Hannover-Meeting Niedrig-malignes NHL. Prof. C. Buske Medizinische Klinik III Klinikum Großhadern LMU München

Transcription

1 Hannover-Meeting 2009 Niedrig-malignes NHL Prof. C. Buske Medizinische Klinik III Klinikum Großhadern LMU München

2 Follikuläres Lymphom

3 Konzepte Wenn wir behanden müssen was sollen wir initial dem Patienten anbieten?

4 Two patient groups: Fit and Non-Fit Patients Group 1 Fit patient Organ function Ä Functional StatusÄ Life expectancy Ä Co-morbidity Å Risk for toxicity Å Go go Intensive Chemotherapy => long-term remissions Group 2 Compromised patient Organ function Å Functional StatusÅ Life expectancy Ç Co-morbidity Ä Risk of Toxicity Ä Slow go Less-intensive Chemotherapy => Lymphoma control Group 3 Frail patient Organ function Å Å Funktional StatusÅ Å Life expectancy Å Å Co-morbidity Ä Ä Risk for Toxicity Ä Ä No go supportive Therapy => Control of syptoms

5 Optimal treatment in follicular lymphoma? Induction Immunochemotherapy Radioimmunochemotherapy Consolidation +/ SCT RIT maintenance Ä Tumor reduction Ä MRD

6 Follicular Lymphoma Therapeutic Options Medically Fit Chemotherapy Rituximab single agent Rituximab plus chemotherapy Radioimmunotherapy

7 First-line treatment for follicular lymphoma: R-chemotherapy Hiddemann et al. CHOP R-CHOP p Patients evaluable Response rate 90% 96% Median TTF 31 months Not reached < OS (estimated 2-year OS) 90% 95% Marcus et al. CVP R-CVP p Patients evaluable Response rate 57% 81% < Median time to progression 15 months 34 months < OS (median follow-up 53 months) 71% 81% < 0.03 Herold et al. MCP R-MCP p Patients evaluable Response rate 75% 92% < Median EFS 19 months Not reached < OS (median) 62 months Not reached Foussard et al. CHVP/IFN-a R-CHVP/IFN-a p Patients evaluable Response rate (CR/CRu) 85% (49%) 94% (76%) < Median EFS 36 months Not reached < OS (median follow-up 60 months) 79% 84% n.s. For HR pts significant!

8 R-CHOP vs CHOP Time to Treatment Failure 56 months follow-up Buske et al., ASH 2008

9 R-CHOP vs CHOP Tme to Treatment Failure Low Risk Buske et al., ASH 2008

10 R-CHOP vs CHOP Tme to Treatment Failure Intermediate Risk Buske et al., ASH 2008

11 R-CHOP vs CHOP Tme to Treatment Failure High Risk Buske et al., ASH 2008

12 R-CHOP vs CHOP Overall Survival Buske et al., ASH 2008

13 Conclusions Several large prospectively randomized Phase III studies Ädemonstrating superiority of Rituximab plus standard chemotherapy compared to chemotherapy alone Immuno-chemotherapy standard in the first line and salvage treatment of advanced stage follicular lymphoma in the medically fit patient

14 Konzepte Welche Immunchemotherapie ist die Beste?

15 Which immunochemotherapy? Å CVP plus Rituximab Å CHOP plus Rituximab Å FC(m) plus Rituximab Å Bendamustine plus Rituximab However, which immunochemotherapy is best? There are now randomized studies comparing different immunochemotherapies in FL, but so far no data!

16 OSHO/GLSG Study Concepts (Follicular Lymphoma, Patients > 65 years) R R-CHOP R-FCM R-MCP CR/PR CR/PR CR/PR R Maintenance with Rituximab Observation

17 StiL study concept (Follicular lymphoma) R R-CHOP R-Bendamustin Observation Observation

18 Konzepte Reicht es nicht aus initial eine optimale Zytoreduktion durchzuführen? Brauchen wir Konsolidierung/Erhaltung?

19 Follicular Lymphomas Stage III/IV Response Rates Best Response rates with rituximab/chemotherapy: OR CR CR/CRu R-CVP 81% 30% 41% R-CHOP 96 % 20% CRu=PR R-MCP 92 % 50% n.a. RCVHP/IFN 94 % n.a. 76 % n.a. = Not available

20 GLSG Therapieverlauf nach Risikoprofil R-CHOP 1.0 Zeit bis zum Therapieversagen 0.8 Überleben Niedrig Risiko Intermediäres Risiko Hochrisiko p= Jahre nach Start der Therapie C. Buske et al. Blood 2006

21 How to treat Medically Fit Follicular Lymphomas Stage III/IV Part 1 Initial cytoreduction Part 2 Consolidation Part 3 Maintenance

22 Optimal treatment in follicular lymphoma? Induction Immunochemotherapy Radioimmunochemotherapy Consolidation +/ SCT RIT maintenance Ä Tumor reduction Ä MRD

23 ASCT in Follicular Lymphoma in 1st Remission GOELAMS: CHVP + IFN vs. HD + ASCT Ä 5-years EFS prolonged (59 vs. 37 %), but no difference in OS GELA: CHVP + IFN vs. HD/TBI + ASCT Ä EFS no difference, OS no difference GLSG: CHOP/R-CHOP cytoreduction: ASCT vs IFN consolidation É PFS significant improvement, OS?

24 Follicular lymphoma ASCT? This is a difficult time for ASCT in advanced stage FL BUT: it stays a most important therapeutical concept it has to be re-evaluated in clinical trials in the era of monoclonal antibody therapy

25 GLSG studies 1996 and 2000 response duration Probability R/ASCT ASCT R/IFN IFN Month after end of induction No. of patients at risk R/ASCT ASCT R/IFN IFN

26 RiCHOP study 2008 for first-line therapy of FL patients aged <65 years 6 x CHOP + 8 x R CR,PR CR,PR R A N D O M I S A T I O N ASCT Rituximab maintenance Rituximab maintenance

27 Optimal treatment in follicular lymphoma? Induction Immunochemotherapy Radioimmunochemotherapy Consolidation +/ SCT RIT maintenance Ä Tumor reduction Ä MRD

28 FIT: 90 Y-Ibritumomab-Tiuxetan as first-line consolidation newly diagnosed follicular lymphoma stage III/IV induction chemotherapy* CR PR ** R Y 90 - Ibritumomab- Tiuxetan (n=208) watch & wait (n=206) NR PD off study FIT: First-line Indolent lymphoma Trial * CVP, CHOP, Fludarabin (combination), etc. ** n = 414 Hagenbeek, ASH 2007 #693

29 Overall PFS for Treatment Groups The 4-year 4 overall PFS is 52% in the 90 Y-ibritumomab arm compared with 31% in the control arm 100 Cumulative Percentage Log-rank P =.0001 HR 0.45 (95% CI: ) 90 Y-ibritumomab arm Median PFS: 53.8 months N = 207 control arm Median PFS: 13.8 months N = Y-ibritumomab Control months

30 PFS for Patients in CR/CRu After Induction The 4-year 4 PFS among patients with a CR after induction is 60% in the 90 Y-ibritumomab arm compared with 44% in the control arm 100 Cumulative Percentage Log-rank P =.015 HR (95% CI: ) 90 Y-ibritumomab: n = 107 median > 67 months Control: n = 108 median 30.8 months 0 90 Y-ibritumomab Control At risk: months

31 PFS for Patients in PR After Induction The 4-year 4 PFS among patients with a PR after induction is 43% in the 90 Y-ibritumomab arm compared with 15% in the control arm 100 Cumulative Percentage At risk: 90 Y-ibritumomab Control Log-rank P <.001 HR 0.36 (95% CI: ) Y-ibritumomab: n = 100 median 29.6 months Control: n = 94 median 6.7 months 4 1 months

32 Effect of Treatment Arm on PFS by First-line Treatment and Response to First-line Treatment PFS No. of Patients Control 90 Y-Ibritumomab Hazard Ratio No. Failed Median PFS, mo No. of Patients No. Failed Median PFS, mo (95% CI)* First-line treatment* CHOP CVP/COP CHOP-like > 67 Fludarabine Chlorambucil Rituximab combination > > ( ) 2.25 ( ) 2.11 ( ) 1.11 ( ) 2.76 ( ) 1.39 ( )

33 RITZ Trial R-Chemo R PR, CR Rituximab Maintenance 90Y-Ibritumomab Rituximab Maintenance

34 Konzepte. IV. Wie sollen wir medically non-fit Patienten behandeln?

35

36 Studiendesign Randomisierung R = 8 x 375mg/m 2 R-Benda R = 8 x 375mg/m 2 4x Benda 90 mg/m 2 d1+2

37 Mantelzell-Lymphome

38 Konzepte Was sollen wir initial dem Patienten anbieten?

39 Immuno-chemotherapy in MCL Lenz, JCO 2005 CHOP R CHOP p-value Patients evaluable Response rate 77% 92% p= CR 9% 32% p= Forstpointner, Blood 2004 FCM R-FCM p-value Patients evaluable survival! Response rate 57% 81% p= 0.28 CR 0 29% p= Herold, ASH 2004 MCP R-MCP p-value Patients evaluable Response rate 63% 71% p=0.51 CR 15% 32% p= 0.08

40 F ludarabine C yclophosphamide M itoxantrone FCM vs. R-FCM Relapsed MCL R PR, CR F ludarabine C yclophosphamide M itoxantrone + Rituximab watch & wait R 4 x Rituximab (month 3) 4 x Rituximab (month 9)

41 FCM vs. R-FCM: MCL Overall survival 1,0,9,8,7,6,5,4 to R-FCM (33/57),3 rand. R-FCM (7/24),2 rand. FCM (5/26),1 0,0 0 1 Dreyling, ASCO 2005 (update) 2 3 years after start of therapy p= (p=0.0033)

42 Konzepte Welche Immunchemotherapie ist die Beste?

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

44 European MCL Network patients <65 years 3 x R-CHOP 3 x R-CHOP PR, CR! 3 x R-CHOP 3 x R-DHAP alternating (stem cell mobilization after course 4) DexaBEAM (stem cell mobilization) Cyclo 120mg/kg + TBI 12 Gray PBSCT PR, CR! TBI 10 Gray Ara-C 4 x 1.5 g/m 2 Melphalan 140 mg/m 2 PBSCT

45 MCL Younger Response rate of induction Documented response % Abort without staging 6 CR 78 32% CRu 46 19% CR+CRu: 51% PR 98 40% CR+CRu+PR: 91% SD 10 4% PD 12 5% ED 0 0%

46 Konzepte Reicht es nicht aus initial eine optimale Zytoreduktion durchzuführen? Brauchen wir Konsolidierung/Erhaltung?

47 European MCL Network ASCT vs. IFN 6x CHOP-like chemotherapy PR, CR 2 cycles consolidation Interferon-Ä maintenance Dreyling, Blood 2005 R E L A P S E DexaBEAM (stem cell harvest) Cyclo 120mg/kg + TBI autologous PBSCT

48 Progression-free survival (after consolidation) PBSCT (31/75) IFN (18/69) years after induction p=0.002 Dreyling, Blood 2005 (updated)

49 European MCL Network patients <65 years 3 x R-CHOP 3 x R-CHOP PR, CR! 3 x R-CHOP 3 x R-DHAP alternating (stem cell mobilization after course 4) DexaBEAM (stem cell mobilization) Cyclo 120mg/kg + TBI 12 Gray PBSCT PR, CR! TBI 10 Gray Ara-C 4 x 1.5 g/m 2 Melphalan 140 mg/m 2 PBSCT

50 European MCL Network patients <65 years 3 x R-CHOP 3 x R-CHOP 3 x R-CHOP 3 x R-DHAP alternating (stem cell mobilization after course 4) DexaBEAM (stem cell mobilization) Cyclo 120mg/kg + TBI 12 Gray TBI 10 Gray Ara-C 4 x 1.5 g/m 2 Melphalan 140 mg/m 2 PBSCT PBSCT

51 FCM vs. R-FCM Relapsed MCL F ludarabine C yclophosphamide M itoxantrone PR, CR F ludarabine C yclophosphamide M itoxantrone + Rituximab watch & wait R 4 x Rituximab (month 3) 4 x Rituximab (month 9)

52 Maintenance vs. Observation in MCL Response duration (R-FCM) P=0.49 Forstpointner, Blood 2006

53 European MCL network studies patients >65 years 4 x R-CHOP 3 x R-FC PR, CR 4 x R-CHOP 3 x R-FC IFN-a maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) PR, CR Rituximab maintenance (all 2 months)

54 MCL Elderly Response rate of induction Documented Response % Abort without staging 8 CR 71 34% CRu 30 14% CR+CRu: 49% PR 72 35% CR+CRu+PR: 84% SD 6 3% PD 19 9% ED 9 4%

55 Kiel vs. GLSG cohort MCL - Historical comparison Kiel/GLSG studies (balanced) Median OS: 2.7 vs 4.8 Herrmann, JCO 2008

56 GLSG cohort FL - Historical comparison Overall Survival GLSG Trials Survival probability MCP CHOP-1 CHOP-2 R-CHOP p< Months since registration

57

58 MRD detection in MCL MRD follow-up elderly patients n = p=0,0001 maintenance MRD level neg 48% 60% 60% DX midterm Post_Ind FUP3 FUP6 FUP9 FUP12

59 MCL Elderly Response duration in CR 7 events

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

61 Mantle cell lymphoma Lenalidomide Wiernik JCO 2008

62 Mantle cell lymphoma Lenalidomide Wiernik ASH 2006 Histology PT Initi Best D a y Re sponse 4 D a y 5 D a y 2 0 D a y 3 0 D a y 5 0 D a y 5 1 D a y 5 3 D a y 5 4 D a y 5 8 D a y 7 5 F C L SB C R u D L C BS C ru D L C TP C ru 2 0 D a y 8 9 D L C KJS C ru 2 0 MCL SLR P R M C L VFG P R F C L GO P R MCL BMF P R 2 0 D L C CD P R M C L JMP P R 2 0 M C L LMM P R TSF RE P R 2 0 M C L ERD P R TS F KBA S D 2 0 D L C RA S D D L C BP S D D L C LG S D M C L ET S D D L C GAW S D M C L GHM XP D 2 0 D L C OW F XP D D L C JET XP D D L C PC XP D D L C RB XP D M C L MR XP D M C L TF XP D D L C JAL XP D M C L JES XP D DLC RF XP D D L C AD XP D F C L RCS XP D M C L FG XP D D a y 9 1 D a y D a y D a y D a y D a y D a y D a y D a y D a y D a y D a y D a y D a y D a y D a y

63 Feasability and efficacy of Lenalidomide maintenance after prior salvage in relapsed MCL Inclusion Criteria Å Å Å histologically proven MCL > 1 prior chemo Regimen Not eligible for/ relapse after ASCT Recruitment N=60 Salvage Therapy R-FC(M) R-DHA(P) R-GemOx Staging PR, CR Response Endpoints Å Å Å Å Å Feasability Duration of Response TTP and PFS OS Safety Lenalidomide 15mg p.o/d daily PD or Toxicity

64 MCL-003 proposal: Study Design Treatment Maximum of 24 months or until Toxicity, PD or Consent Withdrawal 1st line induction treatment PR / CR (90%) A B Lenalidomide (15 mg daily d1-21, q28 days) N = 191 Observation N = 191 ÇPhase 3, 1:1 Randomized, comparative, maintenance study post-completion of standard chemotherapy ÇNewly Diagnosed MCL Patients with PR or CR after Initial Chemotherapy ÇTransplant ineligible ÇPrimary endpoint: PFS ÇGlobal Participation in Study: Europe, US, other countries around the world

65 MCL-003 proposal

66 MCL-003 proposal

67 European MCL Network Discussion of lenalidomide maintenance

68 Altered pathways in MCL Jares, Nature Reviews 2007

69 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!

70 Progression-free survival (red) responders (blue), non-responders (green) median TTP 6.2 months (median follow-up 13.4 months) Goy ASCO 2006, Fisher JCO 2006

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

72 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/m 2 day 1 Ara-C 2 x 1 2 g/m 2 day 2 +/- Bortezomib 1,5 mg/m 2 day 1, 4 Study aim: - Response rate - Progression-free/overall survival - Toxicity/feasability

73 Targeting protein Translation mtor inhibitors: CCI-779 (Temsirolimus) - response rate: 38% (13/34 pts), 1 CR, 12 PR - duration of response: 6.9 months - median follow-up 11 months (range, 6.7 to 24.6+) - thrombocytopenia? Witzig, JCO 2005

74 Study Design MCL confirmed locally Relapsed / refractory to 2-7 prior therapies Required rituximab anthracycline alkylating agent R A N D O M I Z E Temsirolimus 175 mg QWx3 then 75 mg QW Temsirolimus 175 mg QWx3 then 25 mg QW Investigator s choice single agent Hess, ASCO 2008

75 Progression Free Survival (ITT) Probability of Progression-Free Survival Months 19 July 2007, date of data cutoff, Independent Assessment TEMSR 175/75 mg TEMSR 175/25 mg Invest Choice Hess, ASCO 2008

76 BERT: BEndamustin/Rituximab/Temsirolimus (phase II) PI: G. Hess, Mainz

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

78 QuickTime and a GIF decompressor are needed to see this picture. annual conference in Munich 2007

79 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 > 65 years 1. Relapse < 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

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

81 Allogeneic transplantation Dose-reduced conditioning concept: - reduced conditioning (Flu/Cy, Flu/Bus, Flu/Mel) - focus on immunsuppression (2 GyTBI,MMF,CyA) - tandem (auto-allo) transplantation Spitzer, Oncologist, 2000

82 Allogeneic transplantation Dose-reduced conditioning Khouri et al, JCO 2003 Robinson et al, Blood 2002

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

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

85 MCL younger Time to treatment failure 47 events

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

87 F ludarabine C yclophosphamide M itoxantrone FCM vs. R-FCM Relapsed MCL R PR, CR F ludarabine C yclophosphamide M itoxantrone + Rituximab watch & wait R 4 x Rituximab (month 3) 4 x Rituximab (month 9)

88 FCM vs. R-FCM: MCL Overall survival 1,0,9,8,7,6,5,4 to R-FCM (33/57),3 rand. R-FCM (7/24),2 rand. FCM (5/26),1 0,0 0 1 Dreyling, ASCO 2005 (update) 2 3 years after start of therapy p= (p=0.0033)

89 MCL elderly Time to treatment failure 74 events

90 MRD detection in MCL MRD follow-up elderly patients n = p=0,0001 maintenance 10-1 MRD level neg 48% 60% 60% DX midterm Post_Ind FUP3 FUP6 FUP9 FUP12

91 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!

92 Progression-free survival (red) responders (blue), non-responders (green) median TTP 6.2 months (median follow-up 13.4 months) Goy ASCO 2006, Fisher JCO 2006

93 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/m 2 day 1 Ara-C 2 x 1 2 g/m 2 day 2 +/- Bortezomib 1,5 mg/m 2 day 1, 4 Study aim: - Response rate - Progression-free/overall survival - Toxicity/feasability

94 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 > 65 years 1. Relapse < 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