Non-Hodgkin s lymphoma. Univ. Prof. Dr. Werner Linkesch Univ. Klinik Graz

Non-Hodgkin s lymphoma Univ. Prof. Dr. Werner Linkesch Univ. Klinik Graz NON-HODGKIN S LYMPHOMA (NHL) Approximately 1.5 million people worldwide are living with non-hodgkin s lymphoma (NHL), and it is estimated that 300,000 people die each year from the disease 1 new case diagnosed every 9 minutes* 81% increase in incidence of NHL between 1973-1990 NHL is the third fastest growing cancer (excluding the US) in terms of population in the world NHL is leading cause of death due to cancer in men aged 20-40 years *US statistics 1

Proposed WHO Classification of Lymphoid Neoplasms B-Cell neoplasms Precursor B-cell neoplasm: Precursor B-lymphoblastic leukemia/lymphoma (precursor B-ALL) Mature (peripheral) B-cell neoplasms: B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of MALT type Nodal marginal zone B-cell lymphoma (+/- monocytoid B cells) Follicular lymphoma Mantle-cell lymphoma Diffuse large B-cell lymphoma Mediastinal large B-cell lymphoma Primary effusion lymphoma Burkitt's lymphoma/burkitt cell leukemia Proposed WHO Classification of Lymphoid Neoplasms T-cell and NK-cell neoplasms Precursor T-cell neoplasm: Precursor T-lymphoblastic lymphoma/leukemia (precursor T-ALL) Mature (peripheral) T-cell neoplasms: T-cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-cell leukemia Adult T-cell lymphoma/leukemia (HTLV1+) Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/sezary syndrome Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type Peripheral T-cell lymphoma, not otherwise characterized Angioimmunoblastic T-cell lymphoma Anaplastic large-cell lymphoma, T/null cell, primary systemic type 2

Major NHL Types Category Percentage Incidence Diffuse Large B Cell Follicular Marginal Zone B-Cell, MALT Peripheral T-cell Small B-lymphocytic (CLL) Mantle cell lymphoma Primary mediastinal large B-cell Anaplastic large T/null cell High grade B-cell, Burkitt-like Marginal Zone B-cell, nodal Precursor T-lymphoblastic 31% 22% 8% 7% 7% 6% 2% 2% 2% 2% 2% Indolent Aggressive Highly aggressive Frequency of NHL Subtypes in Adults Composite lymphomas (12%) Small lymphocytic (6%) Follicular (22%) Mantle cell (6%) Peripheral T-cell (6%) Marginal zone B-cell, MALT (5%) Diffuse large B-cell (31%) Other subtypes with a frequency <2% (9%) Marginal zone B-cell, nodal (1%) Lymphoplasmacytic (1%) Armitage et al. J Clin Oncol 1998;16:2780 2795 3

NHL-Etiology Etiology typically unknown Strong association with long-term immunosuppressive therapy Pathogen: EBV (Burkitt s lymphoma, PTLD) HHV-8 (body cavity, multiple myeloma) Hepatitis C HTLV-1 (Adult T-cell leukemia, lymphoma) Helicobacter pylori (MALT lymphoma) C. jejuni Immunoproliferative small intestinal disease (IPSID) Chlamydie psitacci (ocular adnexal lymphoma) Incidence rate of NHL 4

NHL histologic type Translocation % of cases affected Protooncogene involved Mechanism of proto-oncogene activation Proto-oncogene function Lymphoplas macytic lymphoma t(9;14)(p13;q32) 50% PAX-5 Transcriptional deregulation Transcription factor regulating B- cell proliferation and differentiation Follicular lymphoma t(14;18)(q32;q21) t(2;18)(p11;q21) t(18;22)(q21;q11) 90% BCL-2 Transcriptional deregulation Negative regulator of apoptosis Mantle cell lymphoma t(11;14)(q13;q32) 70% BCL-1/ cyclin D1 Transcriptional deregulation Cell cycle regulator MALT lymphoma t(11;18)(q21;q21) t(1;14)(p22;q32) 50% rare API2/MLT BCL-10 Fusion protein Trancriptional deregulation API2 has antiapoptotic activity Anti-apoptosis (?) Diffuse large B-cell lymphoma der(3)(q27) 35% BCL-6 Transcriptional deregulation Transcriptional repressor required for GC formation Burkitt lymphoma t(8;14)(q24;q32) t(2;8)(p11;q24) t(8;22)(q24;q11) 80% 15% 5% c-myc Transcriptional deregulation Transcription factor regulating cell proliferation and growth Anaplastic large T-cell lymphoma t(2;5)(p23;q35) 60%* NPM/ALK Fusion protein ALK is a tyrosine kinase 5

The aggressive lymphomas DLCL Peripheral T cell lymphoma Anaplastic large cell lymphomas FL, grade III Mantle cell lymphoma 6

Survival Patterns are Different for Indolent and Aggressive NHL Probability of survival (%) 100 75 50 25 Indolent NHL (e.g. Follicular lymphoma) Aggressive NHL (e.g. Diffuse large B-cell lymphoma) 0 0 1 2 3 4 5 6 7 8 Years The Non-Hodgkin s Lymphoma Classification Project. Blood 1997;89:3909 3918 7

Diffuse large B cell Lymphoma (DLBCL) Most frequent NHL type (31%) Clinics: Usually aggressive Phenotype: Histologic subset and Immunophenotype: CD19+; CD22+; CD10-/+; SIg+ Putative cell of origin: Large transformed B-cells harbouring somatic hypermutation of the Ig genes (ongoing mutations in some cases) Staginguntersuchungen 8

Internationaler Prognose-Index Günstig Ungünstig 1. Alter 2. Stadium 3. Zahl der E-Manifestationen 4. Allgemeinzustand ECOG 5. LDH i. S. < 60 Jahre vs. > 60 Jahre I/II vs. III/IV 0; 1 vs. 2 0; 1 vs. 2 normal vs. erhöht INTERNATIONAL PROGNOSTIC INDEX Risk (factors) Distribution CR Five-year DFS Fivefor those in CR survi Low (0-1) Low intermediate (1) High intermediate (2) High (3) 22% 92% 86% 83 32% 78% 66% 69 32% 57% 53% 46 14% 46% 58% 32 9

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CHOP DeVita VT Advanced diffuse histiocytic lymphoma, a potentially curable disease. Lancet 1975 Cyclophosphamide 750 mg/m2 d1 Adriamycine 50mg/ m2 d1 Vincristine 1,4 mg/m2 d1 Prednisone 100mg d1-5 CD20 Expression in B-Cell Development Bone marrow Blood, lymph Pluripote nt stem cell Lymphoid stem cell Pre-B-cell B-cell Activated B-cell CD20 Plasma cell Press. Semin Oncol 1999;265(suppl 14):58 65 11

Rituxan (Rituximab) Chimeric Murine/Human antibody Complement Binds specifically to CD20 antigen on normal and malignant pre-b and mature B lymphocytes CD20 expressed by >90% of B-cell NHL No CD20 on human stem cells, progenitor cells, or normal plasma cells Malignant B Cell Rituximab Lyses lymphocytes via: Antibody dependent cell mediated cytotoxicity Induction of apoptosis CD20 FC Receptor Effector cell GELA LNH-98.5: study design Cyclophosphamide 750mg/m 2 Doxorubicine 50mg/m 2 Vincristine 1.4mg/m 2 Prednisone 40mg/m 2 /d x 5 days 3 weeks 8 cycles CHOP MabThera 375mg/m 2 Patients 60 80 years old with untreated DLCL Primary endpoint: eventfree survival events: progression, relapse, new alternative treatment, death from any cause Intent-to-treat analysis 399 patients with a median follow-up of 4 years 12

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MabThera plus ICE (R-ICE) Patients: 45 Second line IPI 1 2: 18 patients CR evaluated with PET scan R-ICE (%) ICE (%) Response rate 81 72 Complete response 55 26 Primary refractory CR 31 16 IPI III/IV 53 16 (Moskowitz et al. ASH 2001) 16

Results of selected studies of pretransplant salvage therapy for aggressive NHL 17

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CD20 is an Ideal Target for Radioimmunotherapy CD20 antigen: Proven target for lymphoma therapy Expressed only on B-lineage cells Does not shed into circulation Malignant B-cell CD20 antigen Does not modulate upon antibody Zevalin binding Zelenetz. Curr Opin Oncol 1999;11:375 380 Press et al. Blood 1987;69:584 591 Wood. Am J Health Sys Pharm 2001;58:215 229 Ibritumomab Tiuxetan 90 Y Rationale der Radioimmuntherapie bei NHL NHL sind von Natur aus sehr strahlensensibel Die Radiotherapie kann bei NHL in frühen Stadien kurativ sein Radioaktiv markierte Antikörper bringen die Strahlung zielgerichtet zum Tumor Die Radioimmuntherapie kann sowohl Ziel- als auch Nachbarzellen vernichten ( Kreuzfeuer- Effekt ) und so auch grosse oder gering vaskularisierter Tumoren erreichen 19

Die Radioimmuntherapie ermöglicht einen Kreuzfeuer-Effekt Nackter Antikörper Radioaktiv markierter Antikörper Before treatment At 2 cycles FDG-PET ( ) At 4 cycles 20

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