phil -ve myeloproliferative disorders Flashcards by Emily Southall

what are myeloid cells

things from bone marrow – granulocytes, monocytes and RBC

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what is polycythaemia

raised Hb concentration and haematocrit %

can be
* relative - lack of plasma = non-malignant
* true - excess erythrocytes

true can be
* secondary - non-malignant
* primary - myeloproliferative neoplasm

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what are the myeloproliferative neoplasms

Ph (Philadelphia Chromosome)negative
* Polycythaemia vera (PV)
* Essential Thrombocythaemia (ET)
* Primary Myelofibrosis (PMF)

Ph positive
* Chronic myeloid leukaemia (CML)

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how can you differentiate true or relative polycythaemia

dilution – label RBC with chromium and albumin with iodine

True – is where RBC is raised

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causes of pseudopolycythaemia

alcohol
obesity
drugs

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causes of secondary polycythaemia

high eyrthropoeitin levels,
expect normal feedback mechanism so when oxygen normalises EPO drops back to normal

appropriately high EPO:
* hugh altitude
* hypoxic lung disease
* cyanotic heart disease
* high affinity Hb - sickling, failure to release Ox

inappropriately high EPO:
* renal disease - cysts, tumours, inflammation - meduloblastomas
* uterine myoma
* other tumours - liver lung

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cause of primary polycythaemia

low EPO
disease involving bone marrow – blood cells growing autonomously even though low EPO

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what are the myeloid haematological malignancies

Acute myeloid leukaemia (blasts >20%
Myelodysplasia (blasts 5-19%)
Myeloproliferative disorders
* Essential thrombocythaemia (megakaryocyte)
* Polycythemia vera (erythroid)
* Primary myeofibrosis
* Chronic myeloid leukaemia

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what are the lymphoid haematological malignancies

Precursor cell malignancy
* Acute lymphoblastic leukaemia (B & T)

Mature cell malignancy
* Chronic Lymphocytic leukaemia
* Multiple myeloma
* Lymphoma (Hodgkin & Non Hodgkin)

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depict normal haematopoiesis

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difference between myeloproliferative neoplasm and acute leukaemia

Myeloproliferative – extra proliferation but no impairment of diff
Acute leukaemia –more proliferation and no diff

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what is CML an excess of

myeloid granulocytic and neutrophils

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what processes are mutated in blood cancer

cellular proliferation
cellular differentiation
apoptosis in lymphoid malignancies -> prolongue cell survival

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mutations involved in blood cancers

DNA point mutations
Chromosomal translocations
* Creation of novel Fusion gene (myeloid malignancies)
* Disruption of proto-oncogene (over expressed)

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how are tyrosine kinases involved in myeloproloferative disorders

normally they:
* transmit growth signals from surface receptors to nucleus
* activated by transfer phos gps to self and downstream protein
* are held tightly in inactive state
* promote cell growth - dont block maturation

activating TK mutations ->
* expansion - increase in mature cells ie
* polycythaemia/essential thrombocytopenia/CML

JAK2 – linked kinase on EPO receptor. When receptor gets EPO = dimerase = change structure = phosphorylate kinase = pass phosphate downstream = cellular proliferation

Excess prolif due to kinase mutations

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JAK2 mutation

Acquired point mutation in JAK2 – recurring single nucleotide mutation at V617F – seen in all cases of polycythaemia vera because of somatic cancer causing mutation

Occurs in ET a megakaryocyte precurser at lower freq -> essential thrombocytopenia.

Can develop malignant haemopoietic cell in myelofibrosis

If mutation there then it is true polycythaemia

diagnosis of myeloproliferative disorders (Ph negative)

based on:
* clinical features
* splenomegaly/hepatomegaly

FBC +- bone marrow biopsy
EPO llevels
mutation testing - phenotype linked to acquired mutation

epi of polycythaemia vera

> male
age 60yrs

polycythaemia vera dx

can be incidental dx on FBC
sx
* blood hyperviscoity -> headache, light headedness, TIA, stroke, visual disturbances, fatigue, dyspnoea
* increased histamine release -> aquagenic pruritus, peptic ulceration

Test for JAK2 V617F mutation

Rx of polycythaemia vera

Aim to reduce HCT : target HCT <45%
* venesection
* Cytoreductive therapy hydroxycarbamide – chemo like agents that stop cell division – if cant cope with venesection (ie older pt)

Aim to reduce risks of thrombosis
* Control HCT
* Keep platelets below 400x109/l

what is essential thrombocytopenia

Chronic MPN mainly involving megakaryocytic/platelet lineage
Sustained thrombocytosis >600x109/L

epidemiology of essential thrombocytopenia

bimodal - 30yrs, 55yrs
in younger gp- females more
in older gp - genders equal

clinical presentation of essential thrombocytopenia

Incidental finding on FBC (50% cases) – plts >600
Thrombosis: arterial or venous – hypercoaguability
* CVA, gangrene, TIA
* DVT or PE

Bleeding: mucous membrane and cutaneous – plts might not function properly so = plt bleeding (mucous rather than deep bleeds)

Headaches, dizziness visual disturbances
Splenomegaly (modest)

Rx for essential thrombocythaemia

aspirin - prevent thrombosis and strokes
Hydroxycarbamide: antimetabolite. Suppression of other cells as well. Brings plts down to normal
Anagrelide: specific inhibition of platelet formation, side effects include palpitations and flushing

Px of essential thrombocythaemia

**normal life span** if prevent stroke etc **Leukaemic transformation in about 5%** after >10 years. Increasing numbers of cell division – chance of survival advantage to subclone Myelofibrosis also uncommon, unless there is fibrosis at the beginning

what is primary myelofibrosis

A clonal myeloproliferative disease associated with reactive bone marrow fibrosis Abnormal clone of haemopoeisis of blood cell production in bone marrow – associated with clone – abnormality is expansion of clone which will pridyce fibroblast growth stimulating factor – fibroblast respond to this and proliferate = lay down collagen extramedullary haematopoiesis

epidemiology of primary myelofibrosis

m=f present in 7th decade Other MPDs (ET & PV) may as terminal phase transform to PMF

clinical presentation and dx of primary myelofibrosis

incidental finding cytopenia - thrombocytopenia/anaemia thrombocytosis can have **massive splenomegaly** - Budd-Chiari syndrome **hepatomegaly** hypermetabolic state * wht loss * fatigue and dyspnoea * night sweats * hyperuricaemia Haemopoesis cant function because fibrosed bone marrow. Haemopoeisis moves to other organs – make blood cells in liver – liver expanded with extramedullary out of the bone marrow haematopoeisis can get haematopoietic deposits in brain and meninges

blood film for primry myelofibrosis

Leucoerythroblastic picture Tear drop poikilocytes Giant platelets Circulating megakaryocytes

DNA in primary myelofibrosis

JAK2 or CALR mutation

bone marrow in primary myelofibrosis

**‘Dry tap’** **Trephine** – core of bone marrow find collagen: * **Increased reticulin or collagen fibrosis** * Prominent **megakaryocyte hyperplasia and clustering with abnormalities** * **New bone formation**

px of primary myelofibrosis

Median 3-5 years but very variable Bad prognostic signs: * Severe anaemia <100g/L * Thrombocytopenia <100x109/l * Massive splenomegaly Prognostic scoring system (DIPPS) * Score 0 -- median survival 15years * Score 4-6– median survival 1.3 years

primary myelofibrosis rx

Supportive: RBC and platelet transfusion often ineffective because of splenomegaly (consumes cells) Cytoreductive therapy: hydroxycarbamide (for thrombocytosis, may worsen anaemia) Ruxolotinib: JAK2 inhibitor (high prognostic score cases) Allogeneic SCT (potentially curative reserved for high risk eligible cases) - massive treatment mortality Splenectomy for symptomatic relief: hazardous and often followed by worsening of condition – can make it better or worse