Myelofibrosis Flashcards
Define chronic idiopathic myelofibrosis.
A clonal myeloproliferative disease with proliferation mainly of megakaryocytes and granulocytic cells, associated with reactive bone marrow fibrosis and extramedullary haematopoieisis
What is the pathophysiology of myelofibrosis?
Results in increased number of abnormal MEGAKARYOCYTES (plt precursors) which inappropriately release cytokines that promote fibroblast proliferation and inhibit collagenase in BM–> collagen deposition –> myelofibrosis.
There is also extramedullary haematopoiesis in liver and spleen
Gain of function mutation V617F in the JAK2 gene is associated with disease progression.
Marrow fibroblasts are POLYCLONAL (suggesting that marrow fibrosis is a reactive process initiated by the expansion of a malignant clone)
What is the aetiology of myelofibrosis?
Primary stem cell defect is unknown
- ~30% will have previous history of polycythaemia rubra vera or essential thrombocytopenia
- A mutation in the gene for the tyrosine kinase JAK2, has been identified in about 58% of patients with PMF. 50 other gene mutations have been identified.
- PMF was observed at 15 to 20 times the expected incidence rate in Hiroshima survivors (on average 6 years after the incident), which raises the possibility of radiation as an aetiological factor
How common is myelofibrosis? Who is most affected?
- Rare
- 1 in 100,000
- M=F
- Peak onset 70s
What are the risk factord for myelofibrosis?
- Radiation exposure
- Industrial solvents exposure e.g. benzene, toluene, and many other aromatic solvents
- Age >65yrs
What are the signs and symptoms of myelofibrosis?
Asymptomatic - e.g. diagnosed after abnormal blood count
Systemic symptoms:
- Cytopaenias - anaemia or thrombocytopenia → bleeding
- Thrombocytosis
- Splenomegaly (massive in 10%)
- Budd-Chiari - hepatic vein thrombosis
- Hepatomegaly (~50%) - LUQ abdominal pain, indigestion
- Hypermetabolic state - FLAWS, pruritus, bone pain, gout.
What investigations would you do for myelofibrosis?
- FBC - variable Hb, WCC and plt. Later anaemia, leukopaenia and thrombocytopenia
- LFTs - abnormal
- Blood film - leucoerythroblastic changes (circulating red and white cell precursors) with characteristic “tear drop” poikilocyte red cells, circulating megakaryocytes
- BM aspirate or biopsy - aspiration usually unsuccessful (“dry tap”)
- Trephine biopsy - shows fibrotic hypercellular marrow
What BM conditions may precede MF?
MF may occur after essential thrombocytopenia or polycythaemia vera
What are the two stages of MF?
Prefibrotic phase - blood changes mild but may be confused with ET, hypercellular marrow
Fibrotic stage - splenomegaly and blood changes, dry tap, prominent collagen fibrosis, later osteosclerosis
What are the blood film findings in CIMF?
- Leucoerythroblastic picture
- Tear drop poikilocytes
- Giant platelets
- Circulating megakaryocytes
Name 2 sites of extramedullary haematopoiesis in CIMF.
Liver
Spleen
What is the management of CIMF?
Symptomatic
- Anaemia- transfusions
- Platelet transfusions - often ineffective
- Splenectomy - for symptomatic relief ;often hazardous and followed by worsening of condition
Cytoreductive therapy: hydroxycarbamide for thrombocytosis, but may lead to worsening anaemia
Thalidomide +/- prednisolone: useful in only selected patients about 20% response rate with improvement of thrombocytopenia and anaemia
Bone marrow transplant in young patients may be curative (experimental)
What is the prognosis with MF?
Median 3-5yr survival
What are the key differences between myeloproliferation, myelodysplasia and leukaemia? Which category does MF fall into?
MPN - proliferation and full differentiation = MF
Leukaemia - proliferation no differentiation
MDS - ineffective proliferation and no differentiation
Other than MF, name another cause of massive splenomegaly.
CML
What mutations are commonly seen in MF?
JAK2 V617F in 60%
Calreticulin in 30%
