Week 3 part 2

Question 1

Clonal haemopoietic stem cell disorders

Answer 1

Clonal haemopoietic stem cell disorders with an increased production of one or more types of haemopoietic cells

Question 2

Pathophysiology of chronic myeloid leukaemia

Answer 2

The Philadelphia chromosome is present in more than 95% of patients with chronic myeloid leukaemia (CML). It is due to a translocation between the long arm of chromosome 9 and 22 - t(9:22)(q34; q11). This results in part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22. The resulting BCR-ABL gene codes for a fusion protein that has tyrosine kinase activity in excess of normal.

BCR-ABL1 POSITIVE

Question 3

Features of chronic myeloid leukaemia

Answer 3

Presentation (60-70 years)
anaemia: lethargy
weight loss and sweating are common
splenomegaly may be marked → abdo discomfort
an increase in granulocytes at different stages of maturation +/- thrombocytosis
decreased leukocyte alkaline phosphatase
may undergo blast transformation (AML in 80%, ALL in 20%)

Question 4

Management of chronic myeloid leukaemia

Answer 4

Imatinib is now considered first-line
hydroxyurea
interferon-alpha
allogenic bone marrow transplant

Question 5

Imatinib mechanism of action

Answer 5

inhibitor of the tyrosine kinase associated with the BCR-ABL defect

very high response rate in chronic phase CML

Question 6

Laboratory features of chronic myeloid leukaemia

Answer 6

normal/↓Hb

leucocytosis with neutrophilia and myeloid precursors (myelocytes), eosinophilia, basophilia

thrombocytosis,

Question 7

Polycythaemia Vera (PV)

Answer 7

Polycythaemia vera (PV) is a myeloproliferative disorder caused by the clonal proliferation of hematopoietic progenitor cells.

Question 8

Polycythaemia Vera (PV) pathophysiology

Answer 8

PV is characterised by an elevation in the red cell mass, typically manifesting as a raised haemoglobin or haematocrit on a full blood count (FBC). It is often accompanied by elevated platelets and/or neutrophils. Around 98% of cases are linked to an acquired mutation of Janus Kinase 2 (JAK2), a tyrosine kinase important in cell signaling pathways.

Question 9

Epidemiology of Polycythaemia Vera (PV)

Answer 9

PV is a rare condition that is uncommon under the age of 40.

PV can present at any age but most commonly presents in the 60’s and is very rare in childhood. It appears to be slightly more prevalent in men.

Question 10

Polycythaemia

Answer 10

Polycythaemia refers to an increase in the red cell mass, it may be divided into primary and secondary causes.

Polycythaemia is a disorder characterised by an elevation in the haemoglobin concentration and/or haematocrit. Polycythaemia can be divided into primary and secondary causes.

Question 11

Primary polycythaemia

Answer 11

This refers to polycythaemia occurring due to a mutation (inherited or acquired) that results in an increase in the red cell mass. Polycythaemia vera is the main cause but a raised red cell mass may also be seen in other myeloproliferative and congenital diseases.

Question 12

In secondary polycythaemia

Answer 12

In secondary polycythaemia the increased red cell mass occurs due to increased erythropoietin (EPO) production. EPO is the main hormone responsible for controlling erythropoiesis (red blood cell production).

This is most commonly due to appropriate rises in EPO secondary to hypoxia, but can also be due to inappropriate rises:
Hypoxia-induced EPO rise:
Smoking
Chronic lung disease
Obesity
Obstructive sleep apnea

Question 13

Relative polycythaemia

Answer 13

Relative polycythaemia refers to an increase in the haematocrit or haemoglobin count in the presence of a normal red cell mass. This results from a decrease in the plasma volume. Causes include dehydration (e.g. diarrhoea/vomiting) and diuretics use.

Question 14

Features of Polycythaemia Vera (PV)

Answer 14

PV may be discovered incidentally on a FBC or present with an often insidious onset and non-specific features.

Patients may be entirely asymptomatic with a raised haemoglobin or haematocrit noted incidentally on blood tests. The diagnosis of PV cannot be made on a single FBC

In patients presenting symptomatically, there is often a history of a gradual, creeping onset.

Question 15

Symptoms and signs of Polycythaemia Vera (PV)

Answer 15

Headache
Visual disturbance
Tinnitus
Itching (especially in a warm bath)
Fatigue
Vertigo
Paresthesia

Plethora
Bruising
Excoriation
Conjunctival injection
Splenomegaly
Erythromelalgia

Question 16

Diagnosis of Polycythaemia Vera (PV)

Answer 16

Genetic testing for JAK2 mutations can help to confirm a diagnosis of PV.

Bloods
The full blood count (FBC) is a key investigation. In polycythaemia a raised haemoglobin and/or haematocrit is seen*:

Male: haemoglobin > 185 g/L and/or haematocrit > 0.52
Female: haemoglobin > 165 g/L an/or haematocrit > 0.48

Question 17

Management of Polycythaemia Vera (PV)

Answer 17

Venesection

Low-dose aspirin - 75mg, once daily
Cytoreductive therapy

Hydroxycarbamide (hydroxyurea)

Question 18

Venesection

Answer 18

Venesection involves the removal of the affected patient’s blood to reduce their circulating red cell mass. This can be completed 200-500ml at a time at intervals dependent on patient factors (e.g. size). This is completed with the target of maintaining a haematocrit of < 0.45.

Question 19

Cytoreductive therapy uses

Answer 19

Cytoreductive therapy is considered in high-risk patients, defined by BSH as:

Age ≥ 65 years and/or
Prior PV-associated arterial or venous thrombosis

It is also considered in low-risk patients with certain features including:
Thrombocytosis (> 1500 × 109/l)
Progressive splenomegaly
Progressive leucocytosis (> 15 × 109/l)
Poor tolerance of venesection

Question 20

Chronic myeloid leukaemia (CML)

Answer 20

Chronic myeloid leukaemia (CML) is a clonal myeloproliferative neoplasm characterised by abnormal clonal expansion of cells of the myeloid lineage

Question 21

Four main types of Leukemia

Answer 21

Acute myeloid leukaemia (AML)
Acute lymphoblastic leukaemia (ALL)
Chronic myeloid leukaemia (CML)
Chronic lymphocytic leukaemia (CLL)

Question 22

Diagnosis of Chronic myeloid leukaemia (CML)

Answer 22

FBC: White cell count (WCC) are elevated in almost all patients with the differential showing marked neutrophilia. Basophils are almost always raised and eosinophils are commonly elevated. Half of patients will have a WCC above 100 x 10⁹/L. Anaemia and thrombocytosis are also often seen.

Question 23

Chronic phase of CML

Answer 23

The vast majority (> 85%) present in the chronic phase of disease. Clinical features are typically non-specific and include fatigue, weight loss and night sweats. Prior to advanced treatment options this phase would tend to last 3-5 years.

Question 24

Blast crisis in CML

Answer 24

This phase resembles an acute leukaemia with the rapid expansion of blasts. Without treatment survival is typically a few months. It is defined by ELN as:

Blasts in blood or marrow ≥30%
Extramedullary blast proliferation, apart from spleen

Question 25

Essential Thrombocythaemia

Answer 25

Chronic myeloproliferative disorder, persistent increase in platelet count. About half of cases are discovered incidentally on FBC and the other half become symptomatic – typically with thrombus formation.

Question 26

Features of essential thrombocythaemia

Answer 26

Associated with thrombotic or haemorrhagic complications, average age 60 years
Good prognosis, risk of transformation to myelofibrosis and AML
Symptoms: may be asymptomatic, burning on the soles and palms, cold peripheries, headache, dizziness
Occlusion of arterioles: ischaemia, gangrene or acrocyanosis.
Haemorrhagic complications: ecchymosis, epistaxis, menorrhagia and GIT haemorrhage.
Splenomegaly unusual, may be painful splenic infarction

Question 27

Platelet count in essential thrombocythaemia

Answer 27

Platelet count usually >600×109/l

Question 28

Diagnosis of essential thrombocythaemia

Answer 28

Diagnosis of exclusion (rule out infection, inflammation, iron deficiency, malignancy)
Investigations: normal ESR, plasma viscosity and fibribnogen levels
50% have acquired JAK2 mutation.
Bone marrow examination: exclude CML, myelofibrosis and myelodysplasia, check iron stores

Question 29

Management of essential thrombocythaemia

Answer 29

Hydroxycarbamide and aspirin is given in high risk cases (elderly, platelets >1500×109/l or previous thromboembolic events)

Low-dose asprin alone in lower risk patients, interferon given in pregnancy

Question 30

Blood film in Chronic myeloid leukaemia (CML)

Answer 30

Blood film: Immature and mature myeloid cells are seen in CML. The proportion of blasts and basophils help to categorise the phase of disease.

Question 31

Primary myelofibrosis (PMF)

Answer 31

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, and anemia with nucleated and teardrop-shaped red blood cells.

Question 32

Diagnosis of Primary myelofibrosis (PMF)

Answer 32

Diagnosis requires bone marrow examination and exclusion of other conditions that can cause myelofibrosis (secondary myelofibrosis).

Question 33

Treatment of Primary myelofibrosis

Answer 33

Treatment is often supportive, but JAK2 inhibitors such as ruxolitinib or fedratinib may decrease symptoms, and stem cell transplantation may be curative.

Question 34

Primary myelofibrosis mutations

Answer 34

Mutations of the Janus kinase 2 (JAK2) gene are present in a high proportion of cases of primary myelofibrosis. JAK2 is a member of the tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF) among other entities. Mutations of the thrombopoietin receptor gene (MPL) or the calreticulin (CALR) gene also may be the cause of primary myelofibrosis.

Question 35

Myeloid stem cell

Answer 35

A myeloid stem cell becomes one of three types of mature blood cells: Red blood cells that carry oxygen and other substances to all tissues of the body. Granulocytes, which are white blood cells that help fight infection and disease. Platelets that form blood clots to stop bleeding.4 Mar 2022