Mantelzell-Lymphom- Aktuelle Standards und Studienkonzepte internet: www.lymphome.de • email: lymphome@medizin.uni-koeln.de Symposium des KML * DGHO 2008 * Wien, 13. Oktober 2008 Mantelzell-Lymphom- Aktuelle Standards und Studienkonzepte M. Dreyling, Dept. of Medicine III Klinikum Grosshadern LMU/München

Mantle cell lymphoma (MCL) Morphology: small to intermediate size lymphoid cells with irregular, cleaved nuclei, cave: round cell, blastoid and pleomorphic variants Immunphenotype: sIg++, l > k , CD19/20/22+, CD5+, CD10-, CD23-, CD11c-, HLA-DR++, CD43+ molecular/cytogenetics: t(11;14)(q13;q32); overexpression of cyclin D1 clinical outcome: predominantly elderly, male patients, extranodal involvement, late stage, poor outcome 83% 20% W. Ludwig, Berlin

Clinical risk factors: MIPI clinical (PALL: PS, age, LDH, leucocyte count) Hoster, Blood 2008

elderly patient (>65) compromised patient young patient (<65) elderly patient (>65) compromised patient First line treatment conventional immuno-chemotherapy (e.g. R-CHOP) Rituximab maintenance ? radioimmunotherapy ? dose-intensified immuno-chemotherapy (either sequential: e.g. R-CHOP =>PBSCT or R-Hyper-CVAD) watch & wait ? Rituximab monotherapy Chlorambucil Bendamustin 1. relapse immuno-chemotherapy (e.g. R-FC, R-Bendamustin) molecular approaches ? autologous PBSCT radioimmunotherapy ? Rituximab maintenance ? high tumor load: immuno-chemotherapy (e.g. R-FC) allo-transplant ? radioimmunotherapy ? Rituximab maintenance ? immuno-chemotherapy (e.g. R-Bendamustin) molecular approaches higher relapse molecular approaches: Bortezomib, CCI-779, Thalidomide/ Lenalidomide, Flavopiridol (preferable in combination) repeat previous therapy (long remissions) Dreyling ASCO 2006

Rituximab + HyperCVAD/M-A in MCL alternate cycles 1 and 2 every 21 days cycle 1, 3, 5, 7 R-hyperCVAD cycle 2, 4, 6, 8 R-M-A day 1 day 21 Rituximab 375mg/m2 (day 1) Methotrexate 200mg/m2 i.v. 2 hours (day 2) Methotrexate 800mg/m2 i.v.continuous 22 h (day 2) Cytarabine 1,000/3,000mg/m2 i.v. 2x 2h (days 3–4) antifungal, antibacterial, antiviral prophylaxis: G-CSF !!! Romaguera, JCO 2005

R-Hyper-CVAD Mantle cell lymphoma 100% 80% 60% 40% 20% 0% 1 2 3 4 5 Progression-free survival 80% 60% 40% Progression 1-Year At Risk or Death Estimate 20% 49 13 89% 0% 1 2 3 4 5 Years from Registration Epner ASH 2007 #387

R-CHOP/High dose Ara-C => ASCT Mantle cell lymphoma R-CHOP/High dose Ara-C => ASCT Geisler Blood 2008

(stem cell mobilization after course 4) (stem cell mobilization) European MCL Network patients <65 years 3 x R-CHOP 3 x R-DHAP alternating 3 x R-CHOP PR, CR! (stem cell mobilization after course 4) 3 x R-CHOP PR, CR! DexaBEAM (stem cell mobilization) TBI 10 Gray Ara-C 4 x 1.5 g/m2 Melphalan 140 mg/m2 Cyclo 120mg/kg + TBI 12 Gray PBSCT PBSCT

MCL Younger Response rate of induction Documented response 189 55% Abort without staging 2 CR 59 31% CRu 40 21% CR+CRu: 52% PR 73 39% CR+CRu+PR: 91% SD 8 4% PD 9 5% ED 0%

MCL younger Time to treatment failure

elderly patient (>65) compromised patient young patient (<65) elderly patient (>65) compromised patient First line treatment conventional immuno-chemotherapy (e.g. R-CHOP) Rituximab maintenance ? radioimmunotherapy ? dose-intensified immuno-chemotherapy (either sequential: e.g. R-CHOP =>PBSCT or R-Hyper-CVAD) watch & wait ? Rituximab monotherapy Chlorambucil Bendamustin 1. relapse immuno-chemotherapy (e.g. R-FC, R-Bendamustin) molecular approaches ? autologous PBSCT radioimmunotherapy ? Rituximab maintenance ? high tumor load: immuno-chemotherapy (e.g. R-FC) allo-transplant ? radioimmunotherapy ? Rituximab maintenance ? immuno-chemotherapy (e.g. R-Bendamustin) molecular approaches higher relapse molecular approaches: Bortezomib, CCI-779, Thalidomide/ Lenalidomide, Flavopiridol (preferable in combination) repeat previous therapy (long remissions) Dreyling ASCO 2006

European MCL network studies patients >60 years 4 x R-CHOP 3 x R-FC PR, CR 4 x R-CHOP 3 x R-FC PR, CR IFN-α maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) Rituximab maintenance (all 2 months)

MCL Elderly Response rate of induction Documented Response 164 50% Abort without staging 6 CR 55 35% CRu 26 16% CR+CRu: 51% PR 51 32% CR+CRu+PR: 84% SD 5 3% PD 19 9% ED 4%

MCL elderly Time to treatment failure 51 events

MCL elderly Response duration in CR 4 events

elderly patient (>65) compromised patient young patient (<65) elderly patient (>65) compromised patient First line treatment conventional immuno-chemotherapy (e.g. R-CHOP) Rituximab maintenance ? radioimmunotherapy ? dose-intensified immuno-chemotherapy (either sequential: e.g. R-CHOP =>PBSCT or R-Hyper-CVAD) watch & wait ? Rituximab monotherapy Chlorambucil Bendamustin 1. relapse immuno-chemotherapy (e.g. R-FC, R-Bendamustin) molecular approaches ? autologous PBSCT radioimmunotherapy ? Rituximab maintenance ? high tumor load: immuno-chemotherapy (e.g. R-FC) allo-transplant ? radioimmunotherapy ? Rituximab maintenance ? immuno-chemotherapy (e.g. R-Bendamustin) molecular approaches higher relapse molecular approaches: Bortezomib, CCI-779, Thalidomide/ Lenalidomide, Flavopiridol (preferable in combination) repeat previous therapy (long remissions) Dreyling ASCO 2006

Bortezomib: Mechanism of action 26S proteasome: degrades tagged proteins Bortezomib: reversible inhibitor of the proteasome Inhibition: prevents proteolysis of tagged proteins Clinical studies: bortezomib cytotoxic to a variety of lymphomas !

Bortezomib Ara-C combination in MCL Efficacy in vitro Weigert Leukemia 2007

Bortezomib Ara-C combination in MCL Pilot phase Weigert, ASH 2006

relapsed MCL (DHAB = R-HAD) European MCL network relapsed MCL (DHAB = R-HAD) Patients: n=250, relapsed MCL after/not appropriate for autologous PBSCT Therapy: Dexamethasone 40 mg day 1-4 Rituximab 375 mg/m2 day 1 Ara-C 2 x 1–2 g/m2 day 2 +/- Bortezomib 1,5 mg/m2 day 1, 4 Study aim: - Response rate - Progression-free/overall survival - Toxicity/feasability

Mantle cell lymphoma Lenalidomide Wiernik ASH 2006

Salvage Therapy R-FC(M) R-DHA(P) R-GemOx Lenalidomide 15mg p.o/d daily Feasability and efficacy of Lenalidomide maintenance after prior immuno-chemotherapy induction in relapsed or refractory mantle cell lymphoma Inclusion Criteria Histologically proven MCL Not eligible / relapse after ASCT > 1 prior chemotherapy Recruitment N=60 Salvage Therapy R-FC(M) R-DHA(P) R-GemOx Response Staging PR, CR Endpoints Feasability Duration of Response TTP and PFS OS Safety Lenalidomide 15mg p.o/d daily PD or Toxicity National centers: Essen, Homburg, Kiel, Mainz, GH-LMU, Tübingen, Ulm

clinical intergroup working party European MCL Network www.european-mcl.net clinical intergroup working party pathology panel molecular markers expression profiling pharmacogenomics MRD/ cytogenetics WHO/ Kiel criteria molecular analysis phase III studies (first line) pathological review virtual tumor bank patient blood sample phase II studies (relapse) new molecular markers signal pathway of resistance MRD remission/ survival data immunostaining of molecular markers central data base: analysis of predictive and prognostic risk factors

European MCL Network: Clinical studies 2008/9 First line < 65 years > 65 years R-CHOP vs. R-CHOP/DHAP PBSCT R-CHOP vs. R-FC anti-CD20 vs. IFN 1. Relapse > 65 years < 65 years R-chemo +/- Bortezomib „Mini“ transplant 2. Relapse (or not qualifying for R-HAD) Radio-immuno consolidation Rad 001 (mTOR) Lenalidomide consolidation Bendamustin/ Temsirolimus www.european-mcl.net