LEUKAEMIAS
Chronic myeloid
leukaemia
Katharine Hanlon
Mhairi Copland
Abstract
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disor-
der resulting from a reciprocal translocation between the long arms of
chromosomes 9 and 22. This is termed the Philadelphia chromosome,
and leads to production of the fusion onco-protein BCR-ABL, a 210
kDa constitutively active tyrosine kinase. CML has three distinct
phases: the chronic, accelerated and blast phases. Most patients
(85%) present in the chronic phase, which is associated with leucocy-
tosis and splenomegaly. More advanced phases are associated with
bone marrow failure and carry a poor prognosis. The introduction of
tyrosine kinase inhibitors (TKIs; imatinib, dasatinib, nilotinib, bosutinib,
ponatinib) has altered the clinical course of CML for most patients,
turning it from a fatal leukaemia to a chronic disorder managed with
oral medication. Patients with chronic-phase CML have excellent
levels of response to TKIs, and individuals with an optimal response
can expect a normal lifespan. However, resistance to TKIs is seen,
particularly in the advanced phases of CML. In these patients, alloge-
neic stem cell transplantation may warrant consideration. With
increasing experience in the use of TKIs, different adverse effect pro-
files are emerging and require consideration when choosing the most
suitable TKI for an individual patient.
Keywords Allogeneic stem cell transplantation; BCR-ABL; chronic
myeloid leukaemia; dasatinib; imatinib; nilotinib; Philadelphia chro-
mosome; ponatinib; quantitative RT-PCR; tyrosine kinase inhibitors
Introduction
Chronic myeloid leukaemia (CML) is a myeloproliferative
neoplasm characterized by an excess of granulocytes (neutro-
phils, basophils, eosinophils). It is a clonal disorder that origi-
nates from a bone marrow haemopoietic stem cell. The
characteristic and diagnostic genetic abnormality in CML is the
Philadelphia chromosome.
Katharine Hanlon MB ChB BSc MRCP FRCPath is a Haematology
Registrar at the Queen Elizabeth University Hospital, Glasgow,
Scotland, UK. Competing interests: KH received travel
reimbursement and a speaker fee for presenting at an educational
meeting sponsored by Shire Pharmaceuticals in March 2015.
Mhairi Copland BSc (Hons) MB ChB PhD FRCP FRCPath is Professor of
Translational Haematology at the University of Glasgow and
Honorary Consultant Haematologist at the Beatson West of Scotland
Cancer Centre, Glasgow, UK. Competing interests: MC has received
research funding from Novartis and Bristol-Myers Squibb, is an
advisory board member for Bristol-Myers Squibb, Novartis, Ariad and
Pfizer, has received honoraria from Bristol-Myers Squibb, Novartis,
Ariad and Pfizer, and has received support for travel accommodation
and registration fees to attend conferences from Bristol-Myers
Squibb and Novartis.
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Please cite this article in press as: Hanlon K, Copland M, Chronic myeloid leukaemia, Medicine (2017), http://dx.doi.org/10.1016/
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Key points
C Chronic myeloid leukaemia (CML) is a clonal myeloproliferative
disorder associated with the Philadelphia chromosome and its
onco-protein product, BCR-ABL
C CML has three progressively more aggressive phases: chronic,
accelerated and blast phases
C Tyrosine kinase inhibitors (TKIs) have revolutionized the
treatment of CML and are the gold standard therapy for
chronic-phase CML
C Co-morbidities should be considered when choosing the most
appropriate TKI for a patient
C Allogeneic stem cell transplantation should be considered for
patients failing two or more TKIs or who have advanced-phase
CML
C Selected patients have successfully stopped TKIs in clinical
trials
Epidemiology
CML has a worldwide annual incidence of 1e1.5 cases per
100,000 population. It can occur at any age, but half of cases are
diagnosed in people >65 years of age. There is a slight male
predominance and a higher incidence among those with radia-
tion exposure.
Pathology and pathogenesis
The presence of the Philadelphia chromosome results in the fusion
oncogene BCR-ABL owing to the juxtaposition of the 30 portion of
the Abelson (ABL) gene from the long arm of chromosome 9 with
the 50 portion of the breakpoint cluster region (BCR) on the long arm
of chromosome 22 (Figure 1, left panel). The resulting constitu-
tively active tyrosine kinase, BCR-ABL, is a 210 kDa protein
essential for the unregulated proliferation of myeloid cells charac-
teristic of CML. With disease progression, additional cytogenetic
abnormalities can develop, as well as mutations of the BCR-ABL
kinase domain, which are associated with treatment resistance.
Disease course
CML is divided into three phases: the chronic, accelerated and
blast phases (Table 1). Approximately 85% of CML patients are
diagnosed in the chronic phase, and 15% in the more aggressive
accelerated or blast phases. Blast-phase CML can be lymphoid or
myeloid and behaves as a poor-prognosis acute leukaemia with
frequent and rapid development of fatal treatment resistance.
Historically, CML had a median survival of 5e7 years. How-
ever, the introduction of BCR-ABL tyrosine kinase inhibitors
(TKIs; e.g. imatinib) has revolutionized its treatment. The 5-year
overall survival in the chronic phase is 92e95%,2 and life ex-
pectancy approaches that of the general population (see Bower
et al. in Further Reading). The outcome in blast-phase CML
1 Ó 2017 Published by Elsevier Ltd.
 LEUKAEMIAS

The pH chromosome
9 9q+
24
2
21
13
1
22q
1 12 Philadelphia
22 chromosome
21
2 1 12
22
31 11 Bcr-Abl
1 fusion protein
3
34 13

Figure 1 Characteristic features of CML. Left: the Philadelphia (Ph) chromosome; right: blood film from a patient with chronic-phase CML,
demonstrating neutrophilia, basophilia and left shift with frequent myelocytes and metamyelocytes.

remains very poor, with a median survival of 7e11 months
despite multiple aggressive therapies.
Diagnosis
Approximately 30% of patients with CML are asymptomatic, the
diagnosis being made following an incidental finding of leucocy-
tosis on a full blood count. Symptoms at presentation are often non-
specific and include fatigue, night sweats, weight loss, abdominal
discomfort as a result of splenomegaly (present in 50e90% patients
at diagnosis) or splenic infarction, spontaneous bleeding or
Criteria required for the diagnosis of chronic, accelerated
and blast-phase CML according to the World Health
Organization (WHO) classification1
Phase WHO diagnostic criteria
Chronic phase Absence of all features listed below
Accelerated phase One or more of the following features:
C Blasts comprise 10e19% of peripheral
blood white cells or nucleated bone
marrow cells
C Peripheral blood basophilia of 20% of
peripheral blood white cells or nucle-
ated bone marrow cells
C Persistent thrombocytopaenia (<100 
109/litre) unrelated to therapy, or
persistent thrombocytosis (>1000 
109/litre) unresponsive to therapy
C Increasing spleen size and white cell
count unresponsive to therapy
C Cytogenetic clonal evolution
Blast phase One or more of the following features:
C Blasts 20% of peripheral blood white
cells or nucleated bone marrow cells
C Extramedullary blast proliferation
C Large foci or clusters of blasts in a bone
marrow biopsy
Table 1
bruising. Patients presenting with very high white cell counts (>100
 109/litre) can have symptoms associated with leucostasis,
including headaches, visual disturbance, dyspnoea and priapism.
Investigations
In CML, the white cell count at diagnosis can range from 15 
109/litre to >200  109/litre. Very high white cell counts are often
associated with symptoms; thrombocytosis can also be a feature.
The blood film shows characteristic features, with expansion of
all types of myeloid cells including neutrophils, basophils, eo-
sinophils and their precursors (Figure 1, right panel). Nucleated
red cells are often seen. A bone marrow aspirate taken during the
chronic phase demonstrates a hypercellular marrow with
myeloid hyperplasia and an increased myeloid:erythroid ratio.
The percentage of blasts in the peripheral blood and bone marrow
is crucial for staging CML (Table 1). A bone marrow trephine
sample shows a packed marrow, and fibrosis can be a feature.
Fluorescence in situ hybridization or cytogenetics on a bone
marrow specimen reveals the Philadelphia chromosome. The
BCR-ABL fusion gene is demonstrated by qualitative polymerase
chain reaction (PCR) of peripheral blood mononuclear cells.
Differential diagnosis
 Acute myeloid leukaemia
 Acute lymphoblastic leukaemia
 Chronic neutrophilic leukaemia
 Myelofibrosis
 Granulocyte-colony stimulating factor (GCSF) therapy
 Severe sepsis
 Chronic eosinophilic leukaemia
 Essential thrombocytosis
 Bone marrow infiltration with non-haematological
malignancy.
Management
Patients presenting with a very high white cell count may require the
cytoreductive agent hydroxycarbamide and leucapheresis to rapidly
reduce the white cell count until the diagnosis has been confirmed.

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j.mpmed.2017.02.004
 LEUKAEMIAS
Since imatinib mesylate was licensed in 2001, TKIs have become the
mainstay of therapy for patients with all phases of CML, and the gold
standard therapy for chronic-phase disease. The European Leuke-
miaNet has developed comprehensive guidelines making recom-
mendations for therapy and monitoring response in CML.3
All currently available TKIs (imatinib, dasatinib, nilotinib,
bosutinib, ponatinib) inhibit BCR-ABL by occupying the ATP-
binding pocket of the kinase domain, preventing phosphoryla-
tion of downstream effector molecules. Nilotinib is a more potent
(30e50) and selective TKI with a much higher affinity than
imatinib for BCR-ABL1. Dasatinib is >300-fold more potent than
imatinib and has activity against the SRC family of kinases as
well as BCR-ABL.
TKIs are metabolized via the cytochrome P450 isoenzyme
CYP3A4. Care needs to be taken when prescribing other drugs
that are CYP3A4 inhibitors or inducers as TKI concentrations can
be significantly increased, resulting in toxicity, or reduced,
resulting in treatment failure.
Therapeutic monitoring
The aim of treatment is to induce haematological, cytogenetic
and molecular remission. Full blood counts should be performed
fortnightly until haematological remission is obtained. Three-
monthly bone marrow aspirates can be taken to monitor the
cytogenetic response, although this has largely been replaced by
three-monthly assessment of BCR-ABL1 by quantitative real-time
(qRT)ePCR of peripheral blood mononuclear cells.
An optimal cytogenetic response is defined as 35% Philadel-
phia chromosome after 3 months and 0% (complete cytogenetic
response (CCyR)) after 6 months of treatment. Detectable Phila-
delphia chromosome after 12 months of treatment means the
treatment has failed. qRT-PCR is much more sensitive and can detect
very small amounts of BCR-ABL1 (sensitivity 4e5 log reduction in
transcript levels from baseline). In newly diagnosed chronic-phase
CML, the aim of therapy is to achieve a major molecular response
(MMR; <0.1% BCR-ABL1:control gene) within 12 months of
commencing TKI therapy. This is considered an optimal response;
patients who achieve MMR have a better long-term outcome.
Comparison of the adverse effect profiles of different TKIs
Adverse effect Imatinib Nilotinib
Myelosuppression þ þ
Transaminitis þ þ
Fluid retention þ þ
Hepatitis B reactivation þ þ
QT prolongation þþ
Cardiovascular events þ þ
Peripheral vascular disease þþ
Cardiac failure
Pleural effusions
Diarrhoea
Elevated lipase þþ
Pulmonary artery hypertension
Hyperglycaemia þ
Elevated lipids þ
Table 2
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Management of chronic-phase CML
TKIs currently available for first-line therapy of chronic-phase
CML are imatinib, nilotinib and dasatinib. Imatinib is
commenced at a dose of 400 mg once daily. After 12 months of
treatment, the seminal IRIS (International Randomized IFN vs
STI571) trial reported a CCyR rate of 69% with imatinib.2
More recent clinical trials comparing imatinib with either
nilotinib (ENESTnd (Evaluating Nilotinib Efficacy and Safety in
Clinical Trials eNewly Diagnosed Patients); imatinib 400 mg
once daily versus nilotinib 300 mg twice daily or 400 mg twice
daily)4 or dasatinib (DASISION; Dasatinib Versus Imatinib Study
in Study in Treatment-Naive CML Patients; imatinib 400 mg once
daily versus dasatinib 100 mg once daily)5 have shown that
these more potent, second-generation TKIs have superior CCyR
and MMR (46% for nilotinib versus 28% for imatinib, and 55%
for dasatinib versus 28% for imatinib) rates to imatinib. How-
ever, despite more rapid and deeper molecular responses, this
has not translated into improved overall survival. Furthermore,
these more potent TKIs have different adverse effect profiles
(Table 2). Full compliance with TKI therapy is essential to obtain
an optimal response. Recent clinical trials have shown that a
proportion of chronic-phase patients with very low or unde-
tectable levels of BCR-ABL transcripts can successfully stop TKI
therapy.
In patients who lose MMR, a kinase domain mutation screen
should be performed to identify resistant mutations and guide
subsequent therapy. Depending on the mutational analysis,
adverse effect profile and first-line TKI used, nilotinib, dasatinib,
bosutinib or ponatinib can be considered for second line therapy.
The third-generation TKI ponatinib is the only TKI effective
against the T315I kinase domain mutation.
Patients failing to respond to treatment with available TKIs
should be considered for allogeneic stem cell transplantation
(alloSCT), providing they can tolerate the procedure and have a
suitable donor. AlloSCT is associated with significant morbidity
and mortality for many patients, especially older or frail in-
dividuals, but is curative in approximately 70% of patients in the
chronic phase.
Dasatinib Bosutinib Ponatinib
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þþ
þþ
þ þ
þþ þ þ
þþ
þ þþ
þ
3 Ó 2017 Published by Elsevier Ltd.
 LEUKAEMIAS
Management of advanced-phase CML
Patients with accelerated-phase CML are treated as for chronic-
phase disease, but if they do not achieve optimal treatment
milestones, they should proceed to alloSCT, if appropriate, at the
earliest opportunity.3 Patients with blast-phase CML often have a
transient haematological response to imatinib alone (50e70% of
patients), with cytogenetic response rates <20%. Patients often
require intensive acute myeloid leukaemia-type chemotherapy
such as FLAG-Ida (fludarabine, cytarabine, idarubicin and GCSF)
in combination with a TKI. Patients with blast-phase disease who
achieve a response (return to chronic phase or better) should
proceed immediately to alloSCT if appropriate.
Prognosis
Patients who have an optimal response to a TKI can expect a
normal life expectancy. In patients with a CCyR or MMR, the risk of
blast phase is 2.1% in the first year and <1% per year thereafter.2
Despite the introduction of TKIs, the outcome for blast-phase CML
remains poor, with an overall survival of <20% at 2 years. A Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponatinib in
KEY REFERENCES
1 Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the
World Health Organization (WHO) classification of myeloid neo-
plasms and acute leukemia: rationale and important changes.
Blood 2009; 114: 937e51.
2 Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of
patients receiving imatinib for chronic myeloid leukemia. New Engl
J Med 2006; 355: 2408e17.
TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.
Question 1
A 69-year-old man presented with blurred vision and head-
aches. He had no significant past medical history.
Clinical examination was normal.
Investigations
 Haemoglobin 100 g/litre (130e180)
 White cell count 416  109/litre (4.0e11.0)
 Neutrophils 140  109/litre (1.5e7.0)
 Myelocytes 110  109/litre
 Promyelocytes 80  109/litre
 Blasts 47  109/litre
 Lymphocytes 22  109/litre (1.5e4.0)
 Basophils 10  109/litre (<0.1)
 Eosinophils 7  109/litre (0.04e0.40)
 Platelets 1150  109/litre (150e400)
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Please cite this article in press as: Hanlon K, Copland M, Chronic myeloid leukaemia, Medicine (2017), http://dx.doi.org/10.1016/
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3 Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet
recommendations for the management of chronic myeloid leuke-
mia: 2013. Blood 2013; 122: 872e84.
4 Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and
risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in
chronic phase: 5-year update of the randomized ENESTnd trial.
Leukemia 2016; 30: 1044e54.
5 Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results
of DASISION: the dasatinib versus imatinib Study in treatment-
naive chronic myeloid leukemia patients trial. J Clin Oncol 2016; 34:
2333e40.
FURTHER READING
Apperley JF. Chronic myeloid leukaemia. Lancet 2015; 385: 1447e59.
Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC,
Andersson TM. Life expectancy of patients with chronic myeloid
leukemia approaches the life expectancy of the general population.
J Clin Oncol 2016; 34: 2851e7.
Philadelphia chromosome-positive leukemias. New Engl J Med
2013; 369: 1783e96.
Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in pa-
tients with chronic myeloid leukaemia who have maintained com-
plete molecular remission for at least 2 years: the prospective,
multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010; 11:
1029e35.
Steegmann JL, Baccarani M, Breccia M, et al. European LeukemiaNet
recommendations for the management and avoidance of adverse
events of treatment in chronic myeloid leukaemia. Leukemia 2016;
30: 1648e71.
What is the most likely diagnosis?
A. Acute myeloid leukaemia
B. Acute lymphoblastic leukaemia
C. Chronic myeloid leukaemia e accelerated phase
D. Chronic myeloid leukaemia e blastic crisis
E. Chronic myeloid leukaemia e chronic phase
Question 2
A 75-year-old woman presented with a 3-week history of short-
ness of breath. She had previously been found to have chronic
myeloid leukaemia, which had been treated with dasatinib for 6
months. She had a history of a myocardial infarction. She also
had a 30 packeyear history of smoking.
On examination, there were dullness and diminished breath
sounds at the base of the right lung.
4 Ó 2017 Published by Elsevier Ltd.
 LEUKAEMIAS

Investigations because of adverse effects. Within 1 year of starting treatment, he

 Full blood count was normal was in a molecular remission (BCR-ABL <0.01%). He was
 Chest X-ray showed a right-sided pleural effusion compliant with nilotinib.

Investigations
What is the most likely mechanism for the effusion?
 Full blood count was normal
A. Leukaemic involvement of the pleura
 Recent BCR-ABL1 transcript levels 5% and 12%
B. Ischaemic cardiomyopathy
 Development of T315I mutation confirmed
C. Fluid overload
D. Lung infarction
E. Adverse drug reaction What is the next most appropriate management change?
A. Change nilotinib to bosutinib
B. Change nilotinib to ponatinib
Question 3
C. Increase the dose of nilotinib
A 46-year-old man had been diagnosed with chronic myeloid D. Intensive acute myeloid leukaemia-type chemotherapy
leukaemia in chronic phase 2 years previously. Initial treatment E. Allogeneic haemopoietic stem cell transplantation
was with imatinib, changed to nilotinib 300 mg twice daily

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Please cite this article in press as: Hanlon K, Copland M, Chronic myeloid leukaemia, Medicine (2017), http://dx.doi.org/10.1016/
j.mpmed.2017.02.004