Week 2 - I - CLL + Myeloproliferative disorders (CML, Polcythaemia (rubra vera, secondary&pseudo), E.T & Myelofibrosis

Question 1

What is a myeloproliferative disorder?

Answer 1

This is a disorder in which there is clonal hameopoietic stem cell disorder causing proliferation (Overgrowth) of one or more haemopoietic lineages

Question 2

How is there difference in myelopoliferative disorders in contrast to leukaemia?

Answer 2

In contrast to leukaemia, the maturation in MPDs is preserved

Question 3

Define MPD again? Although not a malignant neoplasm like other cancers, MPNs are classified within the haematological neoplasm. What are the four different types of myloproliferative disorder?

Answer 3

This is a clonal haemaopoietic stem cell disorder characterised by increased proliferation of one or more haemopoietic lineages 4 types Chronic myeloid leukaemia Essential thrombocytosis Polycythaemia vera Myelofibrosis

Question 4

How are the 4 types of MPD categeorised?

Answer 4

The myeloproliferative disorders can be categorised by the presence of BCR-ABL1 coded for by the philadelphia chromsome (reciprocal translocation of chromsome 9and22) which is present in chronic myeloid leukaemia or BCR-ABL1 negative Which is seen in polycthaemia vera, essential thrombocytosis, idiopathic myelobrosis

Question 5

In chonic myeloproliferative disorders, the cells are still able to mature down the lineages but there are too many red blood cells and/or too may platelets and or too many grnaulcoytes What is there the over-prduction of in each of the MPDs?

Answer 5

Chronic myeloid leuakemia - over production of granulcoytes

Polycthaemia vera - over production of red blood cells

Essential thrombocytosis - over production of platelets

Myelofibrosis

Question 6

When may you consider a myleoproliferative disorder?

Answer 6

These MPDs are only considered if there is no reactive explanation MPDs are classified as haematological malignancies even though they are not typical cancers - They are not due to reactive change bacterial, low iron for platelets etc

Question 7

Is this person likely to have polycthaemia vera? Explain answer

Answer 7

Unlikely This man has severe hypoxia, therefore his hypoxic drive will be causing an increase in the secretion of EPO from the interstitial fibroblasts of the kidneys, therefore causing the bone marrow to produce more red cells even though he is not anaemic - due to the clinical history this seems like a reactive change due to COPD

Question 8

What is chronic myeloid leuaemia?

Answer 8

CML is a cancerous disease cause by the uncontrolled proliferation of myeloid cells Usually the granulocytes and their precursors but can also affect the platelets

Question 9

What are the different phases of chronic myeloid leukaemia? What happens in these phases?

Answer 9

Chronic phase - lasting months-few years with few symptoms Accelerate phase with increasing symptoms Blast crisis - features of acute leukaemia in this phase

Question 10

How long do the chronic and accelerated phase all together last? Is maturation present at all three stages?

Answer 10

Chronic and accelerated phase lasts about 3-5 years In these phases there is uncontrolled proliferation but maturation is present The blast crisis is reminiscent of acute leukaemia with maturation defect now present - over production of primitive cells

Question 11

Describe the differences in morphology here?

Answer 11

Chronic phase - can see the neutrophilia present here - over production of mature cells Accelerated phase - more primitive cells do feature here Blast crisis - only primitive cells on microscopy now can be seen

Question 12

What are the symptoms of CML? What can arise due to the increased viscosity of the blood in these conditions? What causes the hyperviscosity?

Answer 12

In most cases, the diagnosis is an incidental finding If not, it usually will present with splenomegaly which can compress the stomach leading to early satiety and weight loss There is usually also hypermatabolic symptoms such as gout due to purine breakdown Due to the hyperleucocytosiis, the blood is hyperviscous which can lead to problems such as priaprism

Question 13

Which age group does CML typically present in? What are the blood changes seen?

Answer 13

Typically presents in those aged 40-60 Low or normal haemoglobin There is a leucocytosis with nuetrophilia and myeloid precursors as well as a basophilia and eosinophilia There is also a thrombocytosis usually Not many conditions cause a basophilia

Question 14

Describe the blood counts shown State which may be the chronic myeloid leukaemia

Answer 14

• * Patient on the left - has the typical leucocytosis associated with a neutrophilia, basophilia and eosinophilia as well as a thrombocytois
• * There is also a low haemoglobin count
• * With the clinical features of weight loss and early satiety also (potenital splenomegaly)
• * This suggest chronic myeloid leukaemia

Patient on the right - collection of pus in pleural cavity - expected neutrophilia here with normal basophil and eosinophil count - reactive change present

Question 15

What type of cells are the arrows pointing to? What is the hallmark cause of chronic myeloid leukaemia?

Answer 15

The arrows are pointing to eosinophils The cells with the dark red staining granules in the cytoplasm are the eosinophils Hallmark cause of CML is the phildelphia chromosome

Question 16

What is the philadelphia chromsome?

Answer 16

This is where there is a reciprocal translocation between the long arms of chromosomes 9 and 22 which forms a fusion gene BCR-ABL on chromsome 22 which has tyrosine kinase activity

Question 17

Philadelphia chromosome results in a new (chimaeric) gene: BCR-ABL1 How is this gene mutation identified? (dont need to carry out immunophenotyping to know the lineage as the cells are mature and can see whether myeloid or lymphoid lineage) What activity does the philadelphia chromosome have and what does it cause?

Answer 17

This gene mutation is identified by cytogentic analysis of the bone marrow This chromosome is defective and unusually short because of reciprocal translocation of genetic material between chromosome 9 and chromosome 22. This gene is the ABL1 gene of chromosome 9 juxtaposed onto the BCR gene of chromosome 22, coding for a hybrid protein: a tyrosine kinase signalling protein that is “always on”, causing the cell to divide uncontrollably.

Question 18

The gene product is a tyrosine kinase which causes abnormal phosphorylation (signalling) leading to the haematological changes in CML The only curable treatment is stem cell/bone marrow transplant What is the mainstay of drug treatment for CML?

Answer 18

This would be treating the patient with a tyrosine kinase inhibitor eg - imatinib or dasatinib

Question 19

What are the features that are common to MPDs that are seen in these diseases? Why can there be gout?

Answer 19

Patients are often asymptomatic

However there is usually an increased cell turnover due to splenomegaly which can cause gout (increased purine breakdown), early satiety and weight loss due to stomach compression

There is also an increase risk of thrombosis - arterial or venous in uncommon sites as well as marrow failure in idiopathic myelofibrosis

Question 20

In polycthaemia vera and essential thrombocytosis There is sometimes a rare vascular peripheral pain disorder in which blood vessels, usually in the lower extremities or hands, are episodically blocked (frequently on and off daily), then become hyperemic and inflamed. There is severe burning pain (in the small fiber sensory nerves) and skin redness. What is this known as?

Answer 20

This is erythromelalgia

Question 21

What is polycthaemia vera?

Answer 21

This is where there is a high haemoglobin/haematocrit accompanied by an erythrocytosis (a true increase in red cell mass) but there can be an increase in other cell lineages as well

Question 22

It is important to distinguish polycthaemia vera from secondary ppolycthaemia and pseudopolycthaemia What are these two conditions?

Answer 22

Secondary polycthaemia is where there is an increase in Hb/Hct with an eryhtrocytosis due to a chronic hypoxia or EPO secreting tumour- reactive changes Pseudopolcythaemia - there is an apparent increase in Hb/Hct but this is only due to plasma volume loss eg diuretics use or dehydration

Question 23

Which is true and which is pseudo polycthaemia?

Answer 23

After centrifuge The left is the true polycthaemia - can see there is a red cell increase here which will cause an increase in Hb/Hct (haemtorctrit - red cell percentage of the total blood volume) The right is pseudopolycythaemia - the red cell volume has remained normal but due to the decreased plasma volume - there will be an increase in the Hct

Question 24

The clinical features of PRV (polycthaemia ruba vera) link with the typical MPD features - splenomegaly , gout, weight loss/early satiety, thrombosis due to hyperviscosity Due to the increased blood viscosity there is an increase in headaches and fatiuge Why are these increased? What is the itch present in PRV known as?

Answer 24

Headaches and fatigues - blood was made to move and therefore decreased flow of blood deprives the brain and body of rapid blood flow The itch is known as an aquagenic pruritus

Question 25

What is this aquagenic pruritus?

Answer 25

This is where this is an itch on exposure to warm water - eg hot bath or shower and Erythromelalgia is also common with this condition

Question 26

What would the blood count reveal?

Answer 26

Inceased RCC, Hb, Hct and can often have increased WCC and platelets on blood count

Question 27

What is the mutation that is often present in patients with polycythaemia and what does this mutation cause?

Answer 27

In over 95% of patients with PRV there is a mutation in the JAK2 pathway JAK2 is a kinase and a mutation in this results in loss of the auto-inhibition leading to a erythropoeisis in the absence of ligand EPO Mutational analysis forms part of initial screening and has replaced a number of other tests in routine practice If this mutation is negative then very unlikely this patient has polycthaaemia ruba vera

Question 28

Due to the majority of patients having the JAK2 mutation, what will measuring EPO show? Most commonly don’t require a bone amrrow biopsy but may sometimes still be useful

Answer 28

EPO levels are expected to be low in patients with PVR - not normally measured anymore anyway

Question 29

What is the treatment of polycthaemia rubra vera? Main problem is that they are an increased risk of having thrombotic events What is given for patients at high risk of thrombosis? What is high risk of thrombosis with this condition meaning?

Answer 29

The patient recieves venesection (phlebotomy) where there is the removal of red cells with the aim to venesect the haemotocrit <0.45 Low dose apsirin (75mg) is given to reduce the risk of clotting In patients with excessive splenomegaly or very high risk of thrombosis , hydroxycarbamide is used - cytotoxic drug High risk means over 60 or previous thrombosis ever Aspirin low dose is still continued

Question 30

What is the myeloproliferative disorder where there are primarily too many platelets produced?

Answer 30

This would be essential thrombycthaemia

Question 31

What is essential thrombocythaemia due to? Why can bleeding occur at very high levels in essential thrombocythaemi?

Answer 31

It is due to a clonal proliferation of megakaryocytes causing a persistently increased platelet level Bleeding may occur at very high platelet levels due to vWF being used up to enable the platelets to bind to the endothelium but then there is decreased functional vWF for platelet adhesion leading to an increased risk of bleeds

Question 32

What are of platelets usually in essential thrombocythaemia which pose a risk for bleeding?

Answer 32

Usually the platelet level is >1000x10^9/L (1,000,000/microlitre) when the deficient vWF for platelet adhesion increases the risk of bleeding

Question 33

What can the microvascular vaso-occlusions present as? What are other conditions that may cause a thrombocytosis and need to be excluded?

Answer 33

May present as atypical chest pain, headache, erythromelalgia, necrose toes due to blockage of the arteries Other thrombocytosis causing conditions Iron deficiency anaemia Post surgery Malignancy Bleeding

Question 34

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Answer 34

On - the right reactive as there has been surgery causing a bleed which has caused EPO to stimulate erythropoiesis as well as thrombopoeisis On the left - absence of reactive features from history, as well as an increased platelet count - ET is a possibility - also history of painful discoloured toe (could be due to clot in a small artery in the toe)

Question 35

After looking at blood film to see the thrombocytosis and the blood count it is important to exlcude the other cause of essential thrombycthaemia Genetic tests can then be carried out to identify the disease, what are these tests? (3 different tests) As well as the genetic tests, bone marrow aspirate/biopsy should be carried out

Answer 35

JAK2 mutation tested for - seen in 50% of patients CALR and MPLmutation if JAK2 is negative In patients without JAK2 mutation, test for CALR (calreticulin)and a small percentage will have an MPL mutation – can test for this is CALR negative If all of these are negative, there still lies a 15% chance that the patient has ET

Question 36

What would be seen on bone marrow aspirate in essential thrombocythaemia?

Answer 36

Would carry out bone marrow biopsy to see an increased number of megakaryocytes - increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei

Question 37

What is the treatment for essential thrombocythaemia? (much the same as for polycthaemia rubra vera) State the difference in low and high risk patients

Answer 37

For low risk patients Give low dose aspirin (anti-platelet) - 75mg dailiy For high risk patients - those over 60 or have had a previous thrombosis Give hydroxycarbamide Interferon alpha and anagralide can also be tried here

Question 38

Talked about chronic myeloid leukaemia, polycthaemia rubra vera and essential thrombocythaemia WHat is the other myeloproliferative disorder? What is the cause of this disorder?

Answer 38

This would be myelofibrosis Can have idiopathic myelofibrosis or Myelofibrosis which is secondary to other myeloproliferative disorders - post polycthaemia or post essential thrombocythaemia

Question 39

Describe some features of idiopathic myelofibrosis?

Answer 39

Bone marrow failure and fibrosis - anaemia, bleeding and infection Extramedullary haematopoiesis - hepatosplenomegaly Also hypercatabolism - severe fever, cachexia weight loss, early satiety

Question 40

What is seen on the blood film in myelofibrosis?

Answer 40

There are tear dropped shaped RBCs - thought to be due to the cells trying to escape the fibrosed marrow and Leucoerythroblastic change

Question 41

What are the abnormally shaped rbc that have the typical tear drop appearance known as? What is used for diagnosis of the condition?

Answer 41

These are known as poikilocytes which are abnormally shaped RBCs as seen on the blood film

On marrow aspiration this reveals a dry aspirate (this shows the needle cannot suck out a sample of semi-liquid marrow) & therefore trephine biopsy is required for diagnosis and reveals a fibrosed bone marrow

Could also do a JAK2 mutation test - +ve 50%

Question 42

As well as having mature granulocytes and red cells in blood, will also see leucoerythroblasts on film (combination of myeloid and leucoblastic precrusors) What are the three main causes of leucoerythroblastic change on blood film? What are the fibres seen on marrow biopsy known as?

Answer 42

This would be reactive causes (sepsis), marrow infiltration (malignancy, primary or metastatic) and myelofibrosis These are known as reticulin fibres

Question 43

What is given as treatment of myelofibrosis?

Answer 43

Supportive care - red cell transfusions and platelet transfusions Prophylactic antibiotics and antifungals due to neutropenia Allogenic stem cell transplant may be curative byt only for a few patietns

Question 44

What drug was approved in 2011 for the treatment of myelofirbrosis? It serves as a JAK1and2 inhibitor and decreases the organomegaly?

Answer 44

Ruxolitinib In November 2011, the FDA approved rutoxlitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis.] Ruxolitinib serves as an inhibitor of JAK 1 and 2. The data showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with improved overall survival compared to placebo.

Question 45

What is the commonest type of leukaemia?

Answer 45

Chronic lymphocytic leukaemia

Question 46

What cell type is chrnic lymphocytic leukaemia due to? What are the signs?

Answer 46

Due to accumulation of mature B cells that have escaped programmed cell death - these are dysfunctional cells Usually asymptomatic Can have enlarged rubbery,non tender lymph nodes, hepatosplenomgealy and symptoms of pancytopenia

Question 47

What is seen on blood film in chronic lymphocytic leukaemia?

Answer 47

There is often smear cells on the blood film - it shows the lymphocytes are fragile and can therefore be damaged during preparation for microscopy

Question 48

What is an association with chronic lympochytic leukaemia? usually seen later

Answer 48

There is usually the production of autoantibodies causing idiopathic thrombocytopenia and autoimmune hemolytic anemia in association with chronic lymphocytic leukaemia

Question 49

What is the treatment of choice in chronic lymphocytic leukaemia? What mutations can occur and if so what is the treatment option? What age group is typically affected?

Answer 49

Treatmnet of choice Flurdarabine + cyclophosphamide + rituximab (FCR) as the primary treatment If cytogenetic analysis reveals a 17p deletion or p53 mutation Offer ibrutinib (Bcell signalling pathway inhibitor which does not require p53 for apoptosis) It mostly affects people over the age of 60 and is rare in people under 40. Children are almost never affected.