11 CML: from chromosomes to targeted therapy

Question 1

What was the first targeted medication against a cancer?

Answer 1

Imatinib

Question 2

What 4 main types of chronic myeloproliferative diseases are there?

Answer 2

primary polycythaemia
Primary thrombocythaemia
Idiopathic myelofibrosis
chronic myeloid leukaemia

Question 3

What is primary polycythaemia?

Answer 3

too many red cells

Question 4

What is primary thrombocythaemia?

Answer 4

too many platelets

Question 5

What is idiopathic myelofibrosis?

Answer 5

too much marrow fibrosis

Question 6

What is chronic myeloid leukaemia?

Answer 6

too many neutrophils

Question 7

Which organs get big if you’ve got too many white cells?

Answer 7

liver and spleen

Question 8

What would CML have previously been treated with?

Answer 8

hydroxycarbamide

transplantation

Question 9

How can you spot CML on a blood film?

Answer 9

more white cexlls
multi-lobulated cells (neuttrophils)
more precursors
blasts (undifferentiated cells which turn into myeloid cells)

Question 10

What would you see in a bone marrow aspirate of someone with CML?

Answer 10

even more precursors than usual

perhaps more immature ones too

Question 11

What would be observed in bone marrow trephine histology of someone with CML?

Answer 11

only some fat lobules, with lots of precursors

Question 12

What chromosome is associated with CML?

Answer 12

Philadelphia chromosome
t(9;22) translocation
BCR:ABL keeps being made

Question 13

What is ABL?

Answer 13

tyrosine kinase

Question 14

How might you see BCR:ABL?

Answer 14

FISH

Question 15

How might CML present?

Answer 15

incidental blood count finding
bleeding problems (posterior eye)

Question 16

What is a normal white cell count?

Answer 16

4-8

Question 17

Name 2 odd symptoms people with CML might get

Answer 17

priapism

gout

Question 18

What is priapism?

Answer 18

very painful erection

Question 19

Why might those with CML get gout?

Answer 19

uric acid build up - DNA breakdown

Question 20

What tests might you do to diagnose CML?

Answer 20

blood count and film

Biochemistry

Question 21

What might blood count and film of someone with CML show?

Answer 21

elevated white cell count

low platelets and haemoglobin

Question 22

What might biochemistry of someone with CML show?

Answer 22

abnormal liver function
impaired renal function (raised urate)
raised lactate dehydrogenase (LDH)

Question 23

What molecular tests would you do to diagnose CML?

Answer 23

FISH (interphase or metaphase)

QPCR

Question 24

Once you treat the patient, you want ot know how much of the gene is still around. How would you test this?

Answer 24

Real time quantitative PCR

Question 25

What is the principe of real time quantitative PCR?

Answer 25

each time the gene is copied, the reporter flourophore is released, giving a signal

the intensity of the signal rises exponentially

compare with known gene (ABL) to know how much BCR/ABL you have

Question 26

Name 5 acute treatment options for CML

Answer 26

hydroxyurea
Leukapheresis
Allopurinol
IV fluids
Analgesia

Question 27

Name 3 types of chronic treatment for CML

Answer 27

Tyrosine kinase inhibitors
Intereron
Allogenic transplantation

Question 28

Name 5 Tyrosine kinase inhibitors

Answer 28

Imatinib
Dasatinib
Nilotinib
Bosutinib
Ponatinib

Question 29

What does leukofouresis do?

Answer 29

takes out blood, spins off white cells

puts everything else back

Question 30

What does allopurinol treat?

Answer 30

gout

Question 31

What does IV do here?

Answer 31

stops renal failure

Question 32

Why give analgesics to someone with CML?

Answer 32

their spleen will be quite painful

Question 33

How does imatinib work?

Answer 33

fits into the ATP binding pocket of BCR/ABL protein

Question 34

How well do patients have to comply to have an adquate response?

Answer 34

take drug >90% of time to get adequate response

Question 35

What is the most frequently reported mechanism of resistance to imatinib?

Answer 35

BCR/ABL mutations

Question 36

What is the most effective next generation BCR:ABL inhibitor?

Answer 36

Ponatinib

even effective against T315l mutations

Question 37

What do you do if the patient just isn’t respondig to normal treatment?

Why is this so difficult?

Answer 37

Haematopoietic SC transplant (post significant chemo and radiotherapy)

patients prone to bleeding, although once they’ve recovered 6 month to a year down the line you’re alright tbh

Question 38

Why are only 30% of patients eligible for HSCT?

Answer 38

age
morbidity
donor availability