Chronic Leukaemia's

Question 1

what is the genetic abnormality in CML?

Answer 1

t(9;22) - philadelphia chromosome
BCR-ABL
- mutation codes for a tyrosine kinase able to autophosphorylate, up regulating the singling pathway for granulocyte production

Question 2

What is the treatment for CML?

Answer 2

Tyrosine Kinase inhibitors - Imatinib, dasatinib, nilotinib

Question 3

How do tyrosine kinase inhibitors work?

Answer 3

block the ATP binding pockets of the tyrosine kinase preventing phosphorylation and leading to cell death

Question 4

what is the natural history of CML?

Answer 4

triphasic illness

1. chronic phase with limited symptoms
2. acceleration phase
3. blast crisis

Question 5

How is the BCR-ABL fusion oncogene detected?

Answer 5

FISH
cytogenetics
reverse transcriptase PCR

Question 6

What are the frequent symptoms of CML?

Answer 6

fatigue
night sweats
malaise and weight loss
LUQ pain, discomfort, satiety
splenomegaly

Question 7

What diagnostic tests should be performed for CML?

Answer 7

FBC
- immature myelocytes, metamyelocytes, basophils and eosinophils
bone marrow - blasts, promyelocytes, myelocytes, eos, baso
cytogenetics
karyotyping
reverse transcriptase PCR

Question 8

What are the goals of treatment in CML?

Answer 8

1. Normalisation of the blood count - haematological remission
2. achieving Ph negativity - cytogenetic remission

Question 9

What are the main reasons for stopping therapy with TKI’s in CML?

Answer 9

1. primary resistance
   - absence of efficacy (rare)
2. acquired (secondary) resistance
   - loss of previously obtained responses
3. intolerance to drug

Question 10

What is the most common reason for TKI resistance?

Answer 10

point mutations in the ABL kinase domain resulting in decreased binding of TKI
- most common mutation is T3151 mutation

Question 11

What drugs are used to treat CML when there is Imatinib resistance?

Answer 11

second generation TKIs:

• dasatinib
• nilotinib
• bosutinib

benefits:
- equivalent efficacy to imatinib with reduced side effects
- effective in imatinib resistance

Question 12

What are the common side effects of TKIs?

Answer 12

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

Question 13

What are the other uses for Imatinib?

Answer 13

GIST tumours

hypereosinophilia with tyrosine kinase rearrangements

Question 14

What is the most common leukaemia?

Answer 14

CLL

Question 15

What is the median age of onset of CLL?

Answer 15

72 years

Question 16

What is the classic finding on a blood film in CLL?

Answer 16

smear cells

small mature lymphocytes

Question 17

What are the cytogenetic findings in CLL?

Answer 17

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

Question 18

What are poor prognostic features of CLL?

Answer 18

Pancytopenia

Rapid doubling time (

Question 19

What is the staging system for CLL?

Answer 19

Binet staging:
A: 100
- treatment not required

B: > 3 involved sites, Hb and plts > 100

C: Hb or plts

Question 20

When do you start treatment in CLL?

Answer 20

Stage B or development of B symptoms

Question 21

What is the treatment of CLL?

Answer 21

Rituximab + Fludrabine + Cyclophosphamide

Question 22

What are the complications of CLL?

Answer 22

Recurrent chest infections
-  Low immunoglobulins - can treat with IVIg but very expensive
Progressive cytopaenias
Immune thrombocytopenia
Autoimmune haemolysis

Question 23

What is hairy cell leukaemia?

Answer 23

a B cell leukaemia with pancytopenia, splenomegaly and no lymphadenopathy caused by a BRAF mutation

Question 24

What are the cytogenetic features of hairy cell leukaemia?

Answer 24

CD103+

also:
B cell leukaemia so: CD19, 20 +
CD25 + (IL-2 receptor)

Question 25

What is the treatment for hairy cell leukaemia?

Answer 25

7 day course of chlorodeoxyadenosine

Question 26

What is the 5 year survival in CML with treatment with TKIs?

Answer 26

90%

Question 27

What targets are monitored with TKI treatment?

Answer 27

monitor BCR-ABL every 3 months
- aim for 4.5 log reduction in BCR-ABL = “complete molecular response”

• likely to do poorly if BCR-ABL not reduced to 10% at 3 months
  “reduction to 10% at 3 months response”

Question 28

What are the side effects of Imatinib?

Answer 28

nausea
fluid retention
rash (can be severe)
diarrhoea
fatigue

Question 29

How do you overcome Imatinib resistance?

Answer 29

increase dose

switch to second generation TKI