CML

Question 1

Epidemology

Answer 1

• 1-2 in 100,000
• increases with age
• can occur n younger patients
  
  • very rate though

Question 2

Molecular Pathogenesis

Answer 2

• excess of myeloid cells
• primary polycythemia : too many red cells
• primary thrombocythemia: too many platelets
• idiopathic myelofibrosis: too much marrow fibrous
• CML: too much neutrophilss

Question 3

What would you see on CML blood film

Answer 3

• lots of neutrophils
• you do have some blasts
  
  • can have differentiating cells from the beginning to the neutrophils

Question 4

What is the Philadelphia chromosome

Answer 4

• all patients with CML will have a BCR-ABL translocation
• BCR chrsomone 22, and ABL on chromosome 9
  
  • these two bind together
  • these have tyrosine kinase activity which causes a proliferative effect

Question 5

how can we identify the philadelphia chromsome

Answer 5

can put fluorescent lobe on on BCR and the other on ABL

Question 6

What is the most common translation

Answer 6

common one is p210 break

Question 7

What are the clinical presentaions

Answer 7

• can be assymoptamtic
  
  • have routine blood counts, see white blood cell are high
  • can get high viscosity
    
    • get tired, bleeding in the retina, anaemic, infection, may get selenology

can get gout, because cells need to be broken down

Question 8

CML

What may you see on a blood count

Answer 8

• Blood count & film
  
  • Elevated White Cell Count
  • Low platelets & Haemoglobin

Question 9

What can you see on biochemistry

Answer 9

• Abnormal Liver Function can occur
• Impaired renal function - Raised urate → damages kidneys
• Raised Lactate Dehydrogenase (LDH)

Question 10

CML

What do you need to rule out

Answer 10

Need to exclude other causes e.g. bacterial infection, other malignancies

Question 11

Explain how PCR is used in CML

Answer 11

• primer at one end
  
  • one for BCR and ABL but near translation point
• heat DNA
• primers anneal on
• if primers re join
• can detect a small amount

Question 12

Why do we use PCR in CML

Answer 12

can use relatime quantitative PCR
allows you to see how much BCR/ABL there is

Question 13

What are the acute treatments of CML

Answer 13

Reduce WBC

• Hydroxycarbamide
  
  • Weak chemotherapy
• Leukapheresis
  
  • Removes WBCs

Prevent hyperuricaemia

• Gout
• Renal failure
• Allopurinol
• IV fluids

Analgesia

Question 14

CML

Chronic treatments

Answer 14

• Tyrosine kinase inhibitors
  
  • Imatinib
  • Dasatinib
  • Nilotinib
  • Bosutinib
  • Ponatinib
  • Asciminib
• interferons
• Allogeneic stem cell transplant
  
  • if this fails for patient can do this and don’t have to take treatment again

Question 15

Explain leukapheresis

Answer 15

take blood out, goes into machine, centrifuge, takes out white blood cells, bring it out

add citrate to keep anti-coagulant

Question 16

Imatinib

Answer 16

is a Tyrosine Kinase Inhibitor Potent inhibition of Abl-K, c-kit and PDGF-R
Salts are soluble in water
Oral bioavailable
Not mutagenic
Imatinib mesylate fits into the ATP binding pocket of BCR/ABL protein

Question 17

How does Imatinib work

Answer 17

BCR-ABL is a tyrosine kinase.
If you add a substate and ATP the substrate gets phosphorylated and ATP becomes ADP.
This then allows for downstream signalling e.g. PI3 kinase or RAS kinase etc.
Imatinib binds to ATP binding pocket of BCR-ABL – prevents phosphorylation of target molecules.
It Maintains BCR-ABL in inactive state and so cell dies.

Question 18

How do we monitor CML

Answer 18

• how big is the spleen is
• how big is the white count
• also look at response→ did white cells go back to normal in one month after treatment
• use PCR for alla that

• you need to take the drug over 90% of the time to get a good response
• if you take it 90% of the time less likely to achieve a major molecular response → which decreases the likelihood of leukemia

Question 19

CML treatment

drug mutations

Answer 19

• kinase domain mutations happen around 30-50% of the time
• can occur in the phosphorylation pocket
• can get resistance in other ways
  
  • may be downstream

Question 20

Can we cure CML

Answer 20

• when you get to the levels when BCR-ABL isn’t detectable, there’s still probably a few million cells cutting about
• if you give imanutib, they don’t grow but they are still there
• these drugs don’t cure leukaemia

• but when you stop the drug after few year
• 72% managed to stay of drugs for about MR4
  
  • called a treatment-free remission
    
    • just being followed up

Question 21

What can treat CML

Answer 21

Haematopoietic stem cells

Question 22

How would we use Haematopoietic stem cells to cure someone

so the process

Answer 22

• High dose (myeloablative) chemotherapy or chemo- radiotherapy for recipient –
• kills leukaemic cells and existing marrow components
  
  • called conditioning
• Re-infusion of haematopoietic stem cells
  
  • Autologous cells (collected if marrow not involved)
    
    • collected from yourself not really helpful
  • Allogeneic from HLA-matched donor (sibling or unrelated)
    
    • point is to recognise the leukaemia as foreign
    • some risk, vulnerable to infection

Question 23

What are the complications of stem cell therpay

Answer 23

• Extreme vulnerability to complications of infection,
• bleeding etc. Immunosuppressed.

Question 24

Around what percent of people are eligbale for HSCT and why

Answer 24

Only around 30% are eligbale for HSCT

• why
  
  • due to age, morbidity and donor avalibality