CML and Myeloproliferative Disorders

Question 1

What is polycythaemia?

Answer 1

Raised Hb concentration and raised haematocrit

Question 2

How can you classify polycythaemia?

Answer 2

Relative: caused by lack of plasma
True: excess of RBC with maintained/increased plasma volume

Question 3

How do you classify true polycythaemia ?

Answer 3

Primary - myeloproliferative neoplasm

Secondary - response to increased EPO

Question 4

What are causes of secondary polycythaemia?

Answer 4

Appropriate:

• high altitude
• hypoxic lung disease
• cyanotic heart disease
• high affinity Hb

Inappropriate

• Renal disease (cyst, tumour)
• Uterine myoma
• Other tumours (liver, lung)

Question 5

What are causes of myeloproliferative neoplasm ?

Answer 5

Ph-

• Polycythaemia vera
• Essential thrombocytopenia
• Primary myelofibrosis

Ph+
- CML

Question 6

What is the difference between myeloproliferative neoplasm and leukaemia in terms of diff/prolif?

Answer 6

myeloproliferative neoplasm: proliferation, but differentiation is maintained

Leukaemia: proliferation, loss of differentiation :((

Question 7

What is the normal role of tyrosine kinases?

Answer 7

Transmit cell growth signals from cell surface receptor to nucleus > PROMOTE GROWTH

Question 8

How are tyrosine kinases activated?

Answer 8

Activated by transferring phosphate groups to self and to downstream proteins

Question 9

What state are TKs normally held in?

Answer 9

Held tightly in INACTIVE state

Question 10

Which TK mutation is present in 100% of polycythaemia vera cases?

Answer 10

JAK2 gene mutation V617F

Question 11

What does JAK2 V617F mutation do?

Answer 11

It constitutively activates the JAK2 signalling pathway

So EPO is no longer required

Question 12

What are other gene mutations sometimes found in MPD?

Answer 12

Calreticulin mutation

Question 13

Which chromosome mutation occurs in chronic myeloid leukaemia?

Answer 13

Philadelphia chromosome (BCR-ABL gene)

Question 14

What is the presentation of CML?

Answer 14

Lethargy 
Hypermetabolism 
Thrombotic event (monoocular blindness, CVA)
Bruising, bleeding 
Massive splenomegaly/hepatomegaly

Question 15

What is FBC in CML?

Answer 15

Normal or raised Hb, platelets

Massive leukocytosis

Question 16

What does the blood firm look like in CML?

Answer 16

High neutrophils, basophils, myelocytes (not blast)

Question 17

What is the natural course of CML?

Answer 17

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

Question 18

What is the Philadelphia chromosome translocation?

Answer 18

Between 9 and 22

Question 19

Explain the two components of the Philadelphia fusion gene

Answer 19

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

Question 20

What are diagnostic techniques for fusion gene identification?

Answer 20

Karyotyping
FISH
RT-PCR (also useful to monitor response to therapy)

Question 21

What is the name of the TK inhibitor used to treat CML=

Answer 21

IMATINIB

Question 22

What are issues with TK inhibitor?

Answer 22

• Some pts fail to achieve complete cytogenetic response
• Non-compliance
• Side effects (fluid retention, pleural effusion)
• Loss of major molecular response (treatment resistance)

Question 23

What other treatment pathways exist if imatinib fails?

Answer 23

1. Switch 2nd/3rd gen TK inhibitor

2. Allogeneic stem cell transplant