Flashcards in Chronic myeloproliferative disorders and chronic myeloid leukaemia Deck (42):
What are chronic myeloproliferative disorders?
- Malignant clonal stem cell disorders of the bone marrow.
1. Polycythaemia Vera
2. Essential thrombocytosis
3. Idiopathic Myelofibrosis
What percentage of chronic myeloproliferative disorders transform into acute leukaemia?
What is polycythaemia vera?
- Increased red cells, +/-neutrophils, +/-platelets
- Distinguish from secondary polycythaemias and relative polycythaemia
What is essential thrombocythaemia?
- Increased platelets
- Distinguish from reactive thrombocytosis
What is myelofibrosis?
- Variable cytopenias with a large spleen
- Distinguish from other causes of splenomegaly
What is the epidemiology of polycythaemia vera?
All ages, peak at 50-70 years
What are the signs and symptoms of polycythaemia vera?
- Itching (aquagenic- hot baths)
- Plethoric face
- Headache, muzziness,
- General malaise
- Peptic ulcer
- Gangrene of the toes
- Engorged retinal veins
How is polycythaemia vera diagnosed?
- Persistent increased Hb/hct >0.5
- Is it:
-- relative V absolute polycthaemia
-- Primary V Secondary polycythaemia
- Detailed History and Examination
- 1st line tests
-- Epo level
What is the cause if primary polycythaemia?
What are the causes of secondary polycythaemia?
Central hypoxic process
- Chronic lung disease
- Right-to-left shunts Heart Disease
- Carbon monoxide poisoning
- High Altitude
EPO production Tumours
- Treatment with androgen preparations
- Postrenal transplant erythrocytosis
- High oxygen-affinity haemoglobin
- Erythropoeitin receptor-mediated
What second line tests should be performed in cases of suspected polycythaemia?
3. USS abdomen
Epo normal or low
1. JAK2 mutation
2. Bone marrow examination
3. EXON12 mutation
For which cytokine receptors is JAK the signalling pathway?
What are the features of the JAK2 mutation?
- 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
The presence of a JAK2 V617F mutation
in peripheral blood DNA is diagnostic of what?
A myeloproliferative disorder?
What is the treatment of polycythaemia vera?
- Venesection - aim for a haematocrit of
What is the prognosis for polycythaemia vera?
- Good - 15 year median survival
- Risk developing AML
- Risk developing Myelofibrosis
What is primary essential thrombocytosis (ET)?
A disease in which abnormal cells in the bone marrow cause an increase in platelets.
What is reactive thrombocytosis?
An elevated platelet count (> 450,000/μL) that develops secondary to another disorder.
What are the causes of reactive thrombocytosis?
- Iron deficiency
- Drug induced (steroids, adrenaline, TPO mimetics)
- Rebound post chemo
How would you perform a thrombocytosis investigation?
- Good history / examination IMPORTANT (e.g.recent normal count prior to surgery)
- Persistent Platelets >450 x109/L
1st line investigations
1. FBC and film
What second-line investigations would you perform in suspected thrombocytosis?
- ? Bone marrow biopsy
- Extensive search for secondary cause
What is the CALR mutation?
- Calreticulin mutation
- cell signalling protein produced in ER (endoplasmic Reticulin)
- Mutation in EXON 9 of gene
- Found in Myeloid progenitors in ET
- Mechanism of action unknown at present but may activate cell signal pathways
- found in upto 90% of JAK2 negative ET
What percentage of ET patients have a JAK2 mutation?
What percentage of ET patients have a CALR mutation?
What is the treatment of ET?
- Assess thrombotic risk
-- Platelet count >1500
-- History of thrombosis
- Antiplatelet treatment
-- Aspirin 75mg daily
- Cytoreduction (only if High risk)
-- 1 or more risk factors
What drugs are used for cytoreduction?
What is the prognosis for ET?
- Overall excellent 20 year median survival
- Risk of AML or Myelofibrosis
- CALR mutated have lower thrombosis risk
What is myelofibrosis?
The proliferation of an abnormal clone of haematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue.
What is the presentation of myelofibrosis?
- B symptoms
- Massive splenomegaly
What investigations should you perform if you suspect myelofibrosis?
- FBC and film
How is the diagnosis of myelofibrosis reached?
- Blood film
- Bone marrow results
- JAK2 mutation 50%
- CALR mutation 30%
What are the possible causes of splenomegaly?
- C Cancer
- H Haematological - Myelofibrosis, CML
- I Infection - Schistosomiasis,malaria
- C Congestion - Liver disease / portal
- A Autoimmune- haemolysis
- G Glycogen storage disorders
- O Other - Amyloid, etc
What is the treatment for myelofibrosis?
- Supportive care
- JAK2 Inhibitors
- Bone marrow Transplant
What is the prognosis for myelofibrosis?
- Median survival 5 years
What is the epidemiology of chronic myeloid leukaemia?
- Rare: Aproximately 1 per 100,000 per year
What are the characteristics of chronic myeloid leukaemia?
- Leucoerythroblastic blood picture
What are the symptoms of CML and their causes?
- Abdominal discomfort: Splenomegaly
- Abdominal pain: Splenic infarction
- Fatigue: Anaemia, catabolic state
- Venous occlusion: Retinal vein, DVT, priapism
- Gout: Hyperuricaemia
What is the treatment for CML?
1. Chronic phase:
- Low dose oral cytotoxic drugs (busulphan, hydroxycarbamide)
2. Acute leukaemic transformation/blast crisis
- Myeloid and Lymphoid types
- Intensive chemotherapy, poor outcome
3. Allogeneic bone marrow transplantation
- Curative in ~ 50% of patients
What is Gleevec (imatinib)?
A small molecule specifically designed to block the active site in the bcr-abl tyrosine kinase.
What is the cause of imatinib resistance?
Activating loop mutations in BCR-ABL confer resistance and loss of disease control.
What new tyrosine kinase inhibitors are available?
Nilotinib and Dasatinib