Rarer Lymphomas. Dr Pam McKay Beatson West of Scotland Cancer Centre

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1 Rarer Lymphomas Dr Pam McKay Beatson West of Scotland Cancer Centre

2 Non Hodgkin Lymphoma Cancer of lymphatic system 6 th commonest cancer in UK (2010) ~12,180 new cases in UK; 54% males 986 in Scotland; male = female

3 NHL by age group, WOSCAN Non Hodgkin Lymphoma Incidence of most subtypes increases with age: >70% of NHL patients are > 60 years at diagnosis in WOSCAN 0 < >=90

4 4 th Edition, 2008

5 WHO classification (2008) Disease entities are stratified according to their cell of origin and also whether they are derived from precursor or mature lymphoid cells > 90% are B cell

6 Classification by cell of origin B cell lymphomas: >25 subtypes diffuse large B cell lymphoma (DLBCL) commonest subtype follicular lymphoma (FL) T cell: ~7% (>20 subtypes) majority are mature T cell lymphomas

7 NHL Classification Angioimmunoblastic Peripheral T cell Unspecified and Anaplastic (Alk ve) 32% (n= 8) WoSCAN Audit Data: 2012 (NHL = 430, T Cell = 25)

8 HMRN data ( ) DLBCL 48% MZL 20% FL 19% T cell lymphomas 6% MCL 5% Burkitts Lymphoma 2%

9 Clinical Behaviour Aggressive (curable) DLBCL Burkitt s lymphoma Lymphoblastic lymphoma Indolent (essentially incurable) Follicular lymphoma Marginal zone lymphoma

10 Examples of Rarer Lymphomas marginal zone lymphoma mantle cell lymphoma hairy cell leukaemia immunosuppression related lymphomas

11 Marginal Zone Lymphoma (MZL) extranodal MZL splenic MZL nodal MZL

12 Extranodal Marginal Zone Lymphoma (ENMZL) MALT lymphoma (mucosal associated lymphoid tissue) clinical presentation depends on location of the lymphoma usually indolent disease, no B symptoms, normal LDH usually localized disease. Can be multifocal or affect different EN sites simultaneously

13 ENMZL stomach small intestine lacrimal glands salivary glands thyroid lung breast skin

14 ENMZL and infection May be associated with chronic stimulation from an underlying pathogen stomach helicobacter pylori small bowel campylobacter lacrimal glands chlamydia psittaci skin borrelia burgdorferii nodal, splenic, EN hepatitis C virus

15 H Pylori in gastric biopsy

16 ENMZL and Connective Tissue Disorders Association between lacrimal, salivary and lung ENMZL and connective tissue disorders especially Sjogren syndrome

17 ENMZL - treatment Gastric antihelicobacter therapy low dose gastric irradiation Lacrimal glands doxycycline if +ve serology for chlamydia low dose radiotherapy if symptomatic observation if not unsightly and not interfering with lid closure or vision

18 ENMZL - treatment Skin +ve serology for borrelia doxycycline (minimum 3 weeks) localised and fully excised observe partially excised and symptomatic low dose RT multifocal low dose RT to symptomatic lesions; Rituximab for widespread troublesome lesions

19 ENMZL - treatment Sites not associated with infections eg salivary glands, breast, lung localised and asymptomatic observe localised and symptomatic low dose irradiation multifocal (lung) usually symptomatic and need treatment R-chemo eg RCVP, RFC

20 Splenic MZL (SMZL) usually present with splenomegaly and cytopenias eg anaemia, thrombocytopenia clonal B cell population detected in peripheral blood may have BM involvement and nodal disease (usually small volume)

21 SMZL indications for treatment bone marrow failure B symptoms bulky LNs or spleen immune complications eg AIHA, ITP watch and wait if asymptomatic

22 SMZL - treatment Rituximab 375mg/m 2 weekly x 4 high response rates % not improved by addition of chemotherapy often sustained response may respond to 2 nd course preferred to splenectomy improved DFS avoids short and long term risks of splenectomy

23 Nodal MZL uncommon (<2% of all lymphomas) often present with incidental lymphadenopathy indications for treatment: cytopenias B symptoms bulky LNs immune complications

24 Nodal MZL - treatment Early stage (I or II with contiguous LNs) IFRT Advanced stage (II-IV) watch and wait asymptomatic or frail/elderly 1 st line therapy: usually extrapolated from FL RCVP or R-chlorambucil (less fit) anthracyclines rarely justified

25 Mantle cell lymphoma (MCL) ~3-10% of all lymphomas indolent lymphoma but worst prognosis of all lymphomas responds well to initial chemotherapy but short duration of remission with OS 4-5 years (previously 2-3 years)

26 Survival of B-cell lymphoma subtypes

27 MCL characterised by t11;14 translocation over expression of cyclin D1 (cell cycle protein)

28 MCL mainly affects elderly males median age years present with widespread disease with lymphadenopathy, splenomegaly, bone marrow, and gi tract involvement common peripheral blood involvement common

29 MCL peripheral blood lymph node

30 Biopsy from terminal ileum H&E cyclin D1

31 MCL - treatment CD20+ but less responsive to rituximab than follicular lymphoma or DLBCL meta-analysis (Schulz, 2007) in favour of rituximab aim of treatment depends on age and fitness essentially incurable

32 MCL - treatment younger, fitter patient HDT and autologous PBSCT aim to achieve as good a response as possible prior to transplant cytarabine most important drug in MCL Rituximab approved in WOSCAN in 2009 in combination with cytarabine containing regimen for those aiming for transplant

33 MCL - treatment Elderly, more frail patients: no standard of care WOSCAN, 2009: rituximab not recommended pending results of NCRI study FC v FCR. ASH abstract, 2011: FC-R superior in terms of RR, PFS and OS R-chemo now standard of care: R-CVP, R-chlorambucil, R-CHOP, R-FC, R-bendamustine

34 MCL R-Bendamustine awaiting licence and SMC approval available in England via CDF (off label therefore needs local governance approval) Rummel et al. Lancet 2013; 381: ; ph III randomised study BR v R-CHOP median PFS: BR 35.4 mths vs R-CHOP 22.1 grade 3 or 4 neutropenia: 10.7% vs 46.5%

35 MCL R-Bendamustine Flinn et al. J Clin Oncol 2013; 31: suppl; abstract 8537 (BRIGHT study) ph III, randomised study. BR vs R-CHOP and R-CVP. CR 50% (BR) vs 27% (R-CHOP/R-CVP). BR better tolerated

36 MCL - Ibrutinib oral Bruton s tyrosine kinase (BTK) inhibitor promising single agent activity in rel/ref MCL ORR 68%, CR 22% (Wang et al, ASH 2012) SHINE (MCL3002): ph 3 double blinded study in elderly patients 65 yrs R- Bendamustine + oral ibrutinib/placebo if CR/PR maintenance R Ibrutinib or placebo continuing until disease progression

37 Hairy Cell Leukaemia rare B cell LPD infiltration of spleen and bone marrow pancytopenia respond well to purine analogues eg cladribine with durable responses often respond equally well at relapse splenectomy no longer standard therapy

38 Hairy cell leukaemia (HCL)

39 Rituximab in HCL strong CD20 expression BCSH guideline recommends rituximab + purine analogue at relapse (studies shown addition of R increased CR rate (89% cf 68%) WOSCAN: advocate rituximab at time of relapse only in those who failed to achieve a CR with 1 st line therapy

40 B cell post transplant lymphoproliferative disorders (PTLD) may occur in association with bone marrow or solid organ transplant eg renal, liver often associated with EBV infection patients with EBV + lymphoma may respond to reduction in IS alone

41 PTLD - BCSH and British Transplant Society Guideline IS reduced to minimum level consistent with organ retention surgical resection and/or RT for localised stage I disease If incomplete response to reduced IS and low risk disease rituximab monotherapy If incomplete response to rituximab or high risk disease or critical organ compromise R-chemo eg R-CHOP

42 Challenges in Lymphoma Treatment Lack of RCT except in commoner lymphomas Diffuse large B cell lymphoma (DLBCL) Standard treatment is R-CHOP Follicular lymphoma (FL) Standard treatment is R-CVP (R-CHOP; R- FC)

43 Rituximab greatest impact in lymphoma treatment in decades DLBCL: Rituximab improved all outcomes by ~15-20% FL: Rituximab improved all outcomes (more difficult to show survival benefit in view of long natural history)

44 Rituximab in other CD20+ B cell lymphomas Rituximab appears to be of benefit in all CD20+ lymphomas efficacy may vary between subtypes even those with weaker CD20 expression eg CLL respond with good effect

45 Rituximab only licensed for use in DLBCL, FL and CLL (approved by SMC and NICE for certain indications) no commercial incentive for manufacturer to apply for a license in the less frequent B cell lymphomas

46 WOSCAN approach, 2009 Guidance for off label use of rituximab in haematological malignancies DLBCL: 1 st line with non-anthracycline regimen DLBCL: 1 st relapse with salvage regimen MCL: 1 st line therapy with cytarabine- containing chemo in those planned for autologous transplant BL 1 st line therapy with CODOX-M/IVAC

47 WOSCAN approach, 2013 Updated guidance to include MCL: patients not suitable for autografting MZL: nodal in conjunction with chemotherapy splenic as single agent ENMZL- in rare cases where systemic treatment required eg multifocal lung or skin lesions

48 Waldenstrom macroglobulinaemia LPHL HCL B cell post transplant LPD SLL

49 Beatson West of Scotland Cancer Centre

50 Any questions?