Path: Haem Flashcards
Differences betwen CLL and SLL?
CLL is primarily seen in the BM
SLL (small lymphocytic lymphoma) seen in the LNs
otherwise they are essentially the same disease process
Complications of CLL
anaemia
hypogammagobulinaemia leading to recurrent infections
splenomegaly
warm AIHA
transformation to high grade lymphoma (Richter’s transformation)
What is Richter’s transformation?
occurs when leukemia cells enter the LN and change into a high-grade, fast-growing non-Hodgkin’s lymphoma.
Patients become unwell very suddenly.
can happen CLL -> DLBC lymphoma
What do smear cells indicate?
CLL
remember: SMEAR C(e)LL(s)
Features of CLL on blood Ix
persistently mildly raised lymphocyte count
smear cells and small/medium size lymphocytes on blood film
epidemiology of CLL
commonest leukemia in adults
>65 yo
(median 65-70)
M>F
Clinical features of CLL
can be asymptomatic (in 80% diagnosed in routine bloods)
- symmetrical painless lymphadenopathy
- BM failure (anaemia, thrombocytopaenia, RECURRENT INFECTIONS (50% deaths))
- B sx (weight loss, low grade fever, night sweats)
- splenomegaly +/- hepatomegaly
- associated with autoimmunity (Evan’s syndrome) - AIHA (w>c), ITP -> it is a disease of immune cells so you also get AID
Which clincial finding helps differentiate CLL and CML?
lymphadenopathy more in CLL
(generally helps differentiate lymphoid from myeloid malignancy)
How commonly is CLL an incidental finding?
80% diagnosed in routine bloods
buzzword for DLBC lymphoma
sheets of large lymphoid cells
can be as a result of Richters transformation CLL -> DLBC
DLBC
diffuse large B cell (lymphoma)
-> aggressive
Mx of DLBC lymphoma
Rituximab - CHOP
auto-SCT or CAR-T for relapse
R-CHOP = rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone
who is affected by DLBC lymphoma?
middle aged and elderly
can be transformed from CLL (Richter’s transformation) or from low grade lymphoma
Ix findings for CLL
- high WCC with lymphocytosis >5 (high % of WBC composed of lymphocytes, small, mature)
- low serum Ig
flow cytometry: confirms monoclonal population (normally CD5+ CD23+) - SMEAR CELLS on blood film
- abnormal BM - lymphocytic replacement
- mutation status: TP53 mutation - worse; IGHV rearrangement: better
Flow cytometry in CLL
confirms monoclonal population
usually CD5+ and CD23+
What mutation status is associated with a better and worse prognosis in CLL?
TP53 mutation - worse
IGHV rearrangement: better
Prognostic fx for CLL
good:
- hypermutated Ig gene
- low ZAP-70 expression
- 13q14 deletion
bad:
- LDH raised
- CD38+ve
- 11q23 deletion
- beta 2 microglobulin level elevated
- older age
Staging for CLL
Binet (A-C) or Rai (0-IV)
Binet
Stage A:
- high WCC
- <3 groups of enlarged LNs
- usually no treatment required
Stage B:
- >3 groups of enlarged LNs
Stage C:
- anaemia or thrombocytopaenia
RAI
0 - isolated lymphocytosis - low risk
I - lymphocytosis plus lymphadenopathy - intermediate risk
II - plus H/S-megaly - intermediate risk
III - plus anaemia (<11g/dL) - high risk
IV - plus thrombocytopaenia (<100 000 / mL) - high risk
Mx of CLL
- watchful waiting if asymptomatic with slowly progressing disease (1/3 pts never need treatment)
- supportive treatment with transfusions, infection prophylaxis (early abx, vaccines, IVIG if recurrent inf`)
- anti-CD20 (rituximab or obinutzumab) with chemotherapy
- oral BTK inhibitors (ibrutinib)
- BCL2 inhibtor (venetoclax)
allogenic HSCT is currently the only curative treatment option and is not routinely performed
What type of AIHA is CLL associated with?
warm AIHA
(remember: CLL is not cool - therefore warm AIHA)
What antibody type causes warm AIHA and cold AIHA?
warm: IgG
cold: IgM
causes of warm AIHA
mainly primary idiopathic
lymphoma
CLL
SLE
methyldopa
Mx of warm AIHA
steroids
splenectomy
immunosuppression
What does blood film in warm AIHA show?
spherocytes
what temp is associated with warm and cold AIHA?
WAIHA 37
CAIHA <37
Mx of cold AIHA
treat underlying condition
avoid the cold
chemotherapy if lymphoma
What causes CAIHA?
primary idiopathic
lymphoma
infections
EBV
mycoplasma
What feature is often also seen with cold AIHA/cold agglutinin disease?
Raynaud’s
What is aplastic anaemia and what can be seen on Ix? How do patients present?
inability of BM to produce adequate blood cells
HSC numbers are reduces in BM trephines (hypocellular BM)
AA typically refers to anaemia but these patients can have a pancytopaenia as well.
Signs and symptoms relate to each cytopaenia, typically present with bleeding problem.
At what age are patients affected by aplastic anaemia?
at any age
peak at
i. 15-24
ii. >60
What conditions is aplastic anaemia linked to?
leukemia, paroxysmal nocturnal hemoglobinuria(PNH)
Classification of aplastic anaemia
Primary:
- 70% idiopahtic (vast majority unexplained pathology, increasingly seeing mutations with NGS)
- 10 % inherited (Fanconi anaemia, deskeratosis congenita, Schwachmann-Diamond Syndrome, Diamond Blackfan syndrome
Secondary (10-15%)
- malignant infiltration of BM
- radiation
- drugs (incl. chemotherapy)
- viruses (e.g. parvovirus B19)
- autoimmune (e.g. SLE)
Management of aplastic anaemia
supportive: transfusions, abx, iron chelation
cessation of causative agent if applicable
drugs: to promote marrow recovery (e.g. growth factors and oxymethalone (androgen)).
immunosuppressants in idiopathic AA
SCT (esp. in young patients)
Inherited causes of aplastic anaemia / BM failure syndrome
Fanconi anaemia
Dyskeratosis Congenita
Schwachmann-Diamond syndrome
Diamond-Blackfan Syndrome
Fanconi anaemia - inheritance pattern
AR
What does Fanconi anaemia cause?
pancytopaenia
also:
skeletal abnormalities (radii (forearm), thumbs, renal malformations, microopthalmia, short stature, skin pigmentation (cafe au lait spots))
No abnormalities in 30%
Complications of fanconi anaemia
MDS (30%)
AML risk (10% progress)
At what age does Fanconi anaemia present
5-10y
incidence of aplastic anaemia cases
2-5 / million / year (globally)
criteria to assess severity of AA
Camitta criteria
- reticulocytes < 1% or <20 x 10^9/L
- neutrophils <0.5 x 10^9/L
- Platelets < 20 x 10^9/L
Bone Marrow <25% cellularity
Commonest form of inherited aplastic anaemia?
Fanconi anaemia
Features of dyskeratosis congenita
Triad:
- skin pigmentation
- nail dystrophy
- leukoplakia
+ BM failure
(have marrow failure, cancer predisposition, somatic abnormalities)
Inheritance pattern of dyskeratosis congenita
X-linked recessive trait (most common - mutated DKC1 gene - defective telomerase)
AD trait (mutate TERC gene)
AR trait (gene not found yet)
Is one gene responsible for Fanconi anaemia?
no
multiple genes appear to be responsible for this illness
What is Kostmann syndrome?
AR disorder
causes severe neutropenia
classical form of mutation in HCLS-1 assocaited protein X-1 (HAX-1)
Schwachmann-Diamond Syndrome - inheritance pattern
AR
Schwachmann-Diamond Syndrome - what does it cause?
Primarily neutropenia +/- others
skeletal abnormalities + SHORT STATURE
endocrine and pancreatic dysfunction (2nd commonest cause of pancreatic insufficiency following CF)
hepatic impairment
AML risk
Which of the inherited causes of BM faliure causes mainly a neutropenia?
Schwachmann-Diamond Syndrome
What malignancy are children/patients with Schwachmann-Diamond syndrome
AML
What is Diamond Blackfan syndrome
pure red cell aplasia
(red progentor cells are affected)
normal WCC and platelets
Which inherited BM failure disorder affects red cells?
Diamond-Blackfan syndrome
At what age do patients with Diamond Blackfan syndrome usually present?
in the 1st year of life
Inheritance pattern of diamond blackfan syndrome
AD
Which drugs can cause aplastic anaemia? (5 categories)
- Predictable (dose-dependent, common)
-> cytotoxic drugs - idiosyncratic (NOT dose dependent, rare)
-> Phenylbutazone (NSAID), gold salts - Abx
-> chloramphenicol
-> sulphonamide - diuretics
-> thiazides - antithyroid drugs
-> carbimazole
What is more common, HL or NHL?
NHL (80%)
HL is 20%
young person with bilateral lymphadenopathy, B sx and pain in LNs when drinking alcohol - dx?
Hodgkin’s lymphoma
Name myeloproliferative disorders
(‘philadelphia chromosome +ve’)
CML
(‘philadelphia chromosome -ve’)
polycythaemia vera
(primary)myelofibrosis
essential thrombocythaemia
what are myeloproliferative disorders?
a group of disorders characterised by a proliferation of malignant haematopoetic stem cells of the myeloid lineage
clonal proliferation of one or more haemapoietic component (i.e. increased production of mature cells)
What mutation are philadelphia chromosome -ve myeloproliferative disorders associated with?
JAK2 mutations (esp. PV - >95%)
What age group is affected by CML?
middle aged typically (40-60yo)
How do patients with CML present?
often diagnosed on routine bloods (large number of differentiated neutrophils)
or present with generally feeling unwell, weight loss, infections, bruising, fevers, fatigue, night sweats
o/e splenomegaly (often massive)
What is the remission rate in CML treated with imatinib?
95%
Mx of CML
1st line: imatinib -> 95% remission
what kind of medication is imatinib?
tyrosine kinase inhibitor
(first generation)
What are the different types of tyrosine kinase inhibitors used in CML?
1st generation: imatinib (indicated in low-risk CP-CML patients)
2nd generation: dasatinib, nilotinib: usually indicated in AP-CML
3rd generation: ponatinib: especially effective in patients with additional mutations
What is known as the philadelphia chromosome?
translocation (9;22)
in what % CML is (9;22) seen?
philadelphia chromosome is seen in 80% CML
How do you detect the philadelphia chromosome and how was this done in the past?
Now: FISH (fluorescence in situ hybridization)
in the past via karyotyping
what does FISH stand for?
fluorescence in situ hybridization
What are the different phases of CML?
- Chronic phase
- Accelerated phase
- Blast phase / Blast crisis
Summarise the chronic phase in CML
<5% blasts in BM/blood
WBC increases over years
- often subclinical
- can persist for up to 10y
How do you manage CML in the chronic phase?
Imatinib (1st generation tyrosine kinase inhibitor)
OR
dasatinib/nilotinib for resistance
EXTREMELY effective and well tolerated
treatment started immediately after dx confirmation regardless of symptoms
molecular remission in CML
in some patients CML treatment with imatinib is considered to be in molecular remission when the BCR-ABL gene transcripts are no longer seen on PCR.
What happens with t(9;22)?
Fusion gene formation
in t(9;22) the BCR-ABL gene is formed and encodes a BCR-ABL non-receptor tyrosine kinase with increased enzyme activity
-> inhibits physiologic apoptosis and increases mitotic rate -> uncontrolled proliferation of functional granulocytes
When can you see spherocytes?
How do they look?
hereditary spherocytosis
AIHA
haemolytic transfusion reaction
sphere shaped RBCs; often a little smaller.
Summarise the accelerated phase of CML
> 10% blasts seen in BM/Blood
increasing manifestations such as splenomegaly, lasting up to a year
less responsive to therapy*
*AMBOSS: second generation TKIs such as dasatinib or nilotinib can be used.
Consider systemic chemotherapy or HSCT if pt is eligible.
How do you manage AP-CML?
imatinib can be used at any stage?
second generation TKIs such as dasatinib or nilotinib can be used.
Consider systemic chemotherapy or HSCT if pt is eligible.
less responsive to treatment compared to CP-CML
Summarise the blast phase in CML?
> 20% blasts seen in BM/blood
resembles acute leukemia
sx: +/- weight loss, night sweats, lethargy
timeframe = months
treatment: similar to AML (aggressive systemic chemotherapy in combination with a TKI), possibly with allogenic SCT for young patients
What cytokine therapy can be used in CML?
IFN-alpha
can be used to reduce leukocyte count
Haematological causes of acquired antibody deficiency
malignancy: CLL, MM
post BM transplant
-> cause secondary (acquired) Ab deficiency
What diseases is chronic ITP associated with?
associated with AI disease
CLL
HIV
hepatitis
who is affected by acute and chronic ITP?
acute: children
chronic: adults
Causes of CML
idiopathic (most commonly)
ionising radiation
aromatic hydrocarbons (esp. benzene)
What is the commonest leukemia in the western world
CLL
When is CD5 normally expressed?
transiently expressed in early stage of B-cell maturation before release into the blood
Outcomes of CLL
1/3 never progress
1/3 treated effectively, die of other cause
1/3 die of CLL (require multiple lines of CLL rx, refractory disease)
Should you avoid any vaccines in CLL?
yes, avoid live vaccines
What is the commonest cause of lymphocytosis in the elderly?
CLL
Is there a genetic component in CLL?
relatives are 7x more likely to develop it
what ethnicity is at higher risk of CLL?
caucasian
How high is the risk of Richters transformation in CLL?
1% risk / year
What type of supportive care in CLL?
early abx
if low IgG can give IVIG for recurrent infections
vaccinations (e.g covid, flu, pneumococcal - avoid live)
Meds to treat CLL
combination immuno-chemotherapy: being suspended by targeted tx
targeted therapy:
BTK inhibitors (ibrutinib)
BCL2 inhibitors (venetoclax)
cellular therapy only for relapsed high risk cases:
allogenic SCT
CAR-T
What is the risk of starting venetoclax in CLL management?
tumour lysis syndrome when initiating therapy -> can be fatal
Indications to treat CLL
progressive lymphocytosis
- >50% increase in 2/12
- lymphocyte doubling time <6/12
progressive BM failure
- Hb <100
- platelets < 100
- neutrophils <1
massive/progressive H/Smegaly
systemic sx (B sx)
AI cytopenias (mx with immunosuppresion, not chemo)
Normal B-cell markers
CD20+
CD19+
CD5- (it is transiently expressed before released into the blood)
CML - detecting disaese approaches
molecular - most sensitive (%BCR-ABL transcripts)
cytogenetic analysis - follows (on 20 metaphases, partial 1-35% Ph +ve, complete 0% Ph +ve)
haematological response (WCC)
-> you can imagine, it is more senistive to measure the BCR-ABL transcripts by PCR than looking at 20 metaphases and seeing what % has Ph Chr
What is the reversal agent for dagibatran?
idarucizumab
What type of medication is dagibatran?
direct thrombin inhibitor
What is the commonest NHL in the UK?
diffuse large B cell lymphoma (40% of total lymphoma cases)
Red cell abnormalities that may be seen in coealiac disease
Target cells
Howell-Jolly bodies
(hyposplenism)
Why is Factor VIII reduced in von Willebrand disease?
vWF prevents the degradation of F8
What is von Willebrand disesaasae?
most common inherited b leading disorder
caused by qualitative or quantitative deficiency in vWF.
Types of von Willebrand disease
Inherited
- type 1 (AD) - low levels of vWF
- type 2 (AD) - poorly functioning vWF
- type 3 (AR) - absent vWF
Acquired
- myelo-/lymphoproliferative d/o
- AID e.g. SLE
- drug SE (e.g. valproate)
- hypothyroidism
- cardiovascular defects (VSD, AS)
How does von Willebrand disease present?
Varying phenotype, from complete deficiency to asymptomatic mild deficiency
bleeding indicative of platelets d/o e.g. mucocutaneous bleeding but can also present with bleeding indicative of coagulation disorders.
What is the commonest inherited bleeding disorder?
von Willebrand disease
What proportion of people is affected by von Willebrand disease?
1 in 10 000
Lab findings in vWD
(mildly) high APTT (may also be normal)
normal PT/INR
low FVIII
low vWF Ag (or normal Ag level with reduced function in type 2)
normal platelet count
-> can be difficult to diagnose and necessitate haem input
Mx of vWD
prophylaxis indicated in some patients
treatment of bleeds (TXA(antifibrinolytic), desmopressin, combined vWF and F8 concentrates
cOCP can be used in menorrhagia
How does desmopressin work in von Willebrand disease? Which types of the disease does it work in?
stimulates the release of vWF from endothelial cells.
works in type 1&2 but not in type 3.
When is treatment needed in vWD?
if symptomatic
prophylactic e.g. before surgery
What medications are contraindicated in vWD?
Platelet aggregation inhibitors (e.g., aspirin, NSAIDs, clopidogrel) and intramuscular injections are contraindicated in von Willebrand disease because they further increase the risk of bleeding!
What chromosomal translocation is seen in mantle cell lymphoma?
t(11;14) involving Cyclin D1
Cyclin D1 deregulation (chr 11)
What group is affected by mantle cell lymphoma?
middle aged men
M>F
middle age
Is mantle cell lymphoma an indolent or aggressive lymphoma?
aggressive
median survival with mantle cell lymphoma
3-5 years
Histological finding: angular/clefted nuclei - dx?
mantle cell lymphoma
Mx of mantle cell lymphoma
rituximab-CHOP and high dose cytarabine
Auto SCT for relapse
oral options for less fit
Mx of mantle cell lymphoma relapse
auto SCT
Level of disease at presentation in mantle cell lymphoma
disseminated
Eselsbrücke for Mantle cell lymphooma
an aggressive and dysregulated middle-aged man in cycling (cyclin D1) in a ‘Mantel’.
He is not cycling far, 3-5km (mean years life expectancy)
He has two children, aged 11 and 14 (t(11;14)).
He is cycling to R-CHOP some wood.
He has citrus fruit on a karabiner (cytarabine).
The buttons of his mantel are clefted and angular.
if he becomes less fit he will have to eat something (oral therapy for less fit) and if he loses himself again (relapse) he will need to auto-SCT to change.
What translocation is seen in Burkitt’s lymphoma and what gene is affected?
t(8;14)
c-myc (oncogene overexpression)
Histology of Burkitt lymphoma
starry sky appearance
Significant infiltrates of homogenous lymphocytes. Macrophages are interspersed between sheets of lymphocytes and clearly contain apoptotic lymphocytes
What different types of Burkitt’s lymphoma are there?
endemic
sporadic
immunodeficiency
Is burkitt’s lymphoma aggressive or indolent?
(very) aggressive + fast growing
Does Burkitt’s lymphoma respond well to meds?
rapidly responsive to rx
Mx of Burkitt’s lymphoma
Rituximab
& secondary CNS prophylaxis
Endemic Burkitt’s lymphoma
most common malignancy in equatorial Africa (and South America)
EBV-associated
characteristic JAW INVOVLEMENT
abdominal masses
Immunodeficiency Burkitt’s lymphoma
In HIV/post-traansplant patients
Non-EBV associated
Sporadic Burkitt’s lymphoma
EBV assocaited
found outside of Africa
jaw less commonly involved
Which lymphomas are low grade and high grade>
High grade:
- Burkitt’s (very aggressive)
- Diffuse large B cell (aggressive)
- mantle cell (aggressive)
Low grade:
- Follicular (indolent)
- Marginal Zone (indolent)
- small lymphocytic (indolent)
Which lymphoma is associated with pain in the affected LNs following alcohol?
Hodgkin’s lymphoma
What proportion of lymphoma is HL and NHL ?
20% HL
80% NHL
Which types of Burkitt’s lymphoma are and are not associated with EBV
EBV associated: endemic + sporadic
Not EBV associated -> immunodeficiency BL
What is the inheritance pattern of hereditary elliptocytosis?
AD
What are sources of Vitamin B12?
meat and dairy products
Causes of vitamin B12 deficiency
dietary (e.g. vegans)
malabsorption
- stomach: lack of intrinsic factor which is produced by gastric parietal cells -> pernicious anaemia, post gastrectomy
(can have anti-IF antibodies or anti-parietal cell antibodies)
- terminal ileum: absorption due to ilial resection, Crohn’s disease, bacterial overgrowth, tropical sprue and tapeworms
Where is intrinsic factor produced?
in the parietal cells in the stomach
what are clinical features of B12 deficiency?
Mouth: glossitis, angular cheilosis
Neuropsychiatric: irritability, depression, psychosis, dementia
neurological: paraesthesiae, peripheral neuropathy, (loss of vibration and proprioception first, absent ankle reflex, spastic paraparesis, subacute combined degeneration of the spinal cord)
What is pernicious anaemia?
autoimmune atrophic gastritis -> achlorhydria and loss of gastric intrinsic factor
What is the most common cause of macrocytic anaemia in the western world?
pernicious anaemia
What age group is affected by pernicious anaemia?
usually >40 yo
Specific test for pernicious anaemia
parietal cell antibodies (90%)
intrinsic factor antibodies (55%)
Schilling test (outdated) - pt swallows radiolabelled B12 and an injection of normal B12(to make sure the radiolabelled vitamin does not bind to sites of depletion).
Levels of radiolabelled vitamin B12 excretion are measured in the urine.
management of B12 deficiency
- replenish stores with IM hydroxocobalamin (B12) with 6 injections over 2 weeks
Nice recommends testing for anti-parietal cell / anti-IF antibodies to check for autoimmune rather than dietary causes; here patients would need 3-monthly IM injections.
What are the commoner autoantibodies found in pernicious anaemia?
anti-parietal cell antibodies (90%)
50% have anti-IF antibodies
Sources of folate
Diet:
green vegetables
nuts
yeast
liver
synthesised by gut bacteria (low body stores, cannot produce de novo)
What are causes of folate deficiency?
- poor diet
- increased demand: pregnancy or increased cell turnover (e.g. haemolysis, malignancy, inflammatory disease and renal dialysis)
- malabsorption: coeliac disease, tropical sprue
- drugs: alcohol, anti-epileptics (phenytoin), methotrexate, trimethoprim
Mx of folate deficiency
oral folic acid
ensure B12 is checked and replaced prior to folic acid as folic acid may exacerbate neuropathy of B12 deficiency
Why should you check B12 levels before starting folic acid replacement?
folic acid may exacerbate neuropathy of B12 deficiency
What is a megaloblastic blood film?
Hypersegmented polymorphs, leucopenia, macrocytosis, aneamia, thrombocytopenia with megaloblasts.
Megaloblasts are red cell precursors with an immature nucleus and mature cytoplasm
b12 and folate are required for nucleus maturation
Macrocytosis with megaloblastic blood film ddx
b12 def
folate def
cytotoxic drugs
macrocytosis with non-megaloblastic blood film ddx
alcohol (most common cause of macrocytosis without anaemia)
reticulocytosis (e.g. in haemolysis)
liver disease
hypothyroidism
pregnancy
What is the commonest cause of macrocytosis without anaemia?
alcohol
What haematological diseases can cause macrocytosis?
myelodysplasia
myeloma
myeloproliferative disorders
aplastic anaemia
