Induction chemotherapy months R-HDC R = Rituximab 1 2 3 4 5 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 months HDC 1 2 3 4 5 MACOPB x 8 weeks MAD BEAM PBSC ASCT 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

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

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

? 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 ?

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

? 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 ?

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

Post-tranplantation toxicity in patients treated with preautografting Rituximab Infections/ fever R vs No-R Bacteremia N° patients Benekli et al BMT 2003 69% vs 44% 62% vs 26% 47 Hoerr et al JCO 2004 76% vs 81% 25% vs 22% 273 Khouri et al JCO 2005 37% vs 47% NA 97

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

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

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

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) Revisione Istologica e studi biologici: Disegno statistico e analisi dati: Responsabile Stefano Pileri (Bologna) Responsabile Gianni Ciccone (Torino)

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

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

Vincristina 1,4 mg/m2 (max 2 mg) g 1 Prednisone 100 mg gg 1-5 MC MAD BEAM PBSC ASCT +14 +28 +42 +70 +98 +126 RESTAGING C +56 +86 +100 Schema 1: R= Rituximab MC = MegaCHOP14 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 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

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

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

STATO ARRUOLAMENTO SETTEMBRE 2006 PAZIENTI – aggiornamento Settembre 2006 TARGET ARRUOLATI TOTALE ARRUOLATI RANDOMIZZATI SCHEMA 1 SCHEMA 1 BIS SCHEMA 2 SCHEMA 2 BIS IPI 2 IPI 3 DROP OUT 376 31 8 7 9 16 15 IIL-DLCL04: 39/79 centri attivi

IIL-DLCL04 R-CHOP14 R-HDC DLBCL cure

Conclusions Addition 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.

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