Chronic Myeloid Leukaemia

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Chronic myeloid leukaemia\: cancer of white blood cells with uncontrolled growth of myeloid cells, crowding out bone
marrow, interfering with normal blood cell production, and causing raised levels of mature granulocytes.
Pathophysiology\: caused by translocation between chromosomes 9 and 22, forming the Philadelphia chromosome and
BCR-ABL gene, which speeds up cell division and inhibits DNA repair.
Symptoms\: often asymptomatic, may include upper abdominal pain, poor appetite, low-grade fever, night sweats, gout,
increased infections, shortness of breath, fatigue, bruising, petechiae, bleeding, neurological de
Clinical
Investigations\: FBC (leucocytosis, increased eosinophils/basophils/granulocytes, anaemia), U&Es, lactate dehydrogenase,
urate, peripheral blood
via FISH/PCR.
Phases\: Chronic (85% at diagnosis, mild/asymptomatic), Accelerated (10-19% myeloblasts, >20% basophils, platelet
abnormalities, cytogenetic evolution, unresponsive splenomegaly/WBC count), Blast crisis (>20% blasts, clusters of blasts,
chloroma).
Management\: tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib) targeting BCR-ABL, blocking phosphorylation of
tyrosine, inhibiting cell proliferation; bone marrow transplantation for those unresponsive to drug treatments, mainly
younger, healthier patients due to serious risks.
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Introduction

Chronic myeloid leukaemia (CML) is a cancer of white blood cells that is characterised by the uncontrolled growth of
myeloid cells in the bone marrow.
This uncontrolled growth leads to myeloid cells crowding out the bone marrow and interfering with the production of
normal blood cells such as platelets, erythrocytes and neutrophils.
In addition to crowding out the bone marrow, the abnormal myeloid cells spill into the peripheral blood. This is re
the full blood count which demonstrates abnormally raised levels of mature granulocytes (neutrophils, basophils and
eosinophils).
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Aetiology

Pathophysiology
CML was the
This abnormality involves a translocation between parts of chromosome 9 and 22, which leads to the formation of the so-
called Philadelphia chromosome.As a result, a gene contained on chromosome 22 called BCR fuses with a gene on chromosome 9 known as ABL. This
creates a hybrid gene known as BCR-ABL.
BCR-ABL can add phosphates to tyrosine residues (a tyrosine kinase) and this allows the gene to activate a cascade of
proteins that control the cell cycle, speeding up cell division.
In addition, the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to
developing further genetic abnormalities.
These two mechanisms (speeding cell division and inhibiting DNA repair) lead to the development of chronic myeloid
leukaemia.
Figure 1. Translocation leading to the BCR-ABL gene fusion.

Clinical features

History
Patients are often asymptomatic when diagnosed with CML, presenting incidentally with an elevated white blood cell
count on a full blood count.
Typical symptoms (if present) of CML include\:
Upper abdominal pain\: due to hepatosplenomegaly
Poor appetite\: an enlarged spleen may compress the stomach
Low-grade fever/night sweats ("B symptoms")
Gout\: increased cell turnover → excess purines → broken down to uric acid
Increased susceptibility to infections\: decreased functional immune cells
Shortness of breath/fatigue\: anaemia
Easy bruising/petechiae/bleeding\: low platelets
Neurological de
Typical clinical
Pallor
Hepatosplenomegaly
Bruising/petechiaeInvestigations
Laboratory investigations
Relevant laboratory investigations include\:
Full blood count\: leucocytosis, increased numbers of eosinophils and basophils, increased granulocytes, anaemia
(normocytic/normochromic)
U&E\: usually normal, useful for a baseline prior to treatment
Lactate dehydrogenase\: may be raised
Urate\: may be raised due to high cell turnover
Peripheral blood
aspirate.
Bone marrow aspirate
Bone marrow aspiration is necessary to stage disease (% of blasts determines chronic vs accelerated vs blast crisis) and
enables cytogenetic sampling to con
The gold standard of diagnosis is the detection of the Philadelphia chromosome, which is present in 95% of people with
CML.
Methods for identifying the Philadelphia chromosome include FISH (
ABL gene.
Phases of CML
The World Health Organisation (WHO) has developed criteria to de
¹
Chronic phase
Approximately 85% of patients with CML are in the chronic phase at the time of diagnosis.
²
During this phase, patients are usually asymptomatic or have only mild symptoms of fatigue or abdominal fullness.
The duration of the chronic phase is variable and without treatment, the disease will usually progress to the accelerated
phase due to the accumulation of genetic mutations in addition to the BCR-ABL gene.
²
Accelerated phase
A patient is said to be in the accelerated phase when any of the following are present\:
10 - 19% myeloblasts in the blood or bone marrow
>20% basophils in the blood or bone marrow
Platelet count \<100,000, unrelated to therapy
Platelet count >1,000,000, unresponsive to therapy
Cytogenetic evolution with new abnormalities in addition to the Philadelphia chromosome
Increasing splenomegaly or white blood cell count, unresponsive to therapy
This phase is signi
²
Blast crisis
survival.
Blast crisis is the
Blast crisis is diagnosed if any of the following are present in a patient with CML\:
>20% myeloblasts or lymphoblasts in the blood or bone marrow
Large clusters of blasts in the bone marrow on biopsy
Development of a chloroma (a solid focus of leukaemia outside the bone marrow)

Management

Tyrosine kinase inhibitorsTyrosine kinase inhibitors target BCR-ABL, blocking the ability of the gene to phosphorylate a tyrosine. This inhibits the
proliferation of malignant cells.
Imatinib is a
second-generation drugs including nilotinib and dasatinib.
Bone marrow transplantation
Bone marrow transplantation is a treatment option for those who do not respond well to drug treatments.
This tends only to be used in younger, otherwise healthy patients.
It does o
suitable for many patients.

References

Vardiman J, Harris N, Brunning R (2002). The World Health Organization (WHO) classi
B l o o d 100 (7)\: 2292–302. Available from\: [LINK]
Classi
. Hematology Am Soc
Hematol Educ Program 2006\: 240–5.

Related notes

Acute Myeloid Leukaemia
Anaemia Overview
Disseminated Intravascular Coagulation (DIC)
Haemolytic anaemia
Haemophilia

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Contents

Introduction
Aetiology
Clinical features
Investigations
Management
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