CML Flashcards
Epidemology
- 1-2 in 100,000
- increases with age
- can occur n younger patients
- very rate though
Molecular Pathogenesis
- 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
What would you see on CML blood film
- lots of neutrophils
- you do have some blasts
- can have differentiating cells from the beginning to the neutrophils
What is the Philadelphia chromosome
- 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
how can we identify the philadelphia chromsome
can put fluorescent lobe on on BCR and the other on ABL
What is the most common translation
common one is p210 break
What are the clinical presentaions
- 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
CML
What may you see on a blood count
- Blood count & film
- Elevated White Cell Count
- Low platelets & Haemoglobin
What can you see on biochemistry
- Abnormal Liver Function can occur
- Impaired renal function - Raised urate → damages kidneys
- Raised Lactate Dehydrogenase (LDH)
CML
What do you need to rule out
Need to exclude other causes e.g. bacterial infection, other malignancies
Explain how PCR is used in CML
- 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
Why do we use PCR in CML
can use relatime quantitative PCR
allows you to see how much BCR/ABL there is
What are the acute treatments of CML
Reduce WBC
- Hydroxycarbamide
- Weak chemotherapy
- Leukapheresis
- Removes WBCs
Prevent hyperuricaemia
- Gout
- Renal failure
- Allopurinol
- IV fluids
Analgesia
CML
Chronic treatments
- 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
Explain leukapheresis
take blood out, goes into machine, centrifuge, takes out white blood cells, bring it out
add citrate to keep anti-coagulant
Imatinib
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
How does Imatinib work
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.
How do we monitor CML
- 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
CML treatment
drug mutations
- 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
Can we cure CML
- 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
- called a treatment-free remission
What can treat CML
Haematopoietic stem cells
How would we use Haematopoietic stem cells to cure someone
so the process
- 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
- Autologous cells (collected if marrow not involved)
What are the complications of stem cell therpay
- Extreme vulnerability to complications of infection,
- bleeding etc. Immunosuppressed.
Around what percent of people are eligbale for HSCT and why
Only around 30% are eligbale for HSCT
- why
- due to age, morbidity and donor avalibality
