Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Elias Campo
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1 Chronic Lymphocytic Leukemia Mantle Cell Lymphoma Elias Campo Hospital Clinic, University of Barcelona
2 Small B-cell lymphomas NAIVE -B LYMPHOCYTE MEMORY CELL CLL MCL FL MZL Small cell size Low proliferation Homing growth patterns Immunomodulation by microenvironment Indolent clinical behavior
3 Lymphoid Cell Circulation and Lymphoid Tissue Compartment Key elements in Small B-cell lymphomas Blood Leukemia Tissue Lymphoma
4 Heterogeneity of Small B-cell Lymphomas CLL FL FL MCL MCL MCL CLL Median: 10 years FL Median: 9 years p 1 0,75 0,5 MCL Median: 3 years 0,
5 Transformation in Small B-Cell Lymphomas Microenvironment B cell Primary Genetic Events Small B-cell neoplasms DLBC Genetic alterations
6 Survival Chronic Lymphocytic Leukemia Most frequent leukemia in Western countries (5-7 cases /100,000 /year) Heterogeneous disease with different stages of progression and molecular subtypes No effective therapy Pathogenesis Unknown initiating genetic alterations Microenvironment Evidence of genetic predisposition Survival 1,0 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0, Binet A Binet B Binet C Years Ig Mutations p = Months
7 Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma Presence of > 5 x10 9 /L monoclonal lymphocytes with the CLL phenotype Extramedullary tissue involvement and cytopenias allow for lower number of atypical lymphocytes SLL is the same disease but restricted to tissues without evidence of leukemic involvement WHO 2008
8 Monoclonal B-cell Lymphocytosis Definitions and Subtypes B-cells 5 x 10 9 /L Monoclonal Κ:λ < 0.3:1 or > 3:1 25% lacking surface IG Absence of other lymphoproliferative disorders or autoimmune disease CLL-like Atypical CLL CLL-like CD5+, CD20(dim), Ig(dim) Atypical CLL CD5+, CD20(bright) or CD23- Non-CLL CD5-, CD20+ Non-CLL
9
10
11
12 SLL: Inter & Perifollicular pattern
13 CLL Phenotype CD23 CD43 IgS w CD5 CD22 w CD19 CD20 w CD79b w
14 CLL Chromosomal Abnormalities and Prognosis ATM p53 Aberration No. Patients (%) Median SRV (months) 17p del (p53) q del (ATM) Trisomy Normal q del Döhner et al. NEJM 2000
15 CLL: From Naive to an Antigen Experienced Cell T Cell-Independent Response UnMutated-CLL Naïve V D J cμ cγ Antigen Selection Ig Somatic Mutations Class Switch Mutated-CLL
16 CD3 PE + CD56 PE-> IGHV mutation status: prognostic impact Unmutated CLL Mutated CLL % 12% ZAP-70 FITC-> Mutated p = Unmutated Hamblin et al. Blood 1999; 94(6): Damle et al. Blood 1999; 94(6): ZAP70
17 Recurrent Somatic Mutations in CLL
18 Clinical Progression and Morphological Transformation in CLL Richter s Syndrome (Clinical manifestations) Morphological Spectrum CLL with minimal morphological changes Large Cell Lymphoma Hodgkin s Lymphoma EBV related proliferative disorders Plasmablastic transformation Transdifferentiation
19 Proliferation Centers and CLL progression
20 Overall Survival of Patients with Conventional and Accelerated CLL and DLBCL Transformation Non-accelerated CLL Accelerated CLL DLBCL-t 75.5 months 34 months 4.3 months p=.008 p=.067 Accelerated CLL Non-accelerated CLL DLBCL-t Gine E et al Haematologica 2010
21 DLBCL Transformation in CLL 2-8% of CLL Median survival < 1 year Clonal relationship in unmutated CLL Clonally unrelated in mutated CLL 1,2 p53 Mutations, NOTCH1 Mutations, p16 deletions 1 Timar et al Leukemia 2004; 18: Mao et al Am J Surg Pathol 2007
22 HL Transformation in CLL Typical HL (<1%) Generally EBV positive Mostly in mutated CLL and clonally unrelated Isolated RS cells in a background of CLL (Not considered HL) CD30 CD15 Mao et al Am J Surg Pathol 2007
23 Mantle Cell Lymphoma Cyclin D1 Probability Years Complete Response 25% (6-50%) 14 der(14) 11 der(11) Duration of CR 1.5 yrs ( yrs) IGH/CCND1 Median Survival 3-4 years
24 Mantle Cell Lymphoma: Cytological Variants Classical Small cell Blastic Pleomorphic
25 MCL Phenotype CD20 CD3 Cyclin D1 CD5
26 MCL: Clinical Characteristics Male to Female 2-8:1 Median age (range 29-85) Stage IV > 60% B Symptoms 35% Generalyzed lymphadenopathy Bulky Disease 18% (5-25%) Extranodal involvement 30-50% Splenomegaly 30-60% Leukemic phase
27 Gastrointestinal Involvement in MCL Clinico-pathological Presentation Lymphomatous Polyposis Microscopical Infiltration Clinical manifestations in % of patients Asymptomatic more common (80%)
28 Probablilitat Adverse prognostic factors in MCL High proliferation Genetic Instability TP53 Mutacions (Klapper W. et al, J Hematop 2009) 1.0 (Beà S. et al, Blood 1999) (Halldórsdóttir AM., et al, Leukemia 2011) normal WT gains >4 gains P= Anys TP53 mut Blastoid morphology (Rosenwald A. et al., LLMPP, Cancer Cell 2003)
29 Molecular Pathogenesis in MCL Naive B lymphocyte Early MCL Classical MCL Blastoid MCL Germline ATM CHK2 t(11;14) Cyclin D1 ATM CHK2 p16/cdk4/rb ARF/MdM2/p53 Rb p27 Complex Karyotypes High Proliferation Jares P et al Nat Cancer Rew 07
30
31 SOX11 Expression in NHL is Highly Specific for MCL MCL, n=89 MCL CCND1- SOX11 CCND1 BL, n=33 DLBCL, n=46 PMBL, n=20 FL, n=44 SOX11 CCND1 Classic MCL CCND1 neg MCL Cyclin D1 Cyclin D1 Sox11 Sox11 Mozos et al Haematologica 2009
32 SOX11
33 Cyclin D1-neg MCL rearrangements Rearrangements No. (%) CCND2 translocation partners CCND1 0 CCND2 22 (52%) CCND3 0 No Cyclin D gene translocation 20 (48%) Undetermined 18% IGH 14% IGL 23% IGK 45%
34 Overall Survival of 34 Cyclin D1-neg MCL Overall survival Overall survival and Ki67 Ki67< 35% Ki67 35% P < 0.05 Median overall survival: 39 months Salaverria et al Blood 2013
35 Cyclin D1
36 MCL with Indolent Clinical Behavior OS from diagnosis OS from treatment Martin P et al JCO 2009
37 MCL with Indolent Clinical Behavior Early stages of the disease In situ Lesions and Mantle zone pattern Low proliferation fraction Early stage disease A distinctive variant of the disease? Leukemic non-nodal (splenomegaly) disease SOX11-negative Hypermutated IGHV Simple karyotypes
38 Conventional vs Indolent MCL Clinical Characteristics Clinical data Conventional MCL (15) Indolent MCL (12) Chemotherapy 15 0 Median 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 ( 5x10 9 /L) 9/11 4/9 + p <0.05 * p=0.002 Fernandez V et al Cancer Res 2010
39 Splenic Involvement in imcl CCND1
40 SOX11 Protein Expression in MCL Cyclin D1 SOX11 Indolent MCL Conventional MCL
41 Overall Survival in MCL patients according to SOX11 Expression Sox11 - Sox11 + P< Fernandez V et al Cancer Res 2010; Royo C et al Leukemia 2012
42 CLL/MCL Conclussions Well defined small B-cell lymphoid neoplasias originated from CD5 + B lymphocytes Heterogeneous clinical and pathological presentation and evolution Increasing recognition of early lesions and indolent variants that may require a more individualized management New genetic and molecular information coming from genomic studies that may be clinically relevant
43 Dr P Jares Dr M Pinyol Investigadora HCP Dr A Enjuanes Dr V Fernàndez Investigadora RTICC Dr S Beà Investigadora FIS Dr I Salaverria Investigador HCP C Royo Dr Ll Colomo HCP Dr A Martínez HCP Dr L Hernández Investigador IDIBAPS Dr V Amador Investigadora RyC Alba Navarro A Mozos Investigador HCP O Salamero Dra O Balague FIS
44 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 RNGTT
45
46 MCL Patients with an Indolent Clinical Course 12 patients with indolent MCL (imcl) that were not treated with chemotherapy and did not have evidence of clinical progression for > 2 years. - Median follow-up 6.4 years, range Detection t(11;14) (Conventional cytogenetics, FISH) and overexpression CCND1 SMZL 4 CLL 2 Leukemic lymphoid neoplasm, NOS 4 In situ MCL 2
47 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) 11/4 7/5 ECOG 2 70% 0 + Intermediate/High MIPI 46% 0 + Lymphadenopathy (>1cm) 15/15 2/12 + Lymphocytosis ( 5x10 9 /L) 9/11 4/9 Evolution Median Follow-up 15 m (0.5-79) 70 m (25-121) Chemotherapy year Overall Survival 49% 100% * + p <0.05 * p=0.002 Fernandez V et al Cancer Res 2010
48 Clinical and Pathological data Pathology cmcl (15) imcl (12) Small cell variant 2 8 Classical 11 4 Blastoid 2 0 CD5 + (%) Evolution Splenectomy 3 5 Chemotherapy at any time year Overall Survival 49% 100% * + p <0.05 * p=0.002 Fernandez V et al Cancer Res 2010
49 Lymph Node Involvement in imcl Cyclin D1 Cyclin D1
50 Splenic Involvement in imcl
51 Indolent and Conventional MCL Share a distinctive Expression Profile Unsupervised analysis B-NHL with leukemic involvement
52 Indolent and Aggressive Lymphomas Indolent (Low grade) Aggressive (High grade) Stable or indolent clinical behavior Not curable with current therapies Small Cell Low proliferation Homing growth patterns Immunomodulation by microenvironment Progressive disease Curable with aggressive therapies Large cells High proliferation Destructive growth pattern Autonomous proliferations
53 Gastrointestinal Involvement in MCL Multiple Polyposis is not exclusive of MCL MCL 12 (34%) FL 14 (40%) MALT 9 (26%) Kodama et al Histopathology 2005; 47:
54 PROBABILITY Classical vs Blastoid MCL Proliferation Genetic Stability No gain (n=8) 1 to 4 gains (n=28) 0.2 >4 gains (n=6) P= YEARS
55 Proliferation Centers Pro-lymphocytes and paraimmunoblasts Proliferating cells CD4 + cells Few follicular dendritic cells No polarization No mantle zone Activated B-cell phenotype (CD23, CD20, IRF4) No germinal Ctr markers (CD10, bcl-6)
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