La presentazione è in caricamento. Aspetta per favore

La presentazione è in caricamento. Aspetta per favore

Ruolo dellautotrapianto nellera dellimmunoterapia con anticorpi monoclonali nei Linfomi Diffusi a grandi cellule B. MEDITERRANEAN SCHOOL OF ONCOLOGY MEDITERRANEAN.

Presentazioni simili


Presentazione sul tema: "Ruolo dellautotrapianto nellera dellimmunoterapia con anticorpi monoclonali nei Linfomi Diffusi a grandi cellule B. MEDITERRANEAN SCHOOL OF ONCOLOGY MEDITERRANEAN."— Transcript della presentazione:

1 Ruolo dellautotrapianto nellera dellimmunoterapia con anticorpi monoclonali nei Linfomi Diffusi a grandi cellule B. MEDITERRANEAN SCHOOL OF ONCOLOGY MEDITERRANEAN SCHOOL OF ONCOLOGY Diagnostic and therapeutic burning questions on lymphoproliferative diseases Rieti Ottobre 2006 Umberto Vitolo SSCVD Chemioimmunoterapia dei disordini Linfoproliferativi Dipartimento di Oncoematologia ASO San Giovanni Battista Torino

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

3 GroupFactors2y OS5y-OS IPI (Shipp1993) Low % 83% Low-int 2 66% 69% High-int 3 59% 46% High % 32% R-IPIFactors 2y-OS4y-OS Very-good 0 92% Good % Poor % 58% Revised International Prognostic Factors (R-IPI) vs Standard IPI ( Sehn et al 2005) Sehn et al ASH 2005

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

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

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

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

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

9 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

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

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

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-ICEICEpR-ICEICEp Paz totali Recidive Refrattari aaIPI L/LI aaIPI HI/H ORR% CR % Kewalramani T et al. Blood 2004; 103 (10): R-ICE + ASCT: aumento risposta pre-ASCT II linea in pz con B-DLCL in recidiva o refrattari R-ICE vs ICE: confronto storico

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

16 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, 45% 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, 45% Study Group R-HDC January 2001-December 2004 January 2001-December pts Control Group HDC August 1991-August 1995 August 1991-August pts 118 pts Vitolo U, Cabras MG, Rossi G, Liberati M et al ASH 2006 R-HDC+ASCT as firts line therapy in poor prognosis (IPI 2-3) DLBCL, age 18-60

17 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 x 4 RR MAD BEAM RR PBSCPBSC ASCTASCT months R-HDCR-HDCR-HDCR-HDC R = Rituximab R R-MEGACEOP14 R 375 mg/m 2 d 1 Epi 110 mg/m 2 d 3 Ctx 1200 mg/m 2 d 3 Vcr 1.4 mg/m 2 d 3 Pdn 40 mg/m 2 dd 1 5 G-CSF 5 mcg/kg dd 5 12 R-MAD Mito 8 mg/m 2 dd 1 3 ARA-C 2 g/m 2 /12h dd 1 3 Dex 4 mg/m 2 /12h dd 1 3 R 375 mg/m 2 d 4 and d -1PBSC G-CSF 5 µg/Kg d 4 months HDCHDCHDCHDC MACOPB x 8 weeks MAD BEAM PBSCPBSC ASCTASCT

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

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

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 Khoury IF et al. J.Clin.Oncol. 2005; 23: 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 HARVESTHARVEST BEAM Day 0 ASCT Day + 1 and + 8 Rituximab 1000 mg/mq Day 0 GM-CSF 250 mcg/mq OS DFS

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? Hoerr AL et al. J.Clin.Oncol P <.04 P <.01 Benekli M et al. B. Marrow Transpl 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)

24 Post-tranplantation toxicity in patients treated with preautografting Rituximab Infections/fever R vs No-R Bacteremia N° patients Benekli et al BMT % vs 44% 62% vs 26% 47 Hoerr et al JCO % vs 81% 25% vs 22% 273 Khouri et al JCO % vs 47% NA97

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

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

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 Phase III randomized, multicenter study in poor-prognosis (IPI2-3) DLBCL young patients. Dose-dense chemotherapy + Rituximab +/- intensified and high dose chemoimmunotherapy with ASCT. 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) Study ID: IIL-DLCL04 Comitato di stesura: Revisione Istologica e studi biologici: Responsabile Stefano Pileri (Bologna) Disegno statistico e analisi dati: Responsabile Gianni Ciccone (Torino)

29 B-DLCL giovani (18-60) IPI 2-3 RC/RP NR Off study R-MegaCHOP14 x 4 R-MAD x 2 BEAM+ASCT NR Off study RANDOMIZATIONRANDOMIZATIONRANDOMIZATIONRANDOMIZATION R-CHOP14 x 4 R-MegaCHOP14 x 2 R-CHOP14 x 4 RESTAGING R-MegaCHOP14 x 4 R-MAD x 2 BEAM+ASCT 188 PZ

30 CRITERI DI INCLUSIONE PS < 3 se non dovuto al linfoma PS < 3 se non dovuto al linfoma Frazione di eiezione cardiaca > 45% Frazione di eiezione cardiaca > 45% Normale funzionalità epatica, renale, polmonare Normale funzionalità epatica, renale, polmonare Markers virali HIV, HBV e HCV negativi Markers virali HIV, HBV e HCV negativi HCV+ senza segni di replicazione in atto confermata istologicamente HCV+ senza segni di replicazione in atto confermata istologicamente AntiHBc+, HbsAg-, AntiHBs+/- (portatori occulti) AntiHBc+, HbsAg-, AntiHBs+/- (portatori occulti) Aspettativa di vita > 3 mesi Aspettativa di vita > 3 mesi Assenza di gravidanza in atto al momento dellinizio della chemioterapia Assenza di gravidanza in atto al momento dellinizio della chemioterapia Consenso informato scritto Consenso informato scritto Età Età 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 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) 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 Stadio II avanzato, III, IV con almeno 2 fattori di rischio sec. aa-IPI

31 R MC R R MAD BEAM RR PBSCPBSC ASCTASCT R RESTAGINGRESTAGING R CC R C R C MAD BEAM RR PBSCPBSC ASCTASCT R RESTAGINGRESTAGING R MC R R RR R RESTAGINGRESTAGING +70 MC R CC R C R C RR R RESTAGINGRESTAGING +70 CC RR CC Schema 1: R= Rituximab MC = MegaCHOP14 Schema 1 bis: R= Rituximab C = CHOP14 Schema 2: R= Rituximab MC = MegaCHOP14 Schema 2 bis: R= Rituximab C = CHOP14 R-MegaCHOP14 Rituximab* 375 mg/m 2 g 1 Ciclofosfamide 1200 mg/m 2 g 1 Doxorubicina 75 mg/m 2 g 1 Vincristina 1,4 mg/m 2 (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/m 2 /die gg 1-3 ARA-C 2000 mg/m 2 /12 h gg 1-3 Desametazone 4 mg/m 2 /12 h gg 1-3 Rituximab* 375 mg/m 2 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

32 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. Revisione Istologica centralizzata e studi biologici 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

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

34 STATO ARRUOLAMENTO SETTEMBRE 2006 PAZIENTI – aggiornamento Settembre 2006 TARGET ARRUOLATI TOTALE ARRUOLATI RANDOMIZZATI SCHEMA 1 SCHEMA 1 BIS SCHEMA 2 SCHEMA 2 BIS IPI 2IPI 3 DROP OUT IIL-DLCL04: 39/79 centri attivi

35 R-CHOP14 R-HDC DLBCLcure IIL-DLCL04

36 Conclusions Addition of Rituximab to HDC It is feasible without additional acute toxicity. It is feasible without additional acute toxicity. It allows to collect lymphoma-free PBSC. It allows to collect lymphoma-free PBSC. The empairment of engraftment, if any, is not clinically relevant. The empairment of engraftment, if any, is not clinically relevant. Preliminary results in DLBCL are encouraging. 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 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 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. Randomized studies are ongoing to compare the efficacy of R- HDC vs R-CHOP.

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


Scaricare ppt "Ruolo dellautotrapianto nellera dellimmunoterapia con anticorpi monoclonali nei Linfomi Diffusi a grandi cellule B. MEDITERRANEAN SCHOOL OF ONCOLOGY MEDITERRANEAN."

Presentazioni simili


Annunci Google