Treatment of Mantle Cell Lymphoma N Milpied University Bordeaux 2

Fisher RI. Ann Oncol. 1996;7(suppl 6):S35-S39. Armitage JO. Management of Mantle Cell Lymphoma. Oncology (Willston Park) Romaguera JE, et al. Cancer. 2003;97: 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

ClassicLymphoblastoidPleomorphic Cytomorphological Variants in MCL

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

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

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

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

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 ( ) 70 m ( ) Chemotherapy150 5-year Overall Survival49%100% * + p <0.05 * p=0.002 Fernandez V et al Cancer Res 2010

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

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

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

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

Treatment in non elderly adults

Induction Consolidation SCT eradicationtumor reduction Optimal treatment in mantle cell lymphoma

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

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

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

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

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

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.

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

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

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

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

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

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

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

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

Response after ASCT nCRCRuPRPDDeath R-CHOP13181 (62%)22 (17%)24 (18%)3 (2%)1 (1%) R-DHAP12979 (61%)27 (21%)19 (15%)2 (2%) ALL (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%)

Time to treatment failure PP Update November 19, 2010, European MCL Network, V p= (one sided sequential test) Hazard Ratio 0.68

Time to treatment failure, Events Update November 19, 2010, European MCL Network, V R-CHOPR-DHAP Evaluable per protocol Events per protocol stable disease progression during induction death in remission ASCT-related 6 (3%) 8 (4%) - secondary malignancy relapse after CR/CRu/PR4922

Remission Duration according to MRD Status after ASCT - Pooled trials - n = 161 * % MRD negative *p < R-CHOP R-CHOP/ R-DHAP % 83% *

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= n = 128

Achievement of MR post Induction is an Independent Prognostic Factor variableHR95% CIp Molecular response 4.2 ( ) MIP score1.9 ( ) 0.01 CR1.0 ( ) 0.1 Treatment arm0.5 ( ) 0.98

Safety During Induction

Safety During ASCT

Update November 19, 2010, European MCL Network, V MCL Younger: Overall Survival

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

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

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

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

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

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, ( ), , ( ), , ( ), 0.65 HD Cyt0.601, ( ), , ( ), , ( ), Rituximab0.844, ( ), , ( ), , ( ), 0.10 Nb ttt lines ≥ , ( ), , ( ), Age > , ( ), , ( ), , ( ), 0.55 n=155 patients

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, ( ), , ( ), , ( ), 0.90 HD Cyt1.27, ( ), , ( ), , ( ), 0.78 Rituximab0.74, ( ), , ( ), , ( ), 0.80 Stage IV1.28, ( ), , ( ), , ( ); Age > , ( ), , ( ), , ( ); n=333 patients

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

Treatment in elderly patients

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

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

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

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

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

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,

Next steps

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

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 Sep 10;27(26): Epub 2009 Aug 3

What about allogeneic stem cell transplantation?

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

Nonmyeloablative allogeneic transplantation Khouri et al, JCO 2003

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

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

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

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

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 (21%) 6 (21%) 41% Strauss Lister Same 6 cycles 1.3mg/m (4%) 6 (25%) 29% BelchSame 6 cycles 1.3mg/m 2 13 untreated 15 treated % 47% GoySame 17 cycles 1.3mg/m treated 8% 21%33%

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)

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 thérapies antérieures incluant obligatoirement (100%): Rituximab + Anthracycline + Agent alkylant 162 patients - LCM confirmé -Rechute et/ou réfractaire 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 Vol 27. N

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

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

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

Wiernik JCO 2008 Mantle cell lymphoma Lenalidomide

PFS (days) Survival probability Zinzani ASH 2008 Lenalidomide maintenance (n = 39) Progression-free survival

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

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

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

Thanks Olivier Hermine Steven Le Gouill