• Share
  • Email
  • Embed
  • Like
  • Save
  • Private Content
Dr. Campo MCL
 

 

Statistics

Views

Total Views
1,721
Views on SlideShare
881
Embed Views
840

Actions

Likes
0
Downloads
9
Comments
0

6 Embeds 840

http://www.jtcancercenter.org 678
http://humccancer.org 145
http://localhost 10
http://184.106.177.112 3
http://jtcancercenter.org 2
http://www.zoominfo.com 2

Accessibility

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    Dr. Campo MCL Dr. Campo MCL Presentation Transcript

    • Biology and Pathology of Mantle Cell Lymphoma Elias Campo Hospital Clinic, University of Barcelona
    • Mantle Cell Lymphoma 1.0 0.8 Probability 0.6 Cyclin D1 0.4 0.2 0.0 0 2 4 6 8 Years Complete Response 25% (6-50%)14 der(14) 11 der(11) Duration of CR 1.5 yrs (0.5-2.5 yrs) Median Survival 3-4 years IGH/CCND1
    • Improvement in Survival of Patients with non-blastoid MCL 1996 to 2004 1975 to 1986• New diagnostic tools and management measures• Application of new therapeutic regimens Herrmann, A. et al. J Clin Oncol; 27:511-518 2009
    • MCL Pathogenesis • Cell Cycle Dysregulation • Dysruption of DNA damage response pathway • Cell survival pathways
    • Mantle Cell Lymphoma: Cytological Variants Classical Small cell Blastic Pleomorphic
    • MCL PhenotypeCD20 CD3 Cyclin D1 CD5
    • Prognostic Value of Proliferation in MCL Ki-67 Ki-67 MIPI-bKatzenberger, T. et al. Blood 2006;107:3407 Hoster, E. et al. Blood 2008;111:558-565
    • Cell Cycle Regulatory Pathways Amplified (10%) BMI-1 Deleted (30%) ARF-INK4a Locus 9 p14/p19arf p16ink4a Amplified (10%) MDM2 CDK4 / Cyclin DMutated (30%) p53 Rb Deleted (<5%) G1 S G2 M APOPTOSIS G1 S 17
    • Genetic Stability DNA Damage Response Pathways DNA damage Replication stress ATM 11 1.0 FS564stop R3008H R23stop 0.8 FS1349stop D2725V FS32stop No gain (n=8)PROBABILITY M1L K2717M 0.6 1 to 4 gains (n=28) ATM 0.4 protein p53 b-adaptin c-Abl Rad-3 PI3-kinase binding binding binding homology domain 0.2 >4 gains (n=6) P=0.02 0.0 0 2 4 6 8 10 Truncated protein Conserved residue YEARS substitution
    • Activated pathways in MCL without apparent genetic alterationsWnt Pathway PI3K, AKT, mTOR Pathway NFkB Pathway Navarro et al Sem Hematol 2011
    • Nucleus stromal cells nurse-like cells AbaDR4 folicullar dentritic cells AbaDR5 macrophages AbaCD38 TRAIL IL10 TNFa IL6 SDFa1 ImiDS VEGF CD31 CD40L TRAIL-R BCR AbaCD20 CD38 VEGF-R CD40T Lymph SrcK CXCR4 ImiDS CD20 IL-4 PK Inh PI3K Akt BAFF CD40L NF-KB Inh mTOR BAFF-R NF-KB CD40 PI3K/Akt/mTOR APRIL Axis Inh TACI Proteasome Inh BCL-2 Inh BCMA HSP90 Inhibitors IAPs Mitochondria HSP-90 DNMT/HDAC Inhibitors IAPs Antagonists Nucleoside Analogs Nucleus B cell neoplasm Saborit-Villarroya et al, Curr Drug Targets. 2010;11:769-80.
    • Molecular Pathogenesis in MCL Early Classical Blastoid Naive B MCL MCL MCLlymphocyte t(11;14) ATM p16/CDK4/Rb Bcl-2/other ARF/MdM2/p53Cyclin D1 CHK2 Increased High CellRb p27 Genomic Proliferation Survival Instability Jares P et al Nat Rev Cancer 2007
    • IGH Somatic Hypermutations in 807 MCL  Highly mutated 111 (13%)  Minimally/borderline mutated 458 (57%)  Truly Unmutated 238 (30%) Hadzidimitriou A et al Blood 2011
    • MCL: From Naive to an Antigen Selected Cell ? UnMutated-MCL T Cell-Independent Response Naïve Boderline Mutated-MCLV D J cμ cγ Antigen Selection Ig Somatic Mutations Class Switch HyperMutated-MCL
    • CD20CD5 CD3
    • Cyclin D1 p27
    • Cyclin D1 Negative MCL Variant Cyclin D1 Cyclin D3 Cyclin D2 Fu et al, Blood 2005
    • SOX11 mRNA Expression in non-HL is Highly Specific of MCL MCL CCND1- MCL, n=89 n=6 SOX11 CCND1BL, n=33 DLBCL, n=46 PMBL, n=20 FL, n=44 SOX11 CCND1 Mozos et al Haematologica 2009
    • Sox11 Protein Expression in MCL MCL Cyclin D1 (SP4) Sox11CyclinD1 negative MCLMozos et al Haematologica 2009
    • SOX11 Expression is Highly Specific of MCL and Recognizes Cyclin D1 Negative tumors Lymphoma Sox11 + Lymphoma Sox11 + MCL CCND1- 39/41 cHL 1/36 MCL 97/112 NLPHL 0/5 DLBCL 0/63 PTCL NOS 0/15 SMZL 0/9 AILT 0/5 MZL 0/11 Hepatosplenic 0/3 FL 0/22 ALK+ 0/3 CLL 0/12 ALK- 0/3 BL 2/8 (3)* T-PLL 2/3 B/T LBL 8/8 T/NK Nasal type 0/3Mozos A et al Haematologica 2009, updated * weak
    • Classical MCL Cyclin D1 SOX11
    • CCND1 p27SOX11 SOX1
    • MCL with Indolent Clinical Behavior OS from diagnosis OS from treatment Martin P et al JCO 2009
    • Conventional vs Indolent MCL Clinical CharacteristicsClinical data Conventional Indolent MCL (15) MCL (12)Chemotherapy 15 0Median Follow-up 15 m (0.5 - 79) 70 m (25-121)5-year Overall Survival 49% 100%*ECOG≥2 70% 0+Intermediate/High MIPI 46% 0+Lymphadenopathy (>1cm) 15/15 2/12+Lymphocytosis (≥5x109/L) 9/11 4/9+ p <0.05* p=0.002 Fernandez V et al Cancer Res 2010
    • iMCL and cMCL Have a Distinct Gene Expression Signature Supervised analysis Indolent and conventional MCL LGALS3BP CSNK1E SOX11 KIAA1909 FARP1 PON2 CNN3 DBN1 HDGFRP3 CDK2AP1 HMGB3 SETMAR CNR1 RNGTTFernandez V et al Cancer Res 2010
    • SOX11 Protein Expression in MCL Cyclin D1 SOX11Indolent MCLConventional MCL
    • Can SOX11 expression recognize a subtype of MCL with different clinicopathological features and outcome? Clinical data SOX11 - SOX11 + (n = 15) (n = 97) High MIPI 33% 46% Lymphn nodes (>1cm) 53% 99% * Splenomegaly 92% 48%* WBC ≥ 10x109/L 57% 18%* Lymphocytosis (≥5x109/L) 83% 24% * Ki67 high >50% 20% 28% Adriamycin-Regimens 67% 72% Complete Response 40% 54% 5-year OS (%) 78% 36%* + p <0.01 Fernandez V et al Cancer Res 2010
    • Overall Survival in MCL patients according to SOX11 Expression 1 SOX11 negative (N=15; dead: 4) .8 .6 Sox11 - .4 PROBABILITY SOX11 positive (N=97; dead: 68) .2 Sox11 + 0 0 2 4 6 8 10 12 14 16 YEARS P< 0.001 Fernandez V et al Cancer Res 2010
    • Cyclin D1
    • Cyclin D1 SOX11Cyclin D1 SOX11
    • “In situ” MCL (17 cases )• Location at diagnosis – Solitary LN 10 – LN several sites 2 – Extranodal 5 – Bone Marrow, Peripheral blood 3/7• SOX11+ 7/16 (44%)• Follow-up – 9 W&W • 2 Progression to overt MCL (4 years) • 4 Alive with stable (2) or no disease (2) (med 8 yr; range 1- 19) • 1 Dead, unrelated cause (1.4 y, 84 year-old) – 4 Chemotherapy Alive No Disease 4 yr – 2 Rx Alive no Disease > 2 yr• 1 incidental finding 3 yr after overt MCL in complete remission Carvajal-Cuenca et al Haematologica 2011
    • Genetically Stable Hypermutated IG Leukemic/ non-nodal type MCL (del)17p “In situ” MCL SOX11-t(11;14) SOX11+ Classical MCL Blastoid MCL Genomic Instability Unmutated Ig
    • Conclusions- MCL pathogenesis integrates alterations in cell cycle, DNA damage response and survival pathways that may be targeted by new therapies- Antigen selection may play a role in the pathogenesis of at least a subgroup of MCL- Cyclin D1 negative MCL can be recognized by SOX11 expression and seem to have similar clinical and genetic characteristics to conventional MCL.- Some MCL have an indolent clinical course and may benefit of a more conservative clinical management. A subset of them seems to correspond to a different biological subtype.- We may recognize early steps in MCL lymphomagenesis that should be managed with caution.
    • AcknowledgmentsHospital Clínic-University National Institute of Healthof Barcelona Bethesda Adrian WiestnerSilvia Bea Wyndham WilsonCristina Royo Elaine JaffeAlba NavarroGuillem ClotAlejandra Martinez Institute of Pathology-WürzburgEva Giné Elena HartmannGonzalo Gutierrez Andreas RosenwaldVerònica FernàndezDolors Colomer Abteilung für Klinische-Pathologie-Neus Villamor StuttgartPedro Jares German OttArmando Lopez-GuillermoUniversity HospitalSchleswig-Holstein-KielChistiane Pott Addenbrooke’s Hospital-CambridgeItziar Salverria Nicola TrimReiner Siebert Wendy ErberUniversity Hospital Munich-Grosshadern-Munich S. Orsola-Malpighi Hospital-BolognaMartin Dreyling Claudio Agostinelli Stefano A Pileri