Chronic Myeloid Leukaemia Flashcards
CML is a disorder of late or early haematopoietic stem cell?
Late - small, mature but dysfunctional cells
What cells are in excess?
The myeloid lineage - especially granulocytes : neutrophils, basophils, eosinophils
CML is part of the chronic….. disorders
Myeloproliferative
Also includes: polycythemia Vera, ET, MMM
Is it more common in men or women?
Men
What age does it typically present?
50-60
What chromosome is present in more than 95% of those with CML?
The Philadelphia chromosome
Describe the pathophysiology
A translocation occurs between the long arm of chromosome 9 and 22 (a reciprocal translocation).
This results in the part of the ABL proto-oncogene from chromosome 9 being fused with the BCR gene from chromosome 22.
What does the result BCR-ABL fusion gene do?
Codes for a fusion protein which has tyrosine kinase activity in excess of normal.
The tyrosine kinase disrupts the cell- increase proliferation and reduces apoptosis
Chromosome 22 post translocation is called…
Philadelphia chromosome
What symptoms and signs occur in the chronic phase?
Weight loss Fever Night sweats Fatigue Splenomegaly Lymphadenopathy
What symptoms/signs are associated with the accelerated phase?
Anaemia - SOB Thrombocytopenia- bleeding Neutropenia - infections Extreme splenomegaly - abdominal pain Extreme pleocytosis (proliferation of malignant cells, can form thrombi)
Why can gout occur?
Due to increased purine breakdown (there is high cell turnover)
What different phases of the disease are there?
Chronic phase
Accelerated (aggressive phase)
Blast crisis
How long does the chronic phase last?
Months or years - few if any symptoms
What happens in the chronic phase?
There may be an increased WCC
Less than 10% of blast cells in blood
What happens in the accelerated phase?
More likely to find blast cells in the blood - approximately 10-20%
More systemic symptoms
What is the blast transformation?
When blood contains more than 20% blast cells
Features of leukaemia (70% transforms to AML, 30% to ALL)
Rapid progression to bone marrow failure - pancytopnia
Once patients reach this stage, mortality high
What does FBC show?
Extreme leukocytosis with whole spectrum of myeloid cells
Basophilia more prominent as disease progresses
Anaemia
Platelets variable (raised in accelerated and blast phase)
Describe the bone marrow biopsy
Hypercellular due to myeloid hyperplasia
Blasts less than 10%
What can be done to look for the cytogenetic abnormality?
Fluorescent in-site hybridisation (FISH)
What treatment is first line for chronic and accelerated phase ?
IMATINIB - a tyrosine kinase inhibitor
How does imatinib work?
A TK inhibitor - prevents action of the BCR-ABL fusion protein (the abnormal protein produced by the Philadelphia chromosome)
What side effects are associated with imatinib?
Usually well tolerated Nausea Headaches Oedema Rash Arthralgia
May cause myelosuppression
In the chronic phase, what percentage will respond to imatinib?
95%
In the blast phase is imatinib useful?
No - may benefit from treatment as for ALL
In the aggressive phase, can imatinib be used?
Yes - can put the disease back into chronic phase
In those who have a poor response to imatinib, what can be done?
Autologous transplant - some of patient’s own BM removed, screened for the disease and if suitable, the stem cells transplanted back.
Lower mortality compared to stem cell transplant from a donor
CML accounts for what percentage of leukaemias?
15%
