Lymphoproliferative Disorders Flashcards
Most lymphomas affect lymph nodes to some extend but can effect the whole ____
body
what is leukaemia?
•Generally used to describe a cancer that you can see in the blood
what is a lymphoma? and how does it present?
- Cancers of lymphoid origin
- Can present with enlarged lymph nodes (lymphadenopathy)
or
•with extranodal involvement (These cells are blood cells so can go anywhere in the body)
or
- with bone marrow involvement
- Systemic (B) symptoms - Weight loss (> 10% in 6 months), fever, night sweats, pruritis, fatigue
Diagnosing a lymphoma/ leukaemia - how is it done?
- > 50 different disease entities, defined by the malignant cell characteristics (Not defined by clinical presentation but rather malignant cell characteristics)
- Biopsy (e.g. lymph node, bone marrow) tells us what type it is – THIS IS HOW THE DIAGNOSIS IS MADE
- Clinical examination and imaging (e.g. CT) tell us where it is – this is STAGING
- Describes the location and extent of the disease
- Gives information about prognosis
- Sometimes influences treatment
where does lymphoproliferative disorders occur?
Malignant counterpart of plasma cells is a myeloma
ALL is typically a bone marrow disease
Plasma cells that release antibody tend to go back to bone marrow and take-up room
what are hodgkin and on-hodgkin lymphomas?
Hodgkin lymphoma is a specific disease
Non-Hodgkin lymphoma is everything else (~ 70 subtypes)
Therefore, non-Hodgkin lymphoma is a broad term! (NHL is not as helpful)
what are the different Lymphoproliferative disorders?
•Non-Hodgkin lymphoma (NHL)
- High-grade (diffuse large B-cell lymphoma)
- Low-grade (e.g. follicular, marginal zone)
- Chronic lymphocytic leukaemia (CLL)
- Hodgkin lymphoma
- Acute lymphoblastic leukaemia (ALL)
NHL is the commonest lymphoma and the commonest of that is diffuse large B-cell lymphoma
what is Acute lymphoblastic leukaemia (ALL)? (leasst common)
•Cancerous disorder of lymphoid progenitor cells
- Normal = Immature, rapidly proliferating cells that differentiate into lymphocytes
- Leukaemia = No differentiation. Instead, rapid, uncontrolled growth and accumulation
- Usually in bone marrow but they can go anywhere
Minimal differentiation and maturation. Fill up bone marrow very quickly
Typically see it arise in bone marrow but can arise anywhere so can behave in funny ways as it is a blood cell and can move anywhere in the body
what is the epidemiology of Acute lymphoblastic leukaemia?
- Incidence 1-2/100,000 population/year
- 75% cases occur in children < 6 years
- 75-90% cases are of B-cell lineage (You do get T cell ALL)
- Present with 2-3 week history of bone marrow failure or bone/joint pain (short history)
Typical ALL case history:
- 17yo male
- 1 month impaired vision (both eyes)
- 1/2 stone weight loss (mild weight loss)
- breathless on minimal exertion
Retinal haemorrhages - Often a source of presentation for some haematological presentations
•Investigations:
- Haemoglobin 38 g/L (120-140)
- White cell count 370 x 109/L (4-11)
- Platelets 68 x 109/L (150-400)
• Bone marrow - 90% B-lymphoblasts (almost full of B lymphoblasts so B-cell ALL)
Profoundly anaemic – coping well as young guy
Very marked leucocytosis (white cell count baove normal range)
Thrombocytopenia (low levels of platelets)
Almost certain its an acute leukaemia
ALL: marrow
what does bone marrow look like in ALL?
Left is normal bone marrow – white fatty lumps, mixed with normal blood cells
Megakaryocytes = make platelets
Nice spread of different cells
Right is full of purple stuff so filled with cells, markedly hypercellular
All pretty much the same cells
Pink is bony trabeculae
what are the characteristics of ALL cells?
- Large cells - Big large abnormal cells. Very primitive and immature
- Express CD19 – all B-cells have this
- CD34, TDT – markers of very early, immature cells
- Not much else – they have not had the chance to develop and mature
Can do immunophenotyping to tell the difference and this can measure if there is things found to it, can tell what m arkers these cells are carrying
May get clues to what type of leukaemia it is
what is the treatment of ALL?
•Standard treatment
- Induction chemotherapy to obtain remission - Give multiagent combination chemotherapy to obtain a remission which is killing off the leukaemia and allowing normal bone marrow to come back in – this is quite easy to achieve in ALL but we need to give a lot more therapy to stop it coming back
- Consolidation therapy - Prolonged consolidation therapy
- CNS directed treatment - High risk of acute leukaemia’s or high grade leukaemia’s or lymphomas involving the CNS
- Maintenance treatment for 18 months
•Stem cell transplantation (if high risk) - If you have a high risk case and you think the risk of relapse is significant then we would do a transplant but it has its own risks so balance that against the risk of relapse
what are some newer therapies for treating ALL?
1) Bi-specifc T-cell engagers (BiTe molecules) – e.g. Blinatumumab
Directing the patients own immune system to kill the cells
Binds to tumour cells and also T cells
2) CAR (chimeric antigen receptor T-cells)
- 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
Taken patient own T cells out. Train T cell to express specific T cell receptor against the CD19 marker and then grown up in the lab and then reinfused to the patient
A bit more like a transplant. Very effective, curative. Very expensive
what are some key side effects with T-cell immunotherapy?
what are some ALL poor risk factors?
- Increasing age (As you get older risk of relapse goes up)
- Increased white cell count (at presentation does worse)
- Cytogenetics/molecular genetics - t(9;22); t(4;11)
- Slow/poor response to treatment (measure how deeply the leukemia is responding)
what is the outcome of ALL?
•Adults with ALL:
- complete remission rate ~90%
- leukaemia-free survival at 5y 30–35%
•Children with ALL
- 5y overall survival ~90%
- Poor risk patients (slow response to induction or Philadelphia positive) 5y OS 45%
Children have a great outcome
ALL: summary
what is the typical presentation?
and how is it treated?
•Typical presentation:
- Bone marrow failure +/- raised white cell count
- Bone pain, infection, sweats
(Bone marrow failure = low counts or raised WCC – not mandatory)
•Treated with multi-agent intensive chemotherapy +/- allogeneic stem cell transplant
Biiopsy is key in diagnosis
where do lymphomas/CLL occur?
These cell starting to move out of bone marrow and into secondary lymphoid tissues
Most lymphomas are B-cell lymphomas
Due to germinal centre = where B cells encounter antigen
how is the CLL diagnosis made?
- Although the term “leukaemia” is used, it is very different to ALL
- Unlike ALL, the abnormal cells are mature - they 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
•Requires a lymphocyte count of > 5 (normal is < 4)
what is the incidence of CLL?
- > 1700 new cases CLL per year in the UK
- Commonest leukaemia worldwide
- 2 males: 1 female
- Occasionally familial
- Rare in far East – this likely indicates a Geographic/ ethnic role in pathogenesis
Most dont die with it, they live with it for long periods
how does CLL present?
- Often assymptomatic at presentation (Often picked up through routine annual blood check. Often completely fine when you first meet them)
- Frequent findings:
- Bone marrow failure (anaemia, thrombocytopenia)
- Lymphadenopathy
- Splenomegaly (30%) (As blood cells they can be found in different places)
- Fever and sweats (< 25%)
•Less common findings:
- Hepatomegaly
- Infections
- weight loss
what are some CLL associated findings?
- Immune paresis (loss of normal immunoglobulin production)
- Haemolytic anaemia
- 20% have positive direct antiglobulin test
- 8% clinical evidence of haemolytic anaemia
what is the name used for CLL Staging?
Binet
What is Binet staging for CLL?
Idea of how extensive the disease is
Stage it by do they have abnormal blood count, do they have enlarged lymph glands
what are the indications for treatment in CLL?
- Progressive bone marrow failure (becoming anaemic)
- Massive lymphadenopathy
- Progressive splenomegaly
- Lymphocyte doubling time <6 months or >50% increase over 2 months
- Systemic symptoms
- Autoimmune cytopenias
CLL:
It’s a ___ grade disorder
___ curable
low
Not
what is the treatment of CLL?
- Often nothing – “watch and wait”
- Cytotoxic chemotherapy e.g. fludarabine, bendamustine (drugs that kill growing cells)
- Monoclonal antibodies e.g. Rituximab, obinatuzumab (target B cell markers)
- Novel agents (target specific pathways):
- Bruton tyrosine kinase inhibitor eg ibrutinib
- PI3K inhibitor eg idelalisib
- BCL-2 inhibitor eg venetoclax
what are some poor prognostic markers in CLL?
- Advanced disease (Binet stage B or C)
- Atypical lymphocyte morphology
- Rapid lymphocyte doubling time (<12 mth)
- CD 38+ expression
- Loss/mutation p53; del 11q23 (ATM gene) (if they have bad genetics)
- Unmutated IgVH gene status
what is the presentation of a lymphoma?
lymphadenopathy/ hepatosplenomegaly (enlarged as that’s where these cells live)
Extranodal disease (these cells can move anywhere)
“B symptoms”
bone marrow involvement
how is the assessment (“staging”) of lymphomas done?
lymph node biopsy/ CT scan/ bone marrow aspirate and trephine
what are the different stages of a lyphoma?
A: absence of B symptoms
B: fever, night sweats, weight loss
3 is above and below the diaphragm
- Any extra nodal disease involvement then you automatically have stage 4
where do lymphomas occur?
how are non-hodgkin lymphomas classified?
lineage (B-cell or T-cell) - Majority are B-cell in origin (90%)
”Grade” - High-grade vs low-grade
Everything that is not Hodgkin lymphoma
what are the different grades of Non-Hodgkin lymphoma and what are they like?
Low grade lymphoma:
- Indolent, often asymptomatic
- responds to chemotherapy but incurable
grow quite slowly, variation between patients
High grade lymphoma:
- Aggressive, fast-growing
- Require combination chemotherapy
- Can be cured
similarities with ALL as they are aggressive fast growing diseases that require combination chemotherapies and they can both be cured. Distinction is in the name depending on where it presents
what are some Specific disease entities of non-hodgkin lymphomas? and what is the treatment?
Diffuse large B-cell lymphoma (commonest high grade lymphoma):
- Commonest subtype of lymphoma (of any kind)
- High-grade lymphoma
Follicular lymphoma:
- 2nd commonest subtype of lymphoma
- Low-grade lymphoma (commonest low grade lymphoma)
- Like CLL, leave alone if not causing problems – “watch and wait”
- Both are treated with combination chemotherapy – typically anti-CD20 (marker expressed on mature B cells) monoclonal antibody + chemo
Both of these lymphomas arise from a transformation of the the germinal centre of a lymph node
what is the epidemiology of hodgkin lymphoma (More specific entity)?
30% of all lymphomas
bimodal age curve:
- 1st peak at 15-35y
- 2nd peak later in life
1.9 males: 1 female
association with Epstein Barr virus; familial and geographical clustering
Familial link
Also geographical variation suggesting there is both genetic and environmental factors
what is the treatment of Hodgkin lymphoma?
Very treatable condition
Combination chemotherapy (ABVD – each letter stands for a different drug) - Typically a combination of chemotherapy drugs used
+/- radiotherapy
Monoclonal antibodies (anti-CD30)
Immunotherapy (checkpoint inhibitors - they switch of inhibitory pathways that allows the immune system to go in and kill these cells)
PET scanning central to assessment of response to treatment
Quiz
Brain and bladder is normal for the glucose that has been injected
Asymmetric
Follicular uncommon in this age group
Inflammatory picture, with anaemia and raised CRP coupled with the age group makes 4 most likely
No extra nodal disease, no bone marrow involvement
Will grow back if you cut it out
Cytotoxic, combination chemotherapy tends to be the main stay
Biopsy is critical
Cd20 so know they are mature
Not immature
CD5 helps us distinguish certain low grade lymphomas
This is a Low grade mature B cell lymphoma
- this is high grade so large aggressive cells so not this
- Not myeloma as not plasma cells
Nodal disease above and below diaphragm
And since it is in bone marrow it is extra nodal so automatically stage 4
Form the cases the most important thing is the biopsy
