Polycythaemia & Myeloproliferative disorders Flashcards
What is polycythaemia?
Excess of red cells
What are myeloproliferative disorders?
Malignant excess of red cells
What may happen in a psuedo polycythaemia?
Decreased plasma volume
What patients are likely to get relative/pseudo polycythaemia?
Alcoholic
Obese
Diuretics
In what situations is raised erythropoietin appropriate?
High altitude
Hypoxic lung disease
Cyanotic heart disease
High affinity haemoglobin
What are some conditions where you get inappropriate raised erythropoietin?
Renal disease (cysts, tumours, inflammation) Uterine myoma Other tumours (liver, lung)
What are the types of myeloid haematological malignancies?
Acute myeloid leukaemia (blasts >20%)
Myelodysplasia (blasts 5-19%)
Myeloproliferative disorders
Chronic myeloid leukaemia
List some myeloproliferative disorders
Essential thrombocytaemia (megakaryocyte) Polycythaemia vera (erythroid) Primary myeofibrosis
How can lymphoid haematological malignancies be subclassified?
Precursor cell malignancy
Mature cell malignancy
Give example of precursor lymphoid cell malignancy
Acute lymphoblastic leukaemia (B&T)
Give examples of mature cell lymphoid malignancy
Chronic lymphocytic leukaemia
Multiple myeloma
Lymphoid (Hodgkin & non Hodgkin)
What is the precursor to RBCs?
BFU-E
What myeloproliferative disorders are Ph negative (Philadelphia)?
Polycythaemia vera (PV) Essential thrombocythaemia (ET) Primary myelofibrosis (PMF)
What MPD neoplasm is Ph positive?
Chronic myeloid leukaemia
Give examples of mutation mechanisms
DNA point mutations
Chromosomal translocations - creation of novel Fusion gene, disruption of proto-oncogene
Where are the mutations associated with Ph negative MPD?
Mutations in JAK2
What is JAK2?
Tyrosine Kinase signalling in haematopoesis
How does normal tyrosine kinases work?
Transmit cell growth signals from surface receptors to nucleus
Activated by transferring phosphate groups to self and downstream proteins
Normally held tightly in inactive state
Promote cell growth do not block maturation
What are the components of MPD diagnosis?
Clinical features - symptoms, splenomegaly
FBC +/- bone marrow biopsy
Erythropoietin level (EPO)
Mutation testing
How is polycythaemia vera usually diagnosed?
Incidental diagnosis on routine blood test
What are the clinical symptoms of polycythaemia vera?
Headaches, light-headedness, stroke
Visual disturbances
Fatigue, dyspnoea
Aquagenic pruritis
What is the aim of polycythaemia vera treatment?
Reduce risk of strokes
Target HCT <45%
Keep platelets below 400x10^9/l
How is polycythemia vera treated?
Venesection (as if donating blood)
Cytoreductive therapy hydroxycarbamine
Aspirin (to prevent stroke)
What is essential thrombocythaemia?
Chronic MPN mainly involving megakaryocytic lineage
Sustained thrombocytosis >600x10^9/L
How is essential thrombocytopaenia usually diagnosed?
Incidental finding on FBC (50%)
What symptoms/clinical signs may be present in essential thrombocytopenia?
Thrombosis: arteria or venous - CVA, gangrene, TIA, DVT, PE
Bleeding: mucous membrane and cutaneous
Headaches, dizziness, visual disturbances
Splenomegaly (modest)
What is the treatment for essential thrombocytopenia?
Aspirin: to prevent thrombosis
Hydroxycarbamide: antimetaboilte, suppression of other cells as well
Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing
What is the prognosis of essential thrombocytopaenia?
Normal life span may not be changed in many patients
Leukaemic transformation in about 5% after >10 years
Myelofibrosis also uncommon, unless there is fibrosis at the beginning
What is primary myelofibrosis?
A clonal myeloproliferative disease associated with reactive bone marrow fibrosis
What may the presentation of primary myelofibrosis be?
Incidental (30%)
Cytopenias: anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: may be massice (Budd-Chiari syndrome)
Hepatomegaly
Hypermetabolic state: weight loss, fatigue, dyspnoea, night sweats, hyperuricaemia
Why does primary myelofibrosis cause massive hepatosplenomegaly?
Bone marrow becomes fibrosed and scarred –> extramedullary haematopoeisis - bone marrow cell production moves to liver and spleen
What are the blood film findings in primary myelofibrosis?
Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes
What are the bone marrow findings in primary myelofibrosis?
Dry tap
Trephine - increased reticulin or collagen fibrosis, prominent megakaryocyte hyperplasia and clustering with abnormalities, new bone formation
What is the prognosis of primary myelofibrosis?
Median 3-5 year survival but variable
What are some bad prognostic signs in primary myelofibrosis?
Severe anaemia <100g/L
Thrombocytopenia <100x10^9/L
Massive splenomegaly
What is the prognostic scoring system for primary myelofibrosis?
DIPPS
Score 0 = median survival 15 years
Score 4-6 - median survival 1.3 years
What are the treatment options for primary myelofibrosis?
Supportive - RBC and platelet transfusion often ineffective because of splenomegaly
Cytoreductive therapy - hydroxycarbamide (for thrombosis, may worsen anaemia)
Ruxolotinib: JAK2 inhibitor (high prognostic score)
Allogenic SCT (potentially curative, reserved for high risk eligible cases)
Splenectomy for symptomatic relief: hazardous and often followed by worsening of condition
What are the clinical symptoms/signs of chronic myeloid leukaemia?
Lethargy/hypermetabolism/thrombotic event: monocular blindness CVA, bruising, bleeding
Massive splenomegaly +/- hepatomegaly
What are the haematological findings in chronic myeloid leukaemia?
Hb and platelets well preserved or raised
Massive leucocytosis 50-200x10^9/L
Blood films: neutrophils and myelocytes, basophilia
Chronic myeloid leukaemia blood film
Leucocytosis between 50 - 500x109/l
Mature myeloid cells
Bi phasic peak Neutrophils and myelocytes
Basophils
No excess (<5%) myeloblasts
Platelet count raised/upper normal (contrast acute leuk)
Diagnosing and monitoring response in chronic myeloid leukaemia
FBC and measure leucocyte count
Cytogenetics and detection of Philadelphia chromosome
RT-PCR of BCR-ABL fusion transcript which can be quantified by RQ-PCR to determine response to therapy
What are the phases of CML?
Chronic phase (median 3-4 years) Advanced phases: accelerated phase (10-19% blasts, median duration 6-12 motnhs); blast crisis (>20% blasts, median survival 3-6 months)
What treatment is available for CML?
Abl Tyrosine Kinase inhibitors (e.g. Imatinib)
How do we monitor response to CML treatment?
Haematological response - WBC <10x10^9/L
Cytogenic response - partial 1-35% Ph positive, complete 0% Ph positive
Molecular (reduction in %BCT-ABL transcripts)
