Theme 7 Haematology: CMPD and CML Flashcards
What is CMPD?
- chronic myeloproliferative disorders
- clonal stem cell disorders of the bone marrow
- malignant –> propagated by an abnormality in the pre cursor progenitor cell in the bone marrow
What are the 3 types of CMPD?
- Polycythaemia vera (PV)
- Essential thrombocytosis (ET)
- Idiopathic myelofibrosis (IMF)
What is polycythaemia vera and why does it occur?
- increased red cells (+/- neutrophils/ platelet)
- bone marrow is making too many red cells due to a mutation in JAK2
What is essential thrombocytosis (ET)?
-increased platelets
What is idiopathic myelofibrosis (IMF)?
variable cytopenias with a large spleen
distinguish from other causes of splenomegaly
For polycythaemia vera, what is?:
- Age distribution
- Symptoms
- Signs
- Age distribution: all ages, peak at 50-70 yrs
- Symptoms: insidious, itching, plethoric (red) face, headache, muzziness, general malaise, tinnitus, peptic ulcer, gout, gangrene of toes
- Signs: plethora, engorged retinal veins, splenomegaly
How do we diagnose PV?
- persistent increased Hb/hct > 0.5
- if haematocrit is above 50% on two different occasions
What is haematocrit?
ratio of volume of red cells to total volume of blood
What are the two different ways to classify PV?
- Relative or absolute polycythaemia
2. Primary or secondary polycythaemia
What is the cause of primary polycythaemia
polycythaemia vera
What are some causes of secondary polycythaemia?
- central hypoxic process - chronic lung disease, smoker
- renal disease
- EPO producing tumours
- drug associated
- idiopathic erythrocytosis
If the EPO is normal or low, does the patient have primary or secondary PV ?
Primary
Which mutation in peripheral blood DNA is diagnostic of a myeloproliferative disorder?
JAK2 V617F
How does JAK2 mutation cause CMPD?
Receptor for EPO is permanently switched off with JAK2 mutation
EPO doesn’t need to bind the cell just keeps multiplying
How do you treat PV?
- take away a pint of blood to lower haematocrit
- aspirin 75mg daily to reduce risk of thrombosis
- treatment to prevent clots
What are the two types of thrombocytosis?
- Primary essential thrombocytosis (ET) –> bone marrow is making too many platelets leaving at risk of thrombosis (platelet > 450 x 10^9)
- Reactive thrombocytosis
What are the causes of reactive thrombocytosis?
- surgery
- infection
- inflammation
- malignancy
- iron deficiency
- hyposplenism
- haemolysis
- drug induced (steroids, adrenaline)
- rebound post chemo
What are the 1st line investigations for thrombocytosis?
- FBC and film
- ferritin
- CRP
- CXR
- ESR
What are the 2nd line investigations for thrombocytosis?
- JAK2
- CALR
- bone marrow biopsy?
- search for secondary cause
Other than the JAK2 mutation, what is the other mutation that can increase risk of ET?
CALR
Calreticulin mutation
How do we treat ET?
- Assess thrombotic risk based on:
- age
- hypertension
- diabetes
- platelet count > 1500
- history of thrombosis - Antiplatelet treatment - aspirin 75 mg daily
- Cytoreduction - only if one or more risk factor
What is cytoreduction?
Impair the bone marrows ability to make cells to reduce platelet count to a normal level
Which drug is an anti-folate drug that inhibits the bone marrows ability to make platelets?
hydroxycarbamide (used for cytoreduction in ET)
What is the presentation of myelofibrosis?
- pancytopenia –> low red cells, white cells and platelets
- drenchy night sweats, persistant fever and more than 10% weight loss
- massive splenomegaly as spleen takes over making RBCs, WBCs and platelets
How to we diagnose myelofibrosis?
- blood film
- bone marrow
- JAK2 mutation in 50%
- CALR mutation in 30%
What are the causes of splenomegaly? (acronym: CHICAGO)
-Cancer
-Haematological - myelofibrosis, CML, CLL, hairy cell leukaemia
-Infection - schistosomiasis, malaria
-Congestion - liver disease
-Autoimmune - haemolysis, SLE
-Glycogen storage disorder
Other - amyloid, sarcoid
In splenomegaly, what is:
- Treatment
- Prognosis
- Supportive care, JAK2 inhibitors, bone marrow transplant
2. Poor, median survival = 5 years
Who gets chronic myeloid leukaemia?
- median age at diagnosis: 55-60 years
- 5x more common in female
What are the haematological characteristics of CML?
- leucocytosis –> very high white cell count
- leucoerythroblastic blood picture
- anaemia
- splenomegaly
What are the symptoms of CML?
- abdominal discomfort
- abdominal pain
- fatigue
- venous occlusion
- gout
- splenomegaly
- splenic infection
- anaemia
- retinal vein, DVT, priapism
- hyperuricaemia
What is meant by the 9:22 chromosome translocation?
- parts of chromosome 9 and 22 can fuse together to make an oncogene
- this is known as the “philadelphia chromosome” in CML
What is Gleevec?
- a small molecule specifically designed to block the active site in the BCR-ACL tyrosine kinase to inhibit tyrosine kinase
- a.k.a imatibin
- revolutional treatment for CML with good survival
- however resistance is a problem
How do we treat CML?
Chronic:
-with TKIs
Acute leukaemic transformation/blast crisis:
-intensive chemotherapy, TKI and bone marrow transplant
What is CML?
- pluripotent stem cell disorder
- defined by the t(9;22) translocation
- driven by BCR-ABL fusion tyrosine kinase
- chronic phase followed by acute transformation
- imatinib has proved highly successful
- BCR-ABL mutations confer resistance to imatibin
