Follicular lymphoma Optimal primary therapy and consolidation ? Seminars in Hematological Oncology * Israel, April M. Dreyling, Dept. of Medicine III University Hospital LMU Grosshadern/Munich

Follicular lymphoma clinical risk factors conventional chemotherapy antibody monotherapy and combination new concepts: maintenance radioimmunotherapy autologous transplantation

Follicular lymphoma grade I/II: Clinical characteristics median age 60 years indolent course (OS 5-10 years) 80% in advanced stage palliative treatment (in relapse) chemosensitive

Follicular Lymphoma grade III: Histology grading according to number of blasts/HPF  grade IIIa clinically/ biologically similar to grade I/II  grade IIIb treated according to aggressive lymphoma FLIII a with centrocytesFLIII b without centrocytes Ott, Blood 2003

FLIPI in follicular lymphoma (n=1795) 36% 37% 27% Solal-Celigny, Blood 2004 Survival probability

R-CHOP in follicular lymphoma Prognostic factor FLIPI Buske, Blood 2006

Therapy in localized stages (I/II) Curative approach with radiation (30-40 Gray) ! - involved field ? - extended field ? - total nodal radiation ? - 2x2 Gray (EORTC) ? - plus 2 Gray TBI ? Wilder et al., 2001

Therapy in advanced stages (III/IV) watch & wait („to live with the disease “) non-curative chemotherapy only in symptomatic cases : B-symptoms hematopoietic insufficiency hyperviscosity syndrome local LN compression rapid progress

Prospective randomised study (follow-up 16 years) : n=309; 65% follicular lymphoma Overall survival Disease-free survival Long term effect watch & wait vs. chlorambucil for asymptomatic advanced stage (low grade) lymphoma Ardeshna, Lancet 2003

Indolent lymphoma: overall survival % s (n=668) (n=513) (n=195) Horning. Semin Oncol 1993

Palliative therapy in follicular lymphoma: What are the critical aims ? event-free survival overall survival ? ? ? quality of life initial response (CR, PR)

Anti CD20 antibody in B-cell lymphocytes Mechanism of action 4 x 375 mg/m2 Rituximab response rate48% (166 patients) time to progression 13 months (responder) toxicityFever, rigors, chills (12% grade III, 3% grade IV) Mc Laughlin, JCO 1998

First line in asymptomatic advanced stage FL Overall response rates % * according to Cheson criteria Colombat, ASH 2006

CR/Cru: med PFS 50.9 months PR: med PFS 23 months SD-PD: med PFS 6.4 months First line in asymptomatic advanced stage FL Progression-free survival Colombat, ASH 2006 median follow-up 84 months

Time to progression, relapse or death Study month Event-free probability R–CVP: median 34 months CVP: median 15 months CVP R–CVP Patients at risk: p< (median FU: 53 months) Marcus, ASH 2006

CVP ± Rituximab in previously untreated FL Summary of results Time to Treatment Failure7 mo27 mo Time to Progression15 mo34 mo Time to new antilymphoma treatment 12 mo49 mo Duration of Response 14 mo 38 mo CVP (n =159) R-CVP (n=162) Overall Response 57 % 81 % p-value < CHOP 92% 26 mo (median FU: 53 months) Marcus, ASH 2006

Follicular lymphoma CHOP vs. R-CHOP CHOP R-CHOP complete induction: CR: 17% 20% PR: 74% 77% MR/SD: 6% 2% PD: 3% 1% ED: 1% 1% OR: 90% 96% p= Hiddemann, Blood 2005

Follicular lymphoma (elderly patients) Progression-free survival (R-CHOP) Buske, ASH 2006 Probability years CHOP (37/109) R-CHOP (78/112) median 2.1 y p<0.0001

P<0.0001Not reached Median event free survival P< % (76%)85% (49%)Response rate (CR/Cru) Patients evaluable p-value 6x R-CHVP/IFN-  12x CHVP/IFN-  Foussard, ASCO 2006 P< Not reached29 monthsMedian event free survival P = %75%Response rate 10596Patients evaluable p-valueR-MCPMCPHerold, ASH 2006 P< months7 monthsMedian time to treatment failure P< %57%Response rate Patients evaluable p-valueR-CVPCVPMarcus, ASH 2006 P< Not reached25/31 monthsMedian time to treatment failure P= %90%Response rate 112/223109/205Patients evaluable p-valueR – CHOPCHOPBuske, ASH 2006 First Line Treatment: Immuno-chemotherapy

Overall survival Study month Event-free probability R–CVP: median not reached CVP: median not reached CVP R–CVP Patients at risk: p= (median FU: 53 months) 4-years OS estimates: 83% vs 77% Marcus, ASH 2006

M 39023: Overall Survival FL patients (median follow-up 47 months) P = Censored 15 events vs 25 events 4-year OS 87% 4-year OS 74% R-MCP: median nr MCP: median nr Survival Distribution Function time (months) Herold, ASH 2006

years Probability CHOP (89/109) R-CHOP (102/112) 4-y OS: CHOP: 81 % R-CHOP: 90% p=0.039 Buske, ASH 2006 Follicular lymphoma (elderly patients) Overall survival (R-CHOP)

Induction Consolidation maintenance SCT => MRD eradication => lymphoma remission Immuno-chemotherapy ! Therapeutic strategies in follicular lymphoma Cure of disease ?

Therapeutic strategies in follicular lymphoma Cure of disease ? Options Consolidation maintenance SCT => MRD eradication 1. Rituximab, IFN-  2. radio-immunotherapy 3. autologous SCT 4. allogeneic

Hainsworth JCO 2005 Rituximab Maintenance vs. Retreatment Follicular lymphoma

Hainsworth JCO 2005 p= Rituximab Maintenance vs. Retreatment Progression-free survival Observation

IFN versus Beobachtung progessionsfreies Überleben nach initialer Therapie years 0 0,25 0,5 0,75 1 p IFN observation p= /84 30/94 IFN maintenance vs. watch & wait follicular lymphoma

GLSG: FCM vs. R-FCM Relapsed indolent lymphoma PR, CR F ludarabine C yclophosphamide M itoxantrone F ludarabine C yclophosphamide M itoxantrone + Rituximab 4 x Rituximab (month 3 & 9) watch & wait Forstpointner Blood 2006

Maintenance vs. Observation Duration of response (only FL after R-FCM) Observation (21/40) Rituximab (32/41) years after end of initial therapy p= Forstpointner, Blood 2006

Maintenance vs. Observation Overall survival (after R-FCM) Observation (49/71) Rituximab (56/67) years after end of initial therapy p= Forstpointner, Blood 2006

RANDOMISATIONRANDOMISATION CHOP every 21 days (maximum six cycles) Rituximab + CHOP every 21 days (maximum six cycles) EORTC phase III trial Observation Rituximab maintenance* CR PR *375mg/m 2 every 3 months for 2 years or until relapse van Oers, Blood 2006 RANDOMISATIONRANDOMISATION

med months median: 51.9 months EORTC phase III trial

OSHO/GLSG study Follicular lymphoma R-CHOP R-FCM R-MCP Rituximab maintenance watch & wait CR/PR R R

Radioimmunotherapy: 90 Y vs. 131 I 90 Y 131 I Gamma emission No Yes Beta emission energy (MeV) Half-life (days) Path length (mm) χ Maximum Mean Beta radiation path length 90 Yttrium 131 Iodine

Low risk !!- age 49 years - 58% IPI % no bulk 131 I Tositumomab (Bexxar) in follicular lymphoma Kaminski, NEJM 2005

Y-labeled anti-CD20-antibody vs. Rituximab Time to progression # C % C # % % % % C # # C % % # # # % % # # # CC C C # # # C CC C C Months Zevalin Rituximab # # # # # # # # # # # # # # # # # # # # # # # # # # # # # C C C C CCCCCC CCC C CC C % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % % C C C C C CCCC CCCCC CC % C p = 0.173

Y-labeled anti-CD20-antibody vs. Rituximab Time to Progression Progression free (%) Zevalin ® (n=73) Rituximab (n=70) All patients CR or CRu Months p=0.182 p=0.173