TERAPIA CONVENZIONALE DEL LINFOMA FOLLICOLARE PIER LUIGI ZINZANI

TERAPIA CONVENZIONALE DEL LINFOMA FOLLICOLARE PIER LUIGI ZINZANI Istituto di Ematologia e Oncologia “L. e A. Seràgnoli” Università degli Studi di Bologna Roma, 9 novembre 2006

SIAMO IN GRADO DI DEFINIRE LA MIGLIOR TERAPIA DI PRIMA LINEA NEL LINFOMA FOLLICOLARE?

Definire una strategia terapeutica nel linfoma follicolare Tener conto di: Obbiettivo Età Contenimento vs Cura < 60, 60 -75, > 75 Incremento RC Sopravvivenza più lunga? PCR negatività End point surrogato di una sopravvivenza più lunga?

Definire una strategia terapeutica nel linfoma follicolare CONTENIMENTO o CURA? Watch and Wait negli stadi avanzati da buttare o ancora attuale?

Contenimento o cura? Trial design 10 -yr Overall survival Obs 34% Chl 35% Ardeshna KM, Lancet 2003

Recommendation Treatment can be safely deferred without no disadvantage on survival for patients with stage III-IV disease, provided that none of the following features occurs: systemic symptoms, high tumor burden, extranodal disease, cytopenia due to marrow involvement, spleen involvement, leukemic phase, serous effusion, high LDH levels [grade A]. Linee Guida SIE, SIES, GITMO 2005

Panel’s considerations The results of the studies reported above suggest that a WW strategy may be still appropriate in selected cases with advanced disease since it allows to improve chemotherapy-free survival, especially in the elderly patients. Linee Guida SIE, SIES, GITMO 2005

Bexxar come agente singolo in prima linea 89% 76 pts con FL stadio III-IV 59% ORR Median FU 5. 1 yrs 57/76 pts CR 15/76 pts PR 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% CR/CRu 95% 75% Kaminski et al N Eng J Med 2005; 352: 441 -449)

Linfoma follicolare COME TRATTARE ? Malattia localizzata Malattia avanzata

L. Follicolare: stadi iniziali Stadi I - II (<15 -20% dei casi) - basso tumor burden: radioterapia locoregionale (30 - 36 Gy) - alto tumor burden o rischio intermedio-alto (FLIPI>2) chemioterapia + radioterapia (front-line)

Linfoma Follicolare in stadio avanzato Terapie di prima linea Autore Terapia ORR RC Brandt 2001 Alchilante in monoterapia o CVP 60 – 70% 20 – 30% Dana 1993 CHOP-Like 60 – 70% 40 – 50% Tsimberidou 2002 FND vs ATT 83 - 94% 60 – 70% Foussard 2001 FM vs CHEP 86 vs 67% 34 vs 5% Zinzani 2002 FM vs CHOP 94 vs 93% 68 vs 37% OS 4. 5 – 9 anni 70 -80% a 5 aa

I Linfomi Follicolari in stadio avanzato sono curabili? Chemioterapia

Rituximab in monoterapia in recidiva: PIVOTAL trial 166 pz con NHL a cellule B a basso grado o follicolare refrattari o recidivati Overall Response Rate Time to Progression TTP= 13 mesi Mc Laughlin et al, J Clin Oncol 1998; 16: 2825 - 33

CHOP e RITUXIMAB SEQUENZIALE come terapia di prima linea nei linfomi follicolari CHOP Overall entry 128 patients *° PCR on BM and PB CHOP *° *° *° PCR on BM and PB Baseline Patients in CR or PR and PCR+ Eligible to Rituximab Molecular follow-up on BM & PB (12, 28 and 44 weeks) Patients in CR or PR but PCRor non responsive and PCR+ Not Eligible to Rituximab Observation Rambaldi A et al , Blood 2002

CHOP e RITUXIMAB SEQUENZIALE come terapia di prima linea nei linfomi follicolari FREEDOM-FROM RECURRENCE della popolazione in studio 100 75 57% 75 50 PCR NEG % 50 44% 25 25 p<. 001 PCR POS 20% 0 0 0 11 22 Months 33 44 0 11 22 33 Months 44 Rambaldi A et al , Blood 2002

Randomized trial of Fludarabine-Mitoxantrone ± Rituximab versus CHOP ± Rituximab as front line treatment for patients with follicular lymphoma Eligible patients FM x 6 CHOP x 6 CLINICAL AND MOLECULAR RESTAGING CR - CR+, PR-, PR+ NR Observation Rituximab CLINICAL AND MOLECULAR RESTAGING Zinzani PL et al, 2004, JCO

FM/CHOP with/without rituximab Combined clinical/molecular response status after the complete sequence of treatment FM CHOP

An International Multi-Centre, Randomized, Open-Label, Phase III Trial Comparing Rituximab Added to CVP Chemotherapy Alone in Untreated Stage III/IV Follicular Non-Hodgkins Lymphoma R a n d o m i z a t i o n CVP x 8 + Rituximab 322 patients CVP x 8 R-CVP: ORR 81%, CR 40%, TTF mediana 27 m CVP: ORR 57%, CR 10%, TTF mediana 7 m Marcus R. et al: Blood; 2005

R+CHOP vs CHOP and IFN maintenance in Follicular Lymphoma: German Low-grade Study Group Randomization FL: 428 pts. RR 96%R-CHOP vs 90% (p=0. 01) TTF not reached vs 2. 6 yrs (p<0. 0001) CHOP Randomization IFN-a TTF maintenance Myeloablative RT-CT + PBCT pts <60 yr Duration of response Hiddemann W. et al: Blood; 106: 3725 -3732; 2005

M 39023: study design • Advanced FL, IC and MCL • 18– 75 years • No prior Rx • Central histology review • Written informed consent R A N D O M I Z E MCP x 6 cycles (q 4 weeks) R-MCP x 6 cycles (q 4 weeks) MCP ± rituximab Rituximab 375 mg/m 2 IV d 1 Mitoxantrone 8 mg/m² IV d 1 + 2 Chlorambucil 3 x 3 mg/m² PO d 1– 5 Prednisolone 25 mg/m² PO d 1– 5 R E S T A G I N G MCP x 2 cycles (q 4 weeks) CR, PR R-MCP x 2 cycles (q 4 weeks) IFN-maintenance for FL SD, PD off treatment Herold M, et al. GLSG Meeting Munich 2004

M 39023: progression-free survival for FL patients (ITT population) Rituximab + MCP median not reached (88. 5% at 19. 7 months) Progression-free survival 1. 00 0. 75 MCP median 19. 7 months 0. 50 0. 25 p<0. 0001 0 0 10 20 Censored 30 Months 40 50 60 Herold M, et al. GLSG Meeting Munich 2004

FCM vs. R-FCM followed by R- Maintenance vs. Observation For Salvage Therapy FCM 62 pts R-FCM 66 pts p OR % 58 79 . 01 CR % 13 33 . 005 PFS p=. 038 OS p=. 003 Forstpointner, Dreyling et al, Blood 2004

Incrementare la risposta Ridurre la malattia al minimo Studi randomizzati: chemioterapia ± Rituximab R-CVP n=162 CVP R-CHOP R-MCP n=159 n=222 n=205 n=105 MCP n=96 R-FCM n=66 FCM n=62 ORR % 81 57 96 90 92 75 78 58 CR % 41 11 20 17 49 25 33 13 PR % 40 47 77 73 43 50 45 45

Studi randomizzati: Chemioterapia ± Rituximab nei linfomi follicolari in stadio avanzato R-CVP: mediana 32 mesi R-FCM: mediana 16 mesi FCM: mediana 10 mesi CVP: mediana 15 mesi 321 pz: R-CVP x 8 vs CVP x 8 Marcus R et al: Blood 2005 128 pz: R-FCM x 4 vs FCM x 4 Forstpointner R et al: Blood 2004 Progression-free survival 1. 00 0. 75 0. 50 0. 25 R-MCP median not reached (88. 5% at 19. 7 months) CHOP MCP median 19. 7 months 0 201 pz FL: R-MCP x 8 vs MCP x 8 0 20 40 Herold M et al: ASH 2004 50 R-CHOP 60 428 pz: R-CHOP x 6 -8 vs CHOP x 6 -8 Hiddemann W et al: Blood 2005

New treatment options have changed the survival of patients with follicular lymphoma SWOG treatment results follicular NHL 1974 -2004 Therapy Pts CHOP 356 46 69 Promace. MOPP 425 48 79 CHOP + Ritux 179 61 91 0. 005 <. 001 P-value 4 -yrs PFS 4 -yrs OS Fisher R et al J. Clin. Oncol 2005

New treatment options have chanced the survival of patients with follicular lymphoma

L. Follicolare in stadio avanzato: linee guida SIE L. follicolari 1 a linea • Frontline chemotherapy, either single-agent alkylators, antracyclines-based polychemotherapy or fludarabinebased polychemotherapy, should be chosen according to patient and disease characteristics [grade B]. • Rituximab concurrent or sequential, should be add to frontline conventional chemotherapy ( Grade B). • Younger patients should not receive single-agent alkylating chemotherapy because it is not able to induce molecular remission and reduce stem cell mobilization potential [grade C]. Haematologica, Sept. 2005

Terapia di 1 a linea del L. follicolare • L’immuno-chemioterapia è lo standard • Quale combinazione è più efficace? R-CVP, R-CHOP, R-FM • Necessari risultati di studi randomizzati R-CVP vs R-CHOP vs R-FM

Rituximab in Remission Induction and Maintenance Treatment of de novo FL Studio PRIMA: R-CVP or R-CHOP or R-FCM or R-MCP Maintenance vs observation R-CVP x 8 R-CHOP x 6 + 2 R R-FCM x 6 + 2 R CR PR R-MCP x 6 + 2 R *375 mg/m 2 every 3 months for 2 years or until relapse R A N D O M I S E D Observation Rituximab maintenance*

Linfoma follicolare in stadio avanzato: problemi aperti § Significato e impatto prognostico della remissione molecolare § Terapie differenziate per rischio ed età? § Ruolo dell’auto-Tx in Ia remissione § Ruolo del mantenimento

Prognostic significance of molecular remission in Autologous Stem Cell Transplantation Freedman AS et al, Blood 1999 Ladetto M, et al. Blood 2002.

PCR negatività dopo CHOP + Rituximab sequenziale in prima linea Analisi PCR Quantitativa Rambaldi A et al: Blood, 2005 PCR + N 48 18 eventi 16 12 5 -yrs FFR 0. 64 0. 32

Linfoma follicolare in stadio avanzato: problemi aperti § Significato e impatto prognostico della remissione molecolare § Terapie differenziate per rischio ed età? § Ruolo dell’auto-Tx in Ia remissione § Ruolo del mantenimento