Lecture 7 - CML: From Chromosomes to Targeted Therapy

Question 1

Is CML a rare or common cancer?
What peak age does it affect?
What is its suggested aetiology?

Answer 1

rare
1.25 per 100,000
10-15% of leukaemias
53yrs (working age)
aeitiology mostly unknown, radiation exposure has been implicated

Question 2

What is semiotics?

Answer 2

the study of symptoms and signs of patients

Question 3

What is the typical clinical presentation of a patient with CML?
What does FBC show?

Answer 3

Common: fatigue, weight loss, sweating
Haemorrhage, easy bruising, discrete ecchymoses
Patient has massive splenomegaly
FBC: low Hb, high WBC, often high platelets

Question 4

What is seen on blood film morphology in CML?

Answer 4

many mature granulocytes, and immature white cells (myelocytes)

Question 5

What is seen on bone marrow aspirate in CML?

Answer 5

immature myelocytes and promyelocytes

Question 6

What is seen on a karyotype of a CML patient?

Explain

Answer 6

asymmetry between chromosomes pairs 9 and 22

- due to translocation between chromosome 9 and 22 (Philadelphia chromosome) and formation of BCR-abl gene

Question 7

What 2 methods are used for molecular diagnosis of CML?

Answer 7

FISH (fluorescence in situ hybridisation

QPCR (quantitative polymerase chain reaction)

Question 8

There are variants of translocation for the BCR-abl gene, what is the most common variant?

Answer 8

p210 BCR-ABL

Question 9

What 3 things does BCR-ABL do in clinical practice?

Answer 9

1. can be used to diagnose CML
2. can be targeted for treatment
3. can be used to monitor disease

Question 10

How can BCR-ABL be targeted for treatment?

Answer 10

Imatinib is tyrosine kinase

- potent inhibitor of ABL-L, Ckit and PDGF-R, salts are soluble in water, oral bioavailable, not mutagenic

Question 11

What is imatinibs mechanism of action?

Answer 11

inhibits the binding to ATP to ABL tyrosine kinase
- binds to ATP binding pocket of BCRABL - prevents phosphorylation of target molecules. Maintains BCR-abl in inactive state

Question 12

What is the history of treatment of CML?

Answer 12

hydroxyurea
combination chemotherapy
bone marrow transplantation (only curative option)
interferon alpha 
imatinib

Question 13

If HSCT is the only curative option, why isn’t this used in every patient?

Answer 13

only around 30% of patients are eligible for HSCT because of age, morbidity, donor availability

Question 14

What was the IRIS trial?

Answer 14

RCT for imatinib
Treatment arm had imatinib
Control arm had IFNalpha and AraC (standard treatment)
There was crossover between the groups

Question 15

How can BCR-ABL be used to monitor disease?

Answer 15

Minimal Residual Disease monitoring of BCR-ABL PCR transcript levels an integral part of management of CML patients on TKI inhibitors

Question 16

What are the three conclusions of imatinib?

Answer 16

• good tolerability/efficacy
• 97% of patients with Complete Cytogeneic Response at 12 months did not progress within 54 months
• if molecular response occurs quickly, good prognosis

Question 17

-

Answer 17

• degree of reduction in disease burden

- time to achieve it

Question 18

Why was the development of 2nd generation TKIs necessary?

Answer 18

some patients developed resistance to imatinib after an initial good effect
- 3nd generation TKI are more potent and achieve deeper response with possibly better long term survival

Question 19

How does resistance arise?

Answer 19

point mutations of bcr-abl that affect binding of imatinib to bcrabl

Question 20

What was the outcome of the trial of ruxolitinib for myelofibrosis?

Answer 20

increased quality of life
increased survival
not curative