Haematology 7 - CML and MPD

Question 1

How can you determine the red cell mass and plasma volume in a blood sample?

Answer 1

Dilution studies
Red cell mass: radioactive chromium
PLasma volume: radioactive iodine labelled albumin

Question 2

Causes of pseudopolycythaemia

Answer 2

Alcohol, diuretics, obesity

Question 3

In CML you have an excess of…

Answer 3

MATURE CELLS (retain ability to differentiate but have excessive proliferation)

Question 4

Outline the two types of mutations in haematological proliferation

Answer 4

Type 1 = cellular proliferation (mature cells)

Type 2 = impair cellular differentiation (blasts)

Question 5

Mutation of TK gene –>

Answer 5

Expansion of mature RBC (PV), platelets (ET) and granulocytes (CML)

Question 6

Role of TKs

Answer 6

Promote cell growth but DO not stop maturation

Question 7

What is JAK2 normally bound to?

Answer 7

Inactive EPO receptor

Question 8

What happens when JAK2 mutated?

Answer 8

JAK2 signalling pathway is constitutively active –> EPO response even in absence of EPO

Question 9

3 MPD associated gene mutations

Answer 9

JAK2 V617F (PV, ET, MF)
Calreticulin (ET, MF)
MPL (ET)

Question 10

Princples of treatment of PRV

Answer 10

Venesection
Cytoreductive therapy (hydroxycarbamide/hydroxyurea)
Aspirin

Aim Hct <45% plts <400x10^9/L

Question 11

One difference between ET and PRV

Answer 11

In ET, Hb not that high

Question 12

Mutations in ET

Answer 12

JAK2, Calreticulin, MPL

Question 13

What is MF characterised by?

Answer 13

Extramedullary haemopoiesis

Question 14

Clinical features of MF

Answer 14

Pancytopaenia,
Massive splenomegaly –> Budd-chiari sx
Hepatomegaly
Hypermetabolic state : WL, fever, fatigue, dyspnoea

Question 15

Blood film in MF

Answer 15

Leucoerythroblastic picture
Tear drop poikilocytes
Giant platelets
Circulating megakaryocytes

Question 16

BM trephine biopsy findings in MF

Answer 16

Increased reticulin or collagen fibrosis
Increased megakaryocytes with clustering
New bone formation

Question 17

Mutations in MF

Answer 17

JAK2 and CALR (calreticulin)

Question 18

Name of the prognostic scoring system in PMF

Answer 18

DIPPS (1 to 6)

Question 19

Monoclonal antibody for MF

Answer 19

Ruxolotinib (JAK inhibitor), used if v high prognostic score

Question 20

CML epidemiology

Answer 20

40-60
M>F
RF: radiation

Question 21

FBC in CML

Answer 21

Hb and plts are normal or raised

Massive leucocytosis

Question 22

Blood film findings in CML

Answer 22

Neutrophils, myeloCYTES, basophilia

Question 23

What are the 3 phases of CML?

Answer 23

Chronic, accelerated and blast phase

Question 24

Differentiate between each phase and outline its prognosis

Answer 24

Chronic: <5% blasts, 5-6 year survival
Accelerated: 5-19% blasts, 6-12 months survival
Blast: >20% blasts, 3-6 months

Question 25

The 9;22 translocation is present in which cells?

Answer 25

ONLY PRESENT IN THE MALIGNANT CELLS, NOT CONSTITUTIONALLY EXPRESSED IN ALL CELLS

Question 26

What are the functions of BCR and ABL, respectively?

Answer 26

``` ABL = tyrosine kinase (usually not v active) BCR = housekeeping gene that is constitutively active ```

Question 27

Diagnostic techniques to dparetect BCR-ABL

Answer 27

FISH Karyotyping RT-PCR amplification and detection

Question 28

What is RT-PCR used for in CML?

Answer 28

Response to treatment as quantifies amount of BCR-ABL

Question 29

How do we assess the response to treatment in CML? (3 methods)

Answer 29

FBC --> haematological repsonse (WBC <10x10^9/L) Cytogenetics --> partial = 1-35% Ph+ve, complete = 0% Ph+ve RQ-PCR --> molecular response (MOST sensitive), looking at reduction in % of abnormal to normal transcripts

Question 30

What is the most sensitive asssesment of response to CML treatment?

Answer 30

Looking at % transcripts using RQ-PCR, can compare % of abnormal to normal transcripts

Question 31

What are the issues of TKIs?

Answer 31

Failure to work (by 18 months) SEs: pleural effusion and fluid retention Non-compliance Acquire ABL mutations --> treatment resistance

Question 32

Name a 1st and 2nd gen TKI

Answer 32

``` 1st = imatinib 2nd = dasatinib ```

Question 33

What is 3rd line treatment?

Answer 33

Allogenic SCT

Question 34

What is faliure to TKIs considered to be?

Answer 34

No CCyR (complete cytogenic response by 1 year) or aquired resistance