A JH

CME Information: Chronic myeloid leukemia: 2014 update

on diagnosis, monitoring, and management
Authors: Elias J. Jabbour and Hagop Kanterjian
CME Editor: Ayalew Tefferi, M.D.

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Blackwell Futura Media Services is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical
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Blackwell Futura Media Services designates this journal-based CME for a maximum of 1 AMA PRA Category 1 CreditTM. Physicians should
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Educational Objectives
Upon completion of this educational activity, participants will be better able to:
1. Define and personalize frontline therapy options in CML-CP
2. Identify milestones of response and when to switch therapy

Activity Disclosures
No commercial support has been accepted related to the development or publication of this activity.
Authors: Elias J. Jabbour discloses consulting work for BAS, Novartis, ARIPD, and Pfizer; as well as consulting work for and research grants
from TEVA. Hagop Kanterjian discloses research grants from BAS, Pfizer, Novartis, ARIPD, and TEVA.
CME Editor: Ayalew Tefferi, M.D. has no conflicts of interest to disclose.
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blinded. As such, the identities of the reviewers are not disclosed in line with the standard accepted practices of medical journal peer review.
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Conflict of Interest. The primary resolution method used was peer review and review by a non-conflicted expert.

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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

AJH Educational Material

A JH

Chronic myeloid leukemia: 2014 update on

diagnosis, monitoring, and management
Elias Jabbour* and Hagop Kantarjian
Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1
2 cases per 100,000 adults, and accounts for ~15% of newly diagnosed cases of leukemia in adults.
Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of
the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on
chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular
consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates
into a Bcr-Abl oncoprotein.
Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib have been
approved by the US Food and Drug Administration for the first-line treatment of patients with newly
diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly
deeper and faster responses; their impact on long-term survival remains to be determined.
Salvage therapy: For patients who fail frontline therapy, second-line options include second and third
generation TKIs. Although second and third generation TKIs are potent and specific BCR-ABL TKIs, they
exhibit unique pharmacological profiles and response patterns relative to different patient characteristics,
such as patients comorbidities, disease stage, and BCR-ABL mutational status. Patients who develop the
T315I gatekeeper mutation display resistance to all currently available TKIs except ponatinib. Allogeneic
transplantation remains an important therapeutic option for CML-CP who have failed at least 2 TKIs, and for
all patients in advanced phase disease.
C 2014 Wiley Periodicals, Inc.
Am. J. Hematol. 89:548556, 2014. V

Introduction
Disease overview
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 12 cases per 100,000 adults, and accounts for 15%
of newly diagnosed cases of leukemia in adults [1]. Central to the pathogenesis of CML is the fusion of the Abelson murine leukemia (ABL) gene
on chromosome 9 with the breakpoint cluster region (BCR) gene on chromosome 22, which results in expression of an oncoprotein, termed BCRABL [2]. BCR-ABL is a constitutively active tyrosine kinase that promotes growth and replication through downstream pathways such as RAS,
RAF, JUN kinase, MYC, and STAT [39]. This influences leukemogenesis by creating a cytokine-independent cell cycle with aberrant apoptotic
signals in response to cytokine withdrawal.
Until a little more than a decade ago, drug therapy for CML was limited to nonspecific agents such as busulfan, hydroxyurea, and interferonalfa (INF-a) [10]. INF-a led to regression of the disease and improved survival but was hindered by a multitude of toxicities. Allogeneic stem cell
transplantation (AlloSCT) was a curative intervention, but carried with it a high risk of morbidity and mortality. Further, alloSCT is only an
option for patients with excellent performance status and an appropriate stem cell donor.
The landscape changed dramatically with the development of small molecule tyrosine kinase inhibitors (TKIs) that was shown to potently interfere with the interaction between the BCR-ABL protein and adenosine triphosphate (ATP), blocking cellular proliferation of the malignant clone
[4]. This targeted approach was found to dramatically alter the natural history of the disease, improving 10-year overall survival (OS) from 20
to 8090% [1,11]. In this review, we will briefly highlight the evidence supporting the use of each of the available TKIs, including how to select an
agent in various circumstances and phases of the disease. AlloSCT is performed rarely in CML, and patients who may benefit from such an intervention will be discussed. Cytogenetic and molecular benchmarks for patients on therapy will be mentioned throughout the article. Finally, appropriate monitoring strategies for patients on the various TKIs will be covered.

Manifestations and Staging

About 30 to 50% of patients with CML diagnosed in the United States are asymptomatic. The disease is found on routine physical examination or
blood tests. CML can be classified into three disease phases: chronic phase (CP), accelerated phase (AP), and blast phase (BP). Diagnosis is most
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Conflict of interest: Nothing to report.

*Correspondence to: Elias Jabbour, MD, MD Anderson Cancer Center, Box 428, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: [email protected]
Received for publication: 3 February 2014; Accepted: 3 February 2014
Am. J. Hematol. 89:548556, 2014.
Published online: in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.23691
C 2014 Wiley Periodicals, Inc.
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commonly made during the CP. Common signs and symptoms of CML
in CP, when present, result from anemia and splenomegaly. These
include fatigue, weight loss, malaise, easy satiety, and left upper quadrant fullness or pain. Rare manifestations include bleeding (associated
with a low platelet count and/or platelet dysfunction), thrombosis (associated with thrombocytosis and/or marked leukocytosis), gouty arthritis
(from elevated uric acid levels), priapism (usually with marked leukocytosis or thrombocytosis), retinal hemorrhages, and upper gastrointestinal ulceration and bleeding (from elevated histamine levels due to
basophilia). Leukostatic symptoms (dyspnea, drowsiness, loss of coordination, and confusion) due to sludging in the pulmonary or cerebral
vessels, are uncommon in CP despite WBC counts exceeding 100 3
109/L. Splenomegaly is the most consistent physical sign in CML, and is
detected in 5060% of cases. Hepatomegaly is less common (1020%).
Lymphadenopathy and infiltration of skin or other tissues are uncommon. When present, they favor Ph-negative CML or AP or BP of CML.
Headaches, bone pain, arthralgias, pain from splenic infarction, and
fever are more frequent with CML transformation. Most patients evolve
into AP prior to BP, but 20% transit into BP without AP warning signals. AP might be insidious or present with worsening anemia, splenomegaly, and organ infiltration; BP presents as an acute leukemia with
worsening constitutional symptoms, bleeding, fever, and infections.

Diagnosis
The diagnosis of typical CML is simple and consists of documenting, in the setting of persistent unexplained leukocytosis (or occasionally thrombocytosis), the presence of the Ph chromosome
abnormality, the t(9;22)(q34;q11), by routine cytogenetics, or the Phrelated molecular BCR-ABL abnormalities by fluorescent in situ
hybridization (FISH) or by molecular studies [1214].
A FISH analysis relies on the colocalization of large genomic
probes specific to the BCR and ABL genes. Comparison of simultaneous marrow and blood samples by FISH analysis shows high concordance. FISH studies may have a false positive range of 110%
depending on the probes used.
Reverse transcriptase-polymerase chain reaction (RT-PCR) amplifies
the region around the splice junction between BCR and ABL. It is highly
sensitive for the detection of minimal residual disease. PCR testing can
either be qualitative (QPCR), providing information about the presence
of the BCR-ABL transcript, or quantitative, assessing the amount of
BCR-ABL message. Qualitative PCR is useful for diagnosing CML;
quantitative PCR is ideal for monitoring residual disease. Simultaneous
peripheral blood and marrow QPCR studies show a high level of concordance. False-positive and false-negative results can happen with
PCR. False-negative results may be from poor-quality RNA or failure of
the reaction; false-positive results can be due to contamination. A 0.51
log difference in some samples can occur depending on testing procedures, sample handling, and laboratory experience [1214].
The Ph chromosome is usually present in 100% of metaphases, often
as the sole abnormality. Ten to fifteen percent of patients have additional
chromosomal changes (clonal evolution) involving trisomy 8, isochromosome 17, additional loss of material from 22q or double Ph, or others.
Eight-five percent of patients have a typical t(9;22); 5% have variant translocations, which can be simple (involving chromosome 22
and a chromosome other than chromosome 9), or complex (involving
one or more chromosomes in addition to chromosomes 9 and 22).
Patients with Ph-variants have response to therapy and prognosis
similar to Ph-positive CML.

Differential Diagnosis
CML must be differentiated from leukemoid reactions, which usually
produce white blood cell counts lower than 50 3 109/L, toxic granulo-

doi:10.1002/ajh.23691

cytic vacuolation, Dohles bodies in the granulocytes, absence of basophilia, and normal or increased LAP levels. The clinical history and
physical examination generally suggest the origin of the leukemoid reaction. Corticosteroids can rarely cause extreme neutrophilia with a left
shift, but this abnormality is self-limited and of short duration.
CML may be more difficult to differentiate from other myeloproliferative or myelodysplastic syndromes. Patients with agnogenic myeloid metaplasia with or without myelofibrosis frequently have
splenomegaly, neutrophilia, and thrombocytosis. Polycythemia vera
with associated iron deficiency, which causes normal hemoglobin and
hematocrit values, can manifest with leukocytosis and thrombocytosis.
Such patients usually have a normal or increased LAP score, a WBC
count <25 3 109/L, and no Ph chromosome.
The greatest diagnostic difficulty lies with patients who have
splenomegaly and leukocytosis but do not have the Ph chromosome.
In some, the BCR-ABL hybrid gene can be demonstrated despite a
normal or atypical cytogenetic pattern. Patients who are Ph negative
and BCR-ABL negative are considered to have Ph-negative CML or
chronic myelomonocytic leukemia. Rarely, patients have myeloid
hyperplasia, which involves almost exclusively the neutrophil, eosinophil, or basophil cell lineage. These patients are described as having
chronic neutrophilic, eosinophilic, or basophilic leukemia and do not
have evidence of the Ph chromosome or the BCR-ABL gene. Isolated
megakaryocytic hyperplasia can be seen in essential thrombocythemia,
with marked thrombocytosis and splenomegaly. Some patients who
present with clinical characteristics of essential thrombocythemia
(with marked thrombocytosis but without leukocytosis) have CML;
cytogenetic and molecular studies showing the Ph chromosome, the
BCR-ABL rearrangement, or both lead to the appropriate diagnosis
and treatment.

Frontline Treatment Options

Presently, there are three commercially available TKIs for the treatment of CML; these include imatinib, dasatinib, and nilotinib. Current guidelines endorse all three as viable options for the initial
management CML-CP (Table I).

Imatinib
Imatinib mesylate (Gleevec, Novartis Pharmaceutical Corporation,
NJ), was the first TKI to receive approval by the Food and Drug
Administration for the treatment of patients with CML-CP. It acts
via competitive inhibition at the ATP-binding site of the BCR-ABL
protein, which results in the inhibition of phosphorylation of proteins
involved in cell signal transduction. It efficiently inhibits the BCRABL kinase, but also blocks the platelet-derived growth factor receptor, as well as the C-KIT tyrosine kinase [15].
The International Randomized Study of Interferon and STI571
(IRIS) study is considered a landmark clinical trial for TKIs and
CML [16]. Investigators randomized 1,106 patients to receive imatinib
400 mg/day or INF-a plus low-dose subcutaneous cytarabine. After a
median follow-up of 19 months, relevant outcomes for patients
receiving imatinib were significantly better than in those treated with
INF-a plus cytarabine, notably the rate of complete cytogenetic
response (CCyR) rate (74 vs. 9%, P < 0.001), and freedom from progression to AP or BP at 12 months (99 vs. 93%, P < 0.001). Further
highlighting the challenge of using IFN-a was the high crossover rate
to imatinib due to intolerance. The responses to imatinib were also
durable, as shown in an 8-year follow up of the IRIS study [11]. Estimated event free survival rate was 81%, and OS rate was 93% when
only CML-related deaths were considered.
While the results using imatinib are quite impressive, only 55% of
patients enrolled in the IRIS study remained on therapy at the 8-year
follow up point. This underscored the need for additional options for

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Jabbour and Kantarjian

TABLE I. Summary of Pivotal Phase III Trials of Approved Tyrosine Kinase Inhibitors for the Treatment of Frontline or Relapsed CML
Follow-up data
Trial

Treatment

No. of patients

Ima 400 mg qd
IFN 1 ara-c

553
553

Nilo 300 mg bid

Nilo 400 mg bid
Ima 400 mg qd

282
281
283

Dasa 100 mg qd
Ima 400 mg qd

259
260

IRIS

ENESTnd

DASISION

Primary end point

% MMR

% PFS at 18 months
97
91 (P < 0.001)
% MMR at 12 months
44
43
22 (P < 0.001 for
both comparisons)
% CCyR at 12 months
77
Imatinib: 66 (P 5 0.007)
Secondary endpoint:
MMR at 12 months:
Dasa: 46 Ima: 28 (P < 0.0001)

77
77
60 (P < 0.0001 for
both comparisons)
74
46

% PFS

% OS

6/8 years
93/92

6/8 years
88/85

5 years
92
95.5 (P  0.03 vs ima)

93.6
96 (P 5 0.04 vs ima)

4 years
90
90.2

92.9
92.1

ara-c: cytarabine; dasa: dasatinib; IFN: interferon; Ima: imatinib; MMR: major molecular response; nilo: nilotinib; OS: overall survival; PFS: progression-free
survival.

patients who had failed or were intolerant to imatinib. This led to the
rational development of second generation TKIs with hopes they would
effectively treat patients unable to continue on imatinib therapy.

Dasatinib
Dasatinib (Sprycel, Bristol-Myers Squibb) is an oral, second generation TKI that is 350 times more potent than imatinib in vitro [17
19]. In addition, it also is known to inhibit the Src family of kinases,
which may also be important in blunting critical cell signaling pathways [20]. Though initially evaluated in patients in the salvage setting, clinicians and researchers were excited to test the possibility that
frontline use of the more potent inhibitors might further improve the
outcome compared to imatinib.
The DASISION trial was a phase III, randomized study comparing
imatinib 400 mg once daily to dasatinib 100 mg once daily in newly
diagnosed patients [21]. Dose escalations were allowed for both drugs
in the setting of suboptimal response as defined per protocol. The
primary outcome was confirmed cCCyR at 12 months. A total of 519
patients were randomized in a 1:1 manner. Patients assigned to dasatinib achieved cCCyR at 12 months more frequently than those on
imatinib (77 vs. 66%, P 5 0.007). Many of the secondary endpoints of
interest were also significantly different between groups favoring the
dasatinib arm. A three-year follow up of the trial was recently published, and illustrated that dasatinib induces more rapid, deeper
responses at early time points compared to imatinib [22]. For
instance, at 3 months, a higher proportion of patients treated with
dasatinib achieved a BCR-ABL transcript level of less than or equal
to 10% (84 vs. 64%, P < 0.0001). Meeting this threshold in either arm
predicted for both progression-free survival and OS. As might be
expected, pleural effusions occurred more frequently in the group
receiving dasatinib (19 vs. <1%).

Nilotinib
Nilotinib (Tasigna, Novartis Pharmaceutical Corporation, NJ) is a
structural analog of imatinib, though its affinity for the ATP binding
site on BCR-ABL is up to 50 times more potent in vitro [23]. Like
dasatinib, nilotinib initially demonstrated the ability to induce hematologic and cytogenetic responses in patients who had failed imatinib.
Similar to the data with dasatinib, nilotinib has also been directly
compared with imatinib in a large, international, randomized study.
In ENESTnd, two doses of nilotinib (300 or 400 mg twice daily) were
compared with imatinib 400 mg once daily [24]. The primary end550

American Journal of Hematology, Vol. 89, No. 5, May 2014

point in this study was the rate of major molecular response (MMR)
at 12 months. This endpoint was achieved at statistically significantly
higher rates for both doses of nilotinib compared with the imatinib
group (44 and 43% vs. 22%, P < 0.001). There was also much less
progression to AP or BP on the nilotinib arm. Recently, a 36 month
follow-up was published, and differences in deep molecular responses
continued to favor nilotinib at either dose [25].
Current guidelines recommend any of the three TKIs: imatinib,
dastinib, or nilotinib as options with a category 1 recommendation
for initial treatment of CML-CP [26]. Second generation TKIs have
shown inducing higher rates of early optimal responses; their impact
on long-term over survival remains to be determined. AlloHSCT or
other chemotherapy agents are not any longer recommended as
upfront treatments for CML-CP given the excellent outcomes and
long-term survival achieved with the TKIs.

Selecting a Frontline Therapy

Comorbidities and TKI toxicity profile
While there are multiple TKIs acceptable for patients with newly
diagnosed patient with CML in CP, each agent has a distinct toxicity
profile, and this should be a consideration when deciding on a therapy.
With that said, most TKIs are reasonably well tolerated when adequate
monitoring and supportive care are in place. For patients at risk of
developing pleural effusions, clinicians may choose to select a TKI other
than dasatinib. This might be relevant for patients with a history of
lung disease (e.g., chronic obstructive pulmonary disease), cardiac disease (e.g., congestive heart failure), or uncontrolled hypertension. Pulmonary arterial hypertension (PAH) is also an important complication
of dasatinib [27], and patients with preexisting PAH may be considered
for alternative TKIs in the frontline setting. Dasatinib also inhibits the
function of platelets [28], and patients taking concomitant anticoagulants may be at an increased risk of hemorrhagic complications [29].
Nilotinib has been associated with hyperglycemia, and caution
should be exercised in patients with uncontrolled diabetes when initiating therapy. During preclinical development, nilotinib was shown
to potentially prolong the QT interval, and parameters were put in
place to monitor for this complication after the drug was approved.
In a retrospective review of 81 patients using the drug in clinical
practice, the QT interval for the entire cohort was not statistically significantly prolonged at any time point during the duration of the

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ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

study [30]. No patient experienced a QT interval >500 msec. While
this study shows that perhaps nilotinib is safer from a cardiac standpoint than once believed, some caution should be used when considering its initiation in a patient with QT prolongation at baseline. In
addition, potassium and magnesium should be repleted to appropriate
serum levels before starting nilotinib or determining an individual
patients QT interval. Patients should always be counseled to take
nilotinib in a fasting state to avoid excess drug exposure. Recently,
nilotinib has been associated with a low, but significant incidence of
vascular events [31]. These events included peripheral artery disease,
but also cerebrovascular accidents and cardiovascular syndromes.
Avoiding nilotinib in patients with significant past vascular histories
may be warranted with the availability of other viable options.
While dasatinib predisposes some patients to pleural effusions,
imatinib tends to cause peripheral edema as one of its chief side
effects. Patients can usually be monitored closely for this after initiation of imatinib, and intermittent use of loop diuretics helps to minimize fluid retention. If patients have significant peripheral edema at
baseline, nilotinib or dasatinib may be considered better first options,
although the etiology of the edema should also be investigated and
considered in the choice of therapy.

Cost
The price of therapies to treat cancer has been on an exponential rise
over the past decade [32]. Of the 12 agents used in cancer care that
were approved in 2012, at least nine of them were priced at over
$100,000 annually [33]. Most of these therapies did not appear to provide a substantial improvement in survival or other measures to justify
such a cost. Recently, an international group of CML experts called
attention to the high prices of TKIs in particular [34]. The case of imatinib was used to illustrate an example of how things have spun out of
control. When first approved, the annual price for imatinib was
$30,000 in the United States. This was the price set to make the development and commercialization of imatinib profitable when it was
expected that most patients would take the drug for perhaps 510 years.
Patients can now remain on imatinib and live a normal lifespan as long
as they are compliant with the medication [35]. Imatinib has also gone
on to receive additional indications, such as the treatment of gastrointestinal stromal tumor [36]. Paradoxically though, with a higher number of patients and a longer duration of therapy, the annual price of
imatinib in 2013 was nearly triple at $90,000. This price is in the same
range as dasatinib and nilotinib, both of which are over $100,000.
At this point, the costs of TKIs are all fairly similar, as they are
priced against each other. However, in the coming years, imatinib is
set to be available as a generic formulation, and the expectation is that
the price will eventually fall dramatically. When this happens, clinicians
will have to weigh the early benefits some patients attain with dasatinib
or nilotinib in the frontline setting against the disparity in cost.
In general, any of the three TKIs currently approved for frontline
use may be selected. These include imatinib, dasatinib, or nilotinib.
While dasatinib and nilotinib have demonstrated superiority over imatinib when early surrogate markers are used, imatinib is still expected
to be highly effective in a large number of CML patients. When
choosing an agent, one can consider issues such as comorbidities,
adverse event profile, and cost to help make the final determination.
Kinase domain mutation profile plays very little, if any role in selecting an initial TKI, but becomes highly relevant in the relapsed setting.

Monitoring Treatment Response:

Surrogate Endpoints and Milestones
Because patients with CML on TKI therapy are expected to live for
a long period of time, surrogate markers of outcome have become

doi:10.1002/ajh.23691

highly important. In general, achieving a deeper and faster response

has been associated with improved outcome, although the result of
molecular testing is dependent on the laboratory and their techniques.
Advances in technology have made available tests that allow traditional bone marrow examinations to be avoided in certain situations.

Important points for monitoring and determining

treatment failure
At baseline, it is imperative that all patients undergo a bone marrow biopsy to firmly establish the diagnosis and provide a sample for
cytogenetic testing. This also allows for proper staging in terms of the
blast and basophil percentage. Presently, it is recommended that
patients have a follow up bone marrow study at 3, 6, and 12 months
after starting therapy [37]. An alternative method to determine cytogenetic response is with the use of FISH on peripheral blood. If a
patient is responding optimally, and the FISH study is negative at 6
or 12 months, it may be reasonable to omit further marrow exams, as
the patient is likely to be in stable CCyR [38,39].
For patients in durable CCyR receiving TKI therapy, periodic
molecular monitoring using RT-Q-PCR is acceptable and useful, but
may lead to erroneous changes in treatment due to discordance in
results between laboratories or even within the same laboratory. This
is harmful to patients, as it leads to potentially discontinuing a useful
therapy that the patient may have been tolerating well. One strategy
to minimize this is to use interphase FISH as a complementary diagnostic test along with the molecular test to detect possible false positive or negative results generated by either assay [39]. For patients in
CCyR, the achievement and maintenance of a MMR is of debatable
significance. Several studies evaluating patients receiving imatinib or
second generation have found that patients in CCyR have similar survival whether there is achievement of MMR or not [22,40,41].
Early molecular response has been shown in a number of studies
to have strong prognostic value. This has been applied to each of the
TKIs that are appropriate for use in the frontline setting. A BCR-ABL
transcript level of <10% at 3 months has repeatedly been shown to
clearly separate groups into high and low risk categories for long
term outcomes (i.e., progression, survival) [22,42,43]. However, the
main question that arises with this information is what to do with a
patient that does not meet the 3 month benchmark? One option is to
switch TKIs early, but there are currently no data proving that this
will alter the long term outcome of the patient. Several experts have
suggested that a follow up measurement at 6 months will help define
patients clearly in need of a change in therapy [37]. This strategy has
been retrospectively analyzed by several large groups with conflicting
results [4446]. The results of two independent study groups have
suggested that all patients with BCR-ABL transcript levels >10% at 3
months do not necessarily have an inferior outcome [45,46]. Those
patients who continued on therapy and achieved transcripts levels
<10% by 6 months had approximately the same long term outcome
as those patients with optimal molecular responses at 3 months.

When to switch therapy

It is still relevant to suggest that the gold standard should be the
achievement of CCyR within 12 months, especially for standard dose
imatinib therapy. For second generation TKIs, CCyR may need to be
achieved sooner for an optimal outcome, for example, within 3 or 6
months [47]. Patients who do not achieve a complete hematologic
response by 3 months should be considered for a change in therapy
(Table II).
One large question is whether to change therapy at 3 months
based on the level of BCR-ABL transcripts. For patients on imatinib,
if the 3 month transcript level is >10%, we suggest an approach similar to what is recommended in the ELN guidelines [37], which is to

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TABLE II. Response Evaluation to TKIs Used as First-Line Therapy (ELN 2013)

Baseline
3 months
6 months
12 months
Any time

Optimal

Warning

Failure

Ph1 < 35% and/or BCR-ABL < 10%

Ph1 0% and/or BCR-ABL < 1%
BCR-ABL < 0.1%
BCR-ABL < 0.1%

CCA in Ph1 cells, High-risk Sokal, or Hasford score

Ph1 3695% and/or BCR-ABL > 10%
Ph1 1 35% and/or BCR-ABL 110%
BCR-ABL 0.11%
CCA in Ph2 cells (27 or 7q2)

Ph1 > 95% and/or No CHR

Ph1 > 35% and/or BCR-ABL > 10%
BCR-ABL > 1% and/or Ph1 > 0%
Loss of CHR
Loss or CCyR
Confirmed loss of MMR
CCA in Ph1 cells

perform serial molecular monitoring between 3 and 6 months to sufficiently determine the response. If patients still have >10% BCRABL transcripts at 6 months, the chances of attaining CCyR are low,
and a change of therapy might be in order. We would also consider
this approach for patients on second generation TKIs, because, as
mentioned previously, very early switching has not yet been shown to
influence the long-term outcome [48]. Another study randomized
patients in CCyR on imatinib for at least 2 years to continue imatinib
or switch to nilotinib [49]. While switching to nilotinib induced
deeper molecular responses, it has yet to translate into an improvement in progression-free survival or other meaningful outcomes.
Patients who meet all of the relevant benchmarks in the first 12
months are monitored periodically using FISH and molecular testing.
If there are clear signs of possible failure, patients should undergo a
bone marrow biopsy with cytogenetics to assess for relapse. Any
degree of cytogenetic relapse calls for a change in therapy, while fluctuating molecular levels during continuous CCyR should only prompt
closer monitoring and a compliance assessment.
In several studies, the achievement of a CCyR (Ph-positive metaphases 0%; BCR-ABL transcripts [IS]  1%) at 12 months or later on
TKI therapy was associated with significant survival benefit compared
with achievement of lesser degrees of response. Therefore, achievement of CCyR is now the primary endpoint of TKI therapy. Achievement of BCR-ABL transcripts ( 0.1% [IS]) was associated with
modest improvements in event-free survival rates, possible longer
durations of CCyRs, but not with a survival benefit. The achievement
of complete molecular response (CMR; nonmeasurable BCR-ABL
transcripts) offers the possibility of treatment discontinuation in clinical trials only. Lack of achievement of MMR or of CMR should not
be interpreted as a need to change TKI therapy or to consider
alloHSCT. Response assessments at earlier times on front-line TKI
therapy (36 months) have shown better outcomes with achievement
of a major cytogenetic response by 36 months on imatinib therapy
(Ph-positive metaphases  35%, or BCR-ABL1 transcripts  10%).
While this is interpreted to mean that a change to second TKI therapy may be considered if such outcome is not obtained, no studies
have shown that changing therapy from imatinib to second TKIs has
improved patients outcome. When nilotinib or dasatinib are used for
front-line therapy, achievement of CCyR by 36 months of TKIs
therapy has been associated with improved outcomes.

Management of TKI Resistance

A problem that may increase due to the widespread use of all of
the commercially available TKIs for CML is increased drug resistance.
One of the most common mechanisms of resistance involves point
mutations in the kinase domain of BCR-ABL, which impairs the
activity of the available TKIs. Second generation TKIs are able to
overcome most of the mutations that confer resistance to imatinib,
though novel mutations rendering the leukemia resistant to dasatinib
and/or nilotinib have emerged. One important mutation, the T315I,
552

American Journal of Hematology, Vol. 89, No. 5, May 2014

is known as the gatekeeper mutation, as it displays resistance to all

currently available TKIs except ponatinib.
Before defining a patient as having TKI-resistance and modifying
therapy, treatment compliance and drug-drug interactions should be
ruled out. Rates of imatinib adherence have been estimated to range
from 75 to 90%, and lower adherence rates correlated to worse outcome [5052]. In one study of 87 patients with CML-CP treated with
imatinib 400 mg daily, adherence rate of 90% or less resulted in
MMR in only 28.4% as compared with 94.5% in patients with >90%
adherence rates (P < 0.001) [50]. CMR rates were 0 vs. 43.8%, respectively, (P 5 0.002), and no molecular responses were observed when
adherence rates were 80% or lower. Lower adherence rates have been
described in younger patients, those with adverse effects of therapy,
and those who have required dose escalations [50].

Second and third generation TKIs

Before their approval to treat first-line CML-CP, both nilotinib
and dasatinib were approved for use in second-line CML-CP following prior therapy including imatinib [53,54]. Clinical studies of
second-line and third line TKIs are summarized in Table III. Based
on these clinical studies, several noteworthy ideas have emerged. First,
second-line treatment with nilotinib or dasatinib can yield high rates
of response in patients who have inadequate response to imatinib,
including high rates of MMR. Second, dose escalation of imatinib can
improve response rates in patients with inadequate response to
standard-dose imatinib, but switching to second-line nilotinib or
dasatinib can be more effective [55]. Several studies that evaluated
second-line nilotinib [56,57] or dasatinib [56,58] and high-dose imatinib (400 mg BID) have demonstrated significantly higher rates of
CHR, CCyR, and MMR with the newer TKIs than with high-dose
imatinib. Moreover, PFS in these studies was better with the newer
TKIs than with high-dose imatinib. In addition, earlier switch to
second-line TKI may be more effective than later switch. In the
TIDEL-II study, patients who had suboptimal response to imatinib
and were switched right away to nilotinib had a higher rate of CMR
at 12 months than patients who had dose escalation of imatinib prior
to being switched to nilotinib [59]. In a retrospective pooled analysis
of three clinical studies of second-line dasatinib for patients resistant
to or intolerant of imatinib, patients who were switched to dasatinib
after the loss of MCyR (early intervention group) had higher rates of
CHR, CCyR, and MMR, as well as 24-month EFS, TFS, and OS, than
patients who were switched after the loss of both MCyR and CHR
(late intervention group) [60]. Although this analysis included studies
with distinct study designs and various dosing schedules of dasatinib,
the core finding that earlier switch to dasatinib was associated with
better outcomes than later switch was reasonably consistent.
Bosutinib was initially studied in patients that were resistant to or
intolerant of imatinib [61]. After a dose escalation period, 500 mg
once daily was selected to go forward as the phase II dose, with the
potential for dose escalation to 600 mg once daily for patients not

doi:10.1002/ajh.23691

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

TABLE III. Summary of Important Phase II Trials of Second and Third Generation TKIs After Prior TKI Failure
Percent Response
Dasatinib
Response
Median follow-up (mo.)
% Resistant to imatinib
% Hematologic Response
CHR
NEL
% Cytogenetic Response
Complete
Partial
% Survival (at 12 months)

Nilotinib

Bosutinib

Ponatinib

CP
AP
MyBP
LyBP
CP
AP
MyBP LyBP
CP
AP
BP
CP
N 5 387 N 5 174 N 5 109 N 5 48 N 5 321 N 5 137 N 5 105 N 5 31 N 5 146 N 5 51 N 5 38 N 5 271
15
74

91

NR
49
11
96

4
93
79
45
19
44
32
7
82

12a
91
50
27
7
36
26
7
50

12a
88
40
29
6
52
46
6
50

24
70
94
76

NR
46
15
87

9
80
56
31
12
NR
20
12
67

3
82
22
11
1
NR
29
10
42

3
82
19
13
0
NR
32
16
42

7
69
85
81

34
13
98

6
NRb
54
54
0
NR
27
20
60

3
NRb
36
36
NR
NR
35
18
50

11
NR
NR
NR
46
NR
91

AP
N 5 79

BP
N 5 94

13
6
96
NR
NR
Ma HR: 57 MaHR: 34
NR
NR
NR
NR
55
36
NR
NR
42
35

AP: accelerated phase; BP: blast phase; CHR: complete hematologic response; CP: chronic phase; LyBP: lymphoid blast phase; MaHR: major hematologic
response; MyBP: myeloid blast phase; NEL: no evidence of leukemia; NR: not reported.

meeting prespecified benchmarks. There were 288 patients enrolled in

the pivotal phase II trial, with more than two thirds of the patients
documented as having imatinib-resistant disease. The primary endpoint was MCyR at 6 months, and this was achieved in 31% of the
patients treated. At any point during follow up, 41% achieved a
CCyR. Bosutinib appeared to retain activity across most known mutations that confer imatinib resistance, except for the T315I. Responses
were independent of whether patients were resistant to or intolerant
of imatinib. The most common toxicities noted were diarrhea, nausea,
vomiting, and rash. Diarrhea occurred in 84% of the patients overall,
with 9% experiencing an event classified as grade 3 (there were no
grade 4 events documented). Other notable adverse events included
myelosuppression and liver function test abnormalities.
Ponatinib is considered a third generation TKI, as it is the first
compound in the class considered to exhibit activity against CML in
the presence of a T315I mutation [62]. It is considered greater than
500 times as potent than imatinib at inhibiting BCR-ABL [63]. Evidence to support the approval of ponatinib was presented in the
phase II PACE trial, where 449 patients with heavily pretreated CML
or Philadelphia chromosome-positive acute lymphoblastic leukemia
were enrolled [64]. Patients were considered for this trial if they were
resistant to or intolerant of dasatinib or nilotinib. Alternatively, any
patient with a T315I mutation could be included. The dose of ponatinib was 45 mg once daily, and patients were stratified by phase of
disease and whether or not there was a T315I mutation. Focusing on
the 267 patients who received ponatinib in the CP, 56% achieved a
MCyR by 12 months, which included 70% of CP patients with a
T315I mutation (n 5 45). Patients responded more favorably if they
had received fewer TKIs. The most common adverse events were
rash, dry skin, and abdominal pain. Other notable toxicities in the
PACE study included hypertension and pancreatitis. Serious events
possibly related to the drug included arterial thrombotic events, and
the rate was reported to increase with longer durations of exposure to
ponatinib. This led to a temporary suspension of the sale of ponatinib
in the United States, as well as the modification or closure of several
clinical trials. Revised labeling and a restricted access program were
put in place allowing the manufacturer to resume its marketing.

How to select a second or third line option

At the time of treatment failure, patients should undergo bone
marrow biopsy to allow proper determination of disease phase and
documentation of any clonal evolution. All patients should have their
CML cells tested for BCR-ABL kinase domain mutations, as this will
help guide the decision on which TKI to select. Dasatinib and nilotidoi:10.1002/ajh.23691

nib retain activity against most of the known mutations that confer
resistance to imatinib [65,66]. When selecting between dasatinib and
nilotinib, in vitro and in vivo data have identified distinct mutations
that exhibit decreased sensitivity to each of the agents [67,68]. The
clinician may tend to favor dasatinib if the patient has the following
mutations at the time of disease progression: Y253H, E255K/V, or
F359C/V. Alternatively, nilotinib may be a better selection in the
presence of the V299L and F317L mutations. For patients lacking
these mutations, the choice once again calls into consideration toxicity profile and cost.
The available data also indicate that bosutinib can be used for
patients with most known mutations that lead to imatinib failure
[61]. Like dasatinib and nilotinib, bosutinib lacks activity against
T315I. Bosutinib may be a reasonable choice for patients who fail
imatinib who are not good candidates for dasatinib or nilotinib.
Bosutinib has a relatively distinct toxicity profile from the other TKIs,
with the predominant problem being diarrhea and other gastrointestinal complaints. Recently, an analysis was conducted to closely characterize the toxicity of bosutinib and the management strategy [69].
Diarrhea was documented in 82% of the overall cohort (n 5 570), the
majority of which was grades 1/2 in severity. Myelosuppression and
liver function test abnormalities were also common. The authors
found that with appropriate supportive care and monitoring, most
patients are able to continue on therapy with periodic dose interruptions or adjustment.
Ponatinib should be considered the agent of choice for any patient
that develops a T315I mutation and in instances where other TKIs
are not indicated. There are currently no other commercially available
TKIs that have activity against this mutation. The risk for thrombotic
events with ponatinib is serious, but the benefits outweigh the risks
for most patients with a T315I mutation, as there are very few viable
options for disease control.
Second and third generation TKIs have not been compared headto-head, so we currently select one or the other based on the side
effect profile, mutations profile, drug interactions, compliance issues,
and the patients preexisting medical conditions. We do a mutational
analysis in patients who are failing imatinib or second generation
TKIs, or those who progress to AP/BP. We do not test baseline mutational analysis on patients with newly diagnosed CML in CP, as it
has not proven to predict treatment outcome either.

Allogeneic stem cell transplantation

The number of patients undergoing alloSCT for CML-CP has
dropped significantly since TKIs were introduced, and has more of
American Journal of Hematology, Vol. 89, No. 5, May 2014

553

Jabbour and Kantarjian

an important role when patients evolve into AP/BC (see below).

However, alloSCT remains an important therapeutic option for CMLCP in the following situations: patients who fail at least 2 TKIs and
potentially patients harboring the T315I mutation after a trial of
ponatinib therapy [70].

Treatment Duration and

Discontinuation
The Stop Imatinib (STIM) trial sought to investigate the risk of
relapse in patients on imatinib with ongoing CMR for >2 years who
stopped treatment [71,72]. At the time of the most recent update, 100
patients had a median follow up of 50 months and were monitored
closely for evidence of molecular relapse. Overall, 61% experienced a
molecular relapse, with 95% of the events occurring within 7 months of
stopping imatinib. Almost all patients were able to re-achieve their
CMR once imatinib therapy was restarted. One patient did have possible loss of cytogenetic response, necessitating a change in therapy to
dasatinib. Having a low-risk Sokal score and duration of imatinib therapy >60 months predicted for continued CMR after therapy cessation.
The results of the STIM trial have been confirmed by other large
groups of CML researchers. The TWISTER study followed 40 patients
who stopped imatinib after being without detectable minimal residual
disease for >2 years [73]. Patients were followed for a minimum of 15
months (median 43 months) from the time they stopped imatinib. Over
the course of the study, 22 of 40 patients became molecularly positive.
Nearly 70% of the molecular relapses occurred within the first 6 months
of treatment cessation. Similar, patients who resumed TKIs were able to
recapture deep molecular responses. Interestingly, highly sensitive
patient specific PCR was able to detect the original CML clone in several of the patients who remained off imatinib for several years. This
indicates that it may not be necessary to completely eradicate the disease to allow patients to enjoy a functional cure.
The previous studies contained heterogeneous groups of patients,
particularly ones exposed to interferon prior to the imatinib era.
There have been conflicting results as to whether prior exposure to
interferon plays a major role in sustaining deep molecular responses
after TKI withdrawal. Therefore, the French group conducted a
follow-up study to STIM enrolling patients who have only been
exposed to imatinib as CML therapy (STIM2) [74]. The inclusion criteria were similar to those used in STIM1. There were 124 patients
identified who stopped imatinib therapy. With a median follow up of
12 months, 48 patients had molecularly relapsed, 94% of which
occurred within 6 months of TKI withdrawal. All patients remained
sensitive to imatinib or a second generation TKI upon rechallenge. It
has also been noted in this study and others that patients with low
level positivity for BCR-ABL transcripts may be able to remain off
therapy with only close monitoring. This was recently addressed systematically by French investigators, where it appeared safe and effective to only resume patients on TKI therapy if their transcript level
became >0.1% (i.e., loss of MMR) [75].
This data indicates that stopping TKI therapy is feasible, and some
patients may actually be cured of the disease. Nevertheless, at present,
stopping TKI therapy should only be done in the context of a clinical
trial.

Advanced Stage CML

Patients with accelerated or blastic phase CML may receive initial
therapy with TKIs (newer generation TKIs like dasatinib or ponatinib
preferred over imatinib) to reduce the CML burden, and be considered for early alloSCT [7680]. Response rates with combinations of
TKIs and chemotherapy are 40% in nonlymphoid BP CML and 70
80% in lymphoid BP CML [8183]. Median survival times are 612
554

American Journal of Hematology, Vol. 89, No. 5, May 2014

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

months, and 1224 months, respectively. The addition of TKIs to
chemotherapy has improved the response rates and prolonged the
median survival time in BP CML.
At present, alloSCT is the only curative therapy for accelerated and
BP CML: overall cure rates are in the range of 1540% and 520%,
respectively [37,70]. Patients with cytogenetic clonal evolution as the
only AP criterion have a long-term event-free survival rate of about
60% [84]. Otherwise, TKIs provide hematologic responses in 80% of
patients and an estimated 4-year survival rates of 4055% in AP
CML, but only a 40% response rate and a median survival of 912
months in BP CML. Patients in the accelerated or BP should be
encouraged to participate in investigational strategies to improve their
prognosis. Patients with de novo CML AP have a better outcome
with front-line TKI therapy than patients who evolve from chronic to
AP. The estimated 68 year survival rates with TKI therapy in de
novo AP CML are 6080% [84]. Such patients may continue on TKI
therapy as their long-term treatment if they achieve a CCyR on TKI
therapy.
AlloHSCT should be considered early on for patients in AP disease
based on response to TKI therapy. The only curative option for
patients in BP disease is AlloSCT. TKIs monotherapy or in combination with chemotherapy may serve as a good option for those who
are not candidates for transplant, or as a bridge to alloHSCT. The
role of TKIs before and after transplant is being currently evaluated.
Accumulating data show that TKIs do not seem to increase transplant
related complications and when used after low intensity conditioning
regimens, may delay relapse rates and need for donor lymphocyte
infusions.

Conclusions and Future Directions

In 2013, CML experts and patients with CML have multiple treatment options in the CML therapeutic armamentarium, including five
TKIs (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib), omacetaxine (protein synthesis inhibition), and several older agents
(hydroxurea, interferon alpha, busulfan, 6-mercaptopurine, cytarabine,
decitabine, etc.). Most patients with CML would be expected to live
their normal functional life, and be potentially functionally, though
not molecularly, cured, as long as they continue therapy with TKI
based regimens, are compliant with the treatment, and are monitored
closely for signs of resistance, to change therapy in a timely manner
and/or consider alloHSCT before CML progression. Future directions
will focus on the potential molecular cure of CML (i.e., achievement
of a durable CMR and its persistence after discontinuation of TKI
therapy). This is not a trivial issue since, with effective TKI therapy,
and full treatment penetration worldwide (to 100% of all diagnosed
patients and continuation of TKI therapy without interruptions) the
prevalence of CML would increase annually and plateau at around
2030 to 2040 at a rate 35 times the incidence. This figure is estimated
to be close to 160,000 patients with CML in the US and about 3 million patients worldwide. This may represent a considerable burden on
patients and the healthcare systems in relation to drug availability,
compliance, potential development of long-term side effects, and
costs. Therefore, it is critical to continue research into therapies that
increase the rates of durable CMRs. This may be achievable with the
current more potent new generation TKIs alone, or in combination
with other available (peg-interferon alpha-2, omacetaxine, and decitabine) or investigational therapies (JAK2 inhibitors, hedgehog inhibitors, stem cell poisons, and vaccines). Such strategies may improve
the eradication of minimal residual disease, potentially obviating the
need for indefinite therapy with TKIs. Further understanding of the
pathophysiologic events downstream of BCR-ABL may help in the
development of new strategies to target them.

doi:10.1002/ajh.23691

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

References

1. Jemal A, Siegel R, Xu J, et al. Cancer statistics,

2010. CA Cancer J Clin 2010;60:277300.
2. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence
and Giemsa staining. Nature 1973;243:290293.
3. Mandanas RA, Leibowitz DS, Gharehbaghi K,
et al. Role of p21 RAS in p210 bcr-abl transformation of murine myeloid cells. Blood 1993;82:
18381847.
4. Okuda K, Matulonis U, Salgia R. Factor independence of human myeloid leukemia cell lines
is associated with increased phosphorylation of
the proto-oncogene Raf-1. Exp Hematol 1994;
22:11111117.
5. Raitano AB, Halpern JR, Hambuch TM. The
Bcr-Abl leukemia oncogene activates Jun kinase
and requires Jun for transformation. Proc Natl
Acad Sci USA 1995;92:1174611750.
6. Sawyers CL, Callahan W, Witte ON. Dominant
negative MYC blocks transformation by ABL
oncogenes. Cell. 1992;70:901910.
7. Shuai K, Halpern J, ten Hoeve J. Constitutive
activation of STAT5 by the BCR-ABL oncogene
in chronic myelogenous leukemia. Oncogene
1996;13:247254.
8. Carlesso N, Frank DA, Griffin JD. Tyrosyl phosphorylation and DNA binding activity of signal
transducers and activators of transcription
(STAT) proteins in hematopoietic cell lines
transformed by Bcr/Abl. J Exp Med 1996;183:
811820.
9. Ilaria RL Jr, Van Etten RA. P210 and P190
(BCR/ABL) induce the tyrosine phosphorylation
and DNA binding activity of multiple specific
STAT family members. J Biol Chem 1996;271:
3170431710.
10. Silver RT, Woolf SH, Hehlmann R, et al. An
evidence-based analysis of the effect of busulfan,
hydroxyurea, interferon, and allogeneic bone
marrow transplantation in treating the chronic
phase of chronic myeloid leukemia: developed
for the American Society of Hematology. Blood
1999;94:15171536.
11. Deininger M, OBrien SG, Guilhot F, et al.
International randomized study of interferon vs.
STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression of events in
patients with newly diagnosed chronic myeloid
leukemia in chronic phase (CML-CP) treated
with imatinib. Blood 2009;114.
12. Jabbour E, Cortes JE, Kantarjian HM. Molecular
monitoring in chronic myeloid leukemia:
response to tyrosine kinase inhibitors and prognostic implications. Cancer 2008;112:21122118.
13. Kantarjian H, Schiffer C, Jones D, Cortes J.
Monitoring the response and course of chronic
myeloid leukemia in the modern era of BCRABL tyrosine kinase inhibitors: practical advice
on the use and interpretation of monitoring
methods. Blood 2008;111:17741780.
14. Schoch C, Schnittger S, Bursch S, et al. Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative
and quantitative PCR for diagnosis and for
follow-up in chronic myeloid leukemia: a study
on 350 cases. Leukemia 2002;16:53.
15. Druker BJ, Lydon NB. Lessons learned from the
development of an abl tyrosine kinase inhibitor
for chronic myelogenous leukemia. J Clin Invest
2000;105:37.
16. OBrien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose
cytarabine for newly diagnosed chronic-phase
chronic myeloid leukemia. N Engl J Med 2003;
348:9941004.
17. Lombardo LJ, Lee FY, Chen P, et al. Discovery
of N-(2-chloro-6-methyl- phenyl)22-(6-(4-(2hydroxyethyl)- piperazin-1-yl)22-methylpyrimidin-4- ylamino)thiazole-5-carboxamide (BMS354825), a dual Src/Abl kinase inhibitor with
potent antitumor activity in preclinical assays. J
Med Chem 2004;47:66586661.
18. OHare T, Walters DK, Stoffregen EP, et al. In
vitro activity of Bcr-Abl inhibitors AMN107 and

doi:10.1002/ajh.23691

19.

20.
21.

22.

23.

24.

25.

26.
27.
28.

29.

30.
31.
32.
33.

34.

35.

36.
37.

38.

39.

BMS-354825 against clinically relevant imatinibresistant Abl kinase domain mutants. Cancer
Res 2005;65:45004505.
Tokarski JS, Newitt JA, Chang CY, et al. The
structure of Dasatinib (BMS-354825) bound
to activated ABL kinase domain elucidates
its inhibitory activity against imatinibresistant ABL mutants. Cancer Res 2006;66:
57905797.
Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004;305:399401.
Kantarjian H, Shah NP, Hochhaus A, et al.
Dasatinib versus imatinib in newly diagnosed
chronic-phase chronic myeloid leukemia. N
Engl J Med 2010;362:22602270.
Jabbour E, Kantarjian HM, Saglio G, et al. Early
response with dasatinib or imatinib in chronic
myeloid leukemia: 3-year follow-up from a
randomized phase 3 trial (DASISION). Blood
2014;123:494500.
Weisberg E, Manley PW, Breitenstein W, et al.
Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell
2005;7:129141.
Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib
versus imatinib for newly diagnosed chronic
myeloid leukemia. N Engl J Med 2010;362:
22512259.
Larson RA, Hochhaus A, Clark RE, et al. Nilotinib vs imatinib in patients with newly diagnosed
Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3year follow up. Leukemia 2012;26:21972203.
OBrien S, Radich JP, Abboud CN, et al.
Chronic myelogenous leukemia, Version 1.2014.
J Natl Compr Canc Netw 2013;11:13271340.
Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hypertension in patients treated by
dasatinib. Circulation 2012;125:21282137.
Quintas-Cardama A, Han X, Kantarjian H,
Cortes J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 2009;114:261263.
Quintas-Cardama A, Kantarjian H, Ravandi F,
et al. Bleeding diathesis in patients with chronic
myeloid leukemia receiving dasatinib therapy.
Cancer 2009;115:24822490.
Kim TD, le Coutre P, Schwarz M, et al. Clinical
cardiac safety profile of nilotinib. Haematologica
2012;97:883889.
Quintas-Cardama A, Kantarjian H, Cortes J.
Nilotinib-associated vascular events. Clin Lymphoma Myeloma Leuk 2012;12:337340.
Smith TJ, Hillner BE. Bending the cost curve
in cancer care. N Engl J Med 2011;364:2060
2065.
Kantarjian HM, Fojo T, Mathisen M, Zwelling
LA. Cancer drugs in the United States: justum
pretiumthe just price. J Clin Oncol 2013;31:
36003604.
Experts in Chronic Myeloid Leukemia. The
price of drugs for chronic myeloid leukemia is a
reflection of the unsustainable prices of cancer
drugs: from the perspective of a large group of
CML experts. Blood 2013;121:44394442.
Gambacorti-Passerini C, Antolini L, Mahon X,
et al. Multicenter independent assessment of
outcomes in chronic myeloid leukemia patients
treated with imatinib. J Natl Cancer Inst 2011;
103:553561.
Gleevec (imatinib) Package Insert. East Hanover,
NJ. Novartis Pharmaceuticals Corporation; 2013.
Baccarani M, Deininger MW, Rosti G, et al.
European LeukemiaNet recommendations for
the management of chronic myeloid leukemia:
2013. Blood 2013;122:872884.
Testoni N, Marzocchi G, Luatti S, et al. Chronic
myeloid leukemia: a prospective comparison of
interphase fluorescence in situ hybridization and
chromosome banding analysis for the definition
of complete cytogenetic response: a study of the
GIMEMA CML WP. Blood 2009;114:4939
4943.
Kantarjian H, Cortes J. Considerations in the
management of patients with Philadelphia
chromosome-positive chronic myeloid leukemia

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.
54.

55.

receiving tyrosine kinase inhibitors. J Clin Oncol

2011;29:15121516.
Hehlmann R, Lauseker M, Jung-Munkwitz S,
et al. Tolerability-adapted imatinib 800 mg/d
versus 400 mg/d versus 400 mg/d plus
interferon-alpha in newly diagnosed chronic
myeloid leukemia. J Clin Oncol 2011;29:1634
1642.
Kantarjian HM, Shan J, Jones D, et al. Significance of increasing levels of minimal residual
disease
in
patients
with
Philadelphia
chromosome-positive chronic myelogenous leukemia in complete cytogenetic response. J Clin
Oncol 2009;27:36593663.
Marin D, Ibrahim AR, Lucas C, et al. Assessment of BCR-ABL1 transcript levels at 3
months is the only requirement for predicting
outcome for patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. J
Clin Oncol 2012;30:232238.
Jain P, Kantarjian H, Nazha A, et al. Early
responses predict better outcomes in patients
with newly diagnosed chronic myeloid leukemia:
results with four tyrosine kinase inhibitor
modalities. Blood 2013;121:48674874.
Neelakantan P, Gerrard G, Lucas C, et al. Combining BCR-ABL1 transcript level at 3 and 6
months in chronic myeloid leukemia: implications for early intervention strategies. Blood
2013;121:37393742.
Nazha A, Kantarjian H, Jain P, et al. Assessment
at 6 months may be warranted for patients with
chronic myeloid leukemia with no major cytogenetic response at 3 months. Haematologica
2013;98:16861688.
Branford S, Roberts N, Yeung DT, et al. Any
BRC-ABL reduction below 10% at 6 months of
therapy significantly improves outcome for
CML patients with a poor response at 3 months.
Blood (ASH Annual Meeting Abstracts) 2013;
122:254.
Jabbour E, Kantarjian HM, OBrien S, et al.
Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early
chronic phase chronic myeloid leukemia: what
is the optimal response? J Clin Oncol 2011;29:
42604265.
Cortes JE, De Souza CA, Lopez JL, et al. Switching to nilotinib in patients with chronic myeloid
leukemia in chronic phase with suboptimal
cytogenetic response on imatinib: first results of
the LASOR trial. Blood (ASH Annual Meeting
Abstracts) 2013;122:95.
Leber B, Cervantes F, Spector N, et al. Achievement and maintenance of deeper molecular
response by switching to nilotinib in patients
with chronic myeloid leukemia in chronic phase
with residual disease on long-term imatinib:
ENESTcmr 36-month follow up. Blood (ASH
Annual Meeting Abstracts) 2013;122:94.
Marin D, Bazeos A, Mahon FX, et al. Adherence
is the critical factor for achieving molecular
responses in patients with chronic myeloid leukemia who achieve complete cytogenetic
responses on imatinib. J Clin Oncol 2010;28:
23812388.
Darkow T, Henk HJ, Thomas SK, et al. Treatment interruptions and non-adherence with
imatinib and associated healthcare costs: a retrospective analysis among managed care patients
with chronic myelogenous leukaemia. Pharmacoeconomics 2007;25:481496.
Noens L, van Lierde MA, De Bock R, et al.
Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with
chronic myeloid leukemia: the ADAGIO study.
Blood 2009;113:54015411.
R (dasaBristol-Myers Squibb Company. SprycelV
tinib) prescribing information. Princeton, NJ:
Bristol-Myers Squibb Company; 2011.
R
Novartis Pharmaceuticals Corporation. TasignaV
(nilotinib) prescribing information. East Hanover, NJ: Novartis Pharmaceuticals Corporation;
2011.
Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose escalation is associated with
durable responses in patients with chronic mye-

American Journal of Hematology, Vol. 89, No. 5, May 2014

555

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

Jabbour and Kantarjian

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

556

loid leukemia after cytogenetic failure on

standard-dose imatinib therapy. Blood 2009;113:
21542160.
Garcia-Gutierrez JV, Herrera P, Abalo LL, et al.
Impact of second-generation tyrosine kinase inhibitors as second line treatment for patients with
chronic myeloid leukemia. Blood 2011;118:632.
Goh HG, Jootar S, Kim HJ, et al. Efficacy of nilotinib versus high-dose imatinib in early chronic
phase CML patients who have suboptimal molecular responses to standard-dose imatinib (RE-NICE
multicenter study). Blood 2011;118:632.
Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose imatinib for chronic-phase
chronic myeloid leukemia resistant to imatinib
at a dose of 400 to 600 milligrams daily: twoyear follow-up of a randomized phase 2 study
(START-R). Cancer 2009;115:41364147.
Yeung DT, Osborn M, White DL, et al. Upfront
imatinib therapy in CML patients with rapid
switching to nilotinib for failure to achieve
molecular targets or intolerance achieves high
overall rates of molecular response and a low
risk of progression - an update of the TIDEL-II
trial. Blood 2011;118:632.
Quintas-Cardama A, Cortes JE, OBrien S, et al.
Dasatinib early intervention after cytogenetic or
hematologic resistance to imatinib in patients
with chronic myeloid leukemia. Cancer 2009;
115:29122921.
Cortes JE, Kantarjian HM, Brummendorf TH,
et al. Safety and efficacy of bosutinib (SKI-606)
in chronic phase Philadelphia chromosomepositive chronic myeloid leukemia patients with
resistance or intolerance to imatinib. Blood
2011;118:45674576.
OHare T, Shakespeare WC, Zhu X, et al.
AP24534, a pan-BCR-ABL inhibitor for chronic
myeloid leukemia, potently inhibits the T315I
mutant and overcomes mutation-based resistance. Cancer Cell 2009;16:401412.
Zhou T, Commodore L, Huang WS, et al. Structural mechanism of the pan-BCR-ABL inhibitor
ponatinib (AP24534): lessons for overcoming
kinase inhibitor resistance. Chem Biol Drug Des
2011;77:111.
Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A
phase 2 trial of ponatinib in Philadelphia
chromosome-positive leukemias. N Engl J Med
2013;369:17831796.
Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL kinase domain mutations in

American Journal of Hematology, Vol. 89, No. 5, May 2014

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors.
Blood 2007;110:40054011.
Jabbour E, Branford S, Saglio G, Jones D. Practical advice for determining the role of BCRABL mutations in guiding tyrosine kinase inhibitor therapy in patients with chronic myeloid
leukemia. Cancer 2011;117:18001811.
Muller MC, Cortes JE, Kim DW, et al. Dasatinib
treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood 2009;114:
49444953.
Hughes T, Saglio G, Branford S, et al. Impact of
baseline BCR-ABL mutations on response to nilotinib in patients with chronic myeloid leukemia in
chronic phase. J Clin Oncol 2009;27:42044210.
Kantarjian HM, Cortes JE, Kim DW, et al.
Bosutinib safety and management of toxicity in
leukemia patients with resistance or intolerance
to imatinib and other tyrosine kinase inhibitors.
Blood, in press.
Jabbour E, Cortes J, Santos FP, et al. Results of
allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia patients
who failed tyrosine kinase inhibitors after developing BCR-ABL1 kinase domain mutations.
Blood 2011;117:36413647.
Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete
molecular remission for at least 2 years: the prospective, multicenter Stop Imatinib (STIM) trial.
Lancet Oncol 2010;11:10291035.
Mahon FX, Rea D, Guilhot J, et al. Long term
follow-up after imatinib cessation for patients in
deep molecular response: the updated results of
the STIM1 study. Blood (ASH Annual Meeting
Abstracts) 2013;122:255.
Ross DM, Branford S, Seymour JF, et al. Safety
and efficacy of imatinib cessation for CML
patients with stable undetectable minimal residual disease: results from the TWISTER study.
Blood 2013;122:515522.
Mahon FX, Nicolini FE, Noel MP, et al. Preliminary report of the STIM2 study: a multicenter
stop imatinib trial for chronic phase chronic
myeloid leukemia de novo patients on imatinib.
Blood (ASH Annual Meeting Abstracts) 2013;
122:654.
Rousselot P, Charbonnier A, Cony-Makhoul P,
et al. Loss of major molecular response as a trig-

76.

77.

78.

79.

80.

81.

82.

83.

84.

ger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic
myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin
Oncol 2014;32:424430.
Apperley JF, Cortes JE, Kim DW, et al. Dasatinib
in the treatment of chronic myeloid leukemia in
accelerated phase after imatinib failure: the
START-A trial. J Clin Oncol 2009;27:34723479.
Oehler VG, Gooley T, Snyder DS, et al. The
effects of imatinib mesylate treatment before
allogeneic transplantation for chronic myeloid
leukemia. Blood 2007;109:17821789.
Carpenter PA, Snyder DS, Flowers ME, et al.
Prophylactic administration of imatinib after
hematopoietic cell transplantation for high-risk
Philadelphia chromosome-positive leukemia.
Blood 2007;109:27912793.
Jabbour E, Cortes J, Kantarjian H, et al. Novel
tyrosine kinase inhibitor therapy before allogeneic stem cell transplantation in patients with
chronic myeloid leukemia: no evidence for
increased transplant-related toxicity. Cancer
2007;110:340344.
le Coutre PD, Giles FJ, Hochhaus A, et al. Nilotinib in patients with Ph1 chronic myeloid leukemia in accelerated phase following imatinib
resistance or intolerance: 24-month follow-up
results. Leukemia 2012;26:11891194.
Thomas DA, Faderl S, Cortes J, et al. Treatment
of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 2004;103:43964407.
Ravandi F, OBrien S, Thomas D, et al. First report
of phase 2 study of dasatinib with hyper-CVAD
for the frontline treatment of patients with Philadelphia chromosome-positive (Ph1) acute lymphoblastic leukemia. Blood 2010;116:20702077.
Quintas-Cardama A, Kantarjian H, GarciaManero G, et al. A pilot study of imatinib, lowdose cytarabine and idarubicin for patients with
chronic myeloid leukemia in myeloid blast
phase. Leuk Lymphoma 2007;48:283289.
Ohanian M, Kantarjian HM, Quintas-Cardama
A, et al. Tyrosine kinase inhibitors as initial
therapy for patients with chronic myeloid leukemia in accelerated phase. Clin Lymphoma
Myeloma Leuk, in press.

doi:10.1002/ajh.23691