CML and Myeloproliferative Disorders Flashcards
What is polycythaemia?
Raised Hb concentration and raised haematocrit
How can you classify polycythaemia?
Relative: caused by lack of plasma
True: excess of RBC with maintained/increased plasma volume
How do you classify true polycythaemia ?
Primary - myeloproliferative neoplasm
Secondary - response to increased EPO
What are causes of secondary polycythaemia?
Appropriate:
- high altitude
- hypoxic lung disease
- cyanotic heart disease
- high affinity Hb
Inappropriate
- Renal disease (cyst, tumour)
- Uterine myoma
- Other tumours (liver, lung)
What are causes of myeloproliferative neoplasm ?
Ph-
- Polycythaemia vera
- Essential thrombocytopenia
- Primary myelofibrosis
Ph+
- CML
What is the difference between myeloproliferative neoplasm and leukaemia in terms of diff/prolif?
myeloproliferative neoplasm: proliferation, but differentiation is maintained
Leukaemia: proliferation, loss of differentiation :((
What is the normal role of tyrosine kinases?
Transmit cell growth signals from cell surface receptor to nucleus > PROMOTE GROWTH
How are tyrosine kinases activated?
Activated by transferring phosphate groups to self and to downstream proteins
What state are TKs normally held in?
Held tightly in INACTIVE state
Which TK mutation is present in 100% of polycythaemia vera cases?
JAK2 gene mutation V617F
What does JAK2 V617F mutation do?
It constitutively activates the JAK2 signalling pathway
So EPO is no longer required
What are other gene mutations sometimes found in MPD?
Calreticulin mutation
Which chromosome mutation occurs in chronic myeloid leukaemia?
Philadelphia chromosome (BCR-ABL gene)
What is the presentation of CML?
Lethargy Hypermetabolism Thrombotic event (monoocular blindness, CVA) Bruising, bleeding Massive splenomegaly/hepatomegaly
What is FBC in CML?
Normal or raised Hb, platelets
Massive leukocytosis
What does the blood firm look like in CML?
High neutrophils, basophils, myelocytes (not blast)
What is the natural course of CML?
First 5 years: disease is in chronic phase, meaning that cells proliferate but maintain ability to differentiate
Accelerated phase: loss of ability of cells to fully differentiate
Blast crisis > DEATH
What is the Philadelphia chromosome translocation?
Between 9 and 22
Explain the two components of the Philadelphia fusion gene
BCR = housekeeping gene, tightly expressed ABL = tyrosine kinase, normally very tightly regulated
SO: BCR-ABL means that the gene is constitutively activated, driving uncontrollable replication
What are diagnostic techniques for fusion gene identification?
Karyotyping
FISH
RT-PCR (also useful to monitor response to therapy)
What is the name of the TK inhibitor used to treat CML=
IMATINIB
What are issues with TK inhibitor?
- Some pts fail to achieve complete cytogenetic response
- Non-compliance
- Side effects (fluid retention, pleural effusion)
- Loss of major molecular response (treatment resistance)
What other treatment pathways exist if imatinib fails?
- Switch 2nd/3rd gen TK inhibitor
2. Allogeneic stem cell transplant
