Non-Hodgkin s lymphoma

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1 Non-Hodgkin s lymphoma Univ. Prof. Dr. Werner Linkesch Leiter der Klinischen Abteilung für Hämatologie LKH-Univ. Klinikum Graz Univ. Klinik für Innere Medizin 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 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 years *US statistics 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

2 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

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

3 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:

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

4 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) The indolent lymphomas Follicular lymphoma Lymphoplasmacytic lymphoma (Waldenström s macroglobulinemia) Extranodal marginal zone B-cell lymphoma (MALT lymphoma) CLL Hairy cell leukemia 4

jejuni Immunoproliferative small intestinal disease (IPSID) Chlamydie psitacci (ocular adnexal lymphoma) The indolent lymphomas Follicular

5 The aggressive lymphomas DLCL Peripheral T cell lymphoma Anaplastic large cell lymphomas FL, grade III Mantle cell lymphoma Staginguntersuchungen 5

6 Follikuläres Keimzentrumslymphom Follicular Lymphoma International Prognostic Index Age > 60 y Ann Arbor stage III-IV Hemoglobin level < 120 g/l Serum LDH level > ULN Number of nodal sites > 4 Solal-Céligny, Blood

stage III-IV Hemoglobin level < 120 g/l Serum LDH

7 Outcome to risk group as defined by the Follicular Lymphoma International Prognostic Index Number of factors* 10-year OS, % (SE) Low (2.7) Intermediate (2.7) High > (2.8) * Factors adversely affecting survival in the FLIPI include age greater than 60 years; Ann Arbor stage III-IV; number of nodal sites greater than 4; serum LDH level greater than the upper limit of normal; and hemoglobin level less than 120 g/l. OS indicates overall survival; SE, standard error; Follikuläres Keimzentrumslymphom Grad I u. II Inzidenz steigend, z.z / / Jahr Altersgipfel Lebensjahr Immunologisches Profil SIg+, CD10+/-, CD 20+/-CD 23-/+, CD 5- Genetik t 14;18, bcl2 Prognose CSIII u. IV 8-10 a, konstante Rezidivrate (15%/a), Transformation 5-10%/a 7

limit of normal; and hemoglobin level less than 120 g/l. OS indicates overall survival; SE, standard error; Follikuläres Keimzentrumslymphom Grad I u. II Inzidenz steigend, z.z. 10-17 / 100 000 / Jahr Altersgipfel 50-60.

8 Therapieindikationen bei indolenten NHL CS I und II immer da kurativer Ansatz! CS III und IV wenn: B Symptome Sonstige Lymphomsymptome Erkrankungsprogression bulky disease Hämatopoetische Insuffizienz (drohende) Komplikationen durch Lymphomkompression Therapiewunsch Experimentelle Therapie bei jungen Patienten Follikuläres Keimzentrumslymphom Grad I u. II Therapie CS I, II, (IIIA) Rx (30-40Gy EF), Intention: kurativ (15-20%) CS III, IV wait and watch (40%!, Therapieindikation nach duchschn. 18 M) (80-85%) CHOP-R, R-CHOP COP (CVP) (Cyclophosphamid, Vincristin, Prednisolon) MCP (Mitoxantron, Chlorambucil, Prednisolon) Leustatin, Fludarabin, FC, FND +/- R Rituximab Monotherapie Radiokonj. Anti CD 20 (Y90, J131) Rx (20-30Gy IF) Autologe Stammzelltransplantation (=SCT) Allogene SCT (myeloablative, non myeloablativ, RIST) 8

Experimentelle Therapie bei jungen Patienten Follikuläres Keimzentrumslymphom Grad I u. II Therapie CS I, II, (IIIA) Rx (30-40Gy EF), Intention: kurativ (15-20%) CS III, IV wait and watch (40%!

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14 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) Diffuse large B cell Lymphoma 14

SIg+ Putative cell of origin: Large transformed B-cells harbouring somatic

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16 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 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 16

old with untreated DLCL Primary endpoint: eventfree survival events: progression, relapse, new

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19 Before treatment At 2 cycles FDG-PET ( ) At 4 cycles 19

20 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 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: Press et al. Blood 1987;69: Wood. Am J Health Sys Pharm 2001;58: Ibritumomab Tiuxetan 90 Y 20

erreichen 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

21 Die Radioimmuntherapie ermöglicht einen Kreuzfeuer-Effekt Nackter Antikörper Radioaktiv markierter Antikörper 131I-Tositumomab (BEXXAR) Therapy as Initial Treatment for Follicular Lymphoma 21

22 FIT Trial - Primary End Point: Median PFS in All Patients* *Median observation period was 3.5 years. Hagenbeek A et al., Blood 2007; 110:#643 FIT Trial: PFS in Patients With CR/CRu After First-Line Therapy Hagenbeek A et al., Blood 2007; 110:#643 22

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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 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