(40) Chronic myeloproliferative disorders Flashcards
1
Q
What are chronic myeloproliferative disorders?
A
Malignant clonal stem cell disorders of the bone marrow
2
Q
Name 3 types of chronic myeloproliferative disorders?
A
- polycythaemia vera
- essential thrombocytosis
- idiopathic myelofibrosis
3
Q
What occurs in 10% of chronic myeloproliferative disorders?
A
Transformation acute leukaemia
4
Q
Name 3 types of blood cells that a stem cell can dvidid into?
A
- erythrocytes (red cells)
- megakaryocytes (platelets)
- granulocytes (neutrophils, eosinophils, basophils)
5
Q
What do you get in polycythaemia vera?
A
Increased red cells +/- neutrophils +/- platelets
6
Q
What must you distinguish polycythaemia vera from?
A
Secondary polycythaemias and relative polycythaemia
7
Q
What do you get in essential thrombocythaemia?
A
Increased platelets
8
Q
What must you distinguish essential thrombocythaemia from?
A
Reactive thrombocytosis
9
Q
What do you get in myelofibrosis?
A
Variable cytopenias with a large spleen
Bone marrow fibrosis and decreased red cells/white cells/platelets
10
Q
What must you distinguish myelofibrosis from?
A
Other causes of splenomegaly
11
Q
At what age does polycythaemia vera occur?
A
All ages but peak at 50-70 years
12
Q
What are the symptoms of polycythaemia vera?
A
Insidious
- aquagenic itching
- plethoric face
- headache
- muzziness
- general malaise
- tinnitus
- peptic ulcer
- gout
- gangrene of the toes
13
Q
What is the common facial appearance in polycythaemia vera?
A
Plethoric face (red, ruddy complexion)
14
Q
In polycythaemia, the itching is aquagenic. What does this mean?
A
Itching caused by water
15
Q
What are the signs of polycythaemia vera?
A
- plethora
- engorged retinal veins
- splenomegaly
16
Q
What is the Hb/hct level in polycythaemia vera?
A
Persistently >0.5
17
Q
What must you distinguish between in PV?
A
- relative vs. absolute polycythaemia
- primary vs. secondary polycythaemia
18
Q
When diagnosing PV, what are the 1st line tests?
A
- FBC
- ferritin
- Epo levels
- UE/LFT
19
Q
Is polycythaemia vera primary or secondary polycythaemia?
A
Primary polycythaemia
20
Q
Secondary polycythaemia might be due to what?
A
- central hypoxic process
- chronic lung disease
- right-to-left shunts heart disease
- CO poisoning
- smoker
- high altitude
- renal disease
- EPO production tumours
- drug associated
- treatment with androgen preparations
- postrenal transplant erythrocytosis
- congenital
- high oxygen-affinity haemoglobin
- erythropoeitin receptor-mediated
- idiopathic erythrocytosis
21
Q
What are the 2nd line tests for PV when epo is elevated?
A
- CXR
- ABG
- USS abdomen
22
Q
What are the 2nd line tests for PV when epo is normal or low?
A
- JAK2 mutation
- bone marrow examination
- EXON12 mutation
23
Q
What are Janus Kinases (JAK)?
A
A family of intracellular, nonreceptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway
24
Q
How many JAKs are there?
A
4
- JAK1
- JAK2
- JAK3
- TYK2
25
JAK is the signally pathway for what?
Cytokine receptors (GM-CSF, GCSF, EPO, TPO, SCF, interleukins)
26
Describe the function of JAK tyrosine kinases
Since members of the type I and type II cytokine receptor families possess no catalytic kinase activity, they rely on the JAK family of tyrosine kinases to phosphorylate and activate downstream proteins involved in their signal transduction pathways. The receptors exist as paired polypeptides, thus exhibiting two intracellular signal-transducing domains
27
Describe the JAK2 mutation in myeloproliferative disorders
- occurs in the JH2 domain (inactive)
- G to T mutation at nucleotide 1849
- phenylalanine for valine at 617 in protein V617F
- destroys a BsaXI site
- patients may be heterozygous or homozygous
28
The presence of a JAK2 V617F mutation in peripheral blood DNA is what?
Diagnostic of a myeloproliferative disorder
29
How is the JAK2 V617F mutation tested for?
- allele specific DNA-based PCR
- control PCR in same reaction for normal gene
- possible results:-
- normal control band only
- mutant + control band
- no bands or mutant only = inadequate material
30
How often the JAK2 V617F mutation occur in the 3 myeloproliferative disorders?
```
PRV = 97%
ET = 57%
IMF = 50%
```
31
How is polycythaemia vera treated?
- venesections aiming for HCT less than 0.45
| - aspirin 75mg daily
32
What is a venesection?
The removal of a volume of blood as a treatment for certain blood disorders
33
What is HCT (haematocrit)?
the proportion of your total blood volume that is composed of red blood cell
34
What is the prognosis for polycythaemia vera?
- good prognosis (15 year median survival)
- risk of developing AML
- risk of developing myelofibrosis
35
What are the 2 types of thrombocytosis?
- primary essential thrombocytosis (ET)
| - reactive thrombocytosis
36
What is there a risk of in ET?
Thrombosis
37
What is the difference between primary essential and reactive thrombocytosis?
Primary essential = body making too many platelets
Reactive = too many platelets due to something else
38
What are the causes of reactive thrombosis?
- surgery
- infection
- inflammation
- malignancy
- iron deficiency
- hyposplenism
- haemolysis
- drug induced
- rebound spot chemo
39
Reactive thrombocytosis can be drug-induced. Give some examples of drugs which can cause it
- steroids
- adrenaline
- TPO mimetics
40
What is TPO?
Thrombopoietin
41
Thrombocytosis is defined as what?
Persistent platelets more than 450 x10^9/L
42
What are the 1st line investigations into thrombocytosis?
- FBC and film
- ferritin
- CRP (check for inflammation)
- CXR
- ESR
(look for secondary causes)
43
What are the 2nd line investigations into thrombocytosis? (if no known cause has been found)
- JAK2
- CALR mutation
- bone marrow biopsy
- extensive search for secondary cause
44
Why do you look for JAK2 mutation while investigating thrombocytosis?
As around 50% of primary essential thrombocytosis cases will have this mutation
45
What is the CALR mutation?
- calreticulin mutation
- cells signalling protein produced in ER
- mutation in EXON 9 of gene
- found in myeloid progenitors in ET
46
What is the mechanism of action of the CALR mutation?
Mechanism of action unknown but may activate cells signal pathways
47
Why is it useful to look for CALR mutation when investigating thrombocytosis?
It is found in up to 90% of JAK2 negative ET
48
How is ET diagnosed?
- JAK2 mutation (50%)
- CALR mutation (45%)
- consider bone marrow biopsy
49
Thrombotic risk should be assessed in ET (platelets high so at risk of stroke, MI, venous thrombosis etc). What are the risk factors?
- age
- hypertension
- smoking
- diabetes
- platelet count over 1500
- history of thrombosis
50
How is ET treated?
- anti-platelet treatment (aspirin 75mg daily)
| - cytoreduction (only if 1 or more risk factors present)
51
Which drugs are used in cytoreduction?
- hydroxycarbamide
- interferon
- anagrelide
- P32 (radioactive phosphorus - used in elderly)
52
What is anagrelide?
A specific inhibitor of megakaryocytes - used in cytoreduction in ET (reduces the number of platelets)
53
What is the prognosis in essential thrombocytopenia?
- overall excellent 20 year median survival
- risk of AML or myelofibrosis
- CALR mutated have lower thrombosis risk
54
How is the prognosis different for those with CALR mutation in ET?
Lower risk of thrombosis
55
How does myelofibrosis present?
- pancytopenia
- B symptoms (fevers, night sweats, weight loss)
- massive splenomegaly
56
What are B symptoms?
3 symptoms associated with blood cancers
- 10% weight loss
- soaking night sweats
- fevers
57
Why do you get splenomegaly in myelofibrosis?
Due to fibrosis in the bone marrow, the spleen takes over making cells = splenomegaly
58
What further symptoms might be caused by the splenomegaly in myelofibrosis?
Pain at the site, pushes on stomach = feel full after small meals, pushes on bladder = urinary frequency
59
What investigations would you do into myelofibrosis?
- FBC and film
| - haematinics
60
What are haematinics?
Nutrients, including iron, folic acid, and vitamin B 12, required for the formation and development of blood cells in bone marrow
61
What do you see on a blood film in myelofibrosis?
- blast cells (open chromatin)
- tear drop shaped red cells
Leucoerythroblastic appearance
62
What do you see in the bone marrow in myelofibrosis?
Fibrosis
63
How is myelofibrosis diagnosed?
- blood film
- bone marrow results
- JAK2 mutation (50%)
- CALR mutation (40%)
64
What are blast cells?
The term "blast cells" refers to myeloblasts or myeloid blasts. These are the very earliest and most immature cells of the myeloid cell line - not normally found circulating in the blood in health individuals
65
What are the causes of splenomegaly? (CHICAGO)
C = cancer
H = haematological - myelofibrosis, CML, CLL, hairy cell leukaemia
I = infection - schistosomiasis, malaria, leishmaniasis, EBV
C = congestion - liver disease/portal hypertension
A = autoimmune - haemolysis
G = glycogen storage disorders
O = other, amyloid etc.
66
What are the 'C' causes of splenomegaly? (CHICAGO)
- cancer
| - congestion (liver disease/portal hypertension)
67
What are the 'H' causes of splenomegaly? (CHICAGO)
Haematological
- myelofibrosis
- CML
- CLL
- hairy cell leukaemia
68
What are the 'I' causes of splenomegaly? (CHICAGO)
Infection
- schistosomiasis
- malaria
- leishmaniasis
- EBV
69
How is myelofibrosis treated?
- supportive care
- JAK2 inhibitors
- bone marrow transplant
70
Why types of supportive care is given to myelofibrosis patients?
- give blood for anaemia
- EPO injections
- give platelets
etc
71
What are JAK2 inhibitors used in myelofibrosis particularly good at?
Reducing splenomegaly
72
Is bone marrow transplant a good option for those with myelofibrosis?
Around half will die from the transplant
73
What is the prognosis for myelofibrosis?
- poor
| - median survival = 5 years
74
What is the incidence of chronic myeloid leukaemia (CML)?
- rare (approx 1 per 100,000 per year)
75
What is the median age at diagnosis of CML?
55-60
Less than 10% ages under 20
76
What is the M:F ratio in CML?
1.5:1
77
What is seen on blood film in CML?
- lots of neutrophils
| - blast cells
78
CML is characterised by what? (clinical features)
- leucocytosis
- leucoerythroblastic blood picture
- anaemia
- splenomegaly
(high white cell count and high blast cells)
79
What are the predictable symptoms of CML?
- abdo discomfort and pain related to splenomegaly and splenic infarction
- fatigue due to anaemia and catabolic state
- retinal haemorrhages, DVT and priapism due to venous occlusion
- gout due to hyperuricaemia
80
How was CML treated in the 20th century?
- low dose oral cytotoxic drugs (busulphan and hydroxycarbamide) and interferon for chronic phase
- intensive chemotherapy for acute leukaemia transformation/blast crisis, with poor outcome
- allogenic bone marrow transplantation, curative in 50% of patients
81
Parts of which chromosome swap over in CML?
Translocation between parts of chromosomes 9 and 22
82
What is formed in the translocation between 9 and 22 in CML?
BCR-ABL fusion gene - an oncogene which tells cells to proliferative
83
What does the BCR-ABL fusion gene code for?
An active tyrosine kinase - it is an oncogene that tells cells to proliferate
84
What happened in 1960 regarding CML?
Nowell and Hungerford describe the "Philadelphia chromosome" in CML
85
What happened in 1973 regarding CML?
Janet Rowley correctly interprets the 9;22 translocation
86
What is the Philadelphia chromosome?
Specific genetic abnormality in chromosome 22 of CML cells -translocation between chromosome 9 and chromosome 22, and contains a fusion gene called BCR-ABL1.
This gene is the ABL1 gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a tyrosine kinase signalling protein that is "always on", causing the cell to divide uncontrollably
87
What is Gleevec? (imatinib mesylate)
A small molecule specifically designed to block the active site in the BCR-ABL tyrosine kinase (drug for CML)
88
Which drug revolutionised the way CML is treated?
Gleevec (imatinib mesylate)
89
How has Imatinib resistance been developed?
Activating loop mutations in BCR-ABL confer resistance and therefore loss of disease control - Gleevec ineffective
90
What has been done to get around the problem of Imatinib/Gleevec resistance?
New tyrosine kinase inhibitors with different active sites
- Nilotinib
- Dasatinib
91
Summarise chronic myeloid leukaemia (CML)
- pluripotent stem cell disorder
- defined by t(9;22)
- driven by BCR-ABL fusion tyrosine kinase
- chronic phase followed by acute transformation
- designer molecule treatment (imatinib) has proved highly successful
- BCR-ABL mutations confer resistance to imatinib
92
How is gout treatment?
- NSAID eg. Diclofenac
| - commence allopurinol (to lower uric acid levels) ONLY when acute gout has settles with NSAID cover
