Myeloproliferative Neoplasms Flashcards
Aetiology/risk factors for MPN
**Risk factors
**Viruses
Environmental - ?ionising radiation
Familial clustering
- Abnormalities in JAK2, CALR, MPL, usually somatic, not germline
- Familial involvement in 5-10%
Diagnosis of MPN
**Blood count abnormalities
**- Most common initial finding leading to dx
- Polycythaemia vera -> increased Hb, HCT, may also have panmyelosis with neutrophilia and thrombocytosis (exclude secondary causes -> OSA, smoking, ETOH, CCHD)
- Essential thrombocytosis
- Primary myelofibrosis (overt fibrotic stage) -> leukoerythroblastic blood film, tear drop RBC
- Primary myelofibrosis (pre-fibrotic) -> thrombocytosis, may alos have mild anaemia, high LDH, splenomegaly
**Other investigations
**FBC, blood fil
Biochem (LDH, Uric acid)
Coagulation -> acquired vWS
Iron studies
Driver mutation testing - JAK2 initial, MPL, CALR subsequent
Spleen assessment
Bone marrow biopsy and cytogenetics
- Recognition of important BM morphology in PV
- Distinguish between prefibrotic MF and ET
- Exclude CML presenting as thrombocytosis
Notes on mutation testing in MPN
**Driver mutation testing
**- Major diagnostic criteria
- Initial test = JAK2V617F (exon 14)
- If JAK 2 negative -> test CALR and MPL if suspected ET or MF. In PV 3% JAK2 mutations spread across exons 12, 13, 14
**Clonal marker testing (ASXL1, EZH2, IDH1/IDH2, SRSF2)
**-Triple negative MPN patients
Provides prognositic info in MF patients eligible for HSCT
-
Notes on CALR mutations
**Somatic mutations of CALR exon 9
**Almost exclusively in myeloid neoplasms with thrombocytosis
ET, OMF, RARS-T
Mutant calreticulin activates JAK-STAT pathway via thrombopoietin receptor
**CALR Tpe 1 (deletion) mutation
**Myelofibrosis phenotype
Significantly higher risk of MF transformation
Male sex predominates
**CALR Type 2 (insertion) mutation
**ET phenotype
Younger patients
Low risk thrombosis
Very high platelet counts
Indolent clinical course
Mortality comparison between MPN subtypes
**Best survival to worse
**1. Essential thrombocythaemia
2. Polycythaemia vera
3. Pre-fibrotic myelofibrosis
4. Overt myelofibrosis
Principles of management MPNs
- Reduce risk of vascular and thrombotic events
- Cytoreductive agents
- Antiplatelets/Anticoagulants
- Cardiovascular risk factors - Symptom burden
- Reduce progression and transformation of disease
- No therapy has been shown to affect the natural history of the disease in regard to overall, leukaemia-free or myelofibrosis free survival
Causes of polycythaemia
**Absolute polycythaemia
**1. Primary - polycythaemia rubra vera
2. Secondary polycythaemia
a. Increased EPO
- Renal disease e.g. PCKD, hydronephrosis, tumour
- Hepatoma
- Cerebellar hemangioma
- Uterine myoma
- Virilising syndromes
- Cushing’s syndrome
- Phaeochromocytoma
- Self-injection of EPO
b. Hypoxic states
- Chronic lung disease
- Pulmonary arteriovenous malformation
- OSA
- Cyanotic congenital heart disease
- Abnormal haemoglobins
- Carbon monoxide poisoning
**Relative polycythaemia
**Dehydration
Smoker’s - carboxyhaemoglobinaemia
Stress polycythaemia
Complications of polycythaemia vera
**Thrombotic complications
**More common than bleeding
Hyperviscosity -> headache, blurred vision, plethora
Thrombosis larger vessels -> arterial (MI, stroke), Venous -> DVT, PE, splanchnic
Thrombosis in small vessels -> cyanosis, erythomelalgia, ulceration or gangrene
**Bleeding (2-10%)
**Epitaxis, brusing, GIT, gum
Severe bleeding unusual
Management of polycythaemia vera
Management of polycythaemia vera
**Venous thrombosis
**Lifelong warfarin - risk of major bleeding higher in MPN patients
DOACs not formally established as treatment of choice
**Notes on aspirin
**Suboptimal 24 hour suppression of thromboxane A2 synthesis by OD dosing
Consider BD in
- Arterial thrombosis history
- Microvascular symptoms not controlled on OD therapy
- High risk patients with CVS risk factors (HTN) and leucocytosis
**Other indications for cytoreductive therapy (aside from those on slide)
**Poor tolerance of phlebotomy
Platelets >1500, WCC > 15
Uncontrolled myeloproliferation (increasing splenomegaly)
Uncontrolled PV-related systemic symptoms
**Cytoreductive therapy
**Hydroxycarbamide - first line, no increased risk of leukaemic transformation
Recombinant interferon (also first line) - 75-90% complete haematologicla response.
Second line - another 1st line agent, busulfan, ruxolitinib
Diagnostic criteria polycythaemia vera
**Rationale for bone marrow biopsy in polycythaemia vera
**Previously missed diagnoses of PV due to masked PV (by iron deficiency)
Provides prognostic information -> cytogenetics (increased risk leukaemia) and reticulin (seen in 20% patients with PV)
Prognostic factors in polycythaemia vera
**Poor prognostic factors
**Age > 61 years
WCC > 10.5
Thrombosis history
Abnormal karyotype
Note HTN risk factor for arterial thrombosis even in low risk patients -> ACEI treatment of choice
Notes on leukaemic transformation of MPN
- Not always preceded by fibrotic phase of the disease (but often)
- PMF > PV > ET
- Consider aggressive chemotherapy followed by allogeneic SCT if eligible
Indications for aspirin in essential thrombocythaemia
Age > 60
CVS risk factors
JAK2 mutation
OD aspirin may be inadequate
**Contraindications to aspirin
**Extreme thrombocytosis
aVWS
Low risk CALR-positive ET
Indications for and options for cytoreductive therapy in essential thrombocythaemia
**Indications
**High risk patients
- Prior thrombosis
- JAK2 mutation and age > 60 years
Additional indications
- Platelets >1500
- Uncontrolled myeloproliferation e.g. symptomatic splenomegaly
- Uncontrolled ET-related systemic symptoms
**First line agents
**Hydroxycarbamide
Recombinant interferon - 25% will discontinue due to side effects, relapse can rapidly occur after discontinuation of therapy (same for PV)
**Second line agents
**Other first line agent
Anagrelide
Busulfan
Diagnosis pre-fibrotic myelofibrosis
**Bone marrow features
**Low gade bone marrow fibrosis
Particular features of megakaryocytes
Other features: compared to ET patients tend to have elevated LDH, leucocytosis, thrombocytosis, mild anaemia, splenomegaly
- Difficult diagnosis clinically, optimum therapy uncertain
See below - need all three major criteria + one minor
Management of pre-fibrotic myelofibrosis
Individualised approach
No therapy or low dose aspirin in asymptomatic patients
Thrombosis prevention
Cytoreductive therapy -> consider if thrombocytosis or leucocytosis or driver mutation
Aspirin/oral anticoagulation if previous arterial or venous thrombosis
Symptom directed therapy for anaemia, splenomegaly or consititutional symptoms
High risk patients may need to be treated as overt PMF
