Aggressive lymphoma

1. We care, We discover, We teach Aggressive lymphoma Kim Linton Senior Lecturer and Honorary Consultant Lymphoma Meeting, 13th October 2010

2. We care, We discover, We teach Definition of aggressive lymphoma • A heterogenous collection of subtypes, not a diagnostic entity • Untreated survival measurable in months • 75 lymphoma subtypes in WHO 2008 classification; at least 2/3 can behave aggressively

3. We care, We discover, We teach UK Incidence • This equates to a UK burden of ~7000 cases of aggressive lymphoma per year (based on 10,920 new NHL diagnoses in the UK in 20071) 1 Cancer Research UK statistics

4. We care, We discover, We teach UK incidence by subtype Source: www.hmrn.org

5. We care, We discover, We teach Common presenting features • More than two-thirds of all NHL cases are diagnosed in people aged 60 and over • In general, symptoms develop rapidly and the patient becomes ill within weeks to months • Clinical features overlap and it’s impossible to diagnose the subtype without a biopsy and (usually) a specialist pathology review

6. We care, We discover, We teach Recognising aggressive lymphoma • Localised or generalised firm, discrete, rubbery and painless lymphadenopathy, typically enlarging over days to weeks • Systemic features (fatigue, anorexia, pruritis, weakness) including B symptoms; ≥ 10% weight loss in 6 months, or unexplained fevers, or drenching (night) sweats • Abnormal blood tests, most commonly anaemia and raised LDH

7. We care, We discover, We teach Survival rates with modern treatment 5-year survival Burkitt’s 70-80% DLBCL 50-60% T cell NHL 30-40% Mantle 5-25%

8. We care, We discover, We teach Treatment principles • Aggressive lymphomas are potentially curable, especially DLBCL and Burkitt’s • Early referral, rapid staging and timely treatment is essential • If in doubt, discuss or refer any cases with suspected aggressive lymphoma • Steroids (oral or iv) are a useful pre-treatment but should only be used if the diagnosis has been made, and with appropriate tumour lysis precautions

9. We care, We discover, We teach The new patient visit - 1 • Full history and examination esp. PS, nodal stations, liver, spleen, oral cavity & testes • Detailed discussion including nature of diagnosis, treatment, side effects and associated outcome • Clear timelines for investigations, start of treatment • Meetthe team including clinical nurse specialist, research nurse +/- psycho-oncology nurse • Written information including lymphoma information pack, treatment leaflet +/- clinical trial

10. We care, We discover, We teach The new patient visit - 2 • Arrange staging investigations: • Bloods: FBC, serum biochemistry including serum lactate dehydrogenase (LDH), uric acid, HIV in selected cases • Bone marrow trephine biopsy • Computed tomography (CT) of the neck, chest, abdomen, pelvis, and primary site of presentation (sometimes MR preferred) • PET-CT (currently only in DLBCL)

11. We care, We discover, We teach The new patient visit - 3 • Arrange pathology review • Arrange other investigations • MUGA to assess LVEF • LP and intrathecal chemotherapy administration in cases with high CNS risk • Semen storage • Calculate prognostic score • loco-regional MDT to discuss case with full results

12. We care, We discover, We teach Diagnostic confirmation • Clinical features • Histomorphology (light microscopy) • Immunophenotype (IHC, flow cytometry) • Cytogenetic features (FISH) • Radiological features (also for staging)

13. We care, We discover, We teach Ann Arbor Staging • Stage I disease in single lymph node or lymph node region • Stage II disease in two or more lymph node regions on  same side of diaphragm • Stage III disease in lymph node regions on both sides of the diaphragm are affected  • Stage IV disease is wide spread, including multiple involvement at one or more extranodal (sites such as the bone marrow) • A = without symptomsB = with symptoms including unexplained weight loss (10% in 6 months prior to diagnosis,  unexplained fever, and drenching night sweats)

14. We care, We discover, We teach IPI to predict survival in DLBCL & TNHL Score 1 point each for: Age > 60, Elevated LDH, PS ≥ 2, Stage lll/lV, Extranodal sites > 1 Low = 0,1; low intermediate = 2, high intermediate = 3, high = 4+ DLBCL (Sehn et al., Blood 2007) T cell NHL (Sonnen et al., 2005)

15. We care, We discover, We teach No widely-used prognostic systems for Mantle and Burkitt’s lymphomas • Mantle lymphoma IPI (MIPI) based on age, performance status, LDH), and leukocyte count awaits validation (Hoster et al., 2008) • No Burkitt’s prognostic score in use • Overlapping clinicopathological prognostic groups and changing treatments highlight a need for new predictors of response

16. We care, We discover, We teach Gene expression profiling and outcome prediction Alizadeh et al, Nature 2000; Wright et al, PNAS 2003 Rosenwald et al, Cancer Cell 2003

17. We care, We discover, We teach Aims of treatment • Symptom control and improved QOL • Disease remission, cure • Minimise early and late toxicity

18. We care, We discover, We teach Principles of treatment • Multi-drug chemotherapy usually with steroids and Rituximab in DLBCL to induce remission • Maintain dose intensity especially in Burkitt’s, using growth factors as needed • Tumour lysis precautions including allopurinol and fluids and in high risk cases, inpatient management for iv fluids,serum electrolyte monitoring / correction +/- rasburicase • CNS prophylaxis and, where indicated, CNS directed therapy (Burkitt’s, testicular) • Response consolidation with BEAM autograft, in first remission in younger, fitter patients with T cell or Mantle lymphoma

19. We care, We discover, We teach Treatment tolerability • Most treatment delivered as outpatient except intensive regimens for Burkitt’s • Toxicity is acceptable especially using CHOP/RCHOP for Tcell and DLBCL • Fludarabine (mantle), ifos/AraC and Burkitt’s regimens associated with a significant risk of NPS

20. Treatment and typical outcomes

21. We care, We discover, We teach Research focus – monoclonal antibodies • Addition of Rituximab to CHOP in DLBCL improves 5 year OS from 46% to 58% (Coiffier 2002) • Adding Rituximab to Mantle lymphoma treatment improves response but not survival (RFC vs FC randomised phase lll trial underway) • Rituximab used in Burkitt’s, but no evidence-base • CHOP + Campath (anti CD52 mab) phase l trial in T cell lymphoma

22. We care, We discover, We teach Research focus – prognostic biomarkers • PET-CT is a sensitive biomarker of metabolic activity and is routinely used to stage and restage DLBCL • A trial is investigating whether early PET after 2 cycles of RCHOP in DLBCL predicts survival • In a pilot study, blood-borne biomarkers of cell death measured in the first week after starting chemotherapy predicted radiological response at the end of planned treatment and survival; larger studies are planned

23. We care, We discover, We teach Research focus – prognostic biomarkers • DLBCL, T cell NHL and Mantle lymphomas are heterogeneous disease entities whose clinical behaviour cannot be predicted accurately • Laboratory techniques to carry out gene expression profiling on routinely collected diagnostic biopsies that we have developed will be used to profile tumours with disparate clinical outcomes to discover molecular-based prognostic biomarkers in aggressive lymphoma

24. We care, We discover, We teach Research focus – late effects • Late effects of treatment (chemotherapy and/or radiotherapy) are a major concern and undermine the quality and duration of life in long-term survivors • A large AZ collaborative research study is underway to develop sensitive blood borne and imaging biomarkers to predict heart damage in patients receiving anthracyclines

25. We care, We discover, We teach Research focus – recently completed studies in DLBCL • Does dose-dense scheduling improve survival • Does the addition of immunotherapy improve outcome and/or reduce cytotoxic requirements and late effects? • Can gemcitabine produce equivalent outcome to doxorubicin in patients with cardiac risk factors?

26. Christie lymphoma website http://www.christie.nhs.uk/research/themes/dg/htu/lymphoma/trials.aspx

27. We care, We discover, We teach Summary • Aggressive lymphomas are a heterogeneous and potentially curable group of diseases • Early recognition, referral and treatment is paramount • Current research aims to • Identify better prognostic biomarkers • Develop risk adapted individualised treatments to overcome adverse prognostic features, improve & minimise late effects of treatment

28. We care, We discover, We teach The Manchester Lymphoma Group John Radford Professor Tim Illidge Professor Richard Cowan Maggie Harris Ed Smith NHS Kim Linton Senior Lecturer Louise Carter Claire Mitchell Specialist Registrars Adam Gibb Clinical Research Fellow Specialist Registrar Susan Neeson Caroline Hamer Suzanne Allibone Research Nurses Tanya Massey Hannah Johnson Emmie Taylor Data Managers Jane Gibson Clinical Nurse Specialist Valerie Goode Nurse Clinician

29. We care, We discover, We teach Clinico-pathological features 1Ko et al., 2009, 2Hoster et al., 2008, 3 * GI Tract, bone, soft tissue, kidney, CNS, testis, lung, orbit, thyroid, salivary gland etc