L07 - CML

Question 1

What is the difference between an acute and a chronic leukaemia?

Answer 1

In acute there is some maturation arrest whereas in chronic there is not so WBCs are produced indefinitely

Question 2

What are the clinical features of CML?

Answer 2

Fatigue, weight loss and sweating
Anaemia
Haemorrage (bruising)
Splenomegaly without hepatomegaly

Question 3

What blood film morphology is classic of CML?

Answer 3

Lots of cells from all stages of differentiation. Cells early in their myeloid differentiation are classic of CML.

Question 4

What are the two types of diagnosis of CML from bone marrow?

Answer 4

Bone marrow trephine histology (remove 1-2cm of bone to look at)
Bone marrow aspirate

Question 5

How does CML appear on bone marrow histology?

Answer 5

Myeloid hyperplasia

Many cells at different stages of development

Question 6

What is is cytogenetics and why is it useful for CML?

Answer 6

It involves laying out the genome to look for abnormalities. Can look for the BCR-Abl translocation that would be chromosome 9 and 22

Question 7

What are the two methods that can be used to diagnose CML at the molecular level?

Answer 7

FISH (flourescent in situ hybridisation)
-Use a flourescent marker to look out for Philadelphia chromosome.
QPCR (quantitive real time polymerise chain reaction)
- can identify and quantify philadelphia chromosome
-Allows quantitive monitoring

Question 8

How does BCR-Abl cause CML?

Answer 8

It uses its inegral tyrosine kinase to phosphorylate downstream proteins that cause cell proliferation and survival. e.g. PI3 kinase

Question 9

What are the three phases of CML?

Answer 9

Chronic phase (80%) - associated with 5-6 year survival
Accelerated phase (10%) - associated with changes in chromosomes
Blast-crisis transformation (10%) - Final stage of CML and behaves like AML.

Question 10

What remains the only curative methods for CML to date?

Answer 10

Haemopoeitic stem cell transplant

Question 11

What type of drug is imatinib and how does it work?

Answer 11

It is a tyrosine kinase inhibitor and works by preventing the binding of ATP to the Abl tyrosine kinase. Without ATP bound it is unable to phosphorylate the downstream proteins and cause a signal transduction cascade that lead to cell proliferation and survival.

Question 12

What are the disadvantages of imatinib?

Answer 12

• Some people in clinical trials aquired resistance to imatinib
• Imatinib was not fully effective in eradicating primitive cell populations with the philadelphia chromosome.

Question 13

How was resistance to imatinib countered?

Answer 13

Production of 2nd generation tyrosine kinase inhibitor such as Dasatinib and nilotinib
They were more potent and achieved a better response.