1. Non-Hodgkin lymphoma

2. Non-Hodgkin’s lymphoma Definition: - clonal tumours of mature and immature B cells, T cells or NK cells - highly heterogeneous, both histologically and clinically

3. Non-Hodgkin lymphoma Epidemiology –annual incidence: 2-18 new cases per 100 000 persons –4% of new cancers each year –age distribution: middle-age patients and the elderly –males are affected more often than females (1.5:1.0) –mature B-cell neoplasms comprise over 90% of lymphomas worldwide –the incidence of lymphomas is increasing wordwide

4. Non-Hodgkin lymphoma Etiology –Viruses: EBV, HTLV1, HHV8, HIV, HCV –Bacteria: Helicobacter pylori, Campylobacter jejuni –Autoimmune disorders –Primary immunodeficiency (SCID, CVID, XLP, Wiskott-Aldrich) –Secondary immunodeficiency (AIDS, PTLD, chemotherapy) –Environmental exposure (herbicide, pesticide)

5. Clinical Presentation Nontender lymph nodes enlargement –cervical, supraclavicular, axillary, inguinal, mediastinal, retroperitoneal, mesenteric, pelvic area Extranodal disease –gastrointestinal, testicular masses, solitary bone lesions, CNS Systemic symptoms (B symptoms) –fever –night sweats –unexplained weight loss (10% per 6 months) Other symptoms –fatigue, weakness –cough, chest pain, shortness of breath, vena cava syndrome –abdominal pain, bowel disturbances, ascites –neurological symptoms –cytopenia, autoimmunologic reaction

6. For the diagnosis of non-Hodgkin lymphoma the histological examination of a lymph node is necessary!

7. Non-Hodgkin’s lymphomas - histological classification

8. Classification of non-Hodgkin’s lymphomas 1. Rappaport-1966 2. Lukes and Collins-1974 3. Dorfman-1974 4. Bennet et al.,-1974 5. Lennert-1974 6. WHO-1976 7. Working Formulation-1982 8. REAL-1994 9. WHO-1999 - 2008

9. REAL /Revised European-American Lymphoma/- WHO classification of lymphoma Precursor B- or T-cell lymphomas Peripheral B- or T-cell lymphomas

10. REAL /Revised European-American Lymphoma/- WHO classification of lymphoma Precursor B cell lymphomas - acute lymphoblastic leukemia - lymphoblastic lymphoma

11. REAL /Revised European-American Lymphoma/- WHO classification of lymphoma Peripheral B cell lymphomas Indolent - Small lymphocytic lymphoma/CLL - Lymphoplasmocytic lymphoma/immunocytoma - Marginal zone lymphoma /MALT-type - Splenic marginal zone B cell lymphoma - Follicular lymphoma, grade 1-3 Aggressive - Diffuse large B cell lymphoma - Mantle cell lymphoma - Burkitt’s lymphoma

12. REAL /Revised European-American Lymphoma/-WHO classification of lymphoma Precursor T cell lymphomas - Acute lymphoblastic leukemia - Lymphoblastic lymphoma

13. REAL /Revised European-American Lymphoma/- WHO classification of lymphoma Peripheral T cell lymphomas –T cell chronic lymphocytic leukemia –T cell chronic prolymphocytic leukemia –Large granular lymphocyte leukemia /LGL/ –Mycosis fungoides /Sézary syndrome –Peripheral T cell lymphomas, unspecified –Angioimmunoblastic T cell lymphoma –Angiocentric lymphoma –Intestinal T cell lymphoma –Adult T cell lymphoma/leukemia –Anaplastic large cell lymphoma

14. Staging Classification Ann Arbor Stage I: involvement of single lymph node region or a single extralymphatic organ or site Stage II:involvement of two or more lymph node regions on same side of diaphragm or localized involvement of an extralymphatic organ or site Stage III:involvement of lymph node regions on both sides of the diaphragm or localized involvement of an extralymphatic Stage IV:diffuse or disseminated involvement of one or more extralymphatic organs with or without lymph nod involvement A. Asymptomatic B. Symptomatic (B symptoms) X. Bulky disease ( > 1/3 widening of mediastinum, > 10cm max.dimension of nodal mass) E. Involvement of a single, localised, extranodal site

15. Staging evaluation for lymphoma (1) –pathologic documentation –physical examination –documentation of B symptoms –laboratory evaluation complete blood count, ESR liver function tests renal function tests lactate dehydrogenase monoclonal protein viral tests (HIV, CMB, EBV, HCV, HBV)

16. Staging evaluation for lymphoma (2) –chest radiograph –ultrasonography –CT scan of chest, abdomen and pelvis –bone marrow aspiration / biopsy –PET –endoscopy –bone radiographs –MRI –cell-surface marker phenotypic analysis –cytogenetics / gene rearrangement analysis

17. Immunophenotyping in B-lymphomas Type/AgSIgCD5CD20CD10CD19CD23CD38CD103 CLL+dim++-++-- FL+vb-+++--- MCL+m++-+--- PLL+b-+-+--- SMZL+m-+-+--- HCL+m-+-+--+ MM---/+---+-

18. Non-Hogdkin lymphoma - cytogenetics

19. International Prognostic Index (IPI) 1.Disease stage (I or II vs III or IV) 2.Age (60  vs >60) 3.Serum LDH concentration ( 1 x normal) 4.ECOG performance status (2< vs  2)

20. Treatment results of aggressive non-Hodgkin’s lymphomas according to the risk group Risk groupNo of risk CR 5-year survival factor % % Low 0-1 8773 Low intermediate 2 6750 High intermediate 3 5543 High 4-5 4426

21. Treatment of lymphoma Chemotherapy Immunotherapy Hematopoietic stem cell transplantation –autologous –allogeneic Radioimmunotherapy Surgery Radiotherapy Antibiotic therapy

22. Treatment of lymphoma First line treatment Treatment of relapse Treatment of refractory disease Treatment of high-risk patients in CR1 Supportive treatment

23. Treatment of lymphoma - chemotherapy Monotherapy –Chlorambucil –Purin analogs Polichemotherapy –COP –CHOP +/- rituximab –CBV –ESHAP –DHAP –EPOCH –CODOX/IVAC –ProMACE-cytaBOM

24. Treatment of lymphoma Immunotherapy –Monoclonal antibodies Anty-CD20 (Rituximab, Mabthera) Anty-CD52 (alemtuzumab, Campath) –Interferons –Interleukin 2 Combination therapy –CHOP+Rituximab Radioimmunotherapy –Zevalin : antyCD20+Y-ibritumomab tiuxetan –Bexxar: antyCD20+ I-tositumomab

25. Follicular lymphoma CVP vs R-CVP (n=321). Marcus R et al. Blood 2005

26. Diffuse large B-cell lymphoma OS in DLBCL > 60 yrs (n=399) CHOP vs CHOP-R. Coiffier et al. NEJM 2002

27. Hematopoietic stem cell transplantation in non-Hodgkin’s lymphomas 1. Refractory disease 2. Relapse 3. High risk in CR1 - T-cell lymphoma - primary mediastinal B-cell lymphoma - mantle cell lymphoma

28. Years 026 13 45 Probability of survival after autologous transplant for follicular lymphoma, by disease status, 2000-2008 Chemosensitive (N=1,995) Chemoresistant (N=160) 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001 SUM10_51.ppt Slide 44

29. Years 026 13 45 Probability of survival after autologous transplant for diffuse large B-cell lymphoma, by disease status, 2000-2008 Chemosensitive (N=6,203) Chemoresistant (N=447) 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 Probability of Survival, % P < 0.0001 SUM10_53.ppt Slide 46