CML and Myeloproliferative Disorders Flashcards by Kat Qiao

What is polycythaemia?

Raised Hb concentration and Haematocrit %

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What are causes of polycythaemia?

Relative: Lack of plasma - Non-malignant

True: Excess erythrocytes

Secondary: Non-malignant
Primary: Myeloproliferative neoplasm

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What are examples of 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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What are dilution studies?

To differentiate between true and relative polycythaemia

Red Cell Mass: 51Cr labelled RBC

Plasma Vol: 131I labelled albumin

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What are causes of relative/pseudo-polycythaemia?

Alcohol

Obesity

Diuretics

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What happens to EPO in primary and secondary true polycythaemia?

Primary: Reduced

Secondary: Elevated

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What are appropriate causes of elevated EPO?

High altitude

Hypoxic lung disease

Cyanotic heart disease

High affinity haemoglobin

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What are inappropriate causes of elevated EPO?

Renal disease (cysts, tumours inflammation)

Uterine myoma

Other tumours (liver, lung)

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What are examples of 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 examples of 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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Which processes are disrupted by mutation?

Cellular proliferation (type 1)

Impair/block cellular differentiation (type 2)

Prolong cell survival (anti-apoptosis)

Mutation mechanisms:

DNA point mutations
Chromosomal translocations:
- Creation of novel fusion gene
- Disruption of proto-oncogene

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What is the normal function of tyrosine kinases?

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.

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What happens when mutations cause activation of tyrosine kinase?

Expansion increase in mature/end cells

Red cells: Polycythaemia

Platelets: Essential thrombocythaemia

Granulocytes: Chronic myeloid leukaemia

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Which genes are associated with myeloproliferative neoplasms?

JAK2

Calreticulin

MPL

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How is the diagnosis of myeloproliferative disorder (Ph negative) made?

Based on combination of:

Clinical features:

Symptoms
Splenomegaly

FBC +/- Bone marrow biopsy

Erythropoietin level (EPO)

Mutation testing: Phenotype linked to acquired mutation

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What is the epidemiology of polycythaemia vera?

Annual incidence 2-3/100000

Slightly more in males 1.2:1

Mean age at diagnosis 60 years

5% below age of 40 years

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How does PV present clinically? How is it diagnosed?

Incidental diagnosis routine FBC (median Hb 184g/l, Hct 0.55).

Symptoms of increased hyper viscosity:

Headaches, light-headedness, stroke
Visual disturbances
Fatigue, dyspnoea

Increased histamine release:

Aquagenic pruritus
Peptic ulceration

Test for JAK2 V617F mutation

How is PV treated?

Aim to reduce HCT:

Target HCT <45%
Venesection
Cytoreductive therapy hydroxycarbamide

Aim to reduce risks of thrombosis:

Control HCT
Aspirin
Keep platelets below 400x109 /l (see treatment of ET)

What is essential thrombocythaemia?

Chronic MPN mainly involving megakaryocytic lineage.

Sustained thrombocytosis >600x109 /L.

Incidence 1.5 per 100000.

Mean age two peaks 55 years and minor peak 30 years.

Females:males - Equal first peak but females predominate second peak.

What is the presentation of essential thrombocythaemia?

Incidental finding on FBC (50% cases).

Thrombosis: Arterial or venous – CVA, gangrene, TIA – DVT or PE.

Bleeding: Mucous membrane and cutaneous.

Headaches, dizziness visual disturbances.

Splenomegaly (modest).

What is the treatment of essential thrombocythaemia?

Aspirin: To prevent thrombosis.

Hydroxycarbamide: Antimetabolite. Suppression of other cells as well.

Anagrelide: Specific inhibition of platelet formation, side effects include palpitations and flushing.

What is the prognosis of essential thrombocythaemia?

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.

Extramedullary haematopoieisis.

Primary presentation:

Incidence 0.5-1.5 /100000
Males=females – 7 th decade.
Less common in younger patients
Other MPDs (ET & PV) may transform to PMF

What is the clinical presentation of primary myelofibrosis? How is it diagnosed?

Incidental in 30%:

Presentations related to:

Cytopenias: Anaemia or thrombocytopenia
Thrombocytosis
Splenomegaly: May be massive
- Budd-Chiari syndrome
Hepatomegaly
Hypermetabolic state:
- Weight loss
- Fatigue and dyspnoea
- Night sweats
- Hyperuricaemia

What are findings of primary myelofibrosis on a blood film?

Leucoerythroblastic picture Tear drop poikilocytes Giant platelets Circulating megakaryocytes

What are findings of primary myelofibrosis in the bone marrow?

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

What are additional findings of primary myelofibrosis?

**Liver and spleen:** Extramedullary haemopoiesis in spleen and liver **DNA:** JAK2 or CALR mutation

What is the prognosis of primary myelofibrosis?

Median 3-5 years but very variable

What are bad prognostic signs of primary myelofibrosis?

Severe anaemia \<100g/L Thrombocytopenia \<100x109 /l Massive splenomegaly

Which prognostic scoring system can be used for primary myelofibrosis?

Prognostic scoring system (DIPPS): **Score 0:** Median survival 15 years **Score 4-6:** Median survival 1.3 years

What is the treatment of primary myelofibrosis?

Limited range of options: **Supportive:** RBC and platelet transfusion often ineffective because of splenomegaly **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. **Splenectomy for symptomatic relief:** Hazardous and often followed by worsening of condition.

What is CML?

Ph positive myeloproliferative neoplasia. Incidence 1-2/100,000 M:F 1.4:1 40-60 years at presentation Radiation exposure risk factor

What are clinical signs of CML?

History: **Lethargy/hypermetabolism/thrombotic event:** Monocular blindness CVA, bruising bleeding. Exam: Massive splenomegaly +/- hepatomegaly

What can be seen in terms of bloods for CML?

**FBC:** * Hb and platelets well preserved or raised * Massive leucocytosis 50-200x109 /L **Blood film:** * Neutrophils and myelocytes (not blasts if chronic phase) * Basophilia

What are laboratory findings for CML?

Leucocytosis between 50 – 500x10 9 /l Mature myeloid cells Biphasic peak: Neutrophils and myelocytes Basophils No excess (\<5%) myeloblasts Platelet count raised/upper normal (contrast acute leuk)

Which translocation produces the Ph chromosome?

t(9;22) BCR-ABL

How does BCR-ABL contribute to myeloproliferative neoplasms?

Expresses a fusion oncoprotein with constitutive tyrosine kinase activity. Drives myeloid proliferation.

Which available diagnostic techniques can be used to identify the translocation/fusion?

Conventional Karyotyping FISH metaphase or interphase karyotyping RT-PCR amplification and detection

How are myeloproliferative diseases and their responses monitored?

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 is the sequelae of disease of CML?

**Chronic phase:** Median 3-4 years duration **Accelerated phase (10-19% blasts):** Median duration 6–12 months **Blast crisis (\>20% blasts):** Median survival 3–6 months

What is the treatment of CML?

**_Chronic phase:_** **Tyrosine kinase Inhibitor (TKI):** Imatinib (1Gen,) Dasatanib, Nilotonib (2G), Bosutinib (3G) **_Failure (1) \> Switch to 2Gen or 3G TKI:_** * No complete cytogenetic response at 1year * Respond but acquire resistance **_Failure (2) \> Consider allogeneic SCT_** * Inadequate response or intolerant of 2G TKIs * Progression to accelerated or blast phase