3s: Myeloproliferative Disorders (MPDs) Flashcards
MPDs arise from…
myeloid progenitor cells
What 2 things control haemopoiesis?
Growth Factors (e.g. EPO)
Receptors (interact with GFs → activation of kinases → phosphorylation of intracellular molecules)
What is the kinase gene fusion in CML?
BCR-ABL
Role Janus Kinases
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
What are MPDs
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
What is the difference between myeloproliferation, myelodysplasia, and leukaemia?
What are some clinical presentations of chronic MPDs
preponderance to thrombosis (arterial)
splenomegaly
haemorrhage (less frequent)
variability in clinical course
Give some examples of chronic BCR-ABL -ve MPDs
Polycythaemia vera (PV)
Essential thrombcythaemia (ET)
idiopathic myelofibrosis
idiopathic erythrocytosis
chronic granulocytic leukaemia
What is PV?
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
What is the clinical presentation of PV?
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
what ix for PV? Which is diagnostic?
- 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
Diagnosis of PV
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
What is pseudopolycthaemia?
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
How do we treat PV?
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)
What are features of idiopathic erythrocytosis
- 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
What are features of idiopathic erythrocytosis
- 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
Prognosis of idiopathic erythrocytosis and polycythaemia vera
- Idiopathic Erythrocytosis: NO adverse prognosis if Hct is maintained
- Polycythaemia Vera: most survive for 10 years, 65% survive 15 years
Causes of death from PV and idiopathic erythrocytosis
thrombosis
leukaemia (risk potentially increased when using hydroxyurea to treat)
myelofibrosis
What is essential thrombocythaemia (ET)?
Mainly megakaryocytic lineage
sustained thrombocytosis >600 x 10^9/L
two peaks in incidence = 55 (major) 30 (minor)
What would you see in ET on BM trephine biopsy histology?
megakaryocyte clustering
Clinical presentation of ET
- 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
ET diagnostic criteria
ET diagnostic criteria
How do we treat ET?
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
Risk stratification in ET
ET prognosis
- Normal life span
- Leukaemic transformation in about 5% after 10 years
- Myelofibrosis is uncommon
What is chronic idiopathic myelofibrosis?
- 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)
Clinical presentation of chronic idiopathic myelofibrosis
- incidental finding (30%)
- thrombocytosis
- hepatomegaly
- cytopaenias (anaemia, thrombocytopenia)
- splenomegaly (may be MASSIVE)
- hypermetabolic state (weight loss, fatigue/dyspnoea, night sweats, hyperuricaemia)
2 stages of myelofibrosis
- Pre-Fibrotic = Blood changes are mild (may be confused with ET), Hypercellular marrow
- Fibrotic = Splenomegaly, Blood changes, Dry tap, Prominent collagen fibrosis, Later osteosclerosis
Haematological changes in chronic idiopathic myelofibrosis
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
Treatment of chronic idiopathic myelofibrosis
- 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
Summary treatment of MPDs
What are Janus kinases? JAK2 V617F gene mechanism
what are two other mutations
JAK2 inhibitors effective?
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
When to do BM examination for MPN
- 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
Prognosis for MF
- Median 3-5-year survival
- BAD prognostic signs = severe anaemia <10 g/dL, thrombocytopaenia <100 x 109/L, massive splenomegaly
primary and secondary causes of polycythaemia
primary and secondary causes of polycythaemia
Causes of pseudo (relative) polycythaemia
PV summary
Myelofibrosis summary
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).
ET summary
