W5 - CML & myeloproliferative disorders

Question 1

Describe the 2 types of polycythaemia (raised Hb concentration and haematocrit %)

Answer 1

1. Relative => lack of plasma => NON-MALIGNANT
2. True => excess erythrocytes:
   A) secondary (NON-MALIGNANT)
   B) primary (myeloproliferative NEOPLASM)

Question 2

Describe the categorisation of primary myeloproliferative neoplasms (MPDs) based on Ph

Answer 2

Ph negative:

• polycythaemia vera (PV)
• Essential thrombocythaemia (ET)
• Primary myelofibrosis (PMF)

Ph positive:
- Chronic myeloid leukaemia (CML)

Question 3

Name 3 risk factors for pseudo (relative) polycythaemia

Answer 3

1. Alcohol
2. Obesity
3. Diuretics

Question 4

What can you check to distinguish primary from secondary true polycythaemia?

Answer 4

Erythropoietin (EPO)!

Primary polycythaemia = REDUCED EPO
Secondary polycythaemia = ELEVATED EPO

Question 5

Categorise the causes of true secondary polycythaemia (non-malignant)

Answer 5

Raised EPO:

1. Appropriate:
   - high altitude
   - cyanotic heart disease
   - high affinity haemoglobin
2. Inappropriate:
   - renal disease (cysts, tumours, inflammation)
   - uterine myoma
   - other tumours (liver, lung)

Question 6

Name the 3 groups of myeloid malignancies, starting with the most acute form

Answer 6

1. Acute myeloid leukaemia (>20% blasts)
2. Myelodysplasia (5-19% blasts)
3. myeloproliferative disorders (MPD neoplasms):
   - essential thrombocythaemia
   - polycythaemia vera
   - primary myelofibrosis
   - Ph + => Chronic myeloid leukaemia

Question 7

Name the 2 groups of lymphoid malignancies, starting with the most acute

Answer 7

1. Precursor cell malignancy => Acute lymphoblastic leukaemia (B & T)
2. Mature cell malignancy:
   - Chronic lymphocytic leukaemia (CLL)
   - Multiple myeloma (MM)
   - Lymphoma (Hodgkin & Non-Hodgkin)

Question 8

Which MPD neoplasm arises with acquired mutations in the erythroblast precursors?

Answer 8

Polycythaemia vera (PV)

Question 9

Describe the cellular pathophysiology behind polycythaemia, essential thrombocythaemia, chronic myeloid leukaemia (CML)

Answer 9

JAK 2 mutations
- JAK2 is involved in tyrosine kinase signalling, which is a signalling cascade for cell growth signals from surface receptor to the nucleus

• JAK2 (unphosphorylated) is associated with the TK receptor => once phosphorylated, dimerises and transmits downstream signalling

In 3 conditions stated, a JAK2 V617F mutation means that tyrosine kinase is ON => increased cellular proliferation!

Question 10

In what % of PV, ET, and PMF do you see JAK2 V617F mutations?

Answer 10

PV – 100% JAK2 mutations
ET – 60% JAK2 mutations
PMF – 60% JAK2 mutations

Question 11

What is the mean age at diagnosis for PV?

Answer 11

60 years

Question 12

How is PV usually picked up? What are the FBC ranges?

Answer 12

Incidental diagnosis following routine FBC;

median Hb 184 g/L, Hct 0.55

Question 13

What are the symptoms (6) of PV?

Answer 13

• CNS: Headaches; light-headedness; stroke; visual disturbances**
• General: fatigue; dyspnoea
• due to increased histamine release: aquagenic pruritus, peptic ulceration (histamine causes stomach to make more acid)

Question 14

After routine tests, what test is specific for PV diagnosis?

Answer 14

Test for JAK2 V617F mutation

Question 15

Describe the management of PV

Answer 15

Aim 1) reduce Hct => target Hct <45%

1. Venesection
2. Cytoreductive therapy using hydroxycarbamide

Aim 2) reduce risk of thrombosis

1. Control Hct
2. aspirin
3. Keep platelets below 400 x 10^9/L => using ET treatments such as anagrelide

Question 16

Which lineage does ET involve?

Answer 16

Mainly the megakaryocyte lineage

Question 17

What is the age of diagnosis of ET? What is the M:F ratio?

Answer 17

Major peak 55 years, minor peak 30 years
F:M equal for 1st peak, F>M for 2nd peak

Question 18

How is ET usually picked up?

Answer 18

Incidental finding on FBC (50%)

Question 19

What are the symptoms/signs of ET?

Answer 19

• asymptomatic (50% of cases)
• thrombosis: arterial or venous:
  => CVA, gangrene, TIA
  => DVT or PE
• bleeding: mucous membranes, cutaneous
• CNS: headaches, dizziness, visual disturbances
• splenomegaly (modest)

Question 20

Describe the management of ET (& reason for each intervention)

Answer 20

1. Aspirin – prevent thrombosis
2. Hydroxycarbamide – antimetabolite. S/E: suppression of other cells
3. anagrelide – specific inhibition of platelet formation. S/E: palpitations, flushing

Question 21

What is the prognosis of patient with ET?

Answer 21

normal lifespan in many

• leukaemia transformation in about 5% after >10 years
• myelofibrosis uncommon unless fibrosis was present at the beginning

Question 22

What is the age of diagnosis of PMF? What is the M:F ratio?

Answer 22

Usually 70s
M=F

Question 23

____ & _____ may transform to PMF

Answer 23

ET & PV

Question 24

What are the symptoms/signs of PMF?

Answer 24

• asymptomatic (30%)
• cytopenias: anaemia or thrombocytopenia
• thrombocytosis
• splenomegaly (MASSIVE)
  => Budd-Chiari syndrome:
• hepatomegaly
• hypermetabolic status:
  => FLAWS
  => hyperuricaemia

Question 25

Why is there a MASSIVE hepatosplenomegaly in PMF?

Answer 25

B/c the BM becomes fibrosed + scarred =\> haematopoiesis can no longer function =\> BM cell production moves to LIVER + SPLEEN = extramedullary haemopoiesis

Question 26

Describe blood film findings (4) for PMF

Answer 26

1. Leuco-erythroblastic picture 2. Tear drop poikilocytes 3. Giant platelets 4. Circulating megakaryocytes

Question 27

Describe BM findings (4) for PMF

Answer 27

1. Dry tap 2. Trephine: =\> increased reticulin or collagen fibrosis =\> prominent megakaryocyte hyperplasia & clustering w/ abnormalities =\> new bone formation

Question 28

What mutation is responsible for PMF?

Answer 28

JAK2 or CALR mutation

Question 29

What is the prognosis for PMF? What are 3 signs of poor prognosis?

Answer 29

Median 3-5 years but very variable; bad prognostic signs: - severe anaemia \<100 g/L - thrombocytopenia \<100x10^9/L - massive splenomegaly Prognostic scoring system is DIPPS

Question 30

Describe the treatment for PMF

Answer 30

Treatment is limited. 1. supportive =\> RBC and platelet transfusion often ineffective due to splenomegaly 2. Cytoreductive therapy =\> hydroxycarbamide (for thrombocytosis) 3. Ruxolitinib =\> JAK2 inhibitor (high prognostic score cases) 4. Allogeneic SCT =\> potentially curative reserved for high-risk eligible cases) 5. Splenectomy for symptomatic relief =\> hazardous and often followed by worsening of condition

Question 31

Ph + MPN is…

Answer 31

CML

Question 32

What is the age of diagnosis of CML? What is the M:F ratio?

Answer 32

40-60s M:F 1.4:1

Question 33

What is a RF for CML?

Answer 33

Radiation exposure

Question 34

What are the symptoms/signs of CML?

Answer 34

- History =\> lethargy, hypermetabolism, bruising, bleeding - Thrombotic event =\> monocular blindness, CVA - MASSIVE splenomegaly +/- hepatomegaly

Question 35

What is the typical FBC for CML?

Answer 35

- Hb & platelets well preserved or raised - MASSIVE leucocytosis 50-500 x 10^9/L

Question 36

What is the typical blood film for CML?

Answer 36

1. high neutrophils 2. high myelocytes \*but NONE of 1+ 2 are in blasts if in chronic phase (\<5% myeloblasts) \*bi-phasic peak between neutrophils and myelocytes 3. basophilia

Question 37

Describe the translocation that produces the Philadelphia chromosome and its MOA

Answer 37

t(9;22) translocation producing bcr-abl = fusion oncoprotein with constitutive tyrosine kinase activity, which drives myeloid proliferation

Question 38

What tests can be used to identify the translocation/fusion in CML?

Answer 38

1. conventional karyotyping 2. FISH metaphase or interphase karyotyping 3. RT-PCR

Question 39

Describe the course of CML before introducing imatinib

Answer 39

Chronic phase (3-4 years) =\> accelerated phase (10-19% blasts; 6-12 months) =\> blast crisis (20%; 3–6-month survival)

Question 40

What drug class is imatinib? What’s its ROA?

Answer 40

ABL Tyrosine kinase inhibitor Oral

Question 41

Name 3 responses used for monitoring and assessing response to CML therapy?

Answer 41

1. haematological response 2. cytogenetic response 3. molecular response

Question 42

Name how haematological (1), cytogenetic (2), and molecular (3) responses can be used to assess CML therapy?

Answer 42

1. haematological =\> complete haematological response WBC \< 10 x 10^9/L 2. Cytogenetic (most imp!) =\> partial = 1-35% Ph positive, complete = 0% Ph positive 3. Molecular =\> RQ-PCR of BCR-ABL transcripts =\> reduction in % BCR-ABL transcripts -\> reduce 100% \> 10% \> 1 % \> 0.1% Major molecular response (MMR) is \<0.1% (3 log reduction)

Question 43

Summarise treatment of CML, and adjunct treatments if presented with TWO failures

Answer 43

1. Chronic phase TKI =\> imatinib (1st generation), dasatanib nilotonib (2G), bosutinib (3G) 2. Failure (1) =\> switch to 2Gen or 3G TKI - no complete cytogenetic response at year 1 - respond but acquire resistance 3. Failure (2) =\> consider allogeneic SCT - inadequate response or intolerance to 2G TKI - Progression to accelerated or blast phase

Question 44

22 yo male – cyanotic congenital heart disease – Hb 210g/L, haematocrit 60%, no splenomegaly. What will the lab result likely show?

Answer 44

Increased serum erythropoietin (EPO)