18. Chronic myelogenous leukaemia

Question 1

chronic myelogenous leukaemia

Answer 1

Most clinically researched haematological malignancy in history!

First malignant disease to be associated with a particular chromosomal abnormality

First to have significant reported success with a molecular targeted therapy – imatinib (Gleevec)

Question 2

chronic myeloidleukaemia CML

Answer 2

Proliferation of mature granulocytes (neutrophils, eosinophils and basophils) and their precursors is the main finding

Accounts for approximately 15% of leukaemias
May occur at any age
Overall incidence of approximately 5-10 cases/million population.

Diagnosis: rarely difficult
Assisted by the characteristic presence of the Philadelphia chromosome, t(9;22) BCR-ABL1+

Varying maturity, lots of blasts present
Translocation between chromosome 9 and 2
Produces tyrosine kinase that is always active
Resistance to apoptosis

Question 3

chronic myeloid leukaemia timeline

Answer 3

translocation in myelocyte so these accumulate

Question 4

Philadelphia chromosome

Answer 4

Reciprocal translocation (Philadelphia chromosome) between the long arm of chromosomes 9 and 22

Results: fusion between proto-oncogene ABL and the BCR gene on chromosome 22. end up with fused product

Resulting chimeric BCR-ABL gene encodes for a protein – causes production of tyrosine kinase, stimulates production of abnormal blood cells. Tyrosine kinase affects Cell cycling, apoptosis, dna repair . Genetic instability so susceptible to more mutations

Leads to increased cell cycling and resistance to apoptosis

Question 5

clinical features of CML

Answer 5

Presenting features include
weight loss and
night sweats

Splenomegaly frequently occurs

Anaemia is common as is bleeding and bruising

In up to 50% cases, diagnosis made incidentally from a routine blood count!

Question 6

blood film CML

Answer 6

Purple arrows: Myeloblasts
Blue arrows: Promyelocyte
Green arrow: Myelocyte

Cells between myelocytes and mature neutrophils
- metamyelocyte = red arrow and - mature neutrophils =
black arrows

Blood film: CML (you would not be expected to identify cells in exam situation but could talk about the variety of levels of maturity that are evident)

Question 7

laboratory findings of CML

Answer 7

Leukocytosis common occurrence 
Increased basophils (common)
Bone marrow usually hypercellular with a raised myeloid/erythroid ratio. 

The Philadelphia chromosome is detected by cytogenetics

BCR-ABL fusion is detectable by FISH (or PCR)

plasma rbc , puffy coat is all wbc
normal individual layeyou wouldn’t see the wbc layer, count is off the scale

Question 8

disease progression of CML

Answer 8

Common course with three well defined phases of disease progression

Chronic Phase (CML-CP)
usually responds well to chemotherapy
Continues on average for 4-6 years

Accelerated phase (CML-AP) 
at some point wont respond to treatment and enters accelerated phase 

Blast Phase (CML-BP) – Fatal acute leukaemia
transformation to acute leukaemia , fatal within a few months of that transformation

Question 9

treatment options Imatinib (Glivec)

Answer 9

BCR-ABL tyrosine kinase inhibitor Imatinib (Glivec)

Controls the blood count and clears the marrow of malignant cells.

Increases the chronic phase and reduces the risk of acute transformation.

Mode of action:
block the binding of ATP to BCR-ABL
inhibits the activity of the kinase and
inhibits the proliferation of BCR-ABL cells.

But…the drug is specific
Molecular resistance to Imatinib starting to emerge
…Second generation tyrosine kinase inhibitors

is targeted, allows healthy cells to be produced and gets rid of malignant cells