1. Treatment of Mantle Cell Lymphoma N Milpied University Bordeaux 2

2. Fisher RI. Ann Oncol. 1996;7(suppl 6):S35-S39. Armitage JO. Management of Mantle Cell Lymphoma. Oncology (Willston Park). 1998. Romaguera JE, et al. Cancer. 2003;97:586-591. Mantle Cell Lymphoma 6% NHL Age>50y M:F ratio = 3:1 Typically advanced stage B symptoms: < 50% cases 90% extranodal involvement: BM, blood, liver, GI, CNS GI tract Macro (rare polyposis coli) Micro/ random biopsies

3. ClassicLymphoblastoidPleomorphic Cytomorphological Variants in MCL

4. Small B cell lymphoma Differential diagnosis CD5CD10CD23bcl-6 Chromosomal Abnormalities LLC (30%) +-+-trisomy 12 lympho- plasmocytoid ----NA Mantle cell +-/+--t(11:14) follicular -+/--/++t(14;18) Marginal Zone ---/+-trisomy 3

5. Dreyling, ASCO 1999 Nickenig, Cancer 2006 CR/Cru 25% European MCL Network Clinical course

6. Hoster, Blood 2008 Univariate risk factors age ECOG performance status B-symptoms spleen involvement tumor size leukocyte or lymphocyte count LDH hemoglobin albumin beta2-microglobulin (PALL: PS, age, LDH, leucocyte count, Ki67) Clinical risk factors: MIPI

7. ©2008 by American Society of Hematology Proliferation index in MCL Determann O et al. Blood 2008;111:2385-2387 Indolent ?

8. Conventional vs Indolent MCL Clinical Characteristics Clinical data Conventional MCL (15) Indolent MCL (12) Age at diagnosis 67 (30-83) 58 (41-75) Gender (M/F)11/47/5 ECOG≥270%0+0+ Intermediate/High MIPI46%0+0+ Lymphadenopathy (>1cm)15/152/12 + Lymphocytosis (≥5x10 9 /L)9/114/9 Evolution Median Follow-up15 m (0.5 - 79) 70 m (25-121 ) Chemotherapy150 5-year Overall Survival49%100% * + p <0.05 * p=0.002 Fernandez V et al Cancer Res 2010

9. Overall Survival in MCL patients according to SOX11 Expression Sox11 - Sox11 + P< 0.001 SOX11 negative (N=15; dead: 4) SOX11 positive (N=97; dead: 68) Fernandez V et al Cancer Res 2010 Courtesy of E Campo

10. SOX11Cyclin D1 Conventional MCL Indolent MCL SOX11 Protein Expression in MCL Courtesy of E Campo

11. MCL with Indolent Clinical Behavior OS from diagnosis OS from treatment Martin P et al JCO 2009

12. Who should be treated rapidly ? Blastoid forms with p53 mutations Rapidly progressing disease Poor performance status Bulky disease Other diseases particularly those with splenomegaly, lymphocytosis, treatment can be delayed –Biological factors (SOX11) ? Ki67 ? –Pet scan +MIPI ? Delay treatment does not impair overall survival

13. Treatment in non elderly adults

14. Induction Consolidation SCT eradicationtumor reduction Optimal treatment in mantle cell lymphoma

15. PR, CR Interferon-  maintenance Cyclo 120mg/kg + TBI autologous PBSCT RELAPSERELAPSE DexaBEAM (stem cell harvest) 6x CHOP-like chemotherapy 2 cycles consolidation Dreyling, Blood 2005 (updated) European MCL Network ASCT vs. IFN

16. HR 0.30 (95% CI 0.14 – 0.66)HR 0.60 (95% CI 0.37 – 0.96) Dreyling ASH 2008 Mantle cell lymphoma High dose consolidation Progression-free survival CR PR

17. Hoster, ASH 2008 CHOP with or without RITUXIMAB Time to treatment failure

18. R+chemo ? Consolidation SCT eradicationtumor reduction Optimal treatment in mantle cell lymphoma ?

19. day 1 day 21 alternate cycles 1 and 2 every 21 days 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) cycle 1, 3, 5, 7 R-hyperCVAD cycle 2, 4, 6, 8 R-M-A antifungal, antibacterial, antiviral prophylaxis: G-CSF !!! Romaguera, JCO 2005 Rituximab + HyperCVAD/M-A in MCL

20. Rituximab + hyperCVAD/M-A in MCL: Failure-free survival according to age Survival probability Months Romaguera JE, et al. J Clin Oncol 2005; 28:7013–7023.

21. SWOG 0213: R-HyperCVAD/MTX-AraC in Patients With Newly Diagnosed MCL Hyper CVAD 2 year PFS 63% 40% treatment arrest High toxicity

22. Nordic MCLprotocols: Final Results Median Obs. Time3 years from entry

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

24. 2 CHOP 1 CHOP + anti-CD20 3 DHAP + anti-CD20 CSP collection TAM 6 + ABMT TBI 10gy GELA 2 CHOP 1 CHOP 3 DHAP CSP collection TAM 8 + ABMT TBI 12gy Protocol GELA 19992002

25. Impact of Rituximab with ARAC Lefrere et al. Haematologica 2004Delarue et al. ASH 2008 Without Rituximab With Rituximab Median EFS : 83 mo Median EFS : 51 mo

26. Mantle Cell Lymphoma Young Patients < 65y European MCL Network GELA

27. PR, CR Cyclo 120mg/kg + TBI 12 Gray PBSCT PR, CR (2+1) x R-CHOP/R- DHAP alternating (2+1) x R-CHOP/R- DHAP alternating stem cell mobilization after course 6 PBSCT TBI 10 Gray Ara-C 4x1.5 g/m 2 Melphalan 140 mg/m 2 4 x R-CHOP 2 x R-CHOP DexaBEAM (stem cell mobilization) DexaBEAM (stem cell mobilization) MCL younger Protocol Design

28. Response Rates after induction PP R-CHOP R-CHOP/ R-DHAP Stop without staging63%94% Evaluable206199 ED00%0 PD105%84% SD105%32% PR10350%7839% CRu2914%3819% CR5426%7236%p=0.032 CR or CRu8340%11155%p=0.0028 CR or CRu or PR18690%18894%p=0.14

29. Response after ASCT nCRCRuPRPDDeath R-CHOP13181 (62%)22 (17%)24 (18%)3 (2%)1 (1%) R-DHAP12979 (61%)27 (21%)19 (15%)2 (2%) ALL260160 (62%)49 (19%)43 (17%)5 (2%)3 (1%) Autologous Stem cell transplantation was performed and documented with the same rate in both arms R-CHOP: 147/186 (79%) vs R-DHAP: 147/191 (77%) Response rate was high in both arms after autologuous stem cell transplantation (97% vs 97%)

30. Time to treatment failure PP Update November 19, 2010, European MCL Network, V0.3 26.11.2010 p=0.0382 (one sided sequential test) Hazard Ratio 0.68

31. Time to treatment failure, Events Update November 19, 2010, European MCL Network, V0.3 26.11.2010 R-CHOPR-DHAP Evaluable per protocol212208 Events per protocol7744 - stable disease10 3 - progression during induction10 8 - death in remission 811 - ASCT-related 6 (3%) 8 (4%) - secondary malignancy 2 3 - relapse after CR/CRu/PR4922

32. Remission Duration according to MRD Status after ASCT - Pooled trials - n = 161 * % MRD negative *p < 0.0001 R-CHOP R-CHOP/ R-DHAP 0 25 50 75 100 51% 83% *

33. Remission Duration according to Clinical Response and MRD Status after Induction CR BM+ PR BM - PR BM+ CR; MRD- Cru/PR; MRD- Cru/PR; MRD+ CR; MRD+ CR BM - CR BM+ PR BM - PR BM+ p=0.0013 n = 128

34. Achievement of MR post Induction is an Independent Prognostic Factor variableHR95% CIp Molecular response 4.2 (1.8- 9.8) 0.001 MIP score1.9 (1.2- 3.1) 0.01 CR1.0 (0.5- 2.2) 0.1 Treatment arm0.5 (0.2- 1.2) 0.98

35. Safety During Induction

36. Safety During ASCT

37. Update November 19, 2010, European MCL Network, V0.3 26.11.2010 37 MCL Younger: Overall Survival

38. Alternating courses of R-CHOP/R-DHAP followed by ASCT Should become the new gold standard

39. Induction R+chemo Consolidation SCT eradicationtumor reduction Optimal treatment in mantle cell lymphoma ? TBI ?

40. PFS OS No impact on OS or PFS. Groupe ICT Groupe non ICT Groupe ICT Groupe non ICT Auto SCT and MCL: Outcome according to TBI or not (from transplantation) Monocentric retrospective study

41. Patients transplanted in PR1 : Effect of Ritux, HD Cytarabine and TBI on RI PR1=155 patients Relapse

42. Effect of Rituximab, HD Cytarabine and TBI on PFS in patients in PR1 at transplant PR1=155 patients PFS

43. Multivariate analysis on PR1 patients at ASCT : effect of TBI, HD Cyt or Ritux on outcomes Relapse incidencePFSOS RR, (95% CI), p value TBI0.52, (0.28-0.966), 0.0380.70, (0.33-1.511), 0.370.835, (0.39-1.79), 0.65 HD Cyt0.601, (0.33-1.086), 0.0920.63, (0.28-1.39), 0.2540.77, (0.34-1.68), 0.511 Rituximab0.844, (0.477-1.5), 0.570.45, (0.20-0.99), 0.0470.523, (0.23-1.14), 0.10 Nb ttt lines ≥ 2 0.965, (0.39-2.35), 0.941.13, (0.43-4.30), 0.594 Age > 570.848, (0.49-1.44), 0.551.52, (0.73-3.18), 0.2591.25, (0.59-2.63), 0.55 n=155 patients

44. Patients in CR at ASCT : Multivariate analysis: no effect of TBI, HD Cyt or Ritux on outcomes Relapse incidencePFSOS RR, (95% CI), p value TBI1.07, (0.624-1.85), 0.80.97, (0.59-1.59), 0.911.03, (0.55-1.93), 0.90 HD Cyt1.27, (0.78-2.04), 0.331.42, (0.88-2.28), 0.1451.08, (0.59-1.96), 0.78 Rituximab0.74, (0.458-1.2), 0.220.8, (0.50-1.28), 0.3621.07, (0.59-1.97), 0.80 Stage IV1.28, (0.693-2.36), 0.441.63, (0.87-3.06), 0.1223.47, (1.23-9.8); 0.006 Age > 551.05, (0.63-1.82), 0.81.28, (0.79-2.01), 0.3022.35, (1.27-4.368); 0.018 n=333 patients

45. Impact of global therapeutic sequence EFS Anthra / HD Cyta => TAM Therapeutic SequenceN= 285 TBI based Anthra => TBI+Alk 52 (18%) Anthra / HD Cyta => TAM 86 (30%) Anthra / HD Cyta => TBI+Alk 18 (6%) Chemo based Anthra => BEAM 56 (20%) Anthra / HD Cyta => BEAM 73 (26%) Touzeau et al. EBMT 2011Pr Le Gouill; China, may 2011 Results

46. Treatment in elderly patients

47. Efficacy of maintenance therapy with rituximab after induction chemotherapy (R-CHOP vs. R-FC) for elderly patients with mantle cell lymphoma not suitable for autologous stem cell transplantation (MCL Elderly Trial) Interim Report October 5, 2010

48. 4 x R-CHOP PR, CR IFN-α maintenance (3 x 3 M IU/week) or Peg-IFN (1mg/kg week) 4 x R-CHOP PR, CR 3 x R-FC Rituximab maintenance (all 2 months) 3 x R-FC European MCL network studies patients >60 years

49. Update October 5, 2010, European MCL Network, V2.1, 29.10.2010 MCL Elderly: RD R vs. IFN PP Hazard Ratio 0.56 p=0.0118 (sequential test)

50. MCL Elderly: OS 140 events p=0.0406 Update October 5, 2010, European MCL Network, V2.1, 29.10.2010

51. MCL Elderly: overall survival related to induction regimen After R-CHOP After R-FC p=0.055 for interaction of induction and maintenance

52. R-FC (n=225) R-CHOP (n=205) Lymphoma4620%3115% Infection136%84% Cardiac31%73% Secondary Tumor42%21% Secondary AML21%00% Pulmonal21%2 Cerebral Bleeding21%00% Leukoencephalopathy00%1 Unknown104%73% Total8240%5828% MCL Elderly: Death Rates (Causes) Update October 5, 2010, European MCL Network, V2.1, 29.10.2010

53. Next steps

54. Preemptive(MRD) +/- SCT Induction Optimal treatment in mantle cell lymphoma ?

55. Pre-emptive treatment with rituximab of molecular relapse after autologous stem cell transplantation in mantle cell lymphoma. Andersen NS et al Andersen NS 160 MCL; 145 ASCT; 78 mol markers 74/ assessable Molecular CR 36 in molecular relapse (med 18.5m) 26 premptive treatment at molecular relapse/92% molecular CR Mol/clin relapse free survival 1.5/3.7y (0.4- 6y) J Clin Oncol. 2009 Sep 10;27(26):4365-70. Epub 2009 Aug 3

56. What about allogeneic stem cell transplantation?

57. Three questions Is there a Graft versus MCL (GV-MCL)? Myelo-ablative allo-SCT in MCL. RIC-ablative allo-SCT in MCL.

58. Nonmyeloablative allogeneic transplantation Khouri et al, JCO 2003

59. FL n=726 MCL n=321 DLBC n=579 p<0.001 Allogeneic SCT for B-cell NHL: overall survival European Group for Blood and Bone Marrow Transplant

60. p<0.001 ASCT versus Allo HSCT : all patients p<0.001

61. Stratification for Allo BMT ? High MIPI Blastic forms High MIPI and MRD positivity after induction ?

62. Bendamustine Bortezomib (FDA approval) Thalidomide/Lenalidomide Temsirolimus (EMEA approval)

63. Fisher JCO 2006, Goy 2009 Bortezomib in relapsed MCL (phase II studies) StudyDesignDose n CR/CR u PRORR O’Connord 1, 4, 8, 11 q 3 wks 8 cycles 1.5mg/m 2 373/2 (13%) 10 (27%) 40% GoySame 6 cycles 1.5mg/m 2 296 (21%) 6 (21%) 41% Strauss Lister Same 6 cycles 1.3mg/m 2 241 (4%) 6 (25%) 29% BelchSame 6 cycles 1.3mg/m 2 13 untreated 15 treated 0 1 6666 46% 47% GoySame 17 cycles 1.3mg/m 2 152 treated 8% 21%33%

64. median TTP 6.2 months (median follow-up 13.4 months) Fisher JCO 2006, Goy 2009 Progression-free survival (red) responders (blue), non-responders (green)

65. Schéma thérapeutique Temsirolimus 175 mg les 3 premières semaines* puis 25 mg par semaine (n=54) Temsirolimus 175 mg les 3 premières semaines* puis 25 mg par semaine (n=54) RANDOMISATIONRANDOMISATION RANDOMISATIONRANDOMISATION 162 patients - LCM confirmé -Rechute et/ou réfractaire - 2-7 thérapies antérieures incluant obligatoirement (100%): Rituximab + Anthracycline + Agent alkylant 162 patients - LCM confirmé -Rechute et/ou réfractaire - 2-7 thérapies antérieures incluant obligatoirement (100%): Rituximab + Anthracycline + Agent alkylant Monothérapie au choix de l’investigateur (MCI) (n=54) Monothérapie au choix de l’investigateur (MCI) (n=54) Temsirolimus 175 mg/sem les 3 premières semaines* puis 75 mg par semaine (n=54) Temsirolimus 175 mg/sem les 3 premières semaines* puis 75 mg par semaine (n=54) * Temsirolimus en perfusion IV de 30 minutes. Prémédication par 25 à 30 mg de diphenydramine ou équivalent administrée 30 minutes avant chaque perfusion de Temsirolimus Doses de Temsirolimus adaptées en fonction de la tolérance. Un schéma de réduction de dose prévu pour chacun des 2 groupes Temsirolimus (T 175/75 ou T 175/25), y compris pour la dose de charge Le traitement de l’étude était continué jusqu’à progression de la maladie, toxicité inacceptable ou pour un maximum de 2 ans Hess et al. JCO 2009. Vol 27. N 23. 3822-3829

66. p=0,0009 Analyse en ITT Amélioration significative de 153% de la SSP dans le groupeT175/75 versus le groupe MCI (4,8 mois versus 1,9 mois; p<0,0009) Survie sans progression (SSP) Supériorité de T175/75 versus MCI Temsirolimus

67. 549 patients with indolent lymphoma, German STiL group, MJ Rummel et al R 375 mg/m 2 d 1 B 90 mg/m 2 d 1-2 Repeat day 28 ASH 2009 Bendamustine in indolent NHL upfront therapy, 18% MCL

68. Thalidomide and Rituxan (R- Thal) 11 pts at first (7), or second (3) relapses, and primary refractory (1) Median age 68 y (range 50-74y) All stage IV, and 7 with high IPI Rituximab 375 mg/m 2 added on d1, 8,15, 22 Thal 200mg d1, and dose escalation to 400mg d15 and then continued until relapse or progression CR 3/11, PR 7/11, SD 1/11 Time to progression in CR patients was longer than the preceding TTP after chemotherapy

69. Wiernik JCO 2008 Mantle cell lymphoma Lenalidomide

70. 0 0.2 0.4 0.6 0.8 1 0100200300 PFS (days) Survival probability Zinzani ASH 2008 Lenalidomide maintenance (n = 39) Progression-free survival

71. Treatment – Maximum of 24 months or until Toxicity, PD or Consent Withdrawal 1st line induction treatment ? Lenalidomide = Rituximab (15 mg daily d1-21, q28 days) Rituximab PR / CR (90%) ® B A MCL-003 proposal: Study Design Phase 3, 1:1 Randomized, comparative, maintenance study post-completion of standard chemotherapy Newly Diagnosed MCL Patients with PR or CR after Initial Chemotherapy Transplant ineligible Primary endpoint: PFS Global Participation in Study: Europe, US, other countries around the world

72. MCL Treatment Prognosis has improved from 3y to 7y median overall survival –Autologous stem cell transplantation –Rituximab: Induction with chemo and maintenance –Cytarabine –MRD Questions remaining: –Role of Pet scan evaluation –Role of new drugs as induction and/or maintenance –Treatment based on MRD

73. Inclusion C1C1 C2C2 C3C3 C4C4 W0W4W8W12 R-CHOP 14 x4 R-DHAP* PBSC collection After C3 or C4 Arm B Maintenance R (375mg/m²) every 2 months for 3 yrs Arm B Maintenance R (375mg/m²) every 2 months for 3 yrs RANDORANDO RANDORANDO Arm A Observation every 2 months for 3 yrs Arm A Observation every 2 months for 3 yrs ASCT R-BEAM ASCT R-BEAM Response using TDM ≥75% ? Evaluation <75% InductionConsolidationMaintenance and FU ≥ 75% TDM PET Biological studies (MRD) Blood BM M2 : every 6 months : M12 M36 : M6,12,18, 24, 30 Before ASCT Before R-DHAP : M42, M48 : every year M72 : M12, 24 : M48 R-DHAP* or R-DHA-Carboplatin or R-DHA-Oxaliplatinum Ongoing trial GOELAMS/GELA

74. Thanks Olivier Hermine Steven Le Gouill