SYMPOSIUM ON ONCOLOGY PRACTICE: HEMATOLOGICAL MALIGNANCIES
CHRONIC MYELOID LEUKEMIA
Chronic Myeloid Leukemia: Diagnosis and Treatment
ALFONSO QUINTÁS-CARDAMA, MD, AND JORGE E. CORTES, MD
Chronic myeloid leukemia (CML) has become a model in research
and management among malignant disorders. Since the discovery
of the presence of a unique and constant chromosomal abnormal-
ity slightly more than 40 years ago, substantial progress has been
made in the understanding of the biology of the disease. This
progress has translated into significant improvement in the long-
term prognosis of patients with this disease. This change came
first with the use of stem cell transplantation and interferon alfa,
but recently it has opened the era of molecularly targeted thera-
pies. Imatinib, a potent and selective tyrosine kinase inhibitor,
may be the best example of our attempts to identify molecular
abnormalities and develop drugs directed specifically at them.
Furthermore, the understanding of at least some of the mecha-
nisms of resistance to imatinib has led to rapid development of
new agents that may overcome this resistance. The outlook today
for patients with CML is much brighter than just a few years ago.
It is our hope that this fascinating journey in CML can be repli-
cated in other malignancies. In this article, we review our current
understanding of this disease.
Mayo Clin Proc. 2006;81(7):973-988
ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia;
AP = accelerated phase; ATP = adenosine triphosphate; BP = blast
phase; CCGR = complete cytogenetic response; CHR = complete hema-
tologic response; CML = chronic myeloid leukemia; CP = chronic phase;
Grb2 = growth factor receptor–bound protein 2; IC50 = inhibitory concen-
tration that results in a 50% reduction in proliferation; MCGR= major
cytogenetic response; MMR = major molecular response; MUD =
matched unrelated donor; Ph = Philadelphia; PI3K = phosphatidylinositol
3-kinase; RT-PCR = reverse transcriptase–polymerase chain reaction;
SCT = stem cell transplantation; STAT = signal transducer and activator
of transcription; TKI = tyrosine kinase inhibitor; WBC = white blood cell
C hronic myeloid leukemia (CML) is a clonal myelopro-
liferative disorder of a pluripotent stem cell1 first de-
scribed by John Hughes Bennett in 1845 at The Royal
Infirmary of Edinburgh.2 It has been classified as a myelo-
proliferative disorder along with agnogenic myeloid meta-
plasia, polycythemia vera, and essential thrombocythe-
mia.3 Chronic myeloid leukemia was the first malignancy
that had a specific chromosomal abnormality uniquely
linked to it after the discovery of a minute chromosome
now known as the Philadelphia (Ph) chromosome,4 later
defined to result from a t(9;22) reciprocal chromosomal
translocation.5 Of critical importance was the demonstra-
tion that this translocation involved the ABL1 (Abelson)
protooncogene in chromosome 9 and the BCR (breakpoint
cluster region) gene in chromosome 22.6,7 Since then, a
constant stream of clinical and basic advances has made
CML one of the most extensively studied human malignan-
cies. The introduction of rationally designed small mol-
ecules that target the tyrosine kinase activity of Bcr-Abl in
the treatment of CML has pioneered the development of
Mayo Clin Proc. • July 2006;81(7):973-988
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
targeted therapies in cancer medicine. In this review, we
summarize the current knowledge of the molecular biology
of CML and discuss the current treatment modalities, in-
cluding the important historical role of recombinant inter-
feron alfa, the development of imatinib mesylate and the
new tyrosine kinase inhibitors (TKIs), stem cell transplan-
tation (SCT), and other novel therapeutic approaches still
in preclinical or early clinical development.
EPIDEMIOLOGY AND ETIOLOGY
Chronic myeloid leukemia is a rare disease worldwide.
Approximately 4600 new cases of CML were diagnosed in
2004 in the United States, among 33,400 new cases of
leukemia. Hence, CML represents 14% of all leukemias
and 20% of adult leukemias. The annual incidence is 1.6
cases per 100,000 adults,8 with a slight male preponderance
(male-female ratio, 1.4:1). The median age at diagnosis
is 65 years. In contrast, CML is exceedingly rare in chil-
dren, and its incidence increases with age.9 There are no
known hereditary, familial, geographic, ethnic, or eco-
nomic associations with CML; therefore, the disease is nei-
ther preventable nor inherited. In most patients, the factor
responsible for the induction of the Ph chromosome is un-
known, although CML has been observed with increased
frequency in individuals exposed to the atom bomb explo-
sions in Japan in 1945, in radiologists, and in patients with
ankylosing spondylitis treated with radiation therapy.10
CLINICAL PRESENTATION AND NATURAL HISTORY
Classically, 3 phases of disease progression are recognized
in CML: chronic phase (CP), accelerated phase (AP), and
blast phase (BP) (Table 1). Currently, nearly 90% of pa-
tients with CML have their conditions diagnosed in the CP.
Frequently, the diagnosis is made incidentally after a rou-
From the Department of Leukemia, The University of Texas, M. D. Anderson
Cancer Center, Houston, Tex.
Dr Cortes has research grant support from Novartis, BMS, The Vaccine Com-
pany, ChemGenex Pharmaceuticals, Ltd, and Breakthrough Therapeutics.
Address correspondence to Jorge E. Cortes, MD, Department of Leukemia,
The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd,
Unit 428, Houston, TX 77030 (e-mail: jcortes@mdanderson.org). Individual
reprints of this article and a bound booklet of the entire Symposium on
Oncology Practice: Hematological Malignancies will be available for purchase
from our Web site www.mayoclinicproceedings.com.
© 2006 Mayo Foundation for Medical Education and Research
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CHRONIC MYELOID LEUKEMIA

TABLE 1. Criteria for Accelerated Phase According to 3

Frequently Used Classifications*

MDACC11 IBMTR12 WHO13

Blasts (%) ≥15 ≥10 10-19†
Blasts and
promyelocytes (%) ≥30 ≥20 NA
Basophils (%) ≥20 ≥20‡ ≥20
Platelets (× 109/L) <100 Unresponsive increase or <100 or >1000 unresponsive
persistent decrease to treatment
Cytogenetics CE CE CE not at the time of diagnosis
White blood cell NA Difficult to control or NA
doubling in <5 d
Anemia NA Unresponsive NA
Splenomegaly NA Increasing NA
Other NA Chloromas, myelofibrosis Megakaryocyte proliferation,
fibrosis
*CE = clonal evolution; IBMTR = International Bone Marrow Transplant Registry; MDACC = M. D. Ander-
son Cancer Center; NA = not applicable; WHO = World Health Organization.
†Blast phase of 20% or more blasts (≥30% for MDACC and IBMTR).
‡Basophils and eosinophils.

tine complete blood cell count is performed for unrelated
reasons. This is due to the fact that patients with CML-CP
have a competent immune system and may remain asymp-
tomatic for prolonged periods. When symptoms appear, they
are generally related to the expansion of CML cells and
consist typically of malaise, weight loss, and discomfort
caused by splenomegaly.14 Leukocytosis is a common fea-
ture of CP, and the white blood cell (WBC) count can be as
high as 1000 × 109/L, leading in rare instances to signs and
symptoms of hyperviscosity, such as retinal hemorrhage,
priapism, cerebrovascular accidents, tinnitus, confusion,
and stupor. After a median of 3 to 5 years, untreated pa-
tients with CML-CP inevitably progress to CML-BP, an
aggressive form of acute leukemia highly refractory to
chemotherapy that is rapidly fatal.15 The risk of transforma-
tion to CML-BP is estimated at 3% to 4% per year.15,16
Chronic myeloid leukemia-AP is characterized by an in-
creasing arrest of maturation that usually heralds transfor-
mation to CML-BP.
Different criteria have been used to define CML-AP.
One commonly used classification defines AP as the pres-
ence of at least 1 of the following hematologic features:
15% or more blasts, 30% or more blasts plus promyelo-
cytes, 20% or more basophils, or platelet counts lower than
100 × 109/L unrelated to therapy.17 Of note, most classifica-
tion systems for CML-AP and CML-BP proposed through-
out the years in the literature were developed before the
introduction of imatinib, and some, such as the recent
World Health Organization proposal,13 have not been vali-
dated in clinical studies and therefore may lack clinical
importance.18 Most discrepancies among different classi-
fications relate to the use of slightly different cutoffs for
hematologic values and other additional minor criteria.
Although patients may become symptomatic, the transition
from CML-CP to CML-AP is usually subclinical, and labo-
ratory monitoring is necessary for detection of disease
progression. The median survival for patients with CML-
AP is 1 to 2 years.19 Most patients’ CML will remain in AP
for 4 to 6 months before progressing to BP.20,21 Classic
criteria define CML-BP by the demonstration of at least
30% of blasts in the peripheral blood or the bone marrow or
the presence of extramedullary blastic foci. The World
Health Organization classification proposes a reduction
from 30% or more to 20% or more blasts for the diagnosis
of CML-BP. Clinically, most patients with CML-BP expe-
rience signs and symptoms related to increasing tumor
burden, including inability to control WBC counts with
previously stable doses of medication, marked constitu-
tional symptoms (fever, night sweats, anorexia, malaise,
weight loss), splenic infarcts due to massive splenomegaly,
bone pain, and increased risk of infections and bleeding.
The presence of cytogenetic abnormalities in addition to
the Ph chromosome (ie, clonal evolution) involves most
frequently trisomy 8, isochromosome 17, and duplicate Ph
chromosome and has been considered a criterion of CML-
AP. However, patients who are classified as having CML-
AP based solely on the presence of clonal evolution appear
to fare better than those whose conditions were diagnosed
on the basis of other clinical features. Immunopheno-
typically, CML-BP can be characterized by myeloid or
lymphoid phenotype. In rare instances, blast cells can be
biphenotypic with a mixed lymphoblastic-myeloblastic
lineage.19,22 Lymphoid CML-BP occurs in 20% to 30%
of patients, myeloid in 50%, and undifferentiated in
25%.22,23 Median survival of patients with lymphoid CML-
BP is 3 to 6 months, with patients with lymphoid CML-BP
having a slightly better prognosis than those with myeloid
phenotype.

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LABORATORY AND PATHOLOGICAL FEATURES
Laboratory findings in CML include leukocytosis with a
remarkable left shift, basophilia, and eosinophilia. Platelet
count may be either high or low, and mild anemia is com-
monly observed. The leukocyte alkaline phosphatase ac-
tivity is reduced, although phagocytic function remains
essentially normal.24 Low values may also be observed in
agnogenic myeloid metaplasia, whereas activity may in-
crease with infection, clinical remission, or at the onset of
BP. The increase in the size of the WBC pool is reflected by
marked elevation of serum B12 levels and unsaturated B12-
binding capacity. During transformation to CML-BP, cir-
culating basophil levels, histamine levels, or both often
increase, but the causative factors and importance of these
phenomena remain unknown.25
The bone marrow of patients with CML is notoriously
hypercellular and devoid of fat.26 In fact, it can be hypoth-
esized that the primary biologic defect in CML is not
unregulated proliferation of leukemic stem cells but rather
discordant maturation, wherein a slight delay in cell matu-
ration within the myeloid compartment results in increased
myeloid mass.27 All stages of myeloid maturation are
present, with predominance of myelocytes. In CP, the sum
of myeloblasts and promyelocytes usually accounts for less
than 10% of the marrow cellularity. A decrease in apopto-
sis of myeloid cells contributes to the expansion of this
compartment and defective adherence of immature CML
cells to marrow stromal cells in vitro,28 with subsequent
early release into the circulation. Megakaryocytes may be
increased, and Gaucher-like cells can be observed in 10% of
cases.29 As CML progresses, varying degrees of reticulin
fibrosis may be seen,30 likely a result of the interaction
between the proliferative clone of megakaryocytes and
cytokines, such as platelet-derived growth factor, transform-
ing growth factor β, and basic fibroblastic growth factor,
whose plasma levels are significantly increased in CML.31
Of note, these cytokines play an important role modulating
angiogenesis, and characteristically the bone marrow from
patients with CML shows the highest number of blood ves-
sels and largest vascular area of all leukemias.31
Blastic cells from patients with lymphoid CML-BP ex-
press terminal deoxynucleotidyl transferase, an enzyme
that catalyzes the polymerization of deoxynucleoside tri-
phosphates and is mainly found in poorly differentiated B
and T cells.32 In most cases of lymphoid CML-BP, blasts
exhibit a B-cell immunophenotype, expressing CD10,
CD19, and CD22. In contrast, myeloid CML-BP closely
resembles acute myeloid leukemia (AML), and blasts stain
with myeloperoxidase and express myeloid markers such
as CD13, CD33, and CD117. Frequently, myeloid markers
such as CD13 and CD33 may be expressed in patients with
Mayo Clin Proc. • July 2006;81(7):973-988
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CHRONIC MYELOID LEUKEMIA
lymphoid CML-BP. Rare cases of megakaryoblastic,33
erythroblastic,34 and mastoblastic35 transformation have
been reported.
PROGNOSTIC SYSTEMS
Because of the difference in clinical aggressiveness be-
tween the initial CP and advanced phases of CML and
because the prognosis in CML can vary significantly even
among patients in the same phase of the disease, several
risk stratification strategies have been developed in an
attempt to prognosticate and guide patient management.
The system most extensively used is the Sokal score, which
was derived from 813 patients with CML collected from 6
European and American series in the 1960s and 1970s.36 In
this system, the hazard ratio for death is calculated from
baseline patient and disease characteristics using the fol-
lowing formula: λi(+)/λo(t) = Exp 0.0116 (age – 43.4) +
0.0345 (spleen – 7.51) + 0.188 [(platelets/700)2 – 0.563] +
0.0887 (blasts – 2.10). This scoring system establishes 3
prognostic groups with hazard ratios of less than 0.8, 0.8 to
1.2, and more than 1.2 and median survivals of approxi-
mately 2.5, 3.5, and 4.5 years, respectively.36 Of note, most
of the patients from whom the Sokal score was derived
were treated with therapies currently not in use, such as
busulfan, intensive chemotherapy, and splenectomy. How-
ever, several studies performed in the 1990s have demon-
strated the applicability of this system in more modern
series. Of 625 patients with CML-CP treated with chemo-
therapy in one study, 168 (27%) were high risk and had a 2-
year actuarial survival of 70% and a subsequent probability
of death of approximately 30% per year. In contrast, the
low-risk group had a 2-year actuarial survival of 91% and a
subsequent risk of death of approximately 17% per year.37
The Sokal system has several limitations. First, in asymp-
tomatic patients whose disease is detectable only by mo-
lecular testing, lead-time bias can be substantial relative to
those whose conditions are diagnosed after presenting with
symptoms. Second, the use of more refined and potent
therapeutic modalities in CML, such as imatinib, has been
associated with the loss of predictive value of some prog-
nostic factors.38 Still, the Sokal score identifies patients
with significantly different probabilities of response to
imatinib, although patients with high-risk scores now have
a much better outcome.
Other scoring systems have been proposed that may be
more applicable to patients treated with interferon alfa. The
best-characterized and most widely used is the Hasford
score,39 which considers patient age, platelet count, periph-
eral blast count, spleen size, eosinophils, and basophils to
determine risk. Some analyses have suggested that this
scoring system is less predictive among patients treated
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CHRONIC MYELOID LEUKEMIA
with imatinib, but others have found it still useful. Finally,
the Gratwohl score system has been developed specifically
for patients undergoing SCT.40
CYTOGENETICS
A conclusive diagnosis of CML relies on cytogenetic and
molecular testing to identify the t(9;22)(q34.1;q11.21) and/
or the BCR-ABL1 hybrid gene, which is pathognomonic of
this disease.4,5 The Ph chromosome results from the bal-
anced translocation of cytogenetic material after a break on
chromosome 9 at band q34.1 that transposes the 3′ segment
of the ABL1 gene to the 5′ segment of the BCR gene on
chromosome 22 at band q11.21.5 The Ph chromosome is
detected in 95% of patients with CML and in 5% of chil-
dren and 15% to 30% of adults with acute lymphoblastic
leukemia (ALL). In addition, approximately 2% of patients
with newly diagnosed AML can present with this cytoge-
netic abnormality.41 Occasionally, translocations that in-
volve 3 or more chromosomes occur and are termed variant
Ph chromosome translocations.42,43 Although initially
thought to confer poor prognosis,44 recent data in patients
treated with imatinib have demonstrated that variant trans-
locations are associated with a similar prognosis compared
with patients with the classic Ph chromosome.45 In 5% of
patients with typical CML phenotype, the Ph chromosome
is not detectable but harbors the BCR-ABL1 rearrange-
ment.46 These patients have the same biology and outcome
as those who express the Ph chromosome. Among the 5%
to 10% of patients with CML clinical features who do not
express the Ph chromosome, 30% to 50% have molecular
evidence of the rearrangement involving BCR and ABL1.
Those who do not express this molecular abnormality (ie,
true Ph chromosome negative) are called atypical CML and
have a different prognosis and treatment.47 The characteris-
tics and management of atypical CML are not covered any
further in this article.
Little is known about the mechanisms involved in trans-
formation to CML-BP, but the acquisition of additional
cytogenetic abnormalities, referred to as clonal evolution,
in Ph chromosome–positive cells has been thought to play
a prime role in CML progression. The most frequent sec-
ondary cytogenetic abnormalities encountered in patients
with clonal evolution are trisomy 8, isochromosome 17,
and duplicate Ph chromosome, which have been linked
to c-Myc overexpression, loss of 17p, and BCR-ABL1
overexpression, respectively.48-50 Other cytogenetic aber-
rancies, such as trisomy 19, trisomy 21, trisomy 17, and
deletion 7, have been implicated in less than 10% of cases
of clonal evolution.51,52 These genetic lesions are more
frequently associated with myeloid than with lymphoid
CML-BP. Nonetheless, a clear correlation between the de-
976 Mayo Clin Proc. • July 2006;81(7):973-988
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velopment of these molecular features and disease progres-
sion has not been established yet. In addition, other mo-
lecular events, such as deletion or inactivation of p53,53
p16,54 and the retinoblastoma gene product55 have been
associated with disease transformation, but like overex-
pression of EVI-1,56 these are relatively infrequent and
therefore not specific to CML-BP.57 Recently, it was sug-
gested that progression of CML to BP probably involves
several events in primitive progenitors, including BCR-
ABL1 amplification, acquisition of resistance to apoptosis,
genomic instability, escape from innate and adaptive im-
mune responses, and activation of β-catenin in granulo-
cyte-macrophage progenitors, resulting in the acquisition
of self-renewal capacity.58 Gene methylation has also been
associated with progression in CML.59-61 The Pa promoter
of ABL1 and the p15 promoter are hypermethylated in 81%
and 24% of patients, respectively. Interestingly, hyper-
methylation of p15, but not of the Pa promoter, is associ-
ated with disease progression. Methylation of the cadherin-
13 gene occurs at an early stage in CML and is associated
with high-risk features and lower probability of response to
interferon alfa.62
Cytogenetic aberrancies have been reported occasion-
ally in Ph chromosome–negative cells during treatment
with interferon alfa and, more recently, with imatinib.
These aberrancies do not represent clonal evolution be-
cause they occur in cells without the Ph chromosome and
should not be considered as part of the definition of AP.
The importance of these events is currently unknown.63 The
most common such cytogenetic abnormalities include tri-
somy 8, monosomy 5 or 7, and deletion 20q.64-66 These
abnormalities frequently regress spontaneously, and it has
been suggested that patients with these abnormalities have
similar long-term outcome as patients without such abnor-
malities. However, occasional cases of progression to
AML or myelodysplastic syndrome have been reported.
MOLECULAR BIOLOGY OF BCR-ABL1
The ABL1 gene is the human homologue of the v-abl
oncogene harbored by the Abelson murine leukemia vi-
rus,67 and it encodes a nonreceptor tyrosine kinase (Figure
1).68 In turn, BCR encodes a protein with serine–threonine
kinase activity. The fusion of these 2 genes results in the
activation of the c-ABL protooncogene to its oncogenic
form.69,70 The breakpoints within the ABL1 gene at 9q34
map to an area spanning more than 300 kilobase (kb) at its
5′ end occur upstream of exon Ib, downstream of exon Ia,
or, more frequently, between the two.71 Alternatively,
breakpoints within BCR localize to 3 main breakpoint clus-
ter regions. In most patients with CML and a third of those
with Ph chromosome–positive ALL, the break occurs
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 CHRONIC MYELOID LEUKEMIA

FIGURE 1. Activation of signal transduction pathways by BCR/ABL. AKT = protein kinase B; ERK =
extracellular signal-regulated kinase; JAK = Janus kinase; MEK = mitogen-activated protein kinase
kinase; PI3K = phosphatidylinositol 3-kinase; SAPK = stress-activated protein kinase; STAT =
signal transducer and activator of transcription.

within a 5.8-kb area spanning BCR exons e12-e16 (for-
merly called b1-b5), referred to as the major breakpoint
cluster region (M-bcr). Because of alternative splicing,
a fusion transcript with either b2a2 or b3a2 junctions
can result and will give rise to a 210-kd hybrid protein
(p210BCR-ABL).72,73 The clinical features and response to
treatment are apparently similar for both transcripts. In
two thirds of patients with Ph chromosome–positive ALL
and rarely in CML, the breakpoints within BCR localize
to an area of 54.4 kb between exons e2′ and e2, termed the
minor breakpoint cluster region (m-bcr), giving rise to an
e1a2 messenger RNA that is translated to a 190-kd pro-
tein (p190BCR-ABL). Patients with CML who carry this tran-
script can present with marked monocytosis and may
have a worse prognosis than those with the typical p210.74
A third breakpoint cluster region (µ-bcr) downstream of
exon 19 has been identified, giving rise to a 230-kd fusion
protein (p230BCR-ABL) linked to cases of chronic neutrophilic
leukemia.75 Although all 3 transcripts can induce a CML-like
disorder in mice, p230BCR-ABL has reduced tyrosine kinase
activity relative to p190BCR-ABL76 and confers only partial
growth factor independence, which parallels the milder clini-
cal course of chronic neutrophilic leukemia.75 All the
isoforms of Bcr-Abl have an active and an inactive configu-
ration. Interestingly, using reverse transcriptase–polymerase
chain reaction (RT-PCR) with a sensitivity of approximately
10–8, the BCR-ABL1 chimerism has been identified in up to
25% to 30% of presumably healthy adults.77,78 One hypoth-
esis to explain this phenomenon is that BCR-ABL1 might not
be the sole genetic lesion necessary for the development of
CML. JunB is a component of the activator protein 1 family
of transcription factors79 Modifications of JunB expression
may have a role in the pathogenesis of CML by modulating
the initiation, progression, and maintenance of the myeloid
differentiation program.80 A recent report in which trans-
genic mice specifically lacking JunB in the myeloid lineage
(JunB–/–Ubi-JunB mice) develop a myeloproliferative disor-
der that resembles human CML, including progression to
BP, seems to support the latter hypothesis.81
Several biological models, such as BCR-ABL1–express-
ing CD34+ cells in culture82,83 or retrovirally transduced
BCR-ABL1+ mouse cells,84 have demonstrated that BCR-
ABL1 is an oncogene that promotes CML pathogenesis.
Numerous pathways are activated in BCR-ABL1–express-
ing cells,85 and phosphorylation at the Y177 site of BCR is
essential for BCR-ABL1 leukemogenesis.86,87 This residue
constitutes a high-affinity docking site for the SH2 domain
of growth factor receptor–bound protein 2 (Grb2). In turn,
Grb2 recruits SOS (a guanine-nucleotide exchanger of
RAS) and the scaffold adapter Grb2-associated binding
protein 2 (GAB2) through its SH3 domain. Phosphoryla-
tion of GAB2 leads to recruitment of phosphatidylinositol
3-kinase (PI3K) and SHP2 (also known as PTPN11),
whereas SOS activates RAS.88 Mutation of Y177 to phenyl-
alanine (Y177F) largely abolishes Grb2 binding and abro-
gates Bcr-Abl–induced RAS activation. Therefore, despite

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CHRONIC MYELOID LEUKEMIA
preservation of the kinase activity of Abl, the Y177F mutant
impedes the transformation of primary bone marrow cul-
tures.86 In an SCT model of CML, BCR-ABL1Y177F has a
greatly reduced ability to induce a myeloproliferative dis-
order in mice.89 Of note, SHP2 is required for normal
activation of the RAS extracellular signal-regulated ki-
nase pathway that most receptor tyrosine kinases signal
through.88 Bcr-Abl also phosphorylates the Src kinases
Lyn, Hck, and Fgr. Once phosphorylated, Hck activates
signal transducer and activator of transcription (STAT)
5.90,91 Importantly, overexpression of Hck/Lyn has been
linked with disease progression, particularly with a lym-
phoid phenotype.92 Therefore, Bcr-Abl promotes hemato-
poietic cell transformation mainly through RAS, PI3K, and
STAT 5 activation. All these elements have been shown to
up-regulate the expression of cyclin D1, thus inducing cell-
cycle progression from G1 to S phase.93,94 When BCR-
ABL1–positive K562 cells were induced to express domi-
nant negative forms of RAS, PI3K, or STAT 5, marked
apoptosis was observed in cells coexpressing 2 of 3 domi-
nant negative mutants in any combination.95 Notably, Bcr-
Abl also enhances SET expression, particularly during pro-
gression to BP.96 SET is a nucleus/cytoplasm-localized
phosphoprotein that potently inhibits the tumor suppressor
protein phosphatase 2A (PP2A). In turn, PP2A is a phos-
phatase that regulates cell proliferation, survival, and dif-
ferentiation.97 Some of the elements involved in Bcr-Abl
signal transduction have been sought as therapeutic targets
in CML.
TREATMENT
The treatment of CML has experienced a great degree of
refinement during the past few years. Until recently, inter-
feron alfa and SCT were the only therapeutic options for
patients with CML. Currently, SCT still remains a valid
option, particularly for patients who do not respond appro-
priately to TKIs, and still remains a potentially curative
therapeutic modality. However, the explosion of the field of
molecularly targeted TKIs in recent years led by imatinib
mesylate has brought about a change in the natural history of
the disease and in the therapeutic approach to CML.
INTERFERON
Recombinant human interferon alfa has shown significant
antitumor and immunomodulatory activity in the treatment
of CML.98,99 Major cytogenetic responses (MCGRs) (<35%
Ph chromosome–positive cells) have been reported in up to
40% of patients and complete cytogenetic responses
(CCGRs) (0% Ph chromosome–positive cells) in up to
25%.100 The addition of cytarabine resulted in a significantly
higher probability of a CCGR in up to 35% of patients.101-105
978 Mayo Clin Proc. • July 2006;81(7):973-988
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The achievement of a CCGR is associated with improved
survival, with 78% of patients who achieved a CCGR alive
at 10 years, establishing the achievement of a CCGR as the
therapeutic goal in the interferon alfa era.106 Furthermore,
approximately 30% of patients in CCGR also had undetect-
able disease by PCR (ie, complete molecular remission);
none of them has relapsed after a median follow-up of 10
years and are therefore probably cured.106,107 Interestingly,
40% to 60% of those in CCGR with the presence of mini-
mal residual disease at the molecular level have not re-
lapsed after 10 years. This has been attributed to interferon
alfa–induced immune modulation, such as the presence of
cytotoxic T lymphocytes specific for PR1, a peptide de-
rived from proteinase 3, which is overexpressed in CML
cells. This phenomenon has been demonstrated in patients
in complete remission after interferon alfa therapy and SCT
but not in those who fail to achieve CCGR or those treated
with chemotherapy.108
STEM CELL TRANSPLANTATION
Stem cell transplantation remains an important treatment
option for patients with CML, particularly younger indi-
viduals with HLA-identical siblings. Initially, SCT was
thought to render the best outcomes when performed
within 12 months from CML diagnosis. It has been re-
ported that SCT performed within the first 24 months, and
in some reports within the first 36 months, from diagnosis
may have similar outcomes.40 Although it was initially
suggested that prior interferon alfa therapy adversely af-
fected the outcome after SCT,109 subsequent trials demon-
strated that this adverse effect was nonexistent,110-113 and
current evidence suggests that prior exposure to imatinib
does not affect the outcome either.114,115 Current registry
data revealed that the post-SCT mortality within the first
year is 10% to 20% even in patients who underwent trans-
plantation in optimal conditions (ie, HLA-matched sibling,
first CP <1 year from diagnosis, age <40 years). In addi-
tion, only one third to one half of patients may have a
suitable HLA-matched sibling, and stringent inclusion cri-
teria, such as age, adequate organ function, and perfor-
mance status, may preclude the possibility of SCT in a
large proportion of patients. A strategy to overcome the
lack of suitable donors is the use of matched unrelated
donors (MUDs).116 Unfortunately, the survival rate of pa-
tients undergoing MUD SCT is still lower when compared
with those receiving grafts from HLA-matched siblings.
The outcome of MUD SCT may be improved by careful
molecular typing, particularly for HLA-A, HLA-B, and
HLA-DRB1.116 However, the use of stringent typing crite-
ria is inevitably linked to a lower probability of finding an
adequate donor. In addition, SCT is fraught with risks such
as graft-vs-host disease, veno-occlusive disease, life-
• www.mayoclinicproceedings.com

threatening infections, risk of secondary malignancy, and
poorer overall quality of life.117 Also, the risk of late relapse
is being increasingly recognized. A recent series analyzed
the long-term follow-up of 89 patients who underwent
transplantation at a single institution.118 After more than 10
years of follow-up, 28 patients (31%) were alive. The mean
time to hematologic or cytogenetic relapse was 7.7 years,
with 5 patients relapsing more than 10 years after SCT. In a
recent study by the Seattle group, 131 patients with early
CML-CP with a median age of 43 years (range, 14-66
years) received targeted busulfan and cyclophosphamide as
a conditioning regimen. At 3 years, the projected non-
relapse mortality rate was 14%, and 78% were projected to
be alive and free of disease. However, 60% of survivors
had extensive chronic graft-vs-host disease 1 year after
transplantation, although only 10% had a Karnofsky score
less than 80%. Notably, 11% of patients had minimal re-
sidual disease documented by PCR but had not relapsed at
the time of the report.119 In contrast, patients with advanced
phase CML who undergo SCT have a 5-year survival prob-
ability of 40% to 60% in the AP and 10% to 20% in the BP.
Notably, the long-term outcome of patients with CML-BP
who achieve a second CP and who are undergoing SCT
appears to be similar to that of patients with CML-AP who
undergo transplantation.
The long-term disease-free survival rate after MUD
SCT for young patients in the early CP stage of disease is
57% compared with 67% in patients receiving grafts from
HLA-matched siblings.120 The incorporation of molecular
matching in recent years has decreased the rate of graft-vs-
host disease and improved the probability of long-term
survival in patients undergoing MUD SCT.
Reduced-intensity conditioning regimens have been
used as a means to make SCT available to a broader num-
ber of patients who otherwise would be ineligible for stan-
dard SCT. This approach takes advantage of the ability of
the T cells harbored in the graft to eliminate the CML cells
(graft-vs-leukemia effect) as opposed to obtaining this ef-
fect by using ablative cytotoxic chemotherapy. This strat-
egy increases tolerability and decreases morbidity and
mortality significantly. Long-term results with reduced-
intensity conditioning regimens are not yet available, but
early results in small series (frequently including still
mostly young patients) report disease-free survival as high
as 85% at 70 months.121 In contrast, a recent study from the
European Bone Marrow Transplant Registry reports a 3-
year overall survival rate of 58% and a progression-free
survival rate of 37%.122 Patients with minimal residual
disease by PCR 12 months after SCT have a risk of relapse
of 30% to 40% compared with less than 5% for those with
negative PCR results.123 However, relapse can be fre-
quently managed successfully with donor lymphocyte infu-
Mayo Clin Proc. • July 2006;81(7):973-988
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CHRONIC MYELOID LEUKEMIA
sion in up to 70% of patients who relapse in the CP,
particularly when administered at the time of molecular
relapse. Alternatively, imatinib can be used in the post-
SCT relapse setting and induces CCGR in more than 40%
of patients treated in the CP.124
IMATINIB MESYLATE
Imatinib mesylate (Gleevec) is an orally bioavailable 2-
phenylaminopyrimidine with targeted inhibitory activity
against the constitutively active tyrosine kinase of the Bcr-
Abl chimeric fusion protein. In addition, imatinib inhibits
other kinases, such as c-Kit, platelet-derived growth factor
α and β, and Abl-related gene (ARG).125,126 Imatinib has
become the standard therapy for CML because of its re-
markable activity and mild toxicity profile. In a phase 1
dose-finding study in patients who were intolerant to or in
whom interferon alfa–based therapy failed, daily doses of
25 to 1000 mg were investigated. Responses among pa-
tients receiving doses lower than 250 mg/d were rare, in
contrast to 98% of patients receiving a dose of at least 300
mg/d who achieved a complete hematologic response
(CHR), including 54% who attained a cytogenetic re-
sponse. Of note, no dose-limiting toxicity was identified,
and the maximum tolerated dose was not reached.127 A
dosage of 400 mg/d was selected for a subsequent phase 2
study, including 454 patients with late CP disease who
were intolerant to or in whom interferon alfa therapy
failed.128 Recently updated data showed that 96% of pa-
tients had achieved a CHR and 55% a CCGR. After a
median follow-up of 5 years, the overall survival rate was
79%.128 This rate is in keeping with results from a recent
single-institution study in which among 261 patients
treated, 73% obtained a MCGR and 63% a CCGR.129 After
a median follow-up of 45 months, 86% of patients are
alive, of whom 80% are free of progression. More than
90% of patients who achieved a CCGR maintained a major
response. The BCR-ABL1/ABL1 ratio by nested PCR was
less than 0.05% in 31% and undetectable in 15% of pa-
tients.129 In the prospective, multicenter phase 3 Interna-
tional Randomized Study of Interferon and STI571, the
efficacy of imatinib was compared with the combination of
interferon alfa and low-dose cytarabine in patients with
newly diagnosed CML-CP. 130 Patients treated with
imatinib (n=553) or interferon alfa and low-dose cytarabine
(n=553) were allowed to cross over to the alternative group
if treatment failure or intolerance was demonstrated.131
Imatinib therapy was superior to interferon alfa plus low-
dose cytarabine regarding hematologic and cytogenetic re-
sponses, tolerability, and transformation to CML-AP. After
a median follow-up of 54 months, the CHR, MCGR, and
CCGR rates were 98%, 92%, and 86%, respectively.132
Progression-free survival is estimated to be 84%, and only
• www.mayoclinicproceedings.com 979
CHRONIC MYELOID LEUKEMIA
1.0
0.8
Proportion surviving
0.6
0.4
0.2
0.0
0 2
FIGURE 2. Survival of patients with early chronic phase chronic myeloid leukemia treated at M. D.
Anderson Cancer Center in different eras compared with those treated with imatinib.
6% of patients have progressed to AP or BP. The overall
annual progression rate has declined to 1.5% in the fourth
year of therapy, compared with 4.8% and 7.5% in the
previous 2 years, suggesting that disease progression may
plateau in the ensuing years. The depth of the response after
12 months of imatinib therapy has important implications
regarding disease progression and relapse. In fact, in 97%
of patients who had a 3-log or greater reduction in BCR-
ABL transcript levels (ie, major molecular response
[MMR]) at 12 months, the probability of remaining free of
progression to AP or BP was 97% at 54 months compared
with 89% for patients in CCGR but not in MMR and 72%
for patients who did not achieve a CCGR at 12 months
(P=.001).132,133 In addition, the median BCR-ABL levels
continue to decrease, with a mean log reduction at 48
months of 3.4 compared with 3.0 at 12 months.134 Although
this study did not document a survival advantage compared
with the interferon alfa arm because of the crossover de-
sign, studies comparing survival of patients treated with
imatinib with historical cohorts treated with interferon
alfa–based therapy demonstrate the anticipated survival
advantage135,136 (Figure 2). These results suggest that a trial
of imatinib must be pursued in every patient before consid-
ering SCT.
The results from the International Randomized Study of
Interferon and STI571 have established imatinib 400 mg/d,
as the standard therapy for CML. However, because the
imatinib dosage selected after the dose-finding phase 1
980 Mayo Clin Proc.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Year Total Dead
95%
Imatinib 230 7
1900-2000 960 334
1982-1989 365 265
1975-1981 132 127
1965-1974 123 122
4 6 8 10 12 14 16
Time from referral (y)
study was based primarily on the excellent responses ob-
tained when doses higher than 300 mg/d were used, it has
been suggested that imatinib at higher dosages (600-800
mg/d) might result in improved outcomes (Table 2). In one
study, 36 patients with CML-CP in whom interferon alfa
therapy failed were treated with imatinib 400 mg twice
daily, resulting in a CCGR rate of 90%, compared with
48% in historical matched controls treated with standard-
dose therapy.141 In addition, 56% of patients had an MMR,
including 41% with undetectable levels. The toxicity pro-
file was similar to that of imatinib, 400 mg, although there
was a higher rate of grade 3 or higher myelosuppression.
Several single-arm, phase 2 studies have used high-dose
imatinib as the starting dose for patients with previously
untreated CML-CP. These studies have documented a
higher rate of CCGR of up to 95% and higher rates of
molecular responses, particularly responses at the level of a
4-log or greater reduction in transcript levels. In addition,
responses occur significantly earlier with high-dose com-
pared with standard-dose therapy.137-139 One study reported
that by multivariate analysis, only treatment with high-dose
imatinib (P=.02) was associated with achievement of an
MMR and that achieving an MMR within the first 12
months of therapy is predictive of a durable cytogenetic
remission.142 Similarly, patients receiving the highest dose
intensity during the first year of therapy have the highest
probability of achieving a major molecular remission at 24
months (89%), whereas those receiving a median daily
• July 2006;81(7):973-988 • www.mayoclinicproceedings.com

dosage less than 600 mg had a significantly lower probabil-
ity both at 12 and at 24 months.143 Thus, these studies
suggest that high-dose imatinib may provide more and
better remissions, but the results from ongoing randomized
studies will determine whether high-dose imatinib provides
only faster responses or whether these translate into pro-
longed progression-free and/or overall survival.
Duration of Imatinib Therapy. Currently, no evidence
exists to support the belief that patients taking imatinib can
safely discontinue therapy once they achieve a complete
molecular response. Most patients who have discontinued
imatinib therapy have rapidly experienced both molecular
and cytogenetic relapse, even when some had sustained un-
detectable levels of BCR-ABL for significant periods.144-146
Recently, Rousselot et al147 described 8 patients who dis-
continued use of imatinib after maintaining undetectable
BCR-ABL levels for 24 months, 4 of whom still tested
PCR negative after a follow-up of 8, 9, 12, and 13 months,
respectively. All these patients had been treated with inter-
feron alfa, suggesting that interferon alfa immunomodula-
tory effects may account for sustained and prolonged mo-
lecular responses observed on therapy discontinuation.
It has been suggested that the most primitive quiescent
leukemic progenitors are insensitive to imatinib in vitro
and are responsible for CML relapse once the inhibitory
pressure of imatinib is removed.148 Emerging data suggest
that resistance of quiescent cells to imatinib is indeed a
Bcr-Abl–dependent phenomenon. 149 Other potential
mechanisms implicated in quiescent CML progenitors in-
clude expression of drug transport proteins such as PgP and
Abcg2, atypical kinase domain mutations,150 and BCR-
ABL overexpression.151
Monitoring of Imatinib Therapy and Minimal Re-
sidual Disease. The significant MMR rate observed with
imatinib and its prognostic implications152,153 have led to the
redefinition of the therapeutic goals in CML. Rather than
aiming solely at achieving a CCGR,106,154 modern CML
therapy should aim for the achievement of molecular re-
sponses. The long-term importance of molecular monitor-
ing in CML has been best exemplified by patients under-
going SCT, in whom detection of BCR-ABL transcripts,
particularly at high levels and 6 months after transplanta-
tion, confer a significantly higher risk of relapse. In these
instances, prompt intervention (eg, donor lymphocyte infu-
sion) has been effective. As mentioned earlier, among pa-
tients who achieve a CCGR with interferon alfa, the risk of
relapse is minimal for those with low transcript levels.107
Patients who achieve undetectable BCR-ABL transcripts
by nested PCR have all had sustained cytogenetic remis-
sions beyond 10 years.106 In the imatinib setting, once a
CCGR is attained, quantitative RT-PCR in peripheral
blood samples at 3-month intervals is the mainstay of
Mayo Clin Proc. • July 2006;81(7):973-988
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CHRONIC MYELOID LEUKEMIA
TABLE 2. Summary of Studies Using High-Dose Imatinib
as Frontline Therapy for Early Chronic Phase
Chronic Myeloid Leukemia*
Dosage No. of CGCR MMR CMR
Study (mg/d) patients (%) (%) (%)
MDACC137 800 175 90 61 32
TIDEL138 600→800 41 90 44 25
RIGHT139 800 114 85 64 44
GIMEMA140 800 100 88 60 NA
*CGCR = complete cytogenetic remission; CMR = complete molecular
remission (BCR-ABL1 undetectable); GIMEMA = Gruppo Italiano
Malattie Ematologiche dell’Adulto; MDACC = M. D. Anderson Cancer
Center; MMR = major molecular response (BCR-ABL1/ABL1 <0.05% or
3-log reduction); RIGHT = Rationale and Insight on Gleevec [imatinib]
High-Dose Therapy; TIDEL = Therapeutic Intensification in de novo
leukemia.
monitoring for most patients. However, the lack of consis-
tency in reporting BCR-ABL transcript levels has been a
source of intense debate. A recent proposal aimed at the
standardization of RT-PCR techniques and result reporting
will greatly help this objective. According to this proposal,
results will be converted by comparing analysis of standard-
ized reference samples with a value of 0.1% corresponding
to MMR in all laboratories.155 After the patient has achieved
a complete cytogenetic remission, RT-PCR should be per-
formed every 3 months and a routine cytogenetic analysis
every 12 months.155 Fluorescence in situ hybridization in
peripheral blood specimens can be used to monitor the cyto-
genetic responses among cytogenetic analyses. In addition,
approximately 5% of patients who obtain a cytogenetic re-
sponse develop clonal karyotypic abnormalities in Ph chro-
mosome–negative cells, primarily consistent with those en-
countered in myelodysplastic syndromes, although only rare
cases of myelodysplastic syndrome or AML have been re-
ported.63 Although the long-term implications of these ab-
normalities are unknown, the risk of transformation to AML
warrants careful follow-up of these patients.
Imatinib Resistance. A subset of patients with CML
will exhibit either primary or secondary resistance to
imatinib. Primary resistance refers to patients never re-
sponding to imatinib, whereas secondary resistance occurs
when a patient who had an initial response to imatinib
eventually loses the response. Among patients treated in
CP, the rate of resistance has been estimated to be less than
2% per year. Several mechanisms of resistance have been
reported, many of them mostly in vitro or in selected pa-
tient samples, and their individual contribution to this phe-
nomenon has not been completely defined. The most fre-
quently identified mechanism of resistance is the develop-
ment of mutations in the Abl tyrosine kinase domain. More
than 40 different BCR-ABL point mutations have been
reported thus far, and new ones continue to be described.156
The region of the Abl kinase where mutations occur is
• www.mayoclinicproceedings.com 981
CHRONIC MYELOID LEUKEMIA

TABLE 3. Results With New Tyrosine Kinase Inhibitors After Failure of Imatinib
in All Phases of CML*
Hematologic response Cytogenetic response
(%) (%)
No. of
Agent and CML phase patients Overall Complete Overall Complete
Phase 1
170
Nilotinib
CP 17 92 92 53 35
CE 10 100 100 90 20
AP 46 72 46 48 13
MyBP 24 42 8 29 4
LyBP 9 33 … 22 11
Dasatinib171,172
CP 40 93 93 63 35
AP 11 81 45 36 18
MyBP 23 61 35 52 26
LyBP 10 80 70 90 30
Phase 2
Dasatinib
CP173 186 90 90 45 33
AP174 107 59 33 36 21
MyBP175 74 51 24 42 27
LyBP and Ph+ ALL176 78 40 26 54 46
*AP = accelerated phase; CE = clonal evolution; CML = chronic myeloid leukemia; CP = chronic
phase; LyBP = lymphoid blast phase; MyBP = myeloid blast phase; Ph+ ALL = Philadelphia
chromosome–positive acute lymphoblastic leukemia.

critical in their ability to confer varying degrees of insensi-
tivity to imatinib. In fact, ranges of 220 to more than 5000
nM/L in the inhibitory concentration that results in a 50%
reduction in proliferation (IC50) have been described in the
various Bcr-Abl mutants.157 The most frequent mutations
are those that map to the P-loop region of the kinase do-
main.157-159 The P-loop region is a glycine-rich structure that
serves as a docking site for phosphate groups of adenosine
triphosphate (ATP). G250E, Q252H, and the highly
imatinib-insensitive Y253F and E255K mutations locate in
this region. Despite not being directly involved in imatinib
binding, these residues have been linked to poor prognosis
in some series, with a median survival of 4 to 5 months.160-163
Other series have refuted this notion.164 The difference in
these series may be due to several factors, including patient
selection and the criteria used to select patients for screen-
ing for mutations. In addition, the first studies that sug-
gested a poor outcome for patients with P-loop mutations
did not address the management of patients after develop-
ing mutations, and it is now clear that several treatment
strategies can overcome resistance through mutations.165
Also, considering that individual mutations have different
levels of resistance to imatinib and other agents, it is more
appropriate to refer to individual mutations rather than
grouping them.155 The imatinib-insensitive T315I mutation
occurs in a highly conserved “gatekeeper” threonine resi-
due near the Bcr-Abl catalytic domain, thus leading to
steric interference with imatinib binding.161,162,166 Other mu-
tations have been described mapping to the catalytic do-
main and the activation loop of Abl, impairing the ability of
the kinase to adopt a close (inactive) spatial conformation
necessary to bind to imatinib.167
Despite the poor prognosis conferred by the T315I mu-
tant, in vitro and clinical data suggest that other mutations
may be clinically relevant.168 Furthermore, other mecha-
nisms of resistance, such as overexpression or amplification
of the BCR-ABL message and/or protein, may influence the
outcome of patients treated with imatinib. Recently, it was
shown that activation of Src kinases and NF-κB may play a
role in imatinib resistance in some patients.92,169
TREATMENT STRATEGIES FOR THE FUTURE
New Bcr-Abl Inhibitors. Several strategies are cur-
rently being developed to overcome imatinib resistance
(Table 3). New Abl TKIs have been developed with
enhanced potency and less stringent binding requirements
and, in some cases, with inhibitory activity against other
kinases involved in mechanisms of resistance to imatinib.
In addition, new agents that block Bcr-Abl in a non–ATP-
competitive manner may represent an alternative for
patients who develop imatinib-insensitive Bcr-Abl kinase
mutations.
Nilotinib (AMN107). Nilotinib is a phenylamino-py-
rimidine derivative with a 20- to 30-fold increased potency
compared with imatinib against Bcr-Abl. Crystallographic
models suggest that this increased potency is a result of

982 Mayo Clin Proc. • July 2006;81(7):973-988 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

nilotinib representing a better topographical fit for the Abl
kinase pocket. However, nilotinib, like imatinib, only binds
the Abl protein in its inactive conformation. Nilotinib
inhibits the tyrosine kinase activity of most clinically
important Bcr-Abl mutants, with the exception of T315I.157
A phase 1/2 study of nilotinib included 106 patients with
imatinib-resistant CML in all phases and 13 patients with Ph
chromosome–positive ALL.170 Patients received nilotinib at
dosages ranging from 50 to 1200 mg/d. In CML, hematolog-
ic response rates ranged from 44% to 89%, and cytogenetic
responses ranged from 22% in lymphoid and myeloid BP to
29% in AP and 50% in CP. Among patients with Bcr-Abl
mutations before nilotinib therapy, 60% had a hematologic
response, and 41% had a cytogenetic response. Nilotinib
dosage was escalated up to 1200 mg/d with good tolerance,
and the maximum tolerated dose was estimated at 600 mg
twice daily. The most common drug-related adverse events
were gastrointestinal, rash, and hematologic. Importantly,
greater exposure to the drug and inhibition of Bcr-Abl
phosphorylation were observed with twice-daily dosing
schedules compared with equivalent total doses admin-
istered on a once-daily schedule.170
Dasatinib (BMS-354825). Because it is possible that
inhibition of Bcr-Abl alone may not be sufficient to eradi-
cate all CML cells, particularly the leukemic imatinib-
insensitive quiescent stem cells, agents with additional in-
hibitory capacity against other kinases have been investi-
gated. Since Src kinases have been implicated in CML
pathogenesis and progression, dual Abl/Src inhibitors may
have enhanced activity compared with imatinib. Among
this new class of compounds, dasatinib has reached the
furthest level of clinical development. Dasatinib is an ATP-
competitive, dual-specific Src- and Abl-kinase inhibitor
with 100- to 300-fold higher potency against Bcr-Abl com-
pared with imatinib and significant activity against c-kit
(IC50, 5 nM), platelet-derived growth factor receptor β
(IC50, 28 nM), and Hck, Fyn, Src, and Lck kinases (IC50,
approximately 0.5 nM).177 However, dasatinib does not in-
hibit the T315I mutant, even in the presence of micromolar
concentrations.157 In phase 2 studies, dasatinib was admin-
istered at 70 mg twice daily to patients with CML in all
phases after imatinib failure. A CHR was achieved by 87%,
66%, 55%, and 46% of patients in CP, AP, myeloid BP,
and lymphoid BP/Ph chromosome–positive ALL, respec-
tively. Among patients in CP, 44% had a CCGR, whereas
46% to 66% of patients with advanced-phase CML had
MCGRs.173-176 In a dose-escalating study, dasatinib ren-
dered 2-log or greater reductions in Bcr-Abl transcripts in
43% of patients in advanced phase, and 37% of patients in
CP achieved 2-log or greater reductions, including 4 pa-
tients in each group who had an MMR.178 Overall, dasatinib
is well tolerated, with myelosuppression and gastrointesti-
Mayo Clin Proc. • July 2006;81(7):973-988
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CHRONIC MYELOID LEUKEMIA
nal toxic effects seen in some patients. Pleural effusions
have also been reported in 10% to 15% of patients, particu-
larly those in BP, and it is usually grade 1 or 2. Despite the
impressive results achieved with dasatinib, it may not
eradicate all quiescent leukemic stem cells, although it may
be more effective at this level than imatinib.149 Another
dual Abl/Src kinase inhibitor termed SKI-606179 is current-
ly being evaluated in phase 1 studies, and others, such as
NS-187 (INNO406),180 AZD0530,181 PD166326,182 and
PD180970,183 may soon follow.
Non–ATP-Competitive Bcr-Abl Inhibitors. Imatinib,
nilotinib, and dasatinib are ATP-competitive inhibitors and
therefore amenable to being affected in their ability to bind
to the Bcr-Abl kinase by the T315I mutation, which is
considered the “gatekeeper” of the kinase domain. Com-
pounds that target binding sites unrelated to the ATP-
kinase domain may overcome this problem. ON012380
targets the substrate-binding site of Bcr-Abl, competing
with natural substrates such as Crkl but not with ATP.184 In
fact, ON012380 causes regression of leukemia induced by
intravenous injection of 32DcI3 cells that express the Bcr-
Abl mutant T315I.184 BIRB796, a p38 mitogen-activated
protein kinase inhibitor, binds with excellent affinity to the
Bcr-Abl T315I mutant (Kd 40 nM), although high concen-
trations of this compound are necessary to inhibit
autophosphorylation of this mutant in Ba/F3 cells (IC50, 1-2
µM).159 In this regard, VX680 (MK-0457), a multikinase
inhibitor that inhibits, among others, aurora A and B ki-
nase, seems to have a more favorable profile against T315I,
although remarkably less affinity for wild-type Bcr-Abl
(IC50, >10 µM).159
Other Therapeutic Options. Other approaches are be-
ing developed for patients who develop resistance to
imatinib. Farnesyl transferase inhibitors, such as lonafarnib
and tipifarnib, have demonstrated activity both as single
agents and in combination with imatinib.185-188 This ap-
proach has rendered anecdotal responses in patients har-
boring the T315I mutant. Homoharringtonine is a Cephalo-
taxus alkaloid that represented the best therapeutic option
in patients in whom interferon alfa–based therapies failed
before the introduction of imatinib in clinical practice.189 Its
potential as salvage therapy in imatinib-resistant CML has
rekindled interest in this drug. Another avenue that has
been pursued in recent years is the use of hypomethylating
agents190,191 and histone deacetylase inhibitors.192-194 In a
phase 2 study, decitabine administered at 15 mg/m2, 5 days
a week for 2 consecutive weeks, rendered a CHR in 34%
and a CCGR in 46% of patients.190,191 These and other
agents with different targets are currently being developed
in an attempt to prevent or overcome resistance to imatinib.
Immune-mediated events play an important role in the
suppression of the CML clone, as evidenced by a subset of
• www.mayoclinicproceedings.com 983
CHRONIC MYELOID LEUKEMIA
patients who maintained a durable CHR after discontinua-
tion of interferon alfa therapy195 and after allogeneic-SCT
due to a graft-vs-leukemia effect.196 These observations
have sparked interest in developing immunologic ap-
proaches to treating CML. One such approach is the use of
vaccines to elicit specific immune responses directed to-
ward CML-restricted tumor antigens. Several vaccines are
currently being developed in clinical studies, which en-
compass the use of BCR-ABL junction-spanning se-
quences,197-199 the nonapeptide PR1 derived from protein-
ase 3,200 leukocyte-derived HSP70-peptide complexes,201
and granulocyte-macrophage colony-stimulating factor se-
creting vaccines.202 The Bcr-Abl breakpoint fusion peptide
vaccine has been already tested in phase 2 clinical stud-
ies.198,199 Bocchia et al199 have reported on 16 patients with
stable residual disease after more than 12 months of imatinib
therapy (n=10) or 24 months of interferon alfa therapy (n=6)
who received 6 vaccinations with a peptide vaccine derived
from the sequence p210-b3a2. Five of 9 patients taking
imatinib obtained a CCGR after vaccination, and 3 had
undetectable levels of b3a2 transcripts by RT-PCR. Among
the patients treated with interferon alfa, 2 achieved a CCGR,
and 3 had improvement in the percentage of Ph chromo-
some–positive metaphases. Overall, these data suggest that
this peptide vaccine may have a role in the management of
patients with CML and minimal residual disease.
SUMMARY
Consensus exists that imatinib therapy is the standard ap-
proach to the treatment of CML, and this modality will be
measured in the future against all new therapies. The recent
addition of the highly potent TKIs nilotinib and dasatinib
has further improved the armamentarium against CML but
also posed new challenges. First, the role of these new
compounds in modern algorithms of CML therapy is still
unknown and must be defined. Despite having shown im-
pressive response rates in patients after imatinib failure or
intolerance, the duration of these responses will be deter-
mined with longer follow-up. Their role in frontline
therapy for CML will also have to be defined. Second, as
our resources for controlling CML improve, the refinement
in molecular monitoring must improve in parallel. In this
regard, the lack of consistency among different laboratories
in BCR-ABL transcript results by current PCR technolo-
gies is still an ongoing problem. Future improvements in
molecular techniques and their standardization by using a
laboratory-specific conversion factor will be crucial to fur-
ther our understanding of the dynamics of molecular re-
sponse to TKIs, providing a uniform method and definition
of MMR and defining the concept of molecular relapse.
Other challenges, such as defining the best treatment for
984 Mayo Clin Proc. • July 2006;81(7):973-988
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patients who develop the Bcr-Abl T315I mutant, under-
standing the mechanism of resistance of patients without
detectable mutations, the emergence of new mechanisms of
resistance such as new mutations to the new TKI and other
agents, developing novel strategies for the management of
minimal residual disease, and delineating the current role
of SCT, will be the subject of arduous investigation in
future years. Despite all these uncertainties, the treatment
prospects of patients with CML have never been brighter.
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The Symposium on Oncology Practice: Hematological Malignancies
will continue in the August issue.
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