Leucemia Mieloide Cronica

1. Chronic myeloid leukaemia
Hugues de Lavallade
LEUKAEMIAS
Abstract
Chronic myeloid leukaemia (CML) is a clonal disorder in which cells of
the myeloid lineage undergo inappropriate clonal expansion, caused by
a BCReABL1 fusion gene resulting from a balanced translocation between
the long arms of chromosomes 9 and 22, t(9;22)(q34;q11), also known as
the Philadelphia (Ph) chromosome. The resulting fusion protein BCReABL
is a cytoplasmic oncoprotein of 210 kDa with constitutively activated tyro-sine
kinase responsible for the clinical features of CML. The disease typi-cally
progresses through three distinct phases e chronic phase,
accelerated phase, and blast crisis e during which the leukaemic clone
progressively loses its ability to differentiate. Imatinib (a tyrosine kinase
inhibitor; TKI) induces a complete cytogenetic response (CCyR) in about
70% of patients and the median survival in chronic phase is estimated
at 25e30 years. Compared with imatinib, second-generation TKIs induce
higher rates of response as initial treatment and have also proved useful
as second-line therapy, with approximately 50% of imatinib-resistant pa-tients
achieving a CCyR. Patients who fail treatment with available TKIs or
with advanced phase disease who have return to chronic phase (‘second’
CP) should be treated with an allogeneic stem cell transplantation,
providing that they can tolerate the procedure and have a donor.
Keywords BCReABL1 fusion gene; chronic myeloid leukaemia; CML;
dasatinib; imatinib; nilotinib; Philadelphia chromosome; tyrosine kinase
inhibitors
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative
neoplasm originating from a single pluripotent haematopoietic
stem cell, in which cells of the myeloid lineage undergo inap-propriate
clonal expansion caused by a molecular lesion. The
characteristic genetic abnormality of CML, the Philadelphia
chromosome, results from a reciprocal translocation of genetic
material on the long arms of one chromosome 9 and one chro-mosome
22. The molecular consequence of this translocation is
the generation of a gene encoding the fusion protein BCReABL1,
a constitutively activated tyrosine kinase. This leads to eventual
replacement of all myeloid tissue by normally differentiating
leukaemia cells. The disease typically progresses through three
distinct phases e chronic phase, accelerated phase, and blast
crisis e during which the leukaemic clone progressively loses its
ability to differentiate.
Epidemiology
The worldwide annual incidence of CML is 1e1.5 cases per
100,000 population. Although the disease may occur at any age, the
median age at presentation is between 50 and 60 years. A higher
incidence of CML is noted among persons with heavy radiation
exposure, and those who have undergone therapeutic irradiation
for malignancy (e.g. lymphoma, breast cancer) have a small but
significantly increased risk. There is no recognized familial influ-ence,
and no causal association between CML and either industrial
chemicals or alkylating agents has been demonstrated.
Cytogenetics and molecular biology
The t(9;22)(q34;q11) translocation juxtaposes the 30 segment of
the c-ABL oncogene (normally encoding the Abelson tyrosine ki-nase)
from the long arm of chromosome 9 to the 50 part of the
breakpoint cluster region (BCR) gene on the long arm of chro-mosome
22, resulting in one shortened chromosome 22 (22q)
(the Ph chromosome) and one elongated chromosome 9 (9qþ)
(Figure 1). At diagnosis, the Philadelphia chromosome (Ph) is
present in approximately 95% of CML cases. The remaining cases
have either variant translocations involving a third and, some-times,
fourth chromosome or cryptic translocations. In these cases,
routine cytogenetic analysis is unable to detect the Ph chromo-some,
and the diagnosis relies on demonstration of the fusion
transcript by either fluorescence in situ hybridization (FISH) or
real-time quantitative polymerase chain reaction (RQ-PCR).
The molecular consequence of t(9;22)(q34;q11) translocation
is the generation of a gene that is expressed as a BCReABL
mRNA transcript, translated into a 210-kDa protein known
as p210BCReABL. The p210BCReABL oncoprotein functions as a
constitutively active tyrosine kinase that can phosphorylate a
number of cytoplasmic substrates with other activities, leading
to alterations in cell proliferation, differentiation, adhesion, and
survival.1,2
The leukaemic clone in CML has a tendency to acquire addi-tional
oncogenic mutations over time, usually associated with
progression to accelerated phases of disease or resistance to
tyrosine kinase inhibitors (TKIs). At the chromosomal level,
changes include amplification of t(9;22), trisomy 8, trisomy 19,
and abnormalities of chromosome 17. At the molecular level,
mutations in the kinase domain of BCReABL account for about
50% of imatinib resistance in patients with CML in chronic phase
and 80% of those in more advanced phases.2
Clinical features
CML presents in the chronic phase in about 90% of patients.
Between 20% and 40% of individuals in whom CP-CML is
diagnosed are asymptomatic and are discovered incidentally.
Common non-specific symptoms at presentation include fatigue,
night sweats, weight loss, or spontaneous bruising or bleeding,
and are normally due to hypercatabolic symptoms, splenomegaly
(detected in 50e90% of patients at diagnosis), splenic infarction,
anaemia, or platelet dysfunction. Males with very high white
blood cell (WBC) counts rarely present with leukostasis-related
priapism. The features of advanced-phase CML are those of
cytopenia (including bleeding), splenic enlargement and general
cachexia.
Investigations
In the peripheral blood, neutrophilia and immature circulating
myeloid cells are hallmark features of CML. More than 50% of
patients present with a WBC count over 100 109/litre, with
Hugues de Lavallade MD PhD is Consultant Haematologist, Department
of Haematological Medicine, King’s College Hospital, London, UK.
Conflicts of interest: none declared.
MEDICINE 41:5 275 2013 Elsevier Ltd. All rights reserved.

2. 1
LEUKAEMIAS
blasts usually accounting for less than 2% of the WBCs. Absolute
basophilia is invariably present, and eosinophilia is common
(Figure 2). The marrow in chronic-phase CML is hypercellular
and typically shows myeloid hyperplasia and an elevated
myeloid-to-erythroid ratio. Maturation of precursors is normal
and dysplastic features are not routinely found.
The quickest way to confirm a suspected case of CML is to
detect in the peripheral blood the presence of either the Ph
chromosome or the chimeric transcripts of the BCReABL fusion
gene. The Ph chromosome can be identified by metaphase cy-togenetics
or fluorescence in situ hybridization (FISH), while the
presence of the BCReABL fusion gene may be confirmed by
RQ-PCR carried out on peripheral bloodederived RNA. Quanti-fication
of BCReABL mRNA at diagnosis is important for
monitoring of minimal residual disease in patients undergoing
therapy. Both FISH and RQ-PCR can detect cryptic chromosomal
translocations, whereas FISH has the advantage of identifying
unusual variant rearrangements that are outside the regions
amplified by the RQ-PCR primers. Although both assays confirm
the diagnosis of CML, a marrow evaluation is mandatory in
order to rule out advanced-stage disease and is also required to
detect the presence of additional chromosomal abnormalities.
Definitions of CML chronic phase, accelerated phase, and blast
crisis are summarized in Table 1. There are many classifications,
including the one by the World Health Organization and the
classification developed by Kantarjian and colleagues, which has
been used by all major studies with TKI and is therefore backed
by data.
Management
Chronic phase
Initial treatment with TKI has become the gold standard for
patients who present in chronic phase, and a complete cytoge-netic
response (CCyR, Table 2) is considered as the minimum
acceptable response, since it translates into improved
transformation-free survival (TFS). Around 70% of patients
achieve CCyR after frontline treatment with imatinib,4,5 and the
8-year probability of being in continuing CCyR while still taking
imatinib or second-line treatment with a second-generation TKI
is at 77%.6 In a randomized trial, higher rates of CCyR have been
reported in patients treated with first-line nilotinib compared to
The Ph chromosome
Bcr-Abl
fusion protein
9 9q+
22q
Philadelphia
chromosome
2
2
3 1
22
1
1
24
21
13
12
12
11
13
21
22
31
34
Figure 1
Figure 2 Blood film from a patient with chronic myeloid leukaemia.
Definitions of chronic, accelerated and blastic phase
Kantarjian criteria3
Chronic phase
C None of the criteria for accelerated phase or blastic phase
Accelerated phase (one of the following)
C 15e29% blasts in peripheral blood or bone marrow
C 30% blasts plus promyelocytes in peripheral blood or bone
marrow
C 20% basophils in peripheral blood or bone marrow
C Platelets 100 109/litre unrelated to therapy
Blastic phase (one of the following)
C Blasts in peripheral blood or bone marrow 30%
C Presence of extramedullary blastic disease
Table 1
Conventional definitions of cytogenetic and molecular
responses to treatment for chronic myeloid leukaemia
Ph-positive marrow
metaphases (%)
Designation
0 Complete cytogenetic response (CCR)
1e35 Partial cytogenetic response (PCyR)
36e65 Minor cytogenetic response
66e95 Minimal cytogenetic response
95 None
Percentages cited above are based on a minimum of 20 analysable
metaphases.
Complete and partial responses are often grouped together as
‘Major cytogenetic responses’ (MCyR).
Ratio of BCR_ABL
Designation
to ABL (%)
0.1% Major molecular response (MMR)
It is generally accepted that CCyR corresponds to an approximate
two-log reduction in transcript levels or 1% on the international
scale. MMR is usually defined as a three-log reduction in transcript
levels or 0.1% on the international scale
Table 2
MEDICINE 41:5 276 2013 Elsevier Ltd. All rights reserved.

3. imatinib (80% vs 65% at 12 months) with a significantly lower
rate of transformation to advanced phase (AP) or blastic phase
(BP) with nilotinib (2.1e3.2% vs 6.7%, respectively).7 However
the benefit of each drug has been considered in isolation, without
accounting for the effect of subsequent therapy.
Patients treated with TKIs should bemonitored closely to assess
their response and detect resistance; once in CCyR, BCReABL
transcript numbers in the blood should be regularly measured. The
achievement of a major molecular response (MMR, see Table 2)
has been shown to be associated with a reduced risk of loss of
CCyR.
In patients who lose CCyR a kinase domain mutation analysis
should be performed and a second-generation TKI introduced
without delay. Second-generation TKIs induce CCyR in approxi-mately
50% of patients who are resistant to imatinib.8,9 Patients
who fail to respond to treatment with available TKIs should be
considered for treatment with allogeneic stem cell transplant
(SCT), providing that they can tolerate the procedure and have a
donor. Allogeneic SCT carries a significant risk of morbidity and
mortality, but is a curative therapy for most patients who survive
the procedure.10
Advanced phase
For patients presenting in blastic transformation who have not
previously been treated with imatinib, transient haematologic
remission rates are 50e70% with cytogenetic response rates
of 12e17%. If blastic transformation evolves under imatinib,
treatment with dasatinib combined with acute leukaemia
chemotherapy as necessary should be given. Responses to TKIs
are transient in advanced phases. Therefore, if a return to chronic
phase (‘second’ CP) or a complete remission has been achieved,
patients should be given further treatment with an allogeneic
SCT provided that they can tolerate the procedure and a donor
has been identified.11 A third-generation TKI, ponatinib, has
shown promising results in patients with chronic or advanced
phase CML who have failed two or three other TKIs, or who
harbour the T315I mutation known to confer resistance to first-and
second-generation TKIs.2
Prognosis
If untreated, the chronic phase of CML typically remains stable
for an average of 3e5 years before patients progress to accel-erated
or blast crisis CML. In the pre-TKI era, patients with
chronic phase CML who were not eligible for an allogeneic SCT
had a median survival of 5e7 years. Since the use of TKIs, the
median survival in chronic phase is estimated at 25e30 years.
Median survival after diagnosis of blast crisis ranges between
7 and 11 months compared to 3e4 months in the pre-imatinib
era. A
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LEUKAEMIAS
MEDICINE 41:5 277 2013 Elsevier Ltd. All rights reserved.