Lecture 8 - Chronic Myeloid Leukaemia

Question 1

What is chronic myeloid leukaemia

Answer 1

• Over proliferation of cells committed to the myeloid lineage
  
  • Numerous granulocytic cells, including immature myeloid cells and band cells (immature neutrophils) The blood smear will change depending on what stage the patient is in.

Question 2

What is the incidence of CML

Answer 2

• Age is a risk factor for the development of CML
• Median age of onset - 57-60 years old
  *Sex balance - more common in males

Question 3

Describe the phases of CML

Answer 3

Chronic - 5-6 years - Mostly mature WBCs in blood and bone marrow. May be no symptoms of leukaemia. If not treated becomes accelerated.
Accelerated - 6-9 months - 5-30% of WBCs in blood and bone marrow are. Symptoms include fever, poor appetite and weight loss.
Blast - 3-6 months - Most WBCs in blood an d bone marrow are immature. Typical symptoms include anaemia and recurrent infections.
Blood films - more WBCs and less RBCs as develops.

Question 4

What is the clinical presentation of CML in the chronic stage?

Answer 4

Clinical presentation of Chronic Phase CML
* Asymptomatic in ~50% of cases
* Common symptoms: fatigue, weight loss/anorexia, abdominal fullness
* Common signs: palpable splenomegaly
Common lab findings: Leukocytosis (increased WBC count), Thrombocytopenia, Anaemia, Basophilia(excessive amounts of basophils.

Question 5

What is the genetic cause of CML?

Answer 5

Genetics of CML
Characterised by the Philadelphia chromosome resulting from the reciprocal translocation t(9;22)(q34;q11) Resulting in BCR/ABL oncogene.
* BCR = breakpoint cluster region; ABL1 = Abelson 1 kinase
* BCR/ABL fusion oncogene exist in 3 forms depending on the breakpoints on the BCR gene (mostly located in the M-BCR region.
* The BCR/ABL fusion oncogenes give rise to 3 distinct fusion proteins (p190, p210, p230 - numbers represent molecular weight) that contain the same ABL1 sequence but different portions of the BCR sequence
* The tyrosine kinase domain on the fusion protein is constitutively active (on all the time) - drives oncogene expression.
* Distinct by components of BCR gene expressed.

Question 6

How is oncogenic formation induced in CML.

Answer 6

STAT5 signalling
* In normal hematopoietic stem cells, JAK2 phosphorylates STAT5 at a tyrosine residue, following which STAT5 translocates to the nucleus to influence gene transcription.
* In CML cells, BCR_ABL phosphorylates STAT5 at the same tyrosine residue close, inducing the same downstream evens independently of JAK2 - bypass regulated system.
* The phosphate group is provided by ATP binding to the BCR-ABL protein.
* Ultimately, this increases cell proliferation and decreases apoptosis.

Question 7

How is CML treated and monitored.

Answer 7

Treatments for CML
Tyrosine kinase inhibitors (TKI) for CML treatment e.g. Imatinib - first line treatment
* Current TKIs are ATP mimetic compounds
* These compete with ATP for the ATP binding site at BCR-ABL1
* This prevents phosphorylation of protein substrates
* Therefore, oncogenic signalling pathways are no longer activated and the cell undergoes apoptosis.
Need to be careful when in remission

CML monitoring
* Haematologic responses - values from complete blood count
○ Complete haematological response when lab values return to normal levels
* Cytogenic response - evaluation of > 20 metaphases for the Ph+ (Philadelphia) chromosome in bone marrow samples
○ BCR?ABL fusion oncogene can be detected by karyotype and fluorescent in-situ hybridisation.
* Molecular responses - quantified by measuring the reduction in BCR-ABL1 mRNA transcripts relative to a standardised baseline using RT-qPCR

CML treatment monitoring
Cytogenetics - CCyR complete cytogenic remission = when )% Ph+ chromosomes rare in metaphase
Molecular responses - Useful for detecting residual disease following CCyR
* MMR - Major molecular response = 3 log reduction in BCR-ABL mRNA levels relative to baseline within 18 months of treatment
* CMR - Complete molecular response = 5 log reduction in BCR-AML mRNA levels relative to baseline
May not be looking for complete response due to side effects of second line TKI and patient circumstances.
Drugs don’t address underlying mutation - instead control and rebalance effects.