Myeloproliferative disorders Flashcards
What is the definition of myeloproliferative?
Myelo = bone marrow lineage(s)
(granulocytes, red cells & platelets)
Proliferative = to grow or multiply by rapidly producing new tissue, parts, cells, or offspring
Is chronic myeloid leukaemia (CML) BCR-ABL1 positive or negative?
BCR-ABL1 positive
Primary myelofibrosis, polycythaemia vera and essential thrombocythaemia are all BCR-ABL1 negative.
What is BCR-ABL1?
An abnormal protein formed by the philadelphia gene.
When should a myeloproliferative disorder (MPN) be considered?
High Granulocyte count
+/-
High Red cell count / haemoglobin
+/-
High Platelet count
+/-
Eosinophilia/basophilia
Splenomegaly
Thrombosis in an unusual place
What are clonal haemopoietic stem cell disorders and how does this compare to acute leukaemia?
Clonal haemopoietic stem cell disorders with an increased production of one or more types of haemopoietic cells.
In contrast to acute leukaemia, maturation is relatively preserved
What is polycythaemia vera?
A clonal haematological malignancy characterised by pronounced symptoms.
An overproduction of RBC’s
Also with increased risk of thrombosis and potential for evolution to myelofibrosis and secondary acute myeloid leukaemia.
Aetiology of polycythaemia vera?
Median age of diagnosis is ~65 years old but can affect younger patients.
JAK2 - kinase mutation present in over 95% of PV patients.
Pathophysiology of PV?
JAK2 mutation (substitution) results in loss of autoinhibition leading to absence of erythropoiesis in the absence of ligand.
How are asymptomatic cases of PV identified?
May be discovered on routine blood count in a person with no related symptoms or there may be non-specific complaints of lethargy and tiredness.
Clinical features of PV?
Increased cell turnover - gout, fatigue, weight loss and sweats.
Symptoms/signs due to splenomegaly.
Marrow failure - fibrosis or leukaemic transformation (transformation risk = low)
Thrombosis - arterial or venous including TIA, MI, claudication, abdominal vessel thrombosis.
Headache, fatigue
Itch - aquagenic pruritis
What is aquagenic pruritis?
Itching that is worse after a hot shower or bath.
Blood test investigations for PV?
FBC, blood film - high haemoglobin/haematocrit accompanied by erythrocytosis (increase in red cell mass) but can also have excessive production of other lineages.
JAK2 mutation status
- If JAK2 negative but high clinical suspicion - erythropoietin levels, bone marrow biopsy.
What are some blood test investigations for secondary PV?
Investigations for secondary/pseudocauses - CXR, O2 sats/ABG’s, drug history.
- Secondary polycythaemia - chronic hypoxia, erythropoietin-secreting tumour etc.
- Pseudopolycythaemia e.g. dehydration, diuretic therapy, obesity).
Management of PV?
Aspirin
Cytotoxic oral chemotherapy e.g. hydroxycarbamide.
What is essential thrombocythaemia?
Uncontrolled production of abnormal platelets
Aetiology of essential thrombocythaemia?
Median age of diagnosis is ~65 years old but can affect younger patients.
Pathophysiology of essential thrombocythaemia?
Platelet function is abnormal, leading to thrombosis
- At high levels can cause bleeding due to acquired von Willebrand disease.
Clinical features of essential thrombocythaemia?
Asymptomatic
Increased cellular turnover - gout, fatigue, weight loss, sweats.
Symptoms/signs due to splenomegaly.
Marrow failure - fibrosis or leukaemic transformation (transformation risk = low)
Thrombosis - arterial or venous including TIA, MI, abdominal vessel thrombosis and claudication.
Bleeding - unpredictable risk
Investigations for essential thrombocythaemia?
Exclude reactive thrombocytosis - blood los, inflammation, malignancy, iron deficiency.
Exclude CML (chronic myeloid leukaemia)
Bloods: genetics
* JAK2 mutation in around 50-60%
* CALR mutation in around 25%
* MLP mutation in around 5%
* 10-20% of patients will be “triple negative”.
Bone marrow biopsy
Management of essential thrombocythaemia?
Antiplatelet agents - aspirin
Cytoreductive therapy to control proliferation
* Hydroxycarbamide
* Anagrelide
* Interferon alpha
What is idiopathic myelofibrosis?
Healthy bone marrow is replaced by fibrosis. Leads to lack of production of normal cells.
Aetiology of idiopathic myelofibrosis?
Mean age of diagnosis ~ 65 years old but can affect younger patients.
Unknown underlying cause
There is an association with the mutations JAK2, CALR or MPL gene.
Clinical features of idiopathic myelofibrosis?
Asymptomatic
Marrow failure - variable degrees
* Anaemia, bleeding, infection.
Bone marrow fibrosis with no alternative cause.
Extramedullary haematopoiesis (liver and spleen)
- Splenomegaly can cause LUQ abdominal pain, complications include portal hypertension.
Catabolism - night sweats, extreme weight loss.
Blood test investigations for idiopathic myelofibrosis?
Leukoerythroblastic film appearances.
Teardrop shaped RBC’s in peripheral blood.
Bone marrow investigations for idiopathic myelofibrosis?
Dry aspirate
Fibrosis on trephine biopsy
Genetic testing investigations for idiopathic myelofibrosis?
JAK2, CALR, MLP mutations
Approx 10% are “triple negative”
Management for idiopathic myelofibrosis?
Supportive - blood transfusion, platelets, antibiotics.
Allogenic stem cell transplantation in few.
Splenectomy (not always recommended)
JAK2 inhibitors e.g. ruxolitinib
