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Year 5 Haematology > 3s: Myeloproliferative Disorders (MPDs) > Flashcards

3s: Myeloproliferative Disorders (MPDs) Flashcards

1
Q

MPDs arise from…

A

myeloid progenitor cells

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2
Q

What 2 things control haemopoiesis?

A

Growth Factors (e.g. EPO)

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

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3
Q

What is the kinase gene fusion in CML?

A

BCR-ABL

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4
Q

Role Janus Kinases

A

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

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5
Q

What are MPDs

A

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
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6
Q

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

A
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7
Q

What are some clinical presentations of chronic MPDs

A

preponderance to thrombosis (arterial)

splenomegaly

haemorrhage (less frequent)

variability in clinical course

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8
Q

Give some examples of chronic BCR-ABL -ve MPDs

A

Polycythaemia vera (PV)

Essential thrombcythaemia (ET)

idiopathic myelofibrosis

idiopathic erythrocytosis

chronic granulocytic leukaemia

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9
Q

What is PV?

A

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

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10
Q

What is the clinical presentation of PV?

A

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
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11
Q

what ix for PV? Which is diagnostic?

A
  • 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
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12
Q

Diagnosis of PV

A

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
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13
Q

What is pseudopolycthaemia?

A

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
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14
Q

How do we treat PV?

A

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)
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15
Q

What are features of idiopathic erythrocytosis

A
  • 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
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15
Q

What are features of idiopathic erythrocytosis

A
  • 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
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16
Q

Prognosis of idiopathic erythrocytosis and polycythaemia vera

A
  • Idiopathic Erythrocytosis: NO adverse prognosis if Hct is maintained
  • Polycythaemia Vera: most survive for 10 years, 65% survive 15 years
17
Q

Causes of death from PV and idiopathic erythrocytosis

A

thrombosis

leukaemia (risk potentially increased when using hydroxyurea to treat)

myelofibrosis

18
Q

What is essential thrombocythaemia (ET)?

A

Mainly megakaryocytic lineage

sustained thrombocytosis >600 x 10^9/L

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

19
Q

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

A

megakaryocyte clustering

20
Q

Clinical presentation of ET

A
  • 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
21
Q

ET diagnostic criteria

A
22
Q

ET diagnostic criteria

A
23
Q

How do we treat ET?

A

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

24
Q

Risk stratification in ET

A
25
Q

ET prognosis

A
  • Normal life span
  • Leukaemic transformation in about 5% after 10 years
  • Myelofibrosis is uncommon
26
Q

What is chronic idiopathic myelofibrosis?

A
  • 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)
27
Q

Clinical presentation of chronic idiopathic myelofibrosis

A
  • incidental finding (30%)
  • thrombocytosis
  • hepatomegaly
  • cytopaenias (anaemia, thrombocytopenia)
  • splenomegaly (may be MASSIVE)
  • hypermetabolic state (weight loss, fatigue/dyspnoea, night sweats, hyperuricaemia)
28
Q

2 stages of myelofibrosis

A
  • Pre-Fibrotic = Blood changes are mild (may be confused with ET), Hypercellular marrow
  • Fibrotic = Splenomegaly, Blood changes, Dry tap, Prominent collagen fibrosis, Later osteosclerosis
29
Q

Haematological changes in chronic idiopathic myelofibrosis

A

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
30
Q

Treatment of chronic idiopathic myelofibrosis

A
  • 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
31
Q

Summary treatment of MPDs

A
32
Q

What are Janus kinases? JAK2 V617F gene mechanism

what are two other mutations

JAK2 inhibitors effective?

A

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

33
Q

When to do BM examination for MPN

A
  • 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
34
Q

Prognosis for MF

A
  • Median 3-5-year survival
  • BAD prognostic signs = severe anaemia <10 g/dL, thrombocytopaenia <100 x 109/L, massive splenomegaly
35
Q

primary and secondary causes of polycythaemia

A
36
Q

primary and secondary causes of polycythaemia

A
37
Q

Causes of pseudo (relative) polycythaemia

A
38
Q

PV summary

A
39
Q

Myelofibrosis summary

A

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).

40
Q

ET summary

A

Year 5 Haematology (7 decks)

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