Biology of Mantle cell lymphoma : Implications for a Rational approach to treatment in the 2015?

Transcription

1 Biology of Mantle cell lymphoma : Implications for a Rational approach to treatment in the 2015? Olivier Hermine MD, PhD Department of Hematology INSERM and CNRS, Imagine Institute Necker Hospital, Paris, France 11th Educational Course of the EBMT Lymphoma Working Party on "Treatment of Malignant Lymphoma: State-of-the-Art and Role of Stem Cell Transplantation Heidelberg (Germany), September 24-26, 2015 #EBMTLymphoma 1

2 Standard MCL treatment R chemotherapy is the standard treatment of MCL High dose ARAC (young), R Bendamustine or R CHOP (ederly) or combination Autologous stem cell transplantation in Young, R maintenance in ederly Allo stem cell transplantation in relapse New drugs, most «chemo-free»

3 New combined Biological MIPI MIPI-c MIPI Group Ki-67 Index MIPI-c Group Low Risk <30% Low Risk Low Risk 30% Low Intermediate Risk Intermediate Risk <30% Low Intermediate Risk Intermediate Risk 30% High Intermediate Risk High Risk <30% High Intermediate Risk High Risk 30% High Risk

4 OS according to MIPI-C In Age groups < 65 years >= 65 years

5 OS according to MIPI-C In Age groups < 65 years >= 65 years Reduce toxicity Cure? Reduce toxicity Cure or no cure? Eva Hoster et al, ASH 2014

6 OS according to MIPI-C In Age groups < 65 years >= 65 years Randomized study With the same backbone Randomized study With the same backbone Eva Hoster et al, ASH 2014

7 OS according to MIPI-C In Age groups < 65 years >= 65 years New strategies AlloSCT New targeted therapies combination New strategies New targeted therapies combination Eva Hoster et al, ASH 2014

8 Relative tumour-load MRD analysis in NHL Diagnosis CR Clinical CR Disease control LIC? MRD Clinical detection limit of residual disease Molecular detection limit of residual disease Time

9 MCL Younger study: Remission duration after Induction according to MRD response PB n=164 BM n = 143 Variable HR 95% CI p Molecular Response 2.4 ( ) MIPI score 1.7 ( ) Treatment arm 0.6 ( ) 0.1 CR 0.9 ( ) 0.68

10 MRD response after induction 100% RR 86% CR 34% 80% 52 60% Elderly 78% 90% 40% 25% Younger 94% 38% 32 40% 20% % R-CHOP R-FC R-CHOP MRD- MRD+ R-CHOP/ R-DHAP

11 Chemotherapy free vs chemotherapy? Better safety and tolerability? Better efficacy? Long term use : Control of the disease vs Cure of the disease Smart and personalized treatment vs Identical for all patients Single agent vs combination or sequential treatment Cost? Biology of Mantle cell and therapeutic implications?

12 MCL: a spectrum of disease indolent MCL (15%) classical MCL (80%) transformed (5%) Modified from Jares, Nature Review 2007

13 Overall Survival in MCL patients according to SOX11 Expression 1.8 SOX11 negative (N=15; dead: 4).6 Sox PROBABILITY.2 SOX11 positive (N=97; dead: 68) Sox YEARS P< Courtesy of E Campo Fernandez V et al Cancer Res 2010

14 Alternative Model of Molecular Pathogenesis in MCL (?) SOX11- Early MCL Genetically Stable Indolent MCL Pre-B cell HMG > Hypermutated Ig? t(11;14) HMG + > Unmutated Ig SOX11+ p53 Classical MCL Blastoid MCL Courtesy of E Campo Increased Genomic Instability

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17 SOX 11 expression and outcome

18 SOX-11 expression and Wnt

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20 Bias of IGHV repertoire in MCL 4 genes represent 46% of the repertoire Stamatopoulos et al., Blood 2007

21 Perez-Galan et al, Blood 2010 B cell receptor signalling pathways

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23 New BTK (GDC-0853)

24 ABT199 And Ibrutinib Chiron et al, Oncotarget 2015

25 NGS results

26 Patterns of exonic mutations across lymphomas show similarly and differentially mutated genes. Subclonal architecture in MCL. Representation of four informative MCL patients with two tumor samples analyzed. Zhang J et al. Blood 2014;123: Beà S et al. PNAS 2013;110:

27 DNA repair. ATM deficiency one of the most frequent oncogenic event in MCL PARP: -Veliparib, Bendamustine, and Rituximab -E7449 ChK1 -GDC-0575 BER -TRC102 (Tracon) ATR -AZ and others

28 Epigenetics HDAC-Inhibitors S78545 (Ribrag) 1/6 PR Vorinostat (Krishbaum) ORR 0% BET inhibitors OTX015 GSK CPI-0610 EZH2 (overexpression SUZ12)? Zhang J et al. Blood 2014;123:

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30 NOTCH1 mutations in MCL 0/29 WES 8/171 (5%) Expanded SOX11 + 5% (5/95) SOX11-0% (0/27) NOTCH1-unmut (n=133, dead=69) NOTCH1-mut (n=8, dead=6) Exon 34, PEST domain Blastoid MCL P=0.026 P= Campos, PNAS 2014

31 Actions of Lenalidomide in MCL Lenalidomide MCL cells ICAM-1 IL-6 TNF IL-1 COX-2 Bone Marrow Stromal Cells VEGF bfgf Bone Marrow Vessels T Lymphocytes IL-2 IFN Lenalidomide Anderson ASH 2001 CD8+ T Cells NK Cells Lenalidomide

32 Cumulative Survival Relative tumor size Ki-67 Proliferation (%) TfR Mantle cell lymphoma a b c In vitro Rituximab A24 d e f concentration (µg/ml) Prevention Treatment (single dose) PBS mab-a PBS mab-a Days Days Lepelletier et al Cancer Res 2007

33 BiTE Technology Mechanism of Action Blinatumomab (MT103; Micromet/Medimmune), a BiTE specific for CD19 and CD3 Patrick A. Baeuerle, Micromet, Inc. San Diego, December, 2009

34 Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway Trends in Molecular Medicine, Volume 21, Issue 1, 2015, Kim C. Ohaegbulam, Amer Assal, Eszter Lazar-Molnar, Yu Yao, Xingxing Zang

35 Cancer immunotherapy Multiple actionable targets Multiple trials ongoing Expression of these targets in MCL? MK3475 (PD1-PDL1) CDX-1127, ArgX (CD27-CD70) MEDI6469: OX40

36 Adoptive T cell therapy: CAR-T cells CAR-T cells (Chimeric antigen receptor-t cells0 T cells transduced with tumor-specific CAR CAR: Single fusion molecule with antigen specificity plus signaling domain Three types of CAR: First/second/generations Based on co-stimulatory receptors Cancer: Solid tumor & hematological malignancies Antigen specific domain Advantages of CAR T cells Live drug Tumor recognition independent of HLA (no HLA typing needed) Multiple antitumor immunomodulators can be engineered Target variety of antigens (protein, carbohydrate, glycolipid) Maus M V et al. Blood 2014;123:

37 Clinical significance of CAR-T cells Target CAR Cancer Objective response CD19 CAR:CD28-CD3z Lymphoma and CLL CD20 CAR:CD137-CD3z ALL 2CR CAR:CD28-CD3z ALL 5CR CAR:CD137-CD28- CD3z NHL CEA CAR-CD3z (1 st gen) Colorectal & breast N=7: 1CR, 5 PR & 1SD N=3: 1PR, 2NED GD2 CAR-CD3z (1 st gen) Neuroblastoma N=19: 3CR ERBB2 CAR:CD28-CD137- CD3z Colorectal cancer N=7: minor responses in two patients N=1, patient died Kershaw et. al Nature Reviews cancer

38 CAR T cells and Ibrutinib synergy

39 Novel Agents In MCL Agent Lenolidamide Palbociclib Everolimus/Temsirolimus Idelalisib, TGR-1202 Ibrutinib, AVL-292 Obatoclax, ABT-199 Vorinostat, Romidepsin Antibodies Target Tumour Microenviroment CDK4/CDK6 mtor PI3K BTK BCL2, BH3/apoptosis HDAC CD79b, CD22

40 B cell receptor signalling pathways Bruton s tyrosine kinase PI3K mtor Perez-Galan et al, Blood 2010

41 Ibrutinib for MCL Wang, NEJM 2013

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43 NFkB & Ibrutinib Rahal, Nature Med. 2013

44 MMM Registry of the EMCL Eha 2015 CCND3 Mutations in patients with moderate clinical benefit to Ibrutinib Primary Resistant Moderate Benefit Oncogene s 12.1% BCR 10.6% MYC ERBB4 BCL2 TEC 4.5% ITK PLCG2 PRKCB (PKCb) CD79A Other 1.5% TAB2 MAP3K14 (NIK) TRAF3 TNFRSF11A (RANK) REL MYD88 NFKBIA (IkBa) NF-κB 28.8% PIM1 MTOR WHSC1 CREBBP MLL2 Individual Patients PIM1/mTOR 18.2% Epigeneti c modifiers 24.2% Balasubramanian et al., ASH 2014; abstract 78 (oral presentation)

45 PI3 kinase inhibitors Class I PI3Ks Class I PI3Ks are heterodimeric proteins containing a regulatory subunit and a catalytic subunit. The regulatory subunits facilitate membrane localization, receptor binding, and activation The catalytic subunits of Class I PI3Ks phosphorylate PIP2 to yield the second messenger PIP3 IDELA binding site Okkenhaug, K. Annu Rev Immunol, :

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47 Responsea Rate ±95% CI Updated results of a phase I study of ipi3k with R and/or B in inhl Rituximab Idelalisib (N=23/32) 100 Benda Idelalisib (N=28/33) BR Idelalisib (N=10/14) All combinations + Idelalisib (N=61/79) % 78% 60 72% 71% % CR % CR 27% CR 26% CR 20 0 a Criterion for response [Cheson 2007] 0 Leonard JP, abstr 68, ICML-12, Lugano 2013

48 CCI 779 +Rituximab Ansell et al ASH 2009 (abs 1665) 71 pts atleast two prior therapies 30% Rituximab refractory ORR 47% CR 20% PR 28% PFS 9.5 m Use of combination T3 (RFC, RCHOP, RDHAP), BERT (Benda-R)

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50 Bendamustine Combinations

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52 MCL: Lenalidomide Trial NHL (MCL subset) NHL (MCL subset) FIL MCL 3 study Salvage therapy Wang et al., 4,5 Phase Phase 2 Phase 2 Phase 2 Phase 1/2 Treatment lenalidomide lenalidomide lenalidomide plus dexamethasone* lenalidomide plus rituximab** Lenalidomide Dose 25mg d1-21/ 28d cycle 25mg d1-21/ 28d cycle 25mg d1-21/ 28d cycle 20mg d1-21/28d cycle Efficacy data Response rates ORR = 53% ORR = 42% ORR = 52% ORR = 57% CR/CRu = 20% CR/CRu = 21% CR/CRu = 24% CR/CRu = 36% median PFS 5.6mo 5.7mo 12mo 11.1mo median DOR 13.7mo NR 18mo 18.9mo median OS ND ND 20mo 24.3mo Study link Study link Study link Study link *: 40mg d / 28d cycle; **: 375 mg/m 2 once weekly for 4 weeks during cycle 1 CR: complete response; DOR: median duration of response; MCL: Mantle cell lymphoma; ND: not determined; NR: not reached; NHL: Non-Hodgkin lymphoma; 1: Habermann ORR: overall et response al (2009) rate; Brit PFS: J Haematol median progression-free 145: 344-9; 2: Witzig survival et al (2011) Ann Oncol 22: ; 3: Zaja et al (2012) Haematologica 97: ; 4: Wang et al., Lancet Oncol. (2012) 13: ; 5: Wang et al., Oral presentation at ICML, (2011) Ann Oncol 22(suppl 4): iv119

53 Lenalidomide in heavily pretreated relapsed/refractory MCL OS Median OS: 19 months (95% CI: ) at median follow-up of 9.9 months Wang, N Engl J Med. 2013

54 Apoptosis New Bcl2-inhibitors IAP inhibitors (BIRC3 mutated in MCL) ABT-199: active in phase I ORR 3/3, 2CR and 1PR IAP? MCL1 inhibitors? mtor inhibition induced MCL-1 down regulation

55 MRD response after induction 100% RR 86% CR 34% 80% 52 60% Elderly 78% 90% 40% 25% Younger 94% 38% 32 40% 20% % R-CHOP R-FC R-CHOP MRD- MRD+ R-CHOP/ R-DHAP

56 PARP inhibitors

57 MCL Elderly: RD ITT R-CHOP R-FC p= for interaction of induction and maintenance Update April 7, 2013, European MCL Network, V1.0,

58 Good efficacy+++ Chemo free Determine molecular parameters of responses No cure Best use in combination with or without chemotherapy? Sequential increase OS (no cross resistance) Best strategy : first line (cure) relapse (Combo +/- Auto or allo) Maintenance? Preemptive?

59 New Drugs Good efficacy+++ Determine molecular parameters of responses No cure Clinical Trial Best Number use in combination of patients with or without chemotherapy? Duration of trials Sequential increase OS (no cross resistance) Early predictors of Best response strategy : first (NGS line (cure)?) relapse (Combo +/- Auto or allo) Maintenance? Preemptive?

60 Options of treatment guiding by MRD Early treatment reduction Risk factor //NGS Treatment modification or preemptive Treatment at molecular relapse +/- Maintenance Immune-Chemotherapy Combination Chemofree? => Remission induction +/- SCT => maintain Remission

61 Options of treatment guiding by MRD Early treatment reduction Treatment modification Treatment modification or preemptive Treatment at molecular relapse +/- Maintenance Immune-Chemotherapy Chemo-free +/- SCT => Remission induction => maintain Remission

62 Options of treatment guiding by MRD Early treatment reduction Treatment modification Treatment modification or preemptive Treatment at molecular relapse +/- Maintenance Immune-Chemotherapy +/- SCT => Remission induction => maintain Remission

63 Options of treatment guiding by MRD Early treatment reduction Treatment modification Treatment modification or preemptive Treatment at molecular relapse +/- Maintenance Immune-Chemotherapy => Remission induction +/- SCT Switch to new substance Chemo-free Drugs, Antibody, Bite, CAR Stem cells => maintain Remission

64 European MCL Network Recommandations First line < 65 years > 60 years > 65 years MCL younger: R-CHOP/DHAP =>ASCT R-CHOP/DHAP + I =>ASCT- RI R-CHOP/DHAP + I => RI MCL elderly R2: R-CHOP vs R-CHOP/Ara-C => Rituximab M +/-Lenalidomide MCL elderly I: BR +/- Ibrutinib => Rituximab M +/- Ibrutinib R-HAD +/- Bortezomib 1. Relapse 2. Relapse (or not qualifying for R-HAD) Ibrutinib vs Temsirolimus BeRT BR-Temsirolimus LENA-BERIT BR-Lenalidomide NLG-MCL4 BR-Lenalidomide T3 protocol chemo- Temsirolimus

65 MCL < 65 years: «LyMa» Rituximab maintenance after ASCT Arm A: Observation R-DHAP x 4 ASCT ( R-BEAM) Vs If PR < 75%: R-CHOPx4 Arm B: Rituximab 375 mg/m2/ every 2 months, 3 years Le Gouill, ICML 2013

66 EFS from time of randomization EFS Observation (95%CI) vs Rituximab (95%CI) 24m: 83.1% (75-89) 93.3% ( ) 36m: 73.4% ( ) 88.1% ( ) 48m: 61.8% ( ) 80.4% ( )

67 Concept 2 Dose reduction or intensification for all R-CHOP/ R-DHAP x 6 ASCT Observation R? R R-CHOP/ R-DHAP x 6 + I ASCT R?I-maintenance R-CHOP/ R-DHAP x 6 + I R?I-maintenance superiority/non-inferiority: time to treatment failure HR: 0.60; 65% vs. 77% vs. 49% at 5 years

68 US intergroup trial

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70 European MCL network studies patients >60 years MCL R2 elderly 4 x R-CHOP 4 x R-CHOP/DHAP PR, CR 4 x R-CHOP 2 x R-CHOP/DHAP Rituximab Lenalidomide maintenance (all 2 months) PR, CR Rituximab maintenance (all 2 months)