lymphoproliferative disorders Flashcards
what is leukaemia
“white blood”
generally used to describe a cancer that you can see in the blood
what is lymphoma and what can they present w/
cancers of lymphoid origin
can present w/ lymphadenopathy or extranodal involvement or w/ bone marrow involvement
systemic (B) symptoms: weight loos (>10% in 6mths), fever, night sweats, pruritus, fatigue
diagnosing a leukaemia/lymphoma
> 70 different types, defined by the malignant cell characteristics
- biopsy - tells us what type it is (THIS IS HOW THE DIAGNOSIS IS MADE)
- clinical examination and imaging - tells us where it is (STAGING)
staging of lymphoma/leukaemia
location and extent of the disease
information about prognosis
sometimes influences treatment
lymphocyte differentiation
when can malignant conditions occur in the process of lymphocyte differentiation
bone marrow: earliest stages of lymphoid cell development e.g. acute lymphoblastic leukaemia
classifications of lymphomas
Hodgkin lymphoma is a specific disease
Non-Hodgkin lymphoma is everything else (~70 subtypes)
- divided into high and low grade
key lymphoproliferative disorders (common to least common)
Non-Hodgkin lymphoma
- high grade (diffuse large B cell lymphoma), low grade (follicular, marginal zone)
Chronic lymphocytic leukaemia (CLL) - presents in a similar way to low grade NHL
Hodgkin lymphoma
Acute lymphoblastic leukaemia (ALL)
how common are the different lymphoproliferative disorders
what is ALL
cancerous disorder of lymphoid progenitor cells
no differentiation, instead there is rapid and uncontrolled growth and accumulation
usually in bone marrow but they can go anywhere
normal lymphoid progenitor cells
immature
rapidly proliferating cells that differentiate into lymphocytes
what condition is this
ALL
how common is ALL
- incidence
- age
- what cell lineage
1-2/100 000 pop/yr
75% cases occur in children <6y/o
75-90% cases are of B cell lineage
how does ALL present
2-3wk hx of bone marrow failure or bone/joint pain
typical ALL hx
17y/o male
1mth impaired vision (both eyes)
1/2 stone weight loss
SOB on minimal exertion
fundoscopy: retinal haemorrhages
blood count for ALL
low Hb
high WCC
low plts
bone marrow - 90% B lymphoblasts
what can be seen here
normal bone marrow
white circles = fat
normal mix of different types of blood cells and platelets
what can be seen here
abnormal bone marrow
hypercellular and uniform cells
ALL cells characteristics
large cells
express CD19
CD34, TDT
haven’t had the chance to develop and mature
what is CD19
marker expressed by all B cells
what do CD34 and TDT indicate
markers of very early immature cells
treatment for ALL
induction chemotherapy to obtain remission
consolidation therapy
CNS directed treatment
maintenance treatment for 18mths
stem cell transplantation - if high risk of relapse
newer therapies for ALL
bi-specific T cell engagers (BiTe molecules)
CAR T cells
example of bi-specific T cell engagers
blinatumumab
how do bi-specific T cell engagers work
binds to tumour cells (CD19) and activates and recruits pts own T cells to attack the leukaemia cells
what are CAR T cells
chimeric antigen receptor T cells
how are CAR T cells made and used
patient/healthy 3rd party T cells harvested
transfected to express a specific T cell receptor expressed on leukaemia cells (CD19)
expanded in vitro
re-infused into patient
can be curative in pts w/ very resistant disease but very expensive
key side effects of T cell immunotherapy
cytokine release syndrome
neurotoxicity
T cell immunotherapy: cytokine release syndrome
fever, hypotension, SOB
CAR T cell effect correlated to presence of CRS - sig. number require ITU support
T cell immunotherapy: neurotoxicity features
confusion w/ normal conscious level
seizure, headache, focal neurology, come
ALL poor risk factors
increasing age
increased WCC
cytogenetics/molecular genetics: t(9;22), t(4;11)
slow/poor response to treatment
ALL outcome
adults:
- complete remission rate ~90%
- leukaemia free survival at 5y 30-35%
children
- 5y overall survival ~90%
- poor risk pts (slow response to induction or philadelphia +ve) 5y OS 45%
what happens to the cells in CLL
abnormal cells are mature - usually resemble normal, well behaved lymphocytes
- grow slowly, or not at all
- classic example of a low grade condition
- carry many of the normal markers that B lymphocytes have
what does a diagnosis of CLL require
lymphocyte count >5 (normal is <4)
CLL incidence
>1700 new cases p/a UK commonest leukaemia worldwide 2M:1F occasionally familial rare in far east
CLL presentation
often asymptomatic
frequently:
- bone marrow failure (anaemia, thrombocytopenia)
- lymphadenopathy
- splenomegaly (30%)
- fever and sweats (<25%)
less commonly:
- hepatomegaly
- infections
- weight loss
CLL associated findings
immune paresis
haemolytic anaemia
- 20% have +ve direct antiglobulin test
- 8% clinical evidence of haemolytic anaemia
what is immune paresis
loss of normal immunoglobulin function
how is CLL staged
Binet staging system
CLL - Binet staging
A - <3 LN areas, median survival same as age matched controls
B - ≥3 LN areas, ~8yrs med survival
C - stage B + anaemia/thrombocytopenia, ~6yrs
CLL indications for treatment
progressive bone marrow failure massive lymphadenopathy progressive splenomegaly lymphocyte doubling time <6mths or >50% increase over 2mths systemic symptoms AI cytopenias
CLL treatment
often nothing - watch and wait
cytotoxic chemotherapy
monoclonal antibodies
novel agents
cytotoxic chemotherapy for CLL
fludarabine
bendamustine
monoclonal antibodies for CLL
rituximab
obinatuzumab
novel agents for CLL
less immunosuppressive, oral treatments
Bruton tyrosine kinase inhibitor e.g. ibrutinib
PI3K inhibitor e.g. idelalisib
BCL-2 inhibitor e.g. venetoclax
CLL poor prognostic markers
advanced disease (stage B/C) atypical lymphocyte morphology rapid lymphocyte doubling time (<12mth) CD38+ expression loss/mutation p53, del 11q23 (ATM gene) unmutated IgVH gene status
presentation of lymphoma
lymphadenopathy/hepatosplenomegaly
extranodal disease
B symptoms
bone marrow invlolvement
assessment/staging of lymphoma
LN biopsy
CT scan
bone marrow aspirate and trephine
staging of lymphoma
I: 1 nodal site of involvement
II: 2 separate nodal sites, either above or below the diaphragm but not both
III: multiple nodal sites, both above and below the diaphragm
IV: extranodal disease involvement
A: absence of B symptoms
B: fever, night sweats, weight loss
how is NHL classified
lineage: B or T cell (90% B cell origin)
grade: high vs low
low grade NHL
indolent, often asymptomatic
responds to chemotherapy but incurable
high grade NHL
aggressive, fast growing
require combination chemo
can be cured
specific types of NHL
diffuse large B cell lymphoma:
- commonest subtype of lymphoma
- high grade
follicular lymphoma:
- 2nd commonest subtype of lymphoma
- low grade
- like CLL, watch and wait if not causing problems
- both arise from a transformation in the germinal centre of a LN
how are diffuse large B cell lymphoma and follicular lymphoma treated
combination chemotherapy:
anti-CD20 monoclonal ab + chemo
how common is HL
30% of all lymphomas
age of HL
M vs F
bimodal age curve:
15-35y/o
2nd peak later in life
1.9M:1F
associations w/ HL
EBV
familial and geographical clustering
treatment of HL
combination chemo (ABVD - 4 different drugs) \+/- radiotherapy monoclonal ab (anti-CD30) - brentuximab immunotherapy (checkpoint inhibitors)
PET scanning central to assessment of response to treatment
