Chronic Leukaemia's Flashcards
what is the genetic abnormality in CML?
t(9;22) - philadelphia chromosome
BCR-ABL
- mutation codes for a tyrosine kinase able to autophosphorylate, up regulating the singling pathway for granulocyte production
What is the treatment for CML?
Tyrosine Kinase inhibitors - Imatinib, dasatinib, nilotinib
How do tyrosine kinase inhibitors work?
block the ATP binding pockets of the tyrosine kinase preventing phosphorylation and leading to cell death
what is the natural history of CML?
triphasic illness
- chronic phase with limited symptoms
- acceleration phase
- blast crisis
How is the BCR-ABL fusion oncogene detected?
FISH
cytogenetics
reverse transcriptase PCR
What are the frequent symptoms of CML?
fatigue night sweats malaise and weight loss LUQ pain, discomfort, satiety splenomegaly
What diagnostic tests should be performed for CML?
FBC
- immature myelocytes, metamyelocytes, basophils and eosinophils
bone marrow - blasts, promyelocytes, myelocytes, eos, baso
cytogenetics
karyotyping
reverse transcriptase PCR
What are the goals of treatment in CML?
- Normalisation of the blood count - haematological remission
- achieving Ph negativity - cytogenetic remission
What are the main reasons for stopping therapy with TKI’s in CML?
- primary resistance
- absence of efficacy (rare) - acquired (secondary) resistance
- loss of previously obtained responses - intolerance to drug
What is the most common reason for TKI resistance?
point mutations in the ABL kinase domain resulting in decreased binding of TKI
- most common mutation is T3151 mutation
What drugs are used to treat CML when there is Imatinib resistance?
second generation TKIs:
- dasatinib
- nilotinib
- bosutinib
benefits:
- equivalent efficacy to imatinib with reduced side effects
- effective in imatinib resistance
What are the common side effects of TKIs?
grade 2 adverse effects are often reasons for patient intolerance and poor compliance: - chronic fatigue - rash - myalgia - n & V - arthralgia grade 3/4 effects - change to another TKI: - cytopaenias - severe rash - liver toxicity
What are the other uses for Imatinib?
GIST tumours
hypereosinophilia with tyrosine kinase rearrangements
What is the most common leukaemia?
CLL
What is the median age of onset of CLL?
72 years
What is the classic finding on a blood film in CLL?
smear cells
small mature lymphocytes
What are the cytogenetic findings in CLL?
CD5 positive B cells
- CD5 is a T cell marker
so: CD 19, 20, 23 PLUS CD5
Ddx: Mantle cell lymphoma
- same cytogenetics BUT CD23 negative
What are poor prognostic features of CLL?
Pancytopenia
Rapid doubling time (
What is the staging system for CLL?
Binet staging:
A: 100
- treatment not required
B: > 3 involved sites, Hb and plts > 100
C: Hb or plts
When do you start treatment in CLL?
Stage B or development of B symptoms
What is the treatment of CLL?
Rituximab + Fludrabine + Cyclophosphamide
What are the complications of CLL?
Recurrent chest infections - Low immunoglobulins - can treat with IVIg but very expensive Progressive cytopaenias Immune thrombocytopenia Autoimmune haemolysis
What is hairy cell leukaemia?
a B cell leukaemia with pancytopenia, splenomegaly and no lymphadenopathy caused by a BRAF mutation
What are the cytogenetic features of hairy cell leukaemia?
CD103+
also:
B cell leukaemia so: CD19, 20 +
CD25 + (IL-2 receptor)
