Pathophysiology

CML is a myeloproliferative disease. It is a malignancy of the pluripotent haematopoietic stem cell, resulting in an increased number of granulocytes, and the presence of the Philadelphia chromosome.

 

The Philadelphia chromosome is formed due to a reciprocal translocation of the long arms of chromosomes 9 and 22. This results in the BCR-ABL gene, which produces a constitutively activated BCR-ABL protein. This protein has tyrosine kinase activity, which increases downstream signaling in myeloid lineage stem cells.

 

The Philadelphia chromosome is found in over 90% of CML patients, and a small subset in ALL patients.

 

It is important to understand the pathophysiology of the disease, as the treatment of CML is based on targeting the BCR-ABL tyrosine kinase protein.1,2

 

Epidemiology

CML is a relatively rare disease, with a frequency of 1.25 per 100,000. The median age of onset is 50 years.2

 

Natural History

The disease has 3 distinct phases: Chronic Phase (CP), Accelerated Phase (AP), and Blast Crisis (BC). Most patients (>85%) present in Chronic Phase.

 

Chronic phase is when there are no features of accelerated phase or blast crisis. Accelerated phase is characterized by blood counts and organomegaly being increasing resistant to treatment, and 10-19% blasts in the peripheral blood.  Blast crisis is characterized by more 20% or more blasts in the peripheral blood, extramedullary blasts, and large clusters of blasts in the bone marrow. Blast crisis is rapidly fatal.1,2  

 

Signs and Symptoms

30% of patients are asymptomatic and picked up on routine Full Blood Counts. Others may have:

• Fatigue

• Lethargy

• Weight Loss

• Sweats

• Splenomegay - this may cause abdominal discomfort, and early satiety

• Gout

• Easy bruising/ bleeding

• Lymphadenopathy is unusual1,2

 

Investigations

 

 

 

 

 

 

 

 

 

 

 

 

 

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Management

Tyrosine Kinase Inhibitors (TKIs)

Tyrosine Kinase Inhibitors (TKIs) are used to treat CML. There are many types, and they come in tablet form. Imatinib (Gleevec is the brand name) was the first of these TKIs. Other TKIs include dasatinib, ponatinib, nilotinib, and Bosutinib.

 

TKIs work by blocking the ATP binding site on BCR-ABL protein, thereby preventing further phosphorylation which is required for downstream signalling pathways.

 

Response to treatment is monitored by measuring haematological, molecular and cytogenetic response:

Haematological response: Full blood counts

Molecular response - MR:  BCR-ABL levels by PCR ,

Cytogenic response - CyR: Karyotyping to look for the number of metaphases which have the Ph chromosome

 

Allogenic stem cell transplantation is the only curative option, however this is offered only to younger patients as the procedure has lower mortality rates in children. For adults, guidelines suggest TKIs as first line.1,2

 

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For Further Interest

The discovery of the BCR-ABL Philadelphia chromosome is considered a revolutionary examplar of cancer management whereby knowledge of the causative genotype has led to targeted therapy.

 

Now, there are several ongoing trials for patients who have achieved Deep Molecular Response (DMR) for many years, to determine the safety of stopping treatment. In these trials, patients who meet strict criteria stop taking their TKI, and are regularly monitored for relapse. If relapse occurs, they are immediately started back on treatment. Studies have shown that response to treatment after stopping is still good.

 

STIM Trial: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(10)70233-3/fulltext

EUROSKI Trial: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30192-X/fulltext

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References

1. Tidy C. Chronic Myeloid Leukaemia [Internet]. Patient UK. 2016 [cited 9 March 2020]. Available from: https://patient.info/doctor/chronic-myeloid-leukaemia-pro#nav-6

2. Provan D, Dokal I, Vos J, Baglin T. Oxford Handbook of Clinical Haematology. 4th ed. Oxford: Oxford University Press; 2015.

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