Ha - CML / Myeloproliferative Disorders

Question 1

Normal haumatopoeisis is regulated by…?What do they interact with?

Answer 1

Growth factors.
These interact with receptors –> tyrosine kinase activation

Question 2

Important enzymes in haematopoeisis? How does mutation affect this?

Answer 2

Janus Kinases
Mutation –> they become constitutively active –> aberrant cell proliferation

Question 3

2 mutations seen in MPNs?

Answer 3

JAK2 V617F mutation
Exon 12 mutation

Question 4

Name 3 myeloproliferative neoplasia which are BCR-ABL negative?

Answer 4

Essential thrombocytosis
Polycythemia Rubra Vera
Myelofibrosis

Question 5

2 main features of MPNs?
Common presentations?

Answer 5

• Assoc with BM fibrosis
• Increased proliferation of mature cells

Question 6

How does blood from MPN patients behave on agar culture?

Answer 6

Cells will grow in absence of EPO or TPO

Question 7

Diagnostic for PCV?

Answer 7

Increased RBCs + JAK2 V617 mutation

Question 8

Epidemiology for PCV - age? sex?

Answer 8

M>F
Generally 60yos

Question 9

Sx of PCV?

Answer 9

Hyper viscosity: headaches, dizziness, stroke, retinal vessel engorgement, visual disturbance, fatigue

Histamine release: AQUAGENIC PRURITIS. peptic ulcers

Gout

Question 10

Haem Ix with results in PCV?

Answer 10

High Hb + Hct + MCV
Often high Plts + WCC

Plasma volume high (from isotope dilution method)
Low EPO

Question 11

Aim of PCV Mx? how is this achieved?

Answer 11

Hct<45% + Plt <400x10^9

• Venesection + cytoreductive therapy
• aspirin + hydroxycarbamide

Question 12

Dx if pt has raised HCt with an JAK2 Exon 12 mutation?

Answer 12

Idiopathic erythrocytosis

Question 13

Features of idiopathic erythrocytosis?
Genetics?
Tx?

Answer 13

• Isolated raised RBCs
• No V617F mutation - often have exon 12 mutation
• Managed with venesection alone

Question 14

What is the disorder?
- 2 age peaks at 30 and 55 yo
- BM dominated by megakaryocytes
- Blood film = large platelets
- Plt count >600*10^9

Answer 14

Essential thrombocytosis

Question 15

Genetics in essential thrombocytosis

Answer 15

• 50% have JAK2 mutation therefore difficult to diagnose in absence of mutation
• Some have TPO receptor mutation

Question 16

Clinical features of essential thrombocytosis

Answer 16

-Thrombosis (stroke/MI/gangrene/haemorrhage)
-Dizziness, headaches, visual
- splenomegaly
- WEIRDLY, BLEEDING

Question 17

Ix results in essential thrombocytosis

Answer 17

Platelets >600*10^9
Blood film: large platelets, megakaryocyte fragments
BM: megakaryocytes + clustering

V617F mutation in 50%

Question 18

Treatment of essential thrombocytosis - give 4 medications (and some of their downfalls)

Answer 18

• Aspirin (prevent thrombosis)
• Hydroxycarbamide (can worsen anaemia)
• Anagrelide, reduces platelet formation (can transform to MF)
• alpha-IFN useful in <40yos.

Question 19

Myelofibrosis - what is it characterised by?
2 types?

Answer 19

• Fibrosis of BM + raised megakaryocytes in BM
• Often in older patients
• Also ANAEMIC

Primary = genetic
Secondary = developed from PRV, ET

Question 20

Major examination finding in myelofibrosis?

Answer 20

MASSIVE Splenomegaly

Question 21

Blood film in myelofibrosis - 4 features

Answer 21

• Tear drop poikilocytes
• Leukoerythroblasts
• Giant platelets
• Circulating megakaryocytes

Question 22

Bone marrow in myelofibrosis - 3 things

Answer 22

“Dry tap”
Lots of fibrosis
Megakaryocytes - clustering

Question 23

Mx of myelofibrosis

Answer 23

Supportive with blood products
- Splenectomy?!
- Hydroxycarbamide (can worsen anaemia)
- Thalidomide
- Steroids
- BMT (experimental)

Question 24

Prognosis of myelofibrosis? poor prognostic factors?

Answer 24

3-5 years
Severe anemia, thrombocytopenia, massive splenomegaly

Question 25

CML - sex? age?

Answer 25

Men>F
40-60 years

Question 26

Typical CML history?

Answer 26

Lethargy/hypermetabolic state (SOB, hyperuricemia, wt loss)/THROMBOTIC EVENT E.G. MONOCULAR BLINDNESS

Question 27

Typical finding on examination of CML patient? why?

Answer 27

massive splenomegaly - chronic therefore time for cells to accumulate

Question 28

FBC result on CML

Answer 28

MASSIVE leukocytosis >50 x10^9

Question 29

Blood film results in CML?

Answer 29

Raised basophils
Raised neutrophil and promyelocytes
<5% BLASTS (if more –> acute leukaemia :( )

Question 30

Natural, untreated history of CML

• what are the 3 phases?

Answer 30

1. Chronic
2. Accelerated
3. Blast crisis

Question 31

In what disease phase are 80% of CML patients diagnosed?

Answer 31

chronic

Question 32

What is the difference between chronic phase and accelerated phase?

Answer 32

Chronic: <5% of cells are blasts
Accelerated: 10-19% are blasts

Question 33

Key mutation seen in CML and result?

Answer 33

Philadelphia chromosome
t(9;22)
This expresses a fusion gene with TK activity

Question 34

Most sensitive away to identify leukaemia cells in the body?

Answer 34

RT-qPCR

Question 35

3 ways to detect leukaemic cells in the body?

Answer 35

FBC - leukocyte levels
Cytogenetic analysis (FISH)
Molecular analysis (RT-qPCR)

Question 36

3 ways to monitor response to Tx in CML?

Answer 36

FBC
FISH
qPCR

Question 37

Main drug used for CML treatment? MOA?

Answer 37

Imatinib
a TKI

Question 38

Survival rate of CML with imatinib treatment?

Answer 38

95% survival at 5 years

Question 39

Why does imatinib not always work? give 3 reasons

Answer 39

Patient non-compliance
- resistance due to point mutation
- SEs - pleural effusion from fluid retention