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 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 *US statistics 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 31% 22% 8% 7% 7% 6% 2% 2% 2% 2% 2% 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 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) The indolent lymphomas • • • • • Follicular lymphoma Lymphoplasmacytic lymphoma (Waldenström’s macroglobulinemia) Extranodal marginal zone B-cell lymphoma (MALT lymphoma) CLL Hairy cell leukemia 4 The aggressive lymphomas • • • • • DLCL Peripheral T cell lymphoma Anaplastic large cell lymphomas FL, grade III Mantle cell lymphoma Staginguntersuchungen 5 Follikuläres Keimzentrumslymphom Follicular Lymphoma International Prognostic Index Age Ann Arbor stage > 60 y III-IV Hemoglobin level < 120 g/L Serum LDH level > ULN Number of nodal sites > 4 Solal-Céligny, Blood 2004 6 Outcome to risk group as defined by the Follicular Lymphoma International Prognostic Index • Number of factors* 10-year OS, % (SE) Low 0-1 Intermediate 2 High >3 70.7 (2.7) 50.9 (2.7) 35.5 (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. 10-17 / 100 000 / Jahr Altersgipfel 50 - 60. Lebensjahr Immunologisches Profil SIg+, CD10+/-, CD 20+/-CD 23-/+, CD 5Genetik t 14;18 , bcl2 Prognose CSIII u. IV 8-10 a, konstante Rezidivrate (15%/a), Transformation 5-10%/a 7 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) (15 -20%) • CS III, IV (80 -85%) Rx (30-40Gy EF), Intention: kurativ wait and watch (40%!, Therapieindikation nach duchschn. 18 M) 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 9 10 11 12 13 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 15 GELA LNH-98.5: study design 2 Cyclophosphamide 750mg/m Doxorubicine 50mg/m Vincristine 1.4mg/m Prednisone 40mg/m /d x 5 days 2 2 • Patients 60–80 years old with untreated DLCL 2 3 weeks 8 cycles • Primary endpoint: eventfree survival – events: progression, relapse, new alternative treatment, death from any cause • Intent-to-treat analysis CHOP MabThera 375mg/m 2 • 399 patients with a median follow-up of 4 years 16 17 18 Before treatment At 2 cycles At 4 cycles FDG-PET (–) 19 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 (“KreuzfeuerEffekt”) und so auch grosse oder gering vaskularisierter Tumoren erreichen CD20 is an Ideal Target for Radioimmunotherapy • CD20 antigen: – Proven target for lymphoma therapy Malignant B-cell – Expressed only on B-lineage cells – Does not shed into circulation CD20 antigen – Does not modulate upon antibody Ibritumomab Zevalin® Tiuxetan binding 90Y 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 20 Die Radioimmuntherapie ermöglicht einen “Kreuzfeuer-Effekt” Nackter Antikörper Radioaktiv markierter Antikörper 131I-Tositumomab (BEXXAR) Therapy as Initial Treatment for Follicular Lymphoma 21 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 23