Aggressive lymphoma

1
Aggressive lymphoma

• Kim Linton
• Senior Lecturer and Honorary Consultant
• Lymphoma Meeting, 13th October 2010

2
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
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
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
Burkitts lymphoma 0.4 52 210
Source www.hmrn.org
5
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 its impossible to
  diagnose the subtype without a biopsy and
  (usually) a specialist pathology review

6
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
Survival rates with modern treatment

• 5-year survival
• Burkitts 70-80
• DLBCL 50-60
• T cell NHL 30-40
• Mantle 5-25

8
Treatment principles

• Aggressive lymphomas are potentially curable,
  especially DLBCL and Burkitts
• 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
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

10
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
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
Diagnostic confirmation

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

13
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
IPI to predict survival in DLBCL TNHL
Score 1 point each for Age gt 60, Elevated LDH,
PS 2, Stage lll/lV, Extranodal sites gt 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
No widely-used prognostic systems for Mantle and
Burkitts lymphomas

• Mantle lymphoma IPI (MIPI) based on age,
  performance status, LDH), and leukocyte count
  awaits validation (Hoster et al., 2008)
• No Burkitts prognostic score in use
• Overlapping clinicopathological prognostic groups
  and changing treatments highlight a need for new
  predictors of response

16
Gene expression profiling and outcome prediction
Alizadeh et al, Nature 2000 Wright et al, PNAS
2003
Rosenwald et al, Cancer Cell 2003
17
Aims of treatment

• Symptom control and improved QOL
• Disease remission, cure
• Minimise early and late toxicity

18
Principles of treatment

• Multi-drug chemotherapy usually with steroids and
  Rituximab in DLBCL to induce remission
• Maintain dose intensity especially in Burkitts,
  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 (Burkitts, testicular)
• Response consolidation with BEAM autograft, in
  first remission in younger, fitter patients with
  T cell or Mantle lymphoma

19
Treatment tolerability

• Most treatment delivered as outpatient except
  intensive regimens for Burkitts
• Toxicity is acceptable especially using
  CHOP/RCHOP for Tcell and DLBCL
• Fludarabine (mantle), ifos/AraC and Burkitts
  regimens associated with a significant risk of NPS

20
Treatment and typical outcomes
21
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 Burkitts, but no evidence-base
• CHOP Campath (anti CD52 mab) phase l trial in T
  cell lymphoma

22
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
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
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
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
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
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
Clinico-pathological features
DLBCL T cell NHL1 Mantle Burkitts
Extranodal disease 30-40 32 gt 1site2
B symptoms 30 501 432
Raised LDH gt50 981
WHO 0-1 most 881 92
Stage 3/4 65-75 501 842 38
Bone marrow ve 10-20 792 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