Chronic Myeloid Leukaemia

Question 1

CML is a disorder of late or early haematopoietic stem cell?

Answer 1

Late - small, mature but dysfunctional cells

Question 2

What cells are in excess?

Answer 2

The myeloid lineage - especially granulocytes : neutrophils, basophils, eosinophils

Question 3

CML is part of the chronic….. disorders

Answer 3

Myeloproliferative

Also includes: polycythemia Vera, ET, MMM

Question 4

Is it more common in men or women?

Answer 4

Men

Question 5

What age does it typically present?

Answer 5

50-60

Question 6

What chromosome is present in more than 95% of those with CML?

Answer 6

The Philadelphia chromosome

Question 7

Describe the pathophysiology

Answer 7

A translocation occurs between the long arm of chromosome 9 and 22 (a reciprocal translocation).

This results in the part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22.

Question 8

What does the result BCR-ABL fusion gene do?

Answer 8

Codes for a fusion protein which has tyrosine kinase activity in excess of normal.

The tyrosine kinase disrupts the cell- increase proliferation and reduces apoptosis

Question 9

Chromosome 22 post translocation is called…

Answer 9

Philadelphia chromosome

Question 10

What symptoms and signs occur in the chronic phase?

Answer 10

Weight loss
Fever
Night sweats
Fatigue
Splenomegaly 
Lymphadenopathy

Question 11

What symptoms/signs are associated with the accelerated phase?

Answer 11

Anaemia - SOB 
Thrombocytopenia- bleeding
Neutropenia - infections 
Extreme splenomegaly - abdominal pain 
Extreme pleocytosis (proliferation of malignant cells, can form thrombi)

Question 12

Why can gout occur?

Answer 12

Due to increased purine breakdown (there is high cell turnover)

Question 13

What different phases of the disease are there?

Answer 13

Chronic phase
Accelerated (aggressive phase)
Blast crisis

Question 14

How long does the chronic phase last?

Answer 14

Months or years - few if any symptoms

Question 15

What happens in the chronic phase?

Answer 15

There may be an increased WCC

Less than 10% of blast cells in blood

Question 16

What happens in the accelerated phase?

Answer 16

More likely to find blast cells in the blood - approximately 10-20%
More systemic symptoms

Question 17

What is the blast transformation?

Answer 17

When blood contains more than 20% blast cells
Features of leukaemia (70% transforms to AML, 30% to ALL)
Rapid progression to bone marrow failure - pancytopnia

Once patients reach this stage, mortality high

Question 18

What does FBC show?

Answer 18

Extreme leukocytosis with whole spectrum of myeloid cells
Basophilia more prominent as disease progresses
Anaemia
Platelets variable (raised in accelerated and blast phase)

Question 19

Describe the bone marrow biopsy

Answer 19

Hypercellular due to myeloid hyperplasia

Blasts less than 10%

Question 20

What can be done to look for the cytogenetic abnormality?

Answer 20

Fluorescent in-site hybridisation (FISH)

Question 21

What treatment is first line for chronic and accelerated phase ?

Answer 21

IMATINIB - a tyrosine kinase inhibitor

Question 22

How does imatinib work?

Answer 22

A TK inhibitor - prevents action of the BCR-ABL fusion protein (the abnormal protein produced by the Philadelphia chromosome)

Question 23

What side effects are associated with imatinib?

Answer 23

Usually well tolerated 
Nausea
Headaches 
Oedema
Rash
Arthralgia 

May cause myelosuppression

Question 24

In the chronic phase, what percentage will respond to imatinib?

Answer 24

95%

Question 25

In the blast phase is imatinib useful?

Answer 25

No - may benefit from treatment as for ALL

Question 26

In the aggressive phase, can imatinib be used?

Answer 26

Yes - can put the disease back into chronic phase

Question 27

In those who have a poor response to imatinib, what can be done?

Answer 27

Autologous transplant - some of patient’s own BM removed, screened for the disease and if suitable, the stem cells transplanted back.

Lower mortality compared to stem cell transplant from a donor

Question 28

CML accounts for what percentage of leukaemias?

Answer 28

15%