aggressive lymphoma kim linton senior lecturer and honorary consultant lymphoma meeting, 13 th...

Aggressive lymphoma

Kim LintonSenior Lecturer and Honorary Consultant

Lymphoma Meeting, 13th October 2010

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


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


UK incidence by subtype


Rate per 100,000 Median age at diagnosis

Expected UK cases per year

DLBCL 7.9 70 4500

Follicular lymphoma

3.1 64 1750

Peripheral T cell NHL

1.1 65 600

Mantle lymphoma 0.8 74 450

Burkitt’s lymphoma

0.4 52 210

Source: www.hmrn.org

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


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


Survival rates with modern treatment


5-year survival

Burkitt’s 70-80%

DLBCL 50-60%

T cell NHL 30-40%

Mantle 5-25%

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


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

Meet the team including clinical nurse specialist, research nurse +/- psycho-oncology nurse

Written information including lymphoma information pack, treatment leaflet +/- clinical trial


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)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


Diagnostic confirmation

Clinical features Histomorphology (light microscopy) Immunophenotype (IHC, flow cytometry) Cytogenetic features (FISH) Radiological features (also for staging)


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)


IPI to predict survival in DLBCL & TNHL

DLBCL (Sehn et al., Blood 2007) T cell NHL (Sonnen et al., 2005)

Score 1 point each for: Age > 60, Elevated LDH, PS ≥ 2, Stage lll/lV, Extranodal sites > 1Low = 0,1; low intermediate = 2, high intermediate = 3, high = 4+


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


Gene expression profiling and outcome prediction

Alizadeh et al, Nature 2000; Wright et al, PNAS 2003

Rosenwald et al, Cancer Cell 2003


Aims of treatment

Symptom control and improved QOL

Disease remission, cure

Minimise early and late toxicity


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


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


Treatment and typical outcomes

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


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


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


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


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?


Christie lymphoma website

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

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


The Manchester Lymphoma Group


John RadfordProfessor

Susan Neeson Caroline Hamer

Suzanne Allibone Research Nurses

Jane GibsonClinical Nurse

SpecialistValerie Goode

Nurse Clinician

Kim LintonSenior Lecturer

Tim IllidgeProfessor

Richard CowanMaggie Harris

Ed SmithNHS

Louise Carter Claire Mitchell

Specialist Registrars

Specialist Registrar

Adam Gibb Clinical Research

Fellow

Tanya Massey Hannah JohnsonEmmie Taylor Data Managers

Clinico-pathological features

DLBCL T cell NHL1 Mantle Burkitt’s

Extranodal disease*

30-40% 32% > 1site2

B symptoms 30% 50%1 43%2

Raised LDH >50% 98%1

WHO 0-1 most 88%1 9%2

Stage 3/4 65-75% 50%1 84%2 38%

Bone marrow +ve

10-20% 79%2 33%

1 Ko et al., 2009, 2 Hoster et al., 2008, 3

* GI Tract, bone, soft tissue, kidney, CNS, testis, lung, orbit, thyroid, salivary gland etc


aggressive lymphoma kim linton senior lecturer and honorary consultant lymphoma meeting, 13 th...

Documents

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