1. Introduction to Low Grade Lymphomas Gena Piliotis

2. Objectives Classification of Low Grade Lymphomas Classification of Low Grade Lymphomas How to diagnose How to diagnose Prognosis Prognosis Treatment options Treatment options

3. Classification WHO – 2007 WHO – 2007 Mature B cell Mature B cell  Low Grade - Mostly nodal Mature T cell Mature T cell  Low Grade - Mostly Skin

4. B Cell Low Grade NHL

5. B Cell Low Grade Lymphomas Follicular Lymphoma Follicular Lymphoma  Grade I, II, III Marginal Zone Marginal Zone  Splenic (with villous lymphs)  Extranodal / MALT (mucosal associated lymphoid tissue)(mucosal associated lymphoid tissue)  Nodal/Disseminated Mantle Cell Lymphoma Mantle Cell Lymphoma Lymphoplasmacytic Lymphoma / Waldenstroms Lymphoplasmacytic Lymphoma / Waldenstroms Hairy Cell Leukemia Hairy Cell Leukemia

6. General Principals All CD 19/20 + All CD 19/20 + All surface immunoglubulin + All surface immunoglubulin + All can have prolonged asymptomatic phase All can have prolonged asymptomatic phase Watch and Wait first line therapy Watch and Wait first line therapy Not curable Not curable Median survival 5-10+ years Median survival 5-10+ years Multiple Treatment options available Multiple Treatment options available Pattern of diminishing returns Pattern of diminishing returns

7. Immunohistochemistry1920SIg510232543103 FM C7 Foll+++-++---- Marg+++------- Mantl++++--+/---+ Hairy+++/----++-+++ SLL++++-+-+-- Lymp++++----+--

8. Stage – Ann Arbor I - Involvement of a single lymph node region or a single extranodal site. I - Involvement of a single lymph node region or a single extranodal site. II - Involvement of two or more lymph nodes on the same side of the diaphragm or localized involvement of an extra lymphatic organ or site and one or more lymph nodes on the same side of the diaphragm. II - Involvement of two or more lymph nodes on the same side of the diaphragm or localized involvement of an extra lymphatic organ or site and one or more lymph nodes on the same side of the diaphragm. III - Involvement of lymph node regions on both sides of the diaphragm that may also be accompanied by involvement of the spleen or by localized involvement of an extra lymphatic organ or site or both. III - Involvement of lymph node regions on both sides of the diaphragm that may also be accompanied by involvement of the spleen or by localized involvement of an extra lymphatic organ or site or both. IV - Diffused or disseminated involvement of one or more extra lymphatic organs or tissues, with or without associated lymph node involvement. IV - Diffused or disseminated involvement of one or more extra lymphatic organs or tissues, with or without associated lymph node involvement. B - B Symptoms B - B Symptoms E - extranodal E - extranodal

9. Follicular Lymphoma Most Common Most Common  25 % of all NHL Variable clinical pattern / prognosis Variable clinical pattern / prognosis  Median survival 7-10 yrs Immunophenotype Immunophenotype  CD 19, 20, 10, bcl2, t(14;18) Histological Grade Histological Grade FLIPI – new international Scoring System FLIPI – new international Scoring System

10. Copyright ©2003 American Society of Hematology. Copyright restrictions may apply. Kadin, M. ASH Image Bank 2003;2003:100691 Figure 1. Low power view of lymph node showing uniform nodular pattern of neoplastic follicles

11. Follicular Histologic Grades Based on number of Large cells / hpf Based on number of Large cells / hpf Grade I Grade I  0-5 centroblasts / hpf Grade II Grade II  6-15 Grade III Grade III  >15  IIIa vs IIIb  ? More like DLBCL?

12. Copyright ©2003 American Society of Hematology. Copyright restrictions may apply. Kadin, M. ASH Image Bank 2003;2003:100691 Figure 6. follicular lymphoma 1/3 with predominance of centrocytes

13. International Scoring Systems IPI IPI  Age >60  Elevated LDH  Stage III/IV  ECOG >2  > 1 extranodal sites FLIPI  Age > 60  Elevated LDH  Stage III/IV  > 4 nodal sites  Hb < 120

14. Prognosis - FLIPI 0-1 risk factors 0-1 risk factors  5 yr OS = 90.6 %  10 yr OS = 71 % 2 risk factors 2 risk factors  5 yr OS = 77.6 %  10 yr OS = 51 % >= 3 risk factors >= 3 risk factors  5 yr OS = 52.5 %  10 yr OS = 36 %

16. Treatment Options Limited Stage I/II Limited Stage I/II  Radiation 3000 – 4000 cGy  40-50 % long term remission  Rare to relapse at site of radiation

17. Treatment Options Advanced Stage Disease Advanced Stage Disease  Watch and Wait  First line  Alkalator based chemo Chlorambucil, CVPChlorambucil, CVP  Combination therapy with Rituxan –Marcus et al, Blood 2005 RCVP vs CVP– 32 vs 15 mos PFSRCVP vs CVP– 32 vs 15 mos PFS Improvements in over all survivalImprovements in over all survival  Add Rituxan to first line

18. Other Treatment Options Purine Analogues – Fludarabine Purine Analogues – Fludarabine  No difference in OS vs CVP first line  Minor difference in PFS  Less salvageable  Use for Second line Anthracyclines – CHOP Anthracyclines – CHOP  No difference in OS vs CVP first line  Better RR but more toxic  Can only use once  ? Transformed patients  Use for Third line

19. Other Treatment Options Maintenance Rituximab Maintenance Rituximab  Double PFS  Emerging evidence to improved OS  Multiple regimens in literature  375 mg/m 2 q 3 mos x 2 years Data mainly from second line regimens Data mainly from second line regimens CCO funding CCO funding  Post first line combo immunochemotherapy  Within 6 months of chemo  Q 3 months x 2 year  Currently only funded once

20. Other Treatment Options Interferon Interferon  Consolidative after high dose chemo  Need high doses, possible improved PFS  Side Effects prohibit Radioimmune Conjugates (anti CD 20) Radioimmune Conjugates (anti CD 20)  Bexxar (I-131) Zevalin (Y-90)  >= 3 rd line  Can respond in Rituxan Failures  Bystander effect  Can have better PFS than prior regimen

21. Other Treatment Options Autologous Stem Cell transplant Autologous Stem Cell transplant  Not standard of care  May improve PFS – but not cure Allogeneic Stem Cell transplant Allogeneic Stem Cell transplant  Possible curative therapy  Still experimental Consider if young and high risk disease Consider if young and high risk disease  FLIPI high  Relapsed < 1 yr after first line

22. Follicular Grade III ? More like DLBCL? ? More like DLBCL? Anthracycline up front Anthracycline up front Grade IIIa Grade IIIa  > 15 centroblasts / hpf  centrocytes still present Grade IIIb Grade IIIb  sheets of centroblasts If behaving more aggressively treat like DLBCL If behaving more aggressively treat like DLBCL

23. Marginal Zone Lymphoma 8-10 % of NHL 8-10 % of NHL Can be associated with Hepatitis C Can be associated with Hepatitis C Immunophenotype Immunophenotype  + CD 19, 20, SIg  - CD 10, 5, 23 Subtypes Subtypes  Splenic Lymphoma with/without villous lymphocytes  Extranodal / MALT  Nodal with/without monocytoid lymphs

24. Subtypes Marginal Zone Lymphoma PFSOS

25. Splenic Marginal Zone Rare – 1% NHL Rare – 1% NHL Spleen and Bone Marrow involved Spleen and Bone Marrow involved Hepatitis C Hepatitis C Autoimmune Cytopenias Autoimmune Cytopenias Indolent Disease Indolent Disease  Median Survival 8-10 yrs

26. Survival of Splenic Marginal zone Patients Survival of Splenic Marginal zone Patients Survival of Splenic Marginal zone who achieve CR vs those who don’t Figure 2. Survival of patients who obtained complete response (CR) and non- complete response (nCR) Figure 1. OS and FFS of the whole series Figure 3. Survival of patients with performance status ECOG 0-1 versus 2-3 at diagnosis

27. Splenic Marginal Zone Treatment Watch and Wait Watch and Wait First Line First Line  Splenectomy Second Line Second Line  Treat like Follicular

28. Extranodal / MALT Mucosal Associated Lymphoid Tissue Mucosal Associated Lymphoid Tissue 5 % of NHL 5 % of NHL Breast, lung, orbit, GI, GU, Skin, H&N Breast, lung, orbit, GI, GU, Skin, H&N Most common in Stomach Most common in Stomach Chronic antigenic stimulation Chronic antigenic stimulation  H pylori  Hepatitis C  Chlamydia  Borrelia

29. Gastric MALT - Staging I - Tumour confined to GI tract I - Tumour confined to GI tract  single or multiple lesions Endoscopic UltrasoundEndoscopic Ultrasound –Mucosal vs Muscularis II - Tumour extending into abdomen II - Tumour extending into abdomen II 1 local perigastric nodesII 1 local perigastric nodes II 2 distant nodesII 2 distant nodes IIE – Penetrating serosa into adjacent organs IIE – Penetrating serosa into adjacent organs IV - Disseminated IV - Disseminated

30. Gastric Malt Prognosis Prognosis  Indolent Disease  Tends to stay localized to stomach  5 yr OS 80-90%

31. Figure 4 Figure 5

32. Gastric Malt - Treatment Localized to Stomach Localized to Stomach  Hpylori eradication alone  60-85 % remissions  May take up to 18 mos Need repeated endoscopiesNeed repeated endoscopies  Can consider if low grade lesions confined to the mucosa  Should be offered to all patients in combination

33. H pylori Eradication Amoxicillin 1gm bid x 10 days Amoxicillin 1gm bid x 10 days Clarithromycin 250 mg bid x 10 days Clarithromycin 250 mg bid x 10 days Omeprazole 20 mg bid x 10 days Omeprazole 20 mg bid x 10 daysor Bismuth 302 mg qid x 14 days Bismuth 302 mg qid x 14 days Metronidazole 50 mg tid x 14 days Metronidazole 50 mg tid x 14 days Tetracycline 50 mg qid x 14 days Tetracycline 50 mg qid x 14 days Omeprazole 20 mg bid x 14 days Omeprazole 20 mg bid x 14 days

34. Gastric MALT – Treatment Radiation Radiation  300 cGy in 15 fractions Chemotherapy Chemotherapy  If radiation refractory  Or disseminated  Treat like follicular

35. Non Gastric Extranodal MALT Localized Localized  2400 cGy in 12 – 3600 cGy in 18 Disseminated Disseminated  Treat like Follicular

36. Nodal Marginal +/- monocytoid lymphs Rare – 1-2 % NHL Rare – 1-2 % NHL Prognosis is poorest among subtypes Prognosis is poorest among subtypes  Median Survival 5 yrs Treatment Options Treatment Options  Like Follicular Lymphoma

37. Nodal Marginal Zone Lymphoma

38. Mantle Cell Lymphoma Behaves like both aggressive and indolent Behaves like both aggressive and indolent Not curable, but aggressive course Not curable, but aggressive course More extranodal disease / organ involvement More extranodal disease / organ involvement Blastic Phase Blastic Phase

39. Mantle Cell Immunophenotype Immunophenotype  + CD 19, 20, 5, 43, FMC7, SIg (IgM/D)  - CD 10, 23  t (11:14)  Cylcin D1 over-expression / bcl-2 + Prognosis Prognosis  Low IPI – 5 yr OS 50%  High IPI – 5 yr OS 0 %

40. Mantle Cell - Treatment Watch and Wait Watch and Wait Clinical Trials Clinical Trials Auto SCT has been disappointing Auto SCT has been disappointing Treat like Follicular Treat like Follicular Consider Allo SCT if young and high risk Consider Allo SCT if young and high risk

41. Hairy Cell Leukemia Rare - <1% of all NHL Rare - <1% of all NHL Pancytopenia / Splenomegally Pancytopenia / Splenomegally Circulating atypical cells Circulating atypical cells “Dry Tap” – bone marrow fibrosis “Dry Tap” – bone marrow fibrosis

42. Copyright ©2003 American Society of Hematology. Copyright restrictions may apply. Kadin, M. ASH Image Bank 2003;2003:100609 Figure 8. Hairy cell leukemia, peripheral blood - Wright-Giemsa stain - Mononuclear cells with surface membrane projections

43. Hairy Cell Leukemia Immunophenotype Immunophenotype  + CD 19, 20, 25, 103, FMC7, SIg  - CD 10, 5, 23 Staging Staging  No standard staging  Age > 50 / nodal involvement Prognosis Prognosis  Favourable, very indolent disease  5 yr OS > 90 %

44. Hairy Cell - Treatment Watch and Wait Watch and Wait  Hb >100 g/L Neuts > 1.0 Plts > 50 First Line First Line  2CDA / cladrabine  7 day continuous / 5 day pulse  RR >80 %  12 yr PFS 54% / OS 87%

45. Hairy Cell - Treatment Second Line Second Line  2CDA  RR > 50% Third Line Third Line  Splenectomey  Interferon  Rituxan

46. Lymphoplasmacytic Lymphoma Rare – 1% NHL Rare – 1% NHL Nodal / Spleen / Bone Marrow involved Nodal / Spleen / Bone Marrow involved Monclonal protein – IgM Monclonal protein – IgM Hyperviscosity Hyperviscosity Autoimmune Complications Autoimmune Complications  AIHA, ITP, vasculitis, cryoglobulins

47. Lymphoplasmacytic Immunophenotype Immunophenotype  + CD 19, 20, 22, 38, 79a, SIg (IgM)  - CD 23, 10, 5 Morphology Morphology  Mature lymphocytes  Plasmacytoid features

48. Lymphoplasmacytic Staging Staging  Use Ann Arbor – but not as helpful Poor Prognostic Features Poor Prognostic Features  Age > 60  Male  Hb <110  IgM > 40  High Beta 2 microglobulin  Low albumen

49. Lymphoplasmacytic Scoring Prognosis (1 point each) Scoring Prognosis (1 point each)  Age >65  Albumen <40  At least 1 cytopenia  At least 2 cytopenia Low (0/1)5yr OS 83% Low (0/1)5yr OS 83% Interm (2)5yr OS 62% Interm (2)5yr OS 62% High (3/4)5yr OS 25% High (3/4)5yr OS 25%

50. Lymphoplasmacytic Watch and Wait Watch and Wait First line First line  Like Follicular Plasma exchange Plasma exchange  Hyperviscocity  Neuropathy Autologous Stem Cell Transplant Autologous Stem Cell Transplant Allogenic Stem Cell Transplant Allogenic Stem Cell Transplant