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YR5 Haematology > CML and Myeloproliferative Disorders > Flashcards

CML and Myeloproliferative Disorders Flashcards

1
Q

What is polycythaemia?

A

Raised Hb conc. + Haematocrit %

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2
Q

What are causes of polycythaemia?

A

Relative: Lack of plasma = Non-malignant (Pseudo)

True: Excess erythrocytes

Primary: Myeloproliferative neoplasm

Secondary: Non-malignant

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3
Q

What are the classes of myeloproliferative neoplasms? Give examples of each

A

Ph (Philadelphia Chr) -ve:

  • Polycythaemia vera (PV) (erythroid)
  • Essential Thrombocythaemia (ET) (megakaryocytic)
  • Primary Myelofibrosis (PMF)

Ph +ve:

  • Chronic myeloid leukaemia (CML)
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4
Q

What are dilution studies used for?

A

To differentiate between true + relative polycythaemia

Red Cell Mass: 51 Cr labelled RBC

Plasma Vol: 131 I labelled albumin

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5
Q

What are 3 causes of relative/pseudo-polycythaemia?

A

Alcohol

Obesity

Diuretics

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6
Q

What happens to EPO in primary and secondary true polycythaemia?

A

Primary: Reduced

Secondary: Elevated

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7
Q

What are 4 appropriate causes of elevated EPO?

A

High altitude

Hypoxic lung disease

Cyanotic heart disease

High affinity haemoglobin

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8
Q

What is the mechanism behind appropriate raise in EPO?

A

Low O2 tension detected by kidneys

Stimulates raise in EPO

Increases Hb production

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9
Q

How do lung, heart and high affinity haemoglobin cause appropriate increase in EPO?

A

Hypoxic lung disease: Less gas exchange, less O2 reaches kidneys

Cyanotic heart: Sending deoxygenated blood to kidneys

High affinity Hb e.g. Sickling thalassemia- fail to release O2 from Hb at lower O2 tensions, starve tissue of O2

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10
Q

What are 3 inappropriate causes of elevated EPO?

A

Renal disease (cysts, tumours, inflammation)

Uterine myoma

Other tumours (liver, lung)

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11
Q

What are examples of lymphoid haematological malignancies?

A

Precursor cell malignancy: ALL (B + T)

Mature cell malignancy: CLL, Multiple myeloma, Lymphoma (Hodgkin + Non Hodgkin)

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12
Q

What are 3 types of myeloid haematological malignancies?

A

Acute myeloid leukaemia (blasts >20%)

Myelodysplasia (blasts 5-19%)

Myeloproliferative disorders: ET, PV, PMF, CML

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13
Q

Which 3 processes in blood cancers are disrupted by mutation?

A

Cellular proliferation (type 1)

Impair/ block cellular differentiation (type 2)

Prolong cell survival (anti-apoptosis)

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14
Q

What is the normal function of tyrosine kinases?

A

Transmit cell growth signals from surface receptors to nucleus.

Activated by transferring phosphate groups to self + downstream proteins.

Normally held tightly in inactive state.

Promote cell growth, do not block maturation.

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15
Q

What happens when mutations cause activation of tyrosine kinase?

A

Expansion increase in mature/ end cells

Red cells: Polycythaemia

Platelets: Essential thrombocythaemia

Granulocytes: Chronic myeloid leukaemia

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16
Q

What occurs when EPO receptor binds erythropoietin?

A

Changes configuration of TK receptor

Phosphorylates JANUS Kinase 2 - ACTIVE

Able to pass phosphate groups to downstream signalling molecules which take the signal from the bound receptor to the nucleus to drive proliferation

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17
Q

Which genes are associated with myeloproliferative neoplasms?

A

JAK2 (100% of PV, 60% of ET + PMF)

Calreticulin

MPL

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18
Q

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

A

Clinical features: Sx + Splenomegaly

FBC +/- BM biopsy

Erythropoietin level (EPO)

Mutation testing: Phenotype linked to acquired mutation

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19
Q

What is the epidemiology of polycythaemia vera?

A

Annually: 2-3/100,000

M > F = 1.2 : 1

Mean age dx: 60y

5% < 40y

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20
Q

How does PV present clinically? How is it diagnosed?

A

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

Sx of increased hyper viscosity

Sx due to increased histamine release

Test for JAK2 V617F mutation

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21
Q

List 6 symptoms caused by blood hyper viscosity in PV

A

Headaches

Light-headedness

Stroke

Visual disturbances

Fatigue

Dyspnoea

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22
Q

Give 2 symptoms caused by increased histamine release in PV

A

Aquagenic pruritis

Peptic ulceration

23
Q

How is PV treated?

A

Aim to reduce HCT: Target HCT <45%

Aim to reduce risks of thrombosis

24
Q

Give 2 ways in which HCT can be reduced in PV?

A

Venesection

Cytoreductive therapy hydroxycarbamide

25
Q

How do we reduce the risk of thrombosis in PV?

A

Control HCT

Aspirin

Keep platelets < 400x10^9/l

26
Q

What is essential thrombocythaemia?

A

Chronic MPN mainly involving megakaryocytic lineage.

Sustained thrombocytosis >600x10^9 /L.

Incidence: 1.5 per 100000.

2 peaks: 55y + minor peak 30y

F : M = Equal 1st peak but F predominate 2nd peak.

27
Q

What is the presentation of essential thrombocythaemia?

A

Incidental finding on FBC (50% cases).

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

Bleeding: Mucous membrane + cutaneous.

Headaches, dizziness, visual disturbances.

Splenomegaly (modest).

28
Q

What is the treatment of essential thrombocythaemia?

A

Aspirin: To prevent thrombosis.

Hydroxycarbamide: Antimetabolite. Reduces platelet count, suppression of other cells as well.

Anagrelide: Specific inhibition of platelet formation, SE: palpitations + flushing.

29
Q

What is the prognosis of essential thrombocythaemia?

A

Normal life span, may not be changed in many

Leukaemic transformation in ~5% after >10 years.

Myelofibrosis also uncommon, unless there is fibrosis at the beginning.

30
Q

What is primary myelofibrosis?

A

Clonal myeloproliferative disease associated with reactive BM fibrosis.

Extramedullary haematopoieisis.

Incidence 0.5-1.5 /100,000

M = F

7 th decade: Less common in young

Other MPDs (ET + PV) may transform to PMF

31
Q

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

A

Incidental in 30%

Presentations related to:

Cytopenias: Anaemia/ thrombocytopenia

Thrombocytosis

Splenomegaly: May be massive.

Hepatomegaly +/- Budd-Chiari syndrome

Sx of Hypermetabolic state

32
Q

What symptoms may be seen due to hyper metabolic state in PMF?

A

Weight loss

Fatigue

Dyspnoea

Night sweats

Hyperuricaemia

33
Q

What are findings of primary myelofibrosis on a blood film?

A

Leucoerythroblastic picture

Tear drop poikilocytes

Giant platelets

Circulating megakaryocytes

34
Q

What are findings of primary myelofibrosis in the bone marrow?

A

‘Dry tap’

Trephine:

  • Increased reticulin or collagen fibrosis
  • Prominent megakaryocyte hyperplasia + clustering with abnormalities
  • New bone formation
35
Q

What are additional findings of primary myelofibrosis?

A

Liver + spleen: Extramedullary haemopoiesis

DNA: JAK2 or CALR mutation

36
Q

What is the prognosis of primary myelofibrosis?

A

Median 3-5 years but very variable

37
Q

What are bad prognostic signs of primary myelofibrosis?

A

Severe anaemia <100g/L

Thrombocytopenia <100x109 /l

Massive splenomegaly

38
Q

Which prognostic scoring system can be used for primary myelofibrosis?

A

Prognostic scoring system (DIPPS):

Score 0: Median survival 15 years

Score 4-6: Median survival 1.3 years

39
Q

What is the limited range of treatment options for primary myelofibrosis?

A

Supportive: RBC + platelet transfusion often ineffective because of hypersplenism

Cytoreductive therapy: Hydroxycarbamide (for thrombocytosis (suppresses clones), 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 + often followed by worsening of condition.

40
Q

What is CML?

A

Ph +ve myeloproliferative neoplasia.

Incidence 1-2/100,000

M > F = 1.4 : 1

40-60y

RF= Radiation exposure

41
Q

What are clinical signs of CML?

A

Lethargy/ Hypermetabolism/ Thrombotic event: Monocular blindness, CVA, bruising, bleeding.

Massive splenomegaly +/- hepatomegaly

42
Q

What can be seen in terms of bloods for CML?

A

FBC: Hb + platelets well preserved or raised

Massive leucocytosis 50-200x109 /L

Blood film: Neutrophils + myelocytes (not blasts if chronic phase)

  • Basophilia
43
Q

What are laboratory findings for CML?

A

Leucocytosis: 50 – 500x10^9 /l

Mature myeloid cells

Biphasic peak: Neutrophils + myelocytes

Basophils

No excess (<5%) myeloblasts

Platelet count raised/ upper normal (contrast acute leuk)

44
Q

Which translocation produces the Ph chromosome?

A

t(9;22)

BCR-ABL

45
Q

How does BCR-ABL contribute to myeloproliferative neoplasms?

A

Expresses a fusion oncoprotein with constitutive tyrosine kinase activity.

Drives myeloid proliferation.

46
Q

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

A

Conventional Karyotyping

FISH metaphase or interphase karyotyping

RT-PCR amplification + detection

47
Q

How are myeloproliferative diseases and their responses monitored?

A

FBC + measure leucocyte count.

Cytogenetics + detection of Philadelphia chr.

RT-PCR of BCR-ABL fusion transcript which can be quantified by RQ-PCR to determine response to therapy.

48
Q

What was the clinical course of CML before Imatinib?

A

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

49
Q

What is the treatment of CML in the chronic phase?

A
  1. Tyrosine kinase Inhibitor (TKI): Imatinib (1Gen,) Dasatanib, Nilotonib (2G), Bosutinib (3G)

2. Failure (1) > Switch to 2Gen or 3G TKI:

No complete cytogenetic response at 1y or Respond but acquire resistance

3. Failure (2) > Consider allogeneic SCT

Inadequate response or intolerant of 2G TKIs

or Progression to accelerated or blast phase

50
Q

How do myeloproliferative neoplasms and acute leukaemia differ with respect to differentiation?

A

M: no impairment of differentiation, excess proliferation

AL: mutations block differentiation, excess proliferation

51
Q

What are the mutation mechanisms in blood cancer?

A

DNA point mutations

Chromosomal translocations: Creation of novel fusion gene/ Disruption of proto-oncogene

52
Q

What is monitored throughout treatment of CML?

A

FBC

Cytogenetics

RQ-PCR

CCyR at 1y (Complete cytogenetic response = 0% Ph +ve metaphases)

53
Q

What is the prognosis for CML?

A

97% FFP at 6y (freedom from progression)

95% 5y survival

2% Annual mortality

54
Q

What are the disadvantages of TKIs?

A

Failure to achieve CCyR

Non-compliance

SE: Fluid retention, pleural effusions

Loss of major molecular response (MMR): Acquiring ABL point mutations leading to resistance, evolution to blast crisis

YR5 Haematology (20 decks)

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