3s: Myeloproliferative Disorders (MPDs)

Question 1

MPDs arise from…

Answer 1

myeloid progenitor cells

Question 2

What 2 things control haemopoiesis?

Answer 2

Growth Factors (e.g. EPO)

Receptors (interact with GFs → activation of kinases → phosphorylation of intracellular molecules)

Question 3

What is the kinase gene fusion in CML?

Answer 3

BCR-ABL

Question 4

Role Janus Kinases

Answer 4

associated with haematopoietic cell GF-R

GF bind to R → JAK activation → STAT pathway activation

JAK2 implicated in myeloid cells

• mutation of this means pathway means activation of STAT pathway is NOT dependent on the cytokines/GF binding to the receptors

STAT transcription factor moves to nucleus → transcription of genes associated with cell growth

Question 5

What are MPDs

Answer 5

group of neoplastic/clonal disorders of haemopoietic stem cells

spontaneous colony growth WITHOUT added EPO/TPO

overproduction of one or more of the mature myeloid cells in the blood

• increased fibrosis in BM with non-clonal reactive fibrosis in BM

Question 6

What is the difference between myeloproliferation, myelodysplasia, and leukaemia?

Answer 6

Question 7

What are some clinical presentations of chronic MPDs

Answer 7

preponderance to thrombosis (arterial)

splenomegaly

haemorrhage (less frequent)

variability in clinical course

Question 8

Give some examples of chronic BCR-ABL -ve MPDs

Answer 8

Polycythaemia vera (PV)

Essential thrombcythaemia (ET)

idiopathic myelofibrosis

idiopathic erythrocytosis

chronic granulocytic leukaemia

Question 9

What is PV?

Answer 9

Non-EPO-driven increased RBC production (high Hb and Hct)

• pseudo-polycythaemia → relative increase in RBCs (i.e. plasma volume decrease)

compensatory increase in plasma volume

different degrees of increase in plts and/or granulocytic cells

mean age 60 years, 5% present <40 years

Question 10

What is the clinical presentation of PV?

Answer 10

Incidental diagnosis of routine blood testing

hyper viscosity:

• headaches, lightheadedness, stroke
• visual disturbances
• fatigue, dyspnoea

Increased histamine release:

• aquagenic pruritus (itch after hot bath)
• peptic ulceration (→ iron deficient polycythaemia = normal Hb but high RBC and MCV

Others:

• variable splenomegaly
• plethora
• erythromelalgia (red painful extremities)
• thrombosis
• retinal vein engorgement
• gout (due to increased red cell turnover)
• absence of other causes of increased Hct

Question 11

what ix for PV? Which is diagnostic?

Answer 11

• high Hb, Hct, MCV, plasma, volume, platelets
• WCC normal/moderately high
• NO circulating immature cells

Specific ix:

• BM trephine biopsy = increased cellularity (mainly erythroid cells) i.e. no fat spaces
• slight moderate reticulin fibrosis and megakaryocytic abnormalities
• low EPO (suppression from feedback loop)
• JAK2 V617F mutation (DIAGNOSTIC)
• Blood volume (isotope dilution) = RBC mass measured by incubating patient’s RBCs with radioactive chromium and plasma volume is measured by incubating plasma with radioactive iodine

Question 12

Diagnosis of PV

Answer 12

Step 1: check for JAK2 V617F (on exon 14) mutation

• if present = PV

There is another mutation in JAK2 in exon 12

• if present = erythrocytosis with no increase in red cells or white cells
• if negative = some may have pseudopolycythaemia, some may have true polycythaemia (2o to increased EPO production or familial)
• causes of increased EPO production = hypoxia, renal disease, tumours

Current diagnostic criteria:

• increased red cell production and increased platelets (sometimes neutrophils)
• JAK2 V61F mutation

Question 13

What is pseudopolycthaemia?

Answer 13

reduced plasma volume in presence of a normal hb → apparent raised Hb concentration

• In true polycythaemia, there is an increase in RBC mass with a roughly proportional increase in plasma volume

Question 14

How do we treat PV?

Answer 14

Reduce viscosity and keep Hct <45%

• venesection (bleeding and iron deficiency stimulates megakaryocytic to produce more platelets)
• cytoreductive therapy for maintence

Reduce risks of thrombosis

• aspirin
• keep plts <400 x 10^9/L (see txs of ET)

Question 15

What are features of idiopathic erythrocytosis

Answer 15

• isolated erythrocytosis
• low EPO
• ABSENCE of JAK2 V617F mutation
• less likely to transform into MF or AML
• Tx’ed with venesection only
• some cases have a mutation in exon 12 of JAK2

Question 15

What are features of idiopathic erythrocytosis

Answer 15

• isolated erythrocytosis
• low EPO
• ABSENCE of JAK2 V617F mutation
• less likely to transform into MF or AML
• Tx’ed with venesection only
• some cases have a mutation in exon 12 of JAK2

Question 16

Prognosis of idiopathic erythrocytosis and polycythaemia vera

Answer 16

• Idiopathic Erythrocytosis: NO adverse prognosis if Hct is maintained
• Polycythaemia Vera: most survive for 10 years, 65% survive 15 years

Question 17

Causes of death from PV and idiopathic erythrocytosis

Answer 17

thrombosis

leukaemia (risk potentially increased when using hydroxyurea to treat)

myelofibrosis

Question 18

What is essential thrombocythaemia (ET)?

Answer 18

Mainly megakaryocytic lineage

sustained thrombocytosis >600 x 10^9/L

two peaks in incidence = 55 (major) 30 (minor)

Question 19

What would you see in ET on BM trephine biopsy histology?

Answer 19

megakaryocyte clustering

Question 20

Clinical presentation of ET

Answer 20

• Incidental finding in half the patients
• Thrombosis (arterial or venous) → CVA, gangrene, TIA, DVT, PE
• Bleeding: mucous membrane and cutaneous
• Minor: headaches, dizziness, visual disturbances
• Splenomegaly is usually modest

Question 21

ET diagnostic criteria

Answer 21

Question 22

ET diagnostic criteria

Answer 22

Question 23

How do we treat ET?

Answer 23

Aspirin (prevent thrombosis)

Anagrelide (inhibit platelet formation, SE = palpitation, flushing)

• WARNING: can accelerate myelofibrosis

Hydroxycarbamide (MAIN TX) = antimetabolite → suppress other cancers as well

• Possibly mild leukaemogenic

Alpha-interferon = patients <40 years old

Question 24

Risk stratification in ET

Answer 24

Question 25

ET prognosis

Answer 25

* Normal life span * Leukaemic transformation in about 5% after 10 years * Myelofibrosis is uncommon

Question 26

What is chronic idiopathic myelofibrosis?

Answer 26

* a clonal myeloproliferative disease with proliferation mainly of* *megakaryocytes and granulocytic cells**, associated with reactive bone marrow fibrosis and* *extramedullary haemopoiesis* * Incidence: 0.5-1.5/100,000; Age: \> 60 years; May occur secondary to other haematological disease (e.g. PV or ET)

Question 27

Clinical presentation of chronic idiopathic myelofibrosis

Answer 27

* incidental finding (30%) * thrombocytosis * hepatomegaly * cytopaenias (anaemia, thrombocytopenia) * splenomegaly (may be MASSIVE) * hypermetabolic state (weight loss, fatigue/dyspnoea, night sweats, hyperuricaemia)

Question 28

2 stages of myelofibrosis

Answer 28

* _Pre-Fibrotic_ = Blood changes are mild (may be confused with ET), Hypercellular marrow * _Fibrotic_ = Splenomegaly, Blood changes, Dry tap, Prominent collagen fibrosis, Later osteosclerosis

Question 29

Haematological changes in chronic idiopathic myelofibrosis

Answer 29

**Blood film:** * leucoerythroblastic (nucleated RBCs and precursors) * _tear drop poikilocytosis_ * others: giant platelets circulating megakaryocytic **Liver and spleen** * extra medullary haemopoiesis **BM** * dry tap * trephine biopsy = increased reticulin/collagen fibrosis, prominent megakaryocytic hyperplasia and clustering with abnormalities, new bone formation

Question 30

Treatment of chronic idiopathic myelofibrosis

Answer 30

* Usually symptomatic * Anaemia → **transfusions** (difficult because of splenomegaly) * Platelet transfusions (usually ineffective if hypersplenism) * **Splenectomy** (often quite hazardous) * Cytoreductive therapy * **Hydroxycarbamide** (may improve the thrombocytosis but it may worsen the anaemia) * **Thalidomide** (has shown some improvement in some patients with thrombocytopaenia and anaemia) * **Bone marrow transplant** may be curative in young patients

Question 31

Summary treatment of MPDs

Answer 31

Question 32

What are Janus kinases? JAK2 V617F gene mechanism what are two other mutations JAK2 inhibitors effective?

Answer 32

Family of **4 tyrosine kinases** with a _kinase_ and a catalytically inactive _pseudokinase_ with regulatory function JAK2 V617F (exon 14) → inactivation of pseudokinase → expression of JAK2 → increase sensitivity and independence from cytokine action * leads to MULTIPLE diseases 2 other mutations: * Exon 12 of JAK2 gene (associated with erythrocytosis) * mutations in TPO-R found in some patients with MF and ET JAK2 Inhibitors have been tested and have shown that they improve the symptoms of the **hypermetabolic state** but there is no conclusive evidence that it improve the haematological parameters

Question 33

When to do BM examination for MPN

Answer 33

* Bone marrow examination may NOT be needed in PV with JAK2 mutations * Bone marrow examination is helpful in thrombocytosis when JAK2 mutation is negative * Bone marrow examination is ALWAYS needed for MF

Question 34

Prognosis for MF

Answer 34

* Median 3-5-year survival * BAD prognostic signs = severe anaemia \<10 g/dL, thrombocytopaenia \<100 x 10⁹/L, massive splenomegaly

Question 35

primary and secondary causes of polycythaemia

Answer 35

Question 36

primary and secondary causes of polycythaemia

Answer 36

Question 37

Causes of pseudo (relative) polycythaemia

Answer 37

Question 38

PV summary

Answer 38

Question 39

Myelofibrosis summary

Answer 39

Budd-Chiari syndrome is **a condition in which the hepatic veins (veins that drain the liver) are blocked or narrowed by a clot (mass of blood cells)**.

Question 40

ET summary

Answer 40