Chronic Myeloid Leukaemia

Question 1

What is CML ?

Answer 1

Abnormal development of myeloid SC affects BM and blood with hypertrophy of spleen (splenomegaly) and liver with death due to suppurination / formation of pus in the blood

Question 2

Who is most affected by CML?

Answer 2

Males, with peak age of diagnosis at 53. Rarely affects <20.

Question 3

What are the RF for CML?

Answer 3

Radiation exposure

Philidelphia chromosome

Question 4

What are the common signs and symptoms of CML?

Answer 4

Splenomegaly
Fatigue
Weight loss
Night sweats
Haemorrhage and easy bruising
Gout
Fever

Question 5

What will a blood count show?

Answer 5

Anaemia, elevate WBCs and platelets

Question 6

What will a blood film morphology show?

Answer 6

Immature immune cells - myelocytes and mature granulocytes

Question 7

What will a BM diagnosis show from a trephine histology?

Answer 7

Immature myelocytes

Question 8

If geneting testing is carried out what will it show?

Answer 8

Philidelphia chromosome - confirms diagnosis when presents with symptoms

Question 9

What is the Philidelphia chromosome?

Answer 9

Translocation of ABL gene on chromsome 9 with BCR gene on chromosome 22. It leads to the generation of a chimeric protein BRC-ABL with TK activity. Responsible for the CML phenotype

Question 10

What test can be done to confirm that BCR and ABL are fusing during metaphase?

Answer 10

FISH

Question 11

Which form of the BCR-ABL protein is the most common?

Answer 11

p210

Also p190 and p230

Question 12

What treatment can be given in CML?

Answer 12

Tyrosine Kinase Inhibitor to inhibit the function of the fusion gene by blocking its TK activity that is constitutively activated by the translocation. Allows long term survival but is not curative

Question 13

How does Imatinib work?

Answer 13

Inhibits ATP binding within ABL TK domain, by binding into the ATP pocket itself. This prevents phosphorylation or target molecules and keeps BCR-ABL inactive.

Question 14

What else can Imatinib inhibit?

Answer 14

PDGFR

Question 15

How is Imatinib administered?

Answer 15

Orally and absorbed in GIT

Question 16

How does TK activity lead to normal signalling?

Answer 16

When a substrate binds to RTK, it activates TK activity to autophosphorylate the tyrosine residues, creating a high affinity docking site for PI3 Kinase to initiates down stream signalling via PI3 kinase pathway for survival, growth and proliferation.

Question 17

What is the only curable option of CML? Why is it not offered first line?

Answer 17

BM transplant but it comes with a high risk of mortality and requires a matched donor.
Only offered to young fit Pts.
Only 30% are eligible due to age, morbidity and donors.

Question 18

How is prognosis predicted for CML patients?

Answer 18

Considers the degree of reduction and how quickly it was achieved.

Question 19

Why are 2nd generation TKIs needed?

Answer 19

Pts can develop resistance to 1st line TKIs, so 2nd generation overcomes this resistance due to an increased potency. e.g. nilotinib

Question 20

Why does resistance develop?

Answer 20

TKI creates a pressure on BCR-ABL and causes the development of new mutations that prevents Imatinib from binding to the ATP pocket.

Question 21

In which Pts is resistance most likely to occur in?

Answer 21

Pts in a more progressed stage of cancer.

Question 22

Why should be tried first before giving a second generation drug when resistance develops?

Answer 22

Increase the concentration of Imatinib.

Question 23

What causes Philidelphia -ve myeloproliferative Neoplasia?

Answer 23

JAK2, MPL and CALP mutations

Question 24

Where does JAK2 mutation occur and what does this cause?

Answer 24

On chromosome 9. It causes cancer of BM with excess RBC production and increased viscosity = POLYCYTHEMIA VERA

Question 25

What does JAK2 normally do?

Answer 25

Mediates further downstream signalling

Question 26

What can be used to treat myeloproliferative neoplasia?

Answer 26

JAK2 inhibitors e.g. Ruxolitinib

Shown to reduce splenomegaly in a few days and increase QoL and survival. Only controls, isn’t a cure.