Haematology 4 - Chronic myeloproliferative neoplasms Flashcards
How should pseudopolychthaemia and polycythaemia vera be differentiated?
Isotype dilution method
Recall 3 causes of pseudopolycythaemia
Alcohol
Obesity
Diuretics
Causes of secondary polycythaemia
(non-malignant)
Classification of myeloproliferative disorders
a) philadelphia negative
- essential thrombocythaemia
- polycythaemia vera
- primary myelofibrosis
b) philadelhpia positive
- CML
**proliferation increased, differentiation normal
What is the most common gene that is mutated in philadelphia negative MPDs?
JAK2- this is a tyrosine kinase
(other genes: calreticulin, MPL)
What is the normal role of janus kinases?
They activate the STAT pathway, which promotes cell growth and replication
How does JAK2 mutation cause uncontrollable replication?
No longer need growth factor to activate
In polycythaemia vera, what else will be abnormal on the FBC other than red cell count?
Pronounced thrombophilia and slight increase in granulocyte count
Recall some symptoms of polycythaemia vera
Due to hyperviscosity:
- Headaches
- visual disturbances
- dyspnoea
Due to increased histamine release:
- peptic ulcer
- aquagenic pruritis
Recall four clinical findings in polycythaemia vera
Plethora
Erythromelalgia (red, painful extremities)
Gout
Retinal vein engorgement
What is the expected level of erythropoietin in polycythaemia vera?
Low
What mutation is present in all patients with polycythaemia vera?
JAK2
Recall 3 ways in which polycythaemia vera can be treated
- Venesection
- Cytoreductive therapy eg hydroxycarbamide
- Aspirin to reduce thrombosis risk
What is idiopathic erythrocytosis?
An isolated erythrocytosis with low EPO, where JAK2 V617 mutation is absent (although JAK mutation in exon 12 may be present)
How should idiopathic erythrocytosis be treated?
Venesection only
How is essential thrombocytothaemia defined?
Chronic myeloproliferative neoplasm with a sustained thrombocytosis > 600 x 10^9/L
Which age group is most at risk of essential thrombocytothaemia?
Bimodal:
Small peak at 30y (M=F)
Larger peak at 55y (F>M)
How does ET present?
- most likely an incidental finding
- or can present with clinical features
a) thrombosis- venous or arterial
b) bleeding - mucous membrane and cutaneous **bc of abormal quality of platelets
Headaches, dizziness, visual disturbance
Modest splenomegaly
investigations
- raised platelet count
- blood film: large platelets and megakaryocyte fragments
- increased BM megakaryocytes (not reactive)
Is there a JAK2 mutation in essential thrombocytothaemia?
Yes in 50%
What is the best treatment for essential thrombocytothaemia?
Hydroxycarbamide to reduce platelet count
Aspirin to reduce risk of thrombosis
and anagrelide- reduce formation of platelets form megakaryocytes
Blood film and trephine biopsy in primary myelofibrosis
Also blood counts:
- high platelet count (you get increased production of abnormal platelets–>pushing out other cells)
- high LDH and high uric acid - reflecting increased RBC turnover
Which condition is “tear drop poikilocytosis” pathognemonic of?
Myelofibrosis
Recall 2 signs of myelofibrosis
- Massive spleen - (and maybe hepatomegaly)
As bone marrow is fibrosed you get extramedullary haematopoiesis
- Anaemia (leukoerythroblastic anaemia)
**can also present with budd chiari syndrome (occlusion of the hepatic vein)
Prognosis of primary myelofibrosis
and treatment options?
BAD. worse than other philadelhpia negative MPDs
Tx: mainly supportive.
What is the best treatment for myelofibrosis?
Ruxolotinib - a JAK2 inhibitor
Even though chronic MPDs are “less deadly”, what is a major risk?
They can tranform into acute leukaemias
How does CML present?
**raised cell counts
**even though you have thrombocytosis, you can present with bleeding or clotting as the platelets are dysfunctional
FBC and blood film features of CML
- leucocytosis (predominantly due to granulocytes)
- biphasic peak: neutrophilia and myelocytes
- basophils raised as well
- <5% myeloblasts (unelss in blast crisis)
- raised (or upper normal) platelet count- contrast with acute leukaemia
Triad: leukocytosis, basophilia, neutrophilia - think CML!!
(you also see a thrombocytosis
Genetics of philadelphia positvie MPD
BCR-ABL1 fusion gene positive
Translocation of chromosome 9 and 22
How do you diagnose and monitor CML?
RT-PCR is most accurate
Clinical phases of CML
Accelerated phase: 10-19% blasts
Blast crisis: >20% blasts
What is the target of imatinib?
Why is imatinib not 100% successful?
Mutated tyrosine kinase (by BCR-ABL gene)
Not 100% successful because you can get resistance to treatment or disease may progress to blast crisis which evades treatment
Which 2 haematological cancers cause massive hepatosplenomegaly with no lymphadenopathy?
- CML
- myelofibrosis
*both examples of MPDs!!
(because of extramedullary haematopoiesis)
(if you have lymphadenopathy, it’s a lymphoid problem)
What does low leukocyte alkaline phosphatase suggest?
CML
How to classify myeloproliferative disorders?
what two conditions can MPNs transform into?
myelofibrosis or acute luekaemia
What causes myelofibrosis?
can be idiopathic or can progress from other MPNs
