Chronic Myeloid Leukaemia Flashcards
What is CML ?
Abnormal development of myeloid SC affects BM and blood with hypertrophy of spleen (splenomegaly) and liver with death due to suppurination / formation of pus in the blood
Who is most affected by CML?
Males, with peak age of diagnosis at 53. Rarely affects <20.
What are the RF for CML?
Radiation exposure
Philidelphia chromosome
What are the common signs and symptoms of CML?
Splenomegaly Fatigue Weight loss Night sweats Haemorrhage and easy bruising Gout Fever
What will a blood count show?
Anaemia, elevate WBCs and platelets
What will a blood film morphology show?
Immature immune cells - myelocytes and mature granulocytes
What will a BM diagnosis show from a trephine histology?
Immature myelocytes
If geneting testing is carried out what will it show?
Philidelphia chromosome - confirms diagnosis when presents with symptoms
What is the Philidelphia chromosome?
Translocation of ABL gene on chromsome 9 with BCR gene on chromosome 22. It leads to the generation of a chimeric protein BRC-ABL with TK activity. Responsible for the CML phenotype
What test can be done to confirm that BCR and ABL are fusing during metaphase?
FISH
Which form of the BCR-ABL protein is the most common?
p210
Also p190 and p230
What treatment can be given in CML?
Tyrosine Kinase Inhibitor to inhibit the function of the fusion gene by blocking its TK activity that is constitutively activated by the translocation. Allows long term survival but is not curative
How does Imatinib work?
Inhibits ATP binding within ABL TK domain, by binding into the ATP pocket itself. This prevents phosphorylation or target molecules and keeps BCR-ABL inactive.
What else can Imatinib inhibit?
PDGFR
How is Imatinib administered?
Orally and absorbed in GIT
How does TK activity lead to normal signalling?
When a substrate binds to RTK, it activates TK activity to autophosphorylate the tyrosine residues, creating a high affinity docking site for PI3 Kinase to initiates down stream signalling via PI3 kinase pathway for survival, growth and proliferation.
What is the only curable option of CML? Why is it not offered first line?
BM transplant but it comes with a high risk of mortality and requires a matched donor.
Only offered to young fit Pts.
Only 30% are eligible due to age, morbidity and donors.
How is prognosis predicted for CML patients?
Considers the degree of reduction and how quickly it was achieved.
Why are 2nd generation TKIs needed?
Pts can develop resistance to 1st line TKIs, so 2nd generation overcomes this resistance due to an increased potency. e.g. nilotinib
Why does resistance develop?
TKI creates a pressure on BCR-ABL and causes the development of new mutations that prevents Imatinib from binding to the ATP pocket.
In which Pts is resistance most likely to occur in?
Pts in a more progressed stage of cancer.
Why should be tried first before giving a second generation drug when resistance develops?
Increase the concentration of Imatinib.
What causes Philidelphia -ve myeloproliferative Neoplasia?
JAK2, MPL and CALP mutations
Where does JAK2 mutation occur and what does this cause?
On chromosome 9. It causes cancer of BM with excess RBC production and increased viscosity = POLYCYTHEMIA VERA
What does JAK2 normally do?
Mediates further downstream signalling
What can be used to treat myeloproliferative neoplasia?
JAK2 inhibitors e.g. Ruxolitinib
Shown to reduce splenomegaly in a few days and increase QoL and survival. Only controls, isn’t a cure.
