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
Risk factors for poor survival in essential thrombocythaemia
Age at diagnosis > 60 years
Leucocytosis >11
Thrombosis history
More recently identified factors -> male gender, elevated LDH, non driver mutations in 53% ET patients
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
Notes on pre-myelofibrosis - prognosis
Compared to ET -> higher risks of bleeding and transformation into overt-MF or AML
Shorter OS
No difference in thrombosis rate
Compared to overt MF -> less constitutional symptoms
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
Symptoms of priary myelofibrosis
**20% aysymptomatic
**Diagnosed on abnormal FBC or splenomegaly
**80% symptomatic
**Low blood counts - symptoms of anaemia, frequent infections, easy brusiing/bleeding
Splenomegaly related abdominal discomfort
Bone pain
Consitutional symptoms - anoreia, unexplained weight loss, night sweats
Gout
Prognostic factors in primary myelofibrosis
**Worse prognosis
**Fibrosis grade
Driver mutations - CARL type 1
Severity of anaemia
MIPSS prognostic score
Management of very low -> intermediate risk primary myelofibrosis
Observation alone unless significant symptoms, anaemia, splenomegaly, leucocytosis (25), platelets >1000
**MF-associated anaemia
**Androgens, prednisone, erythropoiesis stimulating agents
Thalidomide rarely used - modest efficacy, toxic (neuropathy)
**Cytoreductive therapy (thrombocytosis, leucocytosis, splenomegaly)
**1st line -> hydroxycarbamide, recombinant interferon
2nd line -> ruxolitinib
Notes on ruxolitinib
JAK2 inhibitor
Improves splenomegaly, constitutional symptoms, may reduce thrombosis risk
Adverse effects -> anaemia, thromboytopaenia
