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Mantelzell-Lymphom- Aktuelle Standards und Studienkonzepte M. Dreyling, Dept. of Medicine III Klinikum Grosshadern LMU

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).

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Mantelzell-Lymphom- Aktuelle Standards und Studienkonzepte M. Dreyling, Dept. of Medicine III Klinikum Grosshadern LMU

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  1. 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 GrosshadernLMU/München

  2. Mantle cell lymphoma (MCL) • Morphology: • small to intermediate size lymphoidcells 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

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

  4. compromised patient elderly patient (>65) young patient (<65) First line treatment conventional immuno-chemotherapy (e.g. R-CHOP) Rituximab maintenance ? radioimmunotherapy ? dose-intensifiedimmuno-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

  5. Rituximab + HyperCVAD/M-A in MCL alternate cycles 1 and 2 every 21 days cycle 1, 3, 5, 7R-hyperCVAD cycle 2, 4, 6, 8R-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

  6. 0 1 2 3 4 5 Mantle cell lymphoma R-Hyper-CVAD 100% Progression-free survival 80% 60% 40% Progression 1-Year At Risk or Death Estimate 20% 49 13 89% 0% Years from Registration Epner ASH 2007 #387

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

  8. 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

  9. MCL YoungerResponse rate of induction

  10. MCL youngerTime to treatment failure

  11. compromised patient elderly patient (>65) young patient (<65) First line treatment conventional immuno-chemotherapy (e.g. R-CHOP) Rituximab maintenance ? radioimmunotherapy ? dose-intensifiedimmuno-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

  12. 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)

  13. MCL ElderlyResponse rate of induction

  14. MCL elderlyTime to treatment failure 51 events

  15. MCL elderlyResponse duration in CR 4 events

  16. compromised patient elderly patient (>65) young patient (<65) First line treatment conventional immuno-chemotherapy (e.g. R-CHOP) Rituximab maintenance ? radioimmunotherapy ? dose-intensifiedimmuno-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

  17. 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 !

  18. Bortezomib Ara-C combination in MCLEfficacy in vitro Weigert Leukemia 2007

  19. Bortezomib Ara-C combination in MCLPilot phase Weigert, ASH 2006

  20. 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

  21. Mantle cell lymphoma Lenalidomide Wiernik ASH 2006

  22. Feasability and efficacy of Lenalidomide maintenance after prior immuno-chemotherapy induction in relapsed or refractory mantle cell lymphoma Recruitment N=60 Inclusion Criteria • Histologically proven MCL • Not eligible / relapse after ASCT • > 1 prior chemotherapy Salvage TherapyR-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

  23. European MCL Network www.european-mcl.net pathology panel molecular markers clinical intergroup working party 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) signal pathway of resistance new molecular markers MRD remission/ survival data immunostaining of molecular markers central data base: analysis of predictive and prognostic risk factors

  24. European MCL Network: Clinical studies 2008/9 First line < 65 years > 65 years R-CHOP vs. R-FC anti-CD20 vs. IFN R-CHOP vs. R-CHOP/DHAP PBSCT 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

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