16. Myeloproliferative Neoplasms Flashcards
List the 4 most common myeloproliferative neoplasms.
What is t(9;22) Philadelphia most commonly associated with? (Shortened chromosome 22 from reciprocal translocation of ch 9 and 22)
What is the JAK2V617F mutation associated with?
What is the BCR-ABL mutation associated with?
CML, polycythemia (rubra) vera, essential thrombocythaemia, myelofibrosis.
CML hallmark (and also in ALL)
Polycythemia vera, essential thrombocythaemia. primary myelofibrosis
CML
What is chronic myeloid leukaemia?
Most people with CML are symptomatic. For those who show symptoms, what might you see?
What does untreated chronic phase CML progress to?
What characteristic features can you see in this CML blood smear?
Dysregulated and uncontrolled proliferation of mature and maturing granulocytic cells, and presence of t(9,22) - Philadelphia chromosome. 15-20% of leukaemia in adults, median age 50y (all myeloproliferative disorders are of older people).
Systemic symptoms: fatigue, night sweats, malaise, weight loss
Splenomegaly: early satiety, LUQ fullness/pain
Increaesed uric acid: acute gout
Hyperviscosity: headache/blurred vision, fluid overload, thrombosis and haemorrhage
Bone pain
Chronic phase -> Accelerated phase -> Blast phase (AML)
See lots of maturing granulocytes and mature cells - eosinophils, myelocytes, neutrophils, basophils. In AML would see blasts. Normally would see few WBC (pic).
How would you diagnose CML?
How does the t(9,22) in CML cause problems?
Raised WCC (+ basophilia - b/c dont usually see them), blood film, bone marrow biopsy (for t(9,22), chromosome G-banding (karyotyping), FISH - fluorescence in situ hybridisation for genes you’re interested in, RT qPCR (amplify genetic material to see treatment response e.g. monitor BCR-ABL transcript levels), low NAP/LAP score (obsolete, allows differentiation between reactive causes or raised WCC).
Causes fusion of ABL1 and BCR genes, which encodes a tyrosine kinase (transfers P from ATP to a protein = on/off switch). Becomes constituitively active and is unregulated by cytokines -> uncontrolled proliferation and cell division, and inhibts DNA repair. Untreated -> acquire more mutations.
How is CML treated?
What is the prognosis?
What is primary polycythaemia (rubra) vera? What does it result from in 95% of cases?
Imatinib and 2nd/3rd gen tyrosine kinase inhibitors (Dasatinib, Nilotinib). Chemo for refractory/accelerated phase/blast crisis. Allogenic haematopoietic SC transplant.
Excellent due to TKIs, normal life expectancy. Small proportion of pts are resistant to TKIs - need chemo +/- BM transplant.
Increased red cell volume due to a clonal malignancy of a marrow SC, uusally >RBC but all 3 cell lines can be increased, characterised by unexplained elevated HCT/RCM. 95% from JAK2 mutation. Median age 60y.
What are some other causes of polycythaemia (increased HCT) than rubra vera?
What are the clinical features of polycythaemia vera?
If increased HCT is apparent/relative then reduced plasma volume. If it is true/absolute then it can be:
Primary: polycythaemia vera
Secondary: hypoxia driven (high altitude, cardiopulmonary disease, defective O2 transport), or hypoxia-independant (renal cysts/tumours (can produce EPO), extrarenal tumours, exogenous EPO/drugs e.g. anabolic steroids)
Many asymptomatic (more so in PV than CML). Plethoric appearance/ruddy cyanosis. Post bath pruritis (itching). Splenomegaly (early satiety etc.), acute gout, headache, blurred vision, erythromelalgia (peripheral microvasculature clogged (pic)), thrombosis (arterial/venous), haemorrhage
What are the 2 stages of diagnosis for polycythaemia vera to rule out secondary causes?
How is PV treated (4 ways)?
What is the prognosis for PV?
Stage 1: history, examination, FBC, ferritin, renal and liver function, JAK2 mutation - definitive! JAKSTAT path turned on and can’t turn off. Small number of people will be JAK2 -ve
Stage 2: serum EPO (low), arterial SO2 (to look for secondary causes), abdo US (splenomegaly, renal tumour), bone marrow biopsy (hypercellular, trilineage growth - panmyelosis), red cell mass study (determines if true or reactive erythrocytosis).
- *1. Venesection (HCT <0.45)** - blood letting to bring down HCT (but wont affect platelet count so ,ay need to use #3)
- *2. Aspirin** - thrombosis risk high
- *3. Myelosuppressive drugs** - hydroxycarbamide, interferon, busulphan
- *4. Future JAK inhibitors?**
Median survival 10-16 yrs, death most commonly from thrombosis, cardiovascular events, progression to myelofibrosis or AML. Also haemorrhage.
What is essential thrombocythaemia?
What are some clinical features of ET?
What are some possible secondary causes of raised plts that must be excluded?
Sustained increase in platelet count due to megakaryocytic proliferation. Not a morphologically or cyteogenetically defined entity, defined by a non-reactive thrombocythaemic state that is not accounted for by another MPN. Median age 60yrs, 10 yr survival rate.
Many are asymptomatic. Thrombosis (atrial and venous), haemorrhage (poor platelet function), erythromelalgia (more so than in PV), splenomegaly, fatigue, malaise, weight loss
Infection, inflammation, iron deficiency, haemorrhage, hyposplenism, malignancy, drugs - steroids. Exclude other myeloid malignancy esp PV and CML.
How is ET diagnosed?
How is ET treated?
What is the prognosis for ET?
JAK2 mutation in about 50%, CALR in 30%, MPL in 10%. Bone marrow biopsy - see increase in megakaryocytes (2), and marked increase in platelets -> clumping (1).
1) Aspirin
2) For higher risk patients - age >60, previous thrombosis, high WCC: myelosuppressive drugs (chemo) - hydroxycarbamide, anagrelide
Most survive >10 yrs. Main problem = risk of thrombosis, bleeding. Transformation to MF (10-20%) and AML (5%)
What are the most common acquired mutations in PV, ET, and primary myelofibrosis?
Most with PV have JAK2. ET and PM roughly the same with around 50% JAK2 and 30% CALR (pic).
What is myelofibrosis?
What are the clinical features?
What are the characteristic features on a blood film of myelofibrosis?
Clonal stem cell malignancy, primary or secondary (from ET or PV). Progressive generalised reactive fibrosis of the bone marrow in association with haematopoeisis of the liver and spleen (myeloid metaplasia - compensation). Fibrosis 20 to hyperplasia of abnormal megakaryocytes stimulating fibroblasts.
Fatigue, weight loss, night sweats, raised WCC (but over time BM failure so it falls), progressive cytopenias, massive splenomegaly, extramedullary-haemopoiesis.
Teardrop poikilocytes + leucoerythroblastic (see bits of everything: nucleated RBC (C), blasts(D)(pic)). Poikilocytes not completely specific for myelofibrosis.
What would you see in a bone marrow biopsy of myelofibrosis?
What would you see in the diagnosis of myelofibrosis?
How is myelofibrosis treated?
What is the prognosis?
Increased reticulin fibrosis, hypercellular, streaming (all scar tissue stretches blood cells) (pic).
50% JAK2 mutation, CALR 30%, MPL 10%, triple negative 10 (worst prognosis). Bone marrow reticulin fibrosis, splenomegaly, anaemia, leucoerythroblastic blood film + teardrop poikilocytes.
Stratify risk (age/blast count), supportive management for older- transfusion, splenectomy/splenic irradiation. If high risk and fit patient - allogenic tx candidate. JAK inhibitors - ruxolitinib, indicated for B symptoms (fever, night sweats, weight loss) and splenomegaly. Chemo if WCC particularly elevated: hydroxycarbamide. Androgens/Danazol to improve BM function
Poor overall, median survival 1yr if high risk, >12 yrs if low risk. Poss progression to AML
