Received: 13 December 2017 | Accepted: 17 December 2017

DOI: 10.1002/ajh.25011

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL A JH

MALIGNANCIES

Chronic myeloid leukemia: 2018 update on diagnosis, therapy

and monitoring

Elias Jabbour | Hagop Kantarjian

Department of Leukemia, The University of

Texas M. D. Anderson Cancer Center,
Houston, Texas
Correspondence
Elias Jabbour, MD Anderson Cancer
Center, Box 428, 1515 Holcombe Blvd,
Houston, Texas 77030.
Email: ejabbour@mdanderson.org
Abstract
Disease overview: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an inci-
dence of 1-2 cases per 100 000 adults. It accounts for approximately 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 gene (ABL1) from chromosome 9q34 with the breakpoint cluster region
(BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromo-
some. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion
oncogene, which in turn translates into a BCR-ABL1 oncoprotein.
Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosuti-
nib are approved by the United States Food and Drug Administration for first-line treatment of
patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second genera-
tion TKIs reported significantly deeper and faster responses; this has not translated into improved
long-term survival, because of the availability of effective salvage therapies.
Salvage therapy: For patients who fail frontline therapy, second-line options include second and
third generation TKIs. Second and third generation TKIs, although potent and selective, exhibit
unique pharmacological profiles and response patterns relative to different patient and disease char-
acteristics, such as patients’ comorbidities, disease stage, and BCR-ABL1 mutational status. Patients
who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs
except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for
patients with CML-CP who have failed at least 2 TKIs, and for all patients in CML advanced phases.

1 | DISEASE OVERVIEW
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm with
an incidence of 1–2 cases per 100 000 adults. It accounts for approxi-
mately 15% of newly diagnosed cases of leukemia in adults. In 2017, 1
it is estimated about 9000 new CML cases will be diagnosed in the
United States, and about 1000 patients will die of CML. Since the
introduction of imatinib in 2000, the annual mortality in CML has
1
decreased from 10%-20% down to 1%-2%. Consequently, the preva-
lence of CML in the United States, estimated at about 25–30 000 in
2000, has increased to an estimated 80–100 0001 in 2017, and will
reach a plateau of about 180 000 cases by 2030.2
Central to the pathogenesis of CML is the fusion of the Abelson
murine leukemia (ABL1) gene on chromosome 9 with the breakpoint
cluster region (BCR) gene on chromosome 22. This results in expression
of an oncoprotein termed BCR-ABL1.3 BCR-ABL1 is a constitutively
active tyrosine kinase that promotes growth and replication through
downstream signaling pathways such as RAS, RAF, JUN kinase, MYC,
and STAT.4–10 This influences leukemogenesis by creating a cytokine-
independent cell cycle with aberrant apoptotic signals in response to
cytokine withdrawal.
Until 2000, drug therapy for CML was limited to nonspecific agents
such as busulfan, hydroxyurea, and interferon-alfa (IFN-a).11 IFN-a led to
disease regression and improved survival but was hindered by its modest
efficacy and associated significant toxicities. Allogeneic stem cell trans-
plantation (allo-SCT) is curative, but carries risks of morbidity and mortal-
ity. Further, allo-SCT is an option only for patients with good performance
status and organ functions, and who have an appropriate donor.

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JABBOUR AND KANTARJIAN
The CML therapeutic landscape changed dramatically with the
development of the small molecule tyrosine kinase inhibitors (TKIs)
that potently interfered with the interaction between the BCR-ABL1
oncoprotein and adenosine triphosphate (ATP), blocking cellular prolif-
eration of the malignant clone. This “targeted” approach altered the
natural history of CML, improving the 10-year survival rate from
approximately 20% to 80%-90%. 1,2,12
In this review, we will highlight the evidence supporting the use of
each of the available TKIs, including how to select an agent under dif-
ferent circumstances and particular phases of CML. Allo-SCT is an
important treatment option in CML chronic phase (CP) post TKIs fail-
ure, and in advanced CML phases, and its role will be reviewed. Cyto-
genetic and molecular benchmarks for patients on therapy will be
discussed. Finally, appropriate monitoring strategies for patients on
TKIs will be addressed.
1.1 | Manifestations and staging
About 50% of patients diagnosed with CML in the United States are
asymptomatic, and are often diagnosed during a routine physical exami-
nation or blood tests. CML can be classified into three phases: CP, accel-
erated phase (AP), and blast phase (BP). Most (90%-95%) patients
present in CML-CP. Common signs and symptoms of CML-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 throm-
bocytosis and/or marked leukocytosis), gouty arthritis (from elevated
uric acid levels), priapism (usually with marked leukocytosis or thrombo-
cytosis), retinal hemorrhages, and upper gastrointestinal ulceration and
bleeding (from elevated histamine levels due to basophilia). Leukostatic
symptoms (dyspnea, drowsiness, loss of coordination, confusion) due to
leukemic cells sludging in the pulmonary or cerebral vessels, are uncom-
mon in CP despite white blood cell (WBC) counts exceeding 100 3 109/
L. Splenomegaly is the most consistent physical sign detected in 40%-
50% of cases. Hepatomegaly is less common (less than 10%). Lymphade-
nopathy and infiltration of skin or other tissues are rare. 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 fre-
quent with CML transformation. Most patients evolve into AP prior to
BP, but 20% transition into BP without AP warning signals. CML-AP
might be insidious or present with worsening anemia, splenomegaly and
organ infiltration; CML-BP presents as an acute leukemia (myeloid in
60%, lymphoid in 30%, megakaryocytic or undifferentiated in 10%) with
worsening constitutional symptoms, bleeding, fever and infections.
1.2 | 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 Philadelphia (Ph) chromosome
abnormality, the t(9;22)(q34;q11), by routine cytogenetics, or the Ph-
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443
related molecular BCR-ABL1 abnormalities by fluorescence in situ
hybridization (FISH) or by molecular studies.13–15
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 1%-5% depending on
the probes used.
Reverse transcriptase-polymerase chain reaction (RT-PCR) ampli-
fies the region around the splice junction between BCR and ABL1. It is
highly sensitive in detecting minimal residual disease. PCR testing can
either be qualitative (QPCR), providing information about the presence
of the BCR-ABL1 transcript, or quantitative, assessing the amount of
BCR-ABL1 transcripts. 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 con-
cordance. 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 0.5-
1 log difference in some samples can occur depending on testing pro-
cedures, sample handling, and laboratory experience.13–15 For correla-
tive purpose and monitoring without necessarily performing repeat
marrow studies, a complete cytogenetic response (CcyR; 0% Ph-
positive metaphases by cytogenetic) is equivalent to a negative FISH
test (6 2%) and BCR-ABL1 transcripts by International Standard [IS]
<1%. A partial cytogenetic response (Ph-positive metaphases 35%) is
equivalent to BCR-ABL1 transcripts 10% [IS].
The Ph chromosome is usually present in 100% of metaphases,
often as the sole abnormality. Ten to 15% of patients have additional
chromosomal changes (clonal evolution) involving trisomy 8, isochromo-
some 17, additional loss of material from 22q or double Ph, or others.
Ninety 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. About 2%-5% of patients present with a morphologic
picture of CML without the Ph-positivity by cytogenetic studies. FISH
and PCR document Ph-negative BCR-ABL1 rearranged CML. Such
patients have similar response and outcome on TKI therapy as patients
with Ph-positive CML.
Bone marrow aspiration is mandatory for all patients in whom
CML is suspected, as it will confirm the diagnosis (eg, cytogenetic anal-
ysis), and provide information needed for staging in terms of the blast
and basophil percentages. Baseline cytogenetic analysis allows the
detection of clonal evolution, particularly i(17)(q10)-7/del7q, and
3q26.2 rearrangements, associated with a relatively poor prognosis.16
Baseline reverse transcriptase-polymerase chain reaction is imperative
to identify the specific type of rearrangement that can be appropriately
followed when assessing for response to TKI therapy. About 2%-5% of
patients have e13a3 or e14a3 (not e13a2 or e14a2) variants of p210
BCR-ABL1 or p230 transcripts that may yield a false negative PCR by
routine probes and (if not tested at diagnosis) would give the false
impression that a patient is in “complete molecular response” on TKI.
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444 JABBOUR AND KANTARJIAN

T AB LE 1 Summary of pivotal phase III trials of approved tyrosine kinase inhibitors for the frontline treatment of chronic myeloid leukemia

BCR-ABL < 10% Longest

Trial Treatment CCyR (%) MMR (%) at 3 months (%) EFS/PFS (%) OS (%) follow-up (years)

At 10 years At 10 years

IRIS Imatinib (n 5 304) 83 93 NR 80 83 11

At 2 years At 5 years At 5 years

DASISION Dasatinib (n 5 259) 86 76 84 85 91 5

Imatinib (n 5 260) 82 64 64 86 90

At 2 years At 5 years At 5 years At 6 years

ENESTnd Nilotinib 300 mg (n 5 282) 87 77 91 95 92 6

Nilotinib 400 mg (n 5 281) 85 77 89 97 96

Imatinib (n 5 283) 77 60 67 93 91

At 12 months At 12 months

BEFORE Bosutinib 400 mg (n 5 268) 77 47 75 96 99.9 18 months

Imatinib (n 5 268) 66 37 57 94 99.7

NR, Not reported.

1.3 | Differential diagnosis 1.4 | Frontline treatment options

CML must be differentiated from leukemoid reactions, which usually
produce white blood cell counts, lower than 50 3 109/L, toxic granulo-
€ hle’s bodies in the granulocytes, absence of baso-
cytic vacuolation, Do
philia, 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 transient and short-lasting.
CML may be more difficult to differentiate from other myeloproli-
ferative or myelodysplastic syndromes. Patients with agnogenic mye-
loid 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 less than 25 3 10 /L, and no Ph abnormality.
9 study is considered a landmark clinical trial for TKIs and CML.18 Investi-
The greatest diagnostic difficulty lies with patients who have spleno-
megaly and leukocytosis but who do not have the Ph chromosome. In
some, the BCR-ABL1 hybrid gene can be demonstrated despite a normal
or atypical cytogenetic pattern. Patients who are Ph negative and BCR-
ABL1 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-ABL1 gene. Isolated megakaryocytic hyperplasia
can be seen in essential thrombocythemia, with marked thrombocytosis
and splenomegaly. Some patients who present with clinical characteris-
tics of essential thrombocythemia (with marked thrombocytosis but
without leukocytosis) have CML; cytogenetic and molecular studies
showing the Ph chromosome, the BCR-ABL1 rearrangement, or both
lead to the appropriate diagnosis and treatment.
The three commercially available TKIs for the frontline treatment of
CML include imatinib, dasatinib, and nilotinib. Current guidelines
endorse all three as options for the initial management of CML in the
chronic phase (CML-CP) (Table 1).
1.4.1 | Imatinib
Imatinib mesylate was the first TKI to receive the Food and Drug
Administration (FDA) approval for the treatment of patients with CML-
CP. It acts via competitive inhibition at the ATP-binding site of the
BCR-ABL1 oncoprotein, which results in the inhibition of phosphoryla-
tion of proteins involved in cell signal transduction. It also blocks the
platelet-derived growth factor receptor and the C-KIT tyrosine
kinase.17
The International Randomized Study of Interferon and STI571 (IRIS)
gators randomized 1106 patients in CML-CP to receive imatinib
400 mg/day or IFN-a and low-dose cytarabine. After a median follow-up
of 19 months, the outcomes for patients receiving imatinib were signifi-
cantly better than those treated with IFN-a and cytarabine, notably the
rates of complete cytogenetic response (CCyR) rate (74% versus. 9%,
P < .001), and freedom-from-progression to AP or BP at 12 months
(99% versus 93%, P < .001). Further highlighting the challenge of using
IFN-a was the high crossover rate to imatinib due to intolerance. With a
median follow-up of almost 11 years, the estimated overall survival rate
for patients who had been assigned to receive imatinib was 83.3% with
a cumulative CCyR rate of 83% and a 10-year major molecular response
(MMR) rate of 93%.19 Despite the high rate of early crossover among
patients assigned to receive IFN-a and cytarabine, the 10-year survival
rate favored the imatinib therapy arm (83.3% versus 78.8%).19
While the results using imatinib are impressive, only 48% of
patients enrolled in the IRIS study remained on therapy at the 10-year

JABBOUR AND KANTARJIAN
follow-up time. This underscored the need for additional treatment
options for patients who had resistance or intolerance to imatinib. This
led to the rational development of second generation TKIs.
1.4.2 | Imatinib generics
Imatinib generics entered the market recently after the Novartis patent
for Gleevec expired. Several groups have reported on the efficacy and
safety of generic imatinib compared to the branded one. The Polish
Adult Leukemia Group (PALG) imatinib generics registry reported on a
large series of patients who started imatinib generic (multiple manufac-
turers) therapy after the diagnosis of CML (group A, n 5 99) or were
switched to generic from branded imatinib (group B, n 5 627) and were
observed for at least 12 months.20 Among patients treated in the front-
line setting (group A), the rates of 3-month partial cytogenetic response
(PCyR), 6-month CCyR, and 12-month MMR were 66%, 53%, and
50%, respectively, similar to the expected rates with branded imatinib.
The rates of resistance and intolerance were also similar (26% and
28%, respectively). Among patients who switched therapy, responses
were maintained in the vast majority, with only 0.3% and 1% of
patients losing a CCyR and MMR, respectively. Similar data were
reported from India. Among 174 patients treated with generics,
response and survival rates were similar to those observed among
1193 patients treated with the branded imatinib. Safety profiles were
similar as well.21
1.4.3 | High-dose imatinib and imatinib-based combinations
Other strategies for frontline therapy include using higher doses of
imatinib or combining a TKI with an additional agent, such as IFN-a. In
the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS)
study, patients were randomized to receive imatinib 400 mg once daily
22
or twice daily (800 mg). MMR rate at 12 months was the study pri-
mary endpoint, with cytogenetic response and time to such responses
collected as secondary outcomes. Patients in the high-dose group
achieved faster CCyR and MMR, but the rates were not significantly
different at 12 months.
Interferon has re-emerged as an interesting therapeutic option in
CML with the advent of pegylated formulations requiring less frequent
administration and showing improved tolerability. In a phase III
randomized study, patients were assigned to one of four treatment
arms: imatinib 400 mg once daily; imatinib 600 mg once daily; imatinib
400 mg once daily plus peginterferon alfa-2a; imatinib 400 mg once
daily plus subcutaneous cytarabine.23 Patients were initially assigned to
receive peginterferon alfa-2a at a dose of 90 mcg once weekly.
Because of a high rate of discontinuation due to toxicity, the dose was
later reduced to 45 mcg once weekly. At 12 months, the rates of CCyR
were similar among the four groups. The imatinib plus peginterferon
alfa-2a treated group obtained higher rates of MMR and deeper molec-
ular responses, but follow-up was not sufficient to define the impact
on long-term outcomes.
The CML-study IV explored whether treatment with imatinib
400mg/day (n 5 400) could be optimized by doubling the dose
(n 5 420), adding interferon (n 5 430) or cytarabine (n 5 158) or using
imatinib after interferon-failure (n 5 128).24 From July 2002 to March
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2012, 1551 newly diagnosed patients in CML-CP were randomized
into a 5-arm study. The study was powered to detect a survival dif-
ference of 5% at 5 years. After a median observation time of 9.5
years, the 10-year overall survival rate was 82%, the 10-year pro-
gression-free survival rate was 80%, and the 10-year relative survival
rate was 92%. In spite of a faster response with imatinib 800 mg,
the survival difference between standard-dose and higher dose ima-
tinib was only 3% at 5 years (less than 5%). In a multivariate analy-
sis, standard-dose imatinib was equivalent to other “optimized “arms.
Patients who reached the 6-months BCR-ABL1 transcripts [IS] <10%
milestone, had a significant survival advantage of about 6% after 10
years regardless of therapy.
1.4.4 | Dasatinib
Dasatinib is an oral, second generation TKI that is 350 times more
potent than imatinib in vitro.25–27 It also inhibits the Src family of
kinases, which may be important in blunting critical cell signaling path-
ways.28 Though initially evaluated in patients in the salvage setting, it
was later compared to imatinib in frontline CML to test the possibility
that frontline use of the more potent TKIs might improve outcomes.
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 with CML.29 The primary outcome was confirmed
CCyR (cCCyR) at 12 months. A total of 519 patients were randomized
(1:1). Patients assigned to dasatinib achieved cCCyR at 12 months
more often than those assigned to imatinib (77% versus 66%,
P 5 .007). Many of the secondary endpoints of interest also favored
the dasatinib arm. A five-year follow-up showed that dasatinib induced
more rapid and deeper responses at early time points compared to ima-
tinib.30 At 3 months, a higher proportion of patients treated with dasa-
tinib achieved BCR-ABL1 transcripts [IS]  10% (84% versus 64%,
P < .0001). Meeting this threshold in either arm predicted better
progression-free survival and overall survival. Transformations to CML-
AP or CML-BP were fewer in patients treated with dasatinib versus
imatinib (4.6% versus 7.3%). However, the 5-year survival was similar
with dasatinib and imatinib (91%, and 90%)
In another multicenter trial, several North American cooperative
groups randomized patients with newly diagnosed CML-CP to either
dasatinib 100 mg once daily or imatinib 400 mg once daily.31 Similar to
the results of the DASISION study, patients treated with dasatinib
achieved higher rate of CCyR compared to patients receiving imatinib
(84% versus 69%, P 5 .04). There was more toxicity experienced in the
dasatinib arm (Grades 3 or 4 adverse events 58% with dasatinib and
35% imatinib), mostly hematologic toxicity.31
A third phase III randomized study, SPIRIT 2, compared imatinib
400 mg daily with dasatinib 100 mg daily.32 The primary endpoint
of this trial is EFS at 5 years, with the rate of achievement of
MMR, a key secondary endpoint. The interim results showed the
12-month MMR rates with dasatinib versus imatinib to be 58% ver-
sus 43% (P < .001). The 12-month CCyR rates were 51% and 40%
respectively (P < .002). Progression rate to CML-AP was 0.7% with
imatinib and 0.5% with dasatinib. The progression rate to CML-BP
was 1.7% versus 1%.
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446
Pleural effusions occurred more frequently on dasatinib (19% ver-
sus <1%). Other side effects of dasatinib included myelosuppression
(20%), and rare pulmonary hypertension (1–2%).
1.4.5 | Lower dose dasatinib
In early clinical trials, dasatinib was found active at lower doses with
better safety profile.33 In a later randomized trial, dasatinib 100 mg
daily was found as effective as 140 mg daily, with a better safety pro-
file.34 Furthermore investigators from the DASISION trial have
reported on the ability to maintain efficacy of dasatinib among patients
who had their dose reduced while improving its safety profile.35 Based
on this rationale, we treated 75 patients with early CML-CP with dasa-
tinib 50 mg daily.36 Ninety-five percent of patient treated achieved a
3-month PCyR. At 12 months, the MMR and molecular response 4.5
(MR4.5) rates were 83% and 74%. These rates compare favorably with
historical data with dasatinib 100 mg daily. In addition, the safety pro-
file was favorable; only one patient discontinued therapy (subdural
hematoma unlikely related) and one patient had his dose reduced to
20 mg daily due to pleural effusion. Such strategy will have a significant
impact on our future practice, mainly due equivalent efficacy, better
safety profile, and lower cost.
1.4.6 | Nilotinib
Nilotinib is a structural analog of imatinib. Its affinity for the ATP bind-
ing site on BCR-ABL1 is 30–50 times more in vitro.37 Like dasatinib,
nilotinib initially demonstrated the ability to induce hematologic and
cytogenetic responses in patients who had failed imatinib.
Similar to dasatinib, nilotinib was also compared to imatinib in a
large, international, randomized study (ENEST-nd). In ENEST-nd, two
doses of nilotinib (300 mg or 400 mg twice daily) were compared to
38
imatinib 400 mg once daily. The primary endpoint was the rate of
MMR at 12 months. This endpoint was achieved at statistically signifi-
cantly higher rates for both doses of nilotinib compared with imatinib
(44% and 43% versus 22%, P < .001). The cumulative incidence of
CCyR by 24 months was 87% with nilotinib 300 mg twice daily, 85%
with nilotinib 400 mg twice daily, and 77% with imatinib 400 mg daily
(P < .001).38
With a minimum follow-up of 5 years, the two arms of nilotinib
demonstrated better early results compared with imatinib.39 The cumu-
lative incidences of MMR by 60 months were 77%, 77%, and 60%,
respectively (P < .0001%). The incidences of BCR-ABL1 transcripts
[IS] < 0.0032% (roughly equivalent to a 4.5 log reduction of disease) by
72 months were 54%, 52%, and 33%, respectively (P < .0001%). The
incidences of transformation to AP or BP were 3.9%, 2.1%, and 7.4%,
respectively (P 5 .06 and .003, respectively). The estimated 5-year EFS
rates were not different, 95%, 97%, and 93%, respectively. The esti-
mated 5-year survival rates were 94%, 96%, and 92%, respectively.
While nilotinib was superior to imatinib across all Sokal score catego-
ries in inducing higher rates of CCyR and MMR, the advantage in
reducing the rates of transformation was more pronounced in patients
with intermediate- and high-Sokal risk CML. The rates of transforma-
tions were 1% and 1% and 0% among patients with low-Sokal risk
treated with nilotinib 300 mg orally twice daily, nilotinib 400 mg orally
JABBOUR AND KANTARJIAN
T AB LE 2 Frontline TKIs therapy: MDACC experience
% Cumulative Imatinib 400 mg Imatinib 800 Nilotinib Dasatinib
CCyR 85 90 99 97
MR4.5 56 74 80 78
twice daily, or imatinib 400 mg orally once. The rates were 2%, 1%,
and 10% among patients with intermediate-Sokal risk and 9%, 5%, and
11% among patients with high-Sokal risk.
In a second randomized trial with the same design that enrolled
267 Chinese patients, the 12-month MMR rate was 52% with nilotinib
compared with 28% with imatinib.40 However, the rates of both CCyR
(84% versus 87%) and progression-free survival (95% each) were simi-
lar at 24 months. In both arms, the estimated 2-year survival rate was
98%.
While nilotinib therapy was overall well tolerated, there was an
increased risk of accumulated vascular events on therapy. The 6-year
cumulative cardiovascular event rates were 9.9%, 15.9%, and 2.5%,
among patients treated with nilotinib 300 mg twice daily, nilotinib
400 mg twice daily, and imatinib 400 mg daily, respectively.39 Other
notable side effects were headache and skin rashes (common 220–
30%- but mild to moderate; alleviated by dose reduction), self-limited
elevation of indirect bilirubin (10%), elevations of blood sugar (10%-
20%), and rare pancreatitis (1%-2%).
1.4.7 | Bosutinib
Bosutinib is a potent dual SRC/ABL kinase inhibitor. The drug first
approved for adults with CML resistant and/or intolerant to prior ther-
apy. Bosutinib was recently evaluated for front-line treatment CML-
CP.41 In a multinational, phase III study, 536 patients with newly diag-
nosed chronic-phase CML were randomly assigned to receive 400 mg
of bosutinib once daily (n 5 268) or imatinib (n 5 268). The major MMR
rate at 12 months (primary end point) was significantly higher with
bosutinib versus imatinib (47% versus 37%, respectively; P 5 .02), as
was the CCyR rate by 12 months (77% versus 66%, respectively;
P 5 .0075). Among treated patients, 22% of patients receiving bosuti-
nib and 27% of patients receiving imatinib discontinued treatment,
mostly for drug-related toxicity (13% and 9%, respectively).41
Grade  3 diarrhea (8% versus 0.8%) and increased ALT (19% versus
1.5%) and AST (10% versus 2%) levels were more common with bosuti-
nib. Cardiac and vascular toxicities were uncommon. Based on these
results, bosutinib received an approval for frontline CML-CP therapy as
of December 2017.
1.4.8 | The MD Anderson Cancer Center (MDACC)
experience (Table 2)
We published the long-term responses and outcomes of patients with
CML-CP and provided a comparison of four commonly used TKIs.32
Unlike previous reports that compared only imatinib 400 mg with
either imatinib 800 mg, dasatinib, or nilotinib in randomized trials, our
study provided a comparative analysis of the four TKIs after a long
follow-up. The analysis included 482 patients treated (July 2000 to
September 2013) in consecutive or parallel clinical trials, with imatinib

JABBOUR AND KANTARJIAN
400 mg daily (n 5 68), imatinib 800 mg daily (n 5 200), dasatinib 50 mg
twice daily or 100 mg daily (n 5 106), or nilotinib 400 mg twice daily
(n 5 108). More patients receiving imatinib 800 mg or second-
generation TKIs (ie, dasatinib or nilotinib) achieved CcyR: 87% for ima-
tinib 400 mg; 90% for imatinib 800 mg; 96% for dasatinib; and 93% for
nilotinib. The MMR rates were 76%, 86%, 90%, and 91%, respectively.
The 4
5 log or higher reduction in BCR-ABL1 transcripts (MR4.5)
response rates were 57%, 74%, 71%, and 71%, respectively. These
findings were consistent over time (3–60 months); where at any time
point, imatinib induced lower rates of cytogenetic and molecular
responses. These landmark assessments contrast with previous reports
where results are reported cumulatively (“by” not “at”) and can be mis-
leading. The 5-year event-free survival significantly differed between
imatinib 400 mg and the other TKI groups (imatinib 800 mg P 5 .029,
dasatinib P 5 .003, nilotinib P 5 .031). However, there was no signifi-
cant difference in the 5-year failure-free survival (P 5 .32, P 5 .075,
P 5 .332), transformation-free survival (P 5 .053, P 5 .038, P 5 .493), or
overall survival (P 5 .563, P 5 .162, P 5 .981). We also compared event-
free and overall survival according to whether or not MMR or MR4.5
response was achieved in addition to CcyR. As expected, in patients
who achieved CcyR, no difference in outcomes was observed regard-
less of whether MMR or MR4.5 response was achieved.42
Current guidelines recommend any of the three TKIs, imatinib, das-
tinib or nilotinib as good therapeutic options with a category 1 recom-
mendation for initial treatment of CML-CP.43 Second generation TKIs
produced higher rate of early optimal responses, but so far have no
impact on long-term survival (probably because of available effective
salvage therapies). The main advantage of second generation TKI is
obtained among patients with high-risk disease; a relevant decrease in
the rate of transformation to AP and a BP was achieved with nilotinib
and dasatinib. As such, second generation TKIs in the frontline setting
could be reserved to patients with higher risk disease. Higher dose ima-
tinib and combination approaches in the frontline setting are investiga-
tional due to conflicting results of different studies to date. These
strategies are also not benign interventions, as they add to the eco-
nomic and toxicity burdens of the overall treatment plan. Allo-SCT or
other chemotherapy agents are not recommended as upfront treat-
ments for CML-CP, given the excellent outcomes and long term sur-
vival achieved with the TKIs. An exception may be in emerging nations
where allo-SCT is a one-time procedure costing $14–20 000, accessi-
ble to most patients. Conversely, generic imatinib in such geographies
(e.g., India) costs only less than $400 per year of therapy. At MD
Anderson Cancer Center (MDACC), patients are currently offered ther-
apy with dasatinib 50 mg daily. Lower dose dasatinib showed equiva-
lent efficacy compared with standard dose in addition to a better
safety profile. This cost-effective strategy may allow achievement of an
optimal response at a lower cost than standard-dose dasatinib, with a
potential molecular cure of CML (higher rate of complete molecular
responses; see below). Because of the higher rates of durable complete
molecular responses with second generation TKIs (which could lead to
discontinuation of TKI therapy and potential molecular cures; discussed
later), considerations of second generation TKIs in younger patients
A JH |
447
with CML (e.g., age <50 years) versus older patients, may be
entertained.
2 | SELECTING A FRONTLINE THERAPY
2.1 | Patient’s age and comorbidities and TKI toxicity
profile
While multiple TKIs are available for patients with newly diagnosed
CML-CP, each has a distinct toxicity profile to consider when deciding
on a therapy. Most TKIs are reasonably well-tolerated with adequate
monitoring and supportive care. For patients at risk of developing pleu-
ral effusions (existing lung injuries), TKIs other than dasatinib should be
selected. This might be relevant for patients with a history of lung dis-
ease (e.g., chronic obstructive pulmonary disease), cardiac disease (e.g.,
congestive heart failure), or uncontrolled hypertension. Pulmonary arte-
rial hypertension (PAH) is also a rare yet important complication of
dasatinib,44 and patients with preexisting PAH may be considered for
alternative TKIs in the frontline setting. Dasatinib also inhibits platelets
function,45 and patients taking concomitant anticoagulants may be at
an increased risk of hemorrhagic complications.46
Nilotinib has been associated with hyperglycemia. Caution should
be exercised in patients with uncontrolled diabetes when initiating
therapy, and avoided or prescribed with caution in patients with diabe-
tes or history of pancreatitis. 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; potassium and magnesium should be repleted to appropriate
serum levels before starting nilotinib or determining an individual
patient’s QT interval. Patients should always be counseled to take nilo-
tinib in a fasting state to avoid excess drug exposure. Nilotinib has also
been associated with vasospastic and vaso-occlusive vascular events,
such as ischemic heart disease, ischemic cerebrovascular events, and
peripheral artery occlusive disease (PAOD).47–50 In the 6-year follow-
up on the ENEST-nd trial,39 approximately 10% of patients experienced
vascular events. Nilotinib use should be limited in patients with risk fac-
tors such as diabetes mellitus or coronary or cerebrovascular artery dis-
ease. Avoiding nilotinib in patients with significant past vascular
histories is warranted with the availability of other viable options. Nilo-
tinib is also given twice daily on empty stomach; this may result in com-
pliance issues.
Imatinib causes bothersome quality-of-life side-effects including
weight gain, fatigue, peripheral and periorbital edema, bone and muscle
aches, nausea and others. However, most are mild to moderate. Less
than 5%-10% experience elevations in creatinine with long-term
therapy.
Finally, the patient’s age plays an important role in the treatment
decision. Patients younger than 50 years are expected to live 301
more years. Therefore, inducing a durable CMR may potentially lead to
therapy discontinuation. Second generation TKIs induce a significantly
higher rate of CMR compared with imatinib. The issue of durable CMR
and potential therapy discontinuation plays a less important role in
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448
elderly patients where the expected survival is shorter and discontinu-
ing therapy is less relevant.
2.2 | Cost
The cost of cancer drugs has risen exponentially over the past dec-
ade.51 All anticancer agents approved in the recent years were priced
at over $120 000 annually.51 When an international group of CML
experts called attention to the high prices of TKIs, the cost history of
imatinib was used to illustrate the problem with the high cancer drug
prices.52 When first approved in the United States, the annual price for
imatinib was less than $30 000, the price set to make the development
and commercialization of imatinib profitable based on cost of research,
population at risk, competitive market, estimated profits, and estimated
shorter-than-realized patient survival. Patients compliant with their
treatment regimen now live a “normal” lifespan and remain on imatinib
indefinitely.53,54 Paradoxically, with a higher number of patients and a
longer duration of therapy, the annual price of imatinib had quadrupled
to $132 000. This price is in the same range as dasatinib and nilotinib,
both priced above $130 000/year of therapy.
In 2016, generic formulations of imatinib became available,
although at a higher price than expected. This price should eventually
fall dramatically below $5–8000/year (as in Canada; the annual price of
generics in India is only $400). Physicians will then have to assess the
“treatment value” of second generation TKI (dasatinib or nilotinib) in
the frontline setting against the generic imatinib in relation to benefits
versus cost. Second generation TKIs may be offered for patients with
high-risk disease, while imatinib and/or its generic formulations will be
offered for patients with low-risk disease. Experts recently assessed,
following a Markov model, the most cost-effective strategy for treating
newly diagnosed CML-CP after imatinib loses patent exclusivity.55
They found that initiating imatinib as frontline treatment and treating
in a stepwise approach, compared to physician choice, costs less and
offer clinically-equivalent utility. In this analysis, the stepwise therapy
was found to have an incremental cost-effectiveness ratio (ICER) of
$227 136/Quality-adjusted life years. The ICER was favorable for step-
wise therapy for each Sokal risk group. Furthermore, the efficacy and
safety of generic imatinib was compared to the patented drug (previ-
ously discussed). Finally, lower dose dasatinib may offer the ultimate
solution with at least equivalent efficacy compared to second genera-
tion TKIs but at a significant lower cost (50% of branded dasatinb
100 mg daily), a price comparable to generic formulation of imatinib.
2.3 | Disease characteristics
For patients with CML-CP it is common to use one of the available risk
stratification scores, such as Sokal56 or Hasford,57 to help predict out-
comes. Patients with low-risk disease are expected to have optimal
responses whith imatinib, dasatinib, or nilotinib. However, selecting a
second generation TKI as frontline therapy (i.e., dasatinib or nilotinib)
based upon the Sokal or Hasford scores was proven more beneficial in
patients with intermediate or high risk disease, as shown in the DASI-
SION and ENEST-nd trials.29,30,38,39 Patients with higher risk disease
JABBOUR AND KANTARJIAN
have a lower likelihood of achieving the early milestones of CCyR and
MMR and, particularly, higher chances of disease transformation to
AP-CML or BP-CML.
Any of the the TKIs currently approved for frontline CML therapy
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 highly effective
in a large number of patients with CML. At MDACC, when choosing an
agent, we consider issues such as comorbidities, patient’s age, adverse
event profile, risk stratification score, and cost. Kinase domain mutation
profile plays no role in selecting an initial TKI, but becomes relevant in
the relapse setting.
3 | 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 are important. In
general, achieving a deeper response faster has been associated with
improved outcome, though the result of molecular testing is dependent
on the laboratory and their techniques. Due to advances in technology,
there are less invasive tests available for treatment monitoring than tra-
ditional bone marrow examinations (except when changing TKI; or in
unusual situations like unexpected myelosuppression to exclude trans-
formation or the development of myelodysplastic syndrome or other
marrow conditions).
3.1 | Important points for monitoring and determining
treatment failure
At baseline, all patients should undergo a bone marrow examination to
establish the diagnosis, assess percentage of blasts and basophils, and
perform cytogenetic analysis to confirm the presence of the Philadel-
phia chromosome and to exclude clonal evolution, particularly i(17)
(q10) 27/del7q, and 3q26.2 rearrangements, associated with a rela-
tively poor prognosis.16 The current recommendation that patients
have a follow up bone marrow study at 3, 6, and 12 months after start-
ing therapy may no longer be necessary.58 An alternative method to
determine cytogenetic response is with the use of FISH and PCR on
peripheral blood. If a patient is responding optimally, and the FISH
study is negative at 6 or 12 months and or BCR-ABL1 transcripts [IS]
<1%, it may be reasonable to omit marrow exams, as the patient is
likely to be in CCyR.59,60
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 a well-tolerated and effective treat-
ment due to discordant results between laboratories or even within the
same laboratory. 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.60 For patients in CCyR, the achievement and maintenance of a
MMR is of debatable significance. Several studies evaluating patients
receiving imatinib or second generation TKIs have found that patients
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JABBOUR AND KANTARJIAN 449

T AB LE 3 Percentage of survival by early molecular response T AB LE 5 MDACC criteria for response/failure and change of
therapy
Study Q-PCR < 10% Q-PCR > 10%
Time (months) Imatinib Second generation TKIs
UK (8-year) 93 54
3–6 MCyR; PCR10% [IS] CCyR; PCR  1% [IS]
MDACC (10-year) 98 94
12 CCyR; PCR  1% [IS] CCyR; PCR  1% [IS]
ENEST-nd 97 87
Later CCyR; PCR  1% [IS] CCyR; PCR  1% [IS]
DASISION 97 86

reasonable to change the TKI from imatinib to second generation TKI

in CCyR have similar survival regardless of whether or not they
achieved MMR.61,62
Early molecular response has been shown to have strong prognos-
tic value (Table 3). This has been shown with each of the 3 TKIs used
in the frontline setting. A BCR-ABL1 transcripts [IS] < 10% at 3 months
separates patients into high and low risk categories for long term out-
comes (i.e., progression, survival).30,39,63,64 The important question is:
how should we advise a patient who does not meet the 3-month
benchmark? One option is to switch TKIs early, but there are no data
indicating this will alter long-term outcome. Several experts suggested
that a follow-up measurement at 6 months will help define patients
clearly in need of a change in therapy.58 This strategy has been retro-
65–67
spectively analyzed by several large groups with conflicting results.
The results of two independent study groups have suggested that all
patients with BCR-ABL1 transcripts > 10% at 3 months do not neces-
sarily have an inferior outcome.66,67 Patients who continued on therapy
and achieved transcripts levels less than 10% by 6 months had the
same long-term favorable outcome as those with optimal molecular
responses at 3 months. Patients with BCR-ABL1 transcripts [IS] >10%
after 6 months have a worse outcome. Still the 4-year survival with 6-
month BCR-ABL1 transcripts [IS] >10% versus <10% are 100% versus
74%. The CML-study IV has established a 6-month BCR-ABL1 tran-
scripts [IS] <10% response as an optimal milestone. Patients who
reached the 6-monts milestone had a significant survival advantage of
about 6% after 10 years regardless of therapy.24 Thus, it may be
for BCR-ABL1 transcripts [IS] >10% after 6 months.66 However, a simi-
lar situation in a patient on second generation TKI (dasatinib, nilotinib)
does not necessarily imply consideration of allo-SCT.
3.2 | When to switch therapy
The aim of therapy in CML should be the achievement of CCyR within
12 months and to continue to be in CCyR at any time beyond 12
months, especially with standard dose imatinib therapy. For second
generation TKIs, CCyR may need to be achieved sooner for an optimal
outcome, for example, within 6 months.68 Patients who do not achieve
a complete hematologic response by 3 months should be considered
for a change in therapy (Tables 4 and 5).
One question is whether to change therapy at 3 months based on
the level of BCR-ABL1 transcripts [IS]. For patients on imatinib therapy,
if the 3-month transcript level is greater than 10%, we suggest an
approach similar to the ELN guidelines:58 perform serial molecular
monitoring between 3 and 6 months to determine the response pre-
cisely. If patients still have greater than 10% BCR-ABL1 transcripts [IS]
at 6 months, the chances of attaining CCyR are low, and a change of
therapy might be in indicated. Furthermore, a 3-month value of 10%
[IS] may not be accurate: in a recent report in 1 sample collected at 3
months and tested 96 times, the mean value was 11% (range, 5%-
16%), with only 31% of tests being 10%.69 This approach also applies
to patients on second generation TKIs, because, as mentioned earlier,

T AB LE 4 Response evaluation to TKIs used as first-line therapy (ELN 2013)

Optimal Warning Failure

Baseline — CCA in Ph1 cells —

High-risk Sokal or Hasford score

3 months Ph1 < 35% Ph1 36 – 95% Ph1 > 95%

And/or And/or And/or
BCR-ABL  10% BCR-ABL > 10% No CHR

6 months Ph1 0% Ph1 1 – 35% Ph1 > 35%

And/or And/or And/or
BCR-ABL < 1% BCR-ABL 1 – 10% BCR-ABL > 10%

12 months BCR-ABL  0.1% BCR-ABL 0.1 – 1% BCR-ABL > 1%

And/or
Ph1 > 0%

Any time BCR-ABL  0.1% CCA in Ph- cells (-7 or 7q-) Loss of CHR

Loss or CCyR

Confirmed loss of MMR

CCA in Ph1 cells

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T AB LE 6 Important response categories in CML
Response Translates into:
BCR-ABL1  10% Significantly improved survival
at 6 months; CCyR later
MMR Modest improvement in EFS;
possible longer duration CCyR; no
survival benefit
CMR Possibility of therapy discontinua-
tion
early switching has not yet shown to influence long-term outcome.70
Another study randomized patients in CCyR on imatinib for at least 2
years to continue imatinib or switch to nilotinib.71 Switching to nilotinib
induced deeper molecular responses, but did not translate into an
improvement in progression-free survival or in other meaningful
outcomes.
Patients who meet all the relevant benchmarks in the first 12
months are monitored periodically using FISH and molecular testing
(molecular testing only if BCR-ABL1 [IS] transcripts consistently below
0.1%). If there are clear signs of possible failure, patients should
undergo a bone marrow examination with cytogenetic studies, and
molecular testing including analysis for mutations. Any degree of cyto-
genetic relapse calls for a change in therapy. Fluctuating molecular lev-
els during continuous CCyR would only prompt closer monitoring and
a compliance assessment.
In several studies, the achievement of a CCyR (Ph-positive meta-
phases 0%; BCR-ABL1 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. Achievement of CCyR
is the primary endpoint of TKI therapy. Achievement of BCR-ABL1 tran-
scripts [IS]  0.1% (MMR) was associated with modest improvements in
event-free survival rates, possible longer durations of CCyR, but not
with a survival benefit. The achievement of CMR (nonmeasurable BCR-
ABL1 transcripts) offers the possibility of treatment discontinuation in
clinical trials only (Table 6). Lack of achievement of MMR or of CMR
should not be interpreted as a need to change TKI therapy or to consider
allo-SCT. Response assessments at earlier times on frontline TKI therapy
(3–6 months) have shown better outcomes with achievement of a major
cytogenetic response by 3 to 6 months on imatinib therapy (Ph-positive
metaphases  35%; BCR-ABL1 transcripts [IS]  10%). While this is
interpreted to mean that a change to second TKI therapy may be consid-
ered if such outcome is not obtained, no studies have shown that chang-
ing therapy from imatinib to second TKIs has improved patients’
outcomes. When nilotinib or dasatinib are used in front-line therapy,
achievement of complete cytogenetic response by 3–6 months of TKIs
therapy has been associated with improved outcomes.
At MDACC, the major treatment milestones are at 6 and 12
months. Patients with BCR-ABL1 transcripts [IS] > 10% at 6 months, or
without CCyR (BCR-ABL1 transcripts [IS]  1%) at 12 months, or with
loss of response at any time are candidates for a switch of therapy. The
choice of TKIs is based on the mutation profiles and patients comorbid-
ities. We do not consider a change of TKI therapy in patients in CCyR
but without MMR.
JABBOUR AND KANTARJIAN
4 | MANAGEMENT OF TKI RESISTANCE
A remaining problem with the widespread use of all commercially avail-
able TKIs is increased drug resistance. A common mechanism of resist-
ance involves point mutations in the kinase domain of BCR-ABL1,
which impairs the activity of the available TKIs. Second generation TKIs
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, T315I known
as the “gatekeeper” mutation, displays resistance to all currently avail-
able TKIs except ponatinib.
Before defining a patient as having TKI resistance and modifying
therapy, treatment compliance and drug-drug interactions should be
assessed. Rates of imatinib adherence have been estimated to range
from 75% to 90%, and lower adherence rates correlated with worse
outcome.72–74 In a study of 87 patients with CML-CP treated with ima-
tinib 400mg daily, an adherence rate of 90% or less resulted in MMR
rate of 28% compared with 94% with greater than 90% adherence rate
(P < .001).72 CMR rates were 0% versus 44% (P 5 .002), and no molec-
ular 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.72
4.1 | 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.75,76 Clinical studies of second-line and third
line TKIs are summarized in Table 7. Based on these studies, several
noteworthy ideas have emerged. First, second-line treatment with nilo-
tinib, dasatinib, or bosutinib 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,77 but
switching to second-line TKI is more effective.78 Several studies that
evaluated second-line nilotinib79,80, dasatinib78,80, or bosutinib81, 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. 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
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.82 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 interven-
tion 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).83 Although this
analysis included studies with distinct study designs and various dosing
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JABBOUR AND KANTARJIAN 451

T AB LE 7 Summary of important phase II trials of 2nd and 3rd generation TKIs after prior TKI failure

Percent response
Dasatinib Nilotinib Bosutinib Ponatinib
CP AP MyBP LyBP CP AP MyBP LyBP CP AP BP CP AP BP
N 5 167 N 5 174 N 5 109 N 5 48 N 5 321 N 5 137 N 5 105 N 5 31 N 5 200 N 5 51 N 5 38 N 5 270 N 5 79 N 5 94

Median 24 14 12 12 48 9 3 3 24 6 3 36 36 36
follow-up
(mo)

% Resistant 74 93 91 88 70 80 82 82 69 NR NR 75 96 -
to imatinib

% Hematologic - 79 50 40 94 56 22 19 85 54 36 NR NR NR
Response

CHR 92 45 27 29 76 31 11 13 81 54 36 NR Ma Ma
HR: 57 HR: 34

NEL – 19 7 6 – 12 1 0 – 0 NR - NR NR

% Cytogenetic - 44 36 52 NR NR NR NR - NR NR - NR NR
Response

Complete 50 32 26 46 45 20 29 32 46 27 35 53 55 36

Partial 13 7 7 6 14 12 10 16 12 20 18 30 NR NR

% Survival At 6 years At 4 years At 4 years At 5 years

91 82 50 50 87 67 42 42 98 60 50 73 59 9

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.

schedules of dasatinib, the essential finding was that earlier switch to
dasatinib was associated with better outcomes.
Bosutinib was initially studied in patients who had resistance to or
intolerance of imatinib.81 After a dose escalation period, 500 mg once
daily was selected as the phase II dose, with the potential for dose
escalation to 600 mg once daily for patients not meeting predefined
benchmarks. A total of 288 patients were enrolled in the pivotal phase
II trial; more than two thirds had imatinib-resistant disease. The primary
endpoint of MCyR at 6 months was achieved in 31%; 41% achieved a
CCyR. Bosutinib appeared to retain activity across most known muta-
tions that confer imatinib resistance, except for T315I. Responses were
independent of whether patients had resistance to or intolerance of
imatinib. The most common toxicities were diarrhea, nausea, vomiting,
and rash. Diarrhea occurred in 84% of patients, with 9% experiencing
grade 3 diarrhea (there were no grade 4 events documented). Other
notable adverse events included myelosuppression and liver function
test abnormalities.
Ponatinib is a third generation TKI, and the first TKI in class to
exhibit activity against CML with T315I mutation.84 It is 500 times as
potent than imatinib at inhibiting BCR-ABL1.85 The approval of ponati-
nib was based on the phase II PACE trial, where 449 patients with
heavily pretreated CML or Ph-positive acute lymphoblastic leukemia
86
(ALL) were treated. Patients were considered for this trial if they had
resistance to or intolerance of dasatinib or nilotinib, or if they had CML
with T315I mutation. The dose of ponatinib was 45 mg once daily, and
patients were stratified by the disease phase, and the presence or
absence of a T315I mutation. Of the 267 patients who received ponati-
nib in CML-CP, 56% achieved a MCyR by 12 months, which included
45/64 (70%) patients with a T315I mutation. Patients responded more
favorably if they had received fewer TKIs. After a median follow up of
5 years, 60% of patients achieved MCyR (primary endpoint) at any
time; 82% of those remained in MCyR at 5 years.87 Furthermore, 40%
of patients achieved a MMR or better. The 5-years survival rate was
73%.87 Arterial occlusive events occurred in 31% of patients (26% seri-
ous). The most common all-grade treatment-emergent adverse events
occurring in  40% of patients with CML-CP were abdominal pain
(46%), rash (46%), thrombocytopenia (45%), headache (43%), constipa-
tion (41%), and dry skin (41%).87 Other notable toxicities include severe
skin rashes (4%-7%), pancreatitis (7%), and severe hypertension (20%).
As of early 2014, ponatinib labeling included a revised warning
regarding the risk of thrombotic events (13% per year), vascular occlu-
sions, heart failure, and hepatotoxicity, revised dosing information and
indications limited to adults with T315I mutation and those for whom
no other TKI is indicated.88 Vascular occlusive adverse events were
more frequent with increasing age and in patients with a prior history
of ischemia, hypertension, diabetes, or hyperlipidemia.87 Factors associ-
ated with an increased risk of vascular occlusion events include older
age, higher dose, history of myocardial infarction or prior vascular
events, and longer duration of CML.87 Studies assessing lower dose-
schedules of ponatinib are ongoing. In the community practice, it may
be safer to use ponatinib 30 mg daily (and lower the dose to 15 mg
daily for toxicities) rather than the FDA approved dose of 45 mg daily.
ABL001 (asciminib) is a small molecule allosteric BCR-ABL1 kinase
inhibitor that occupies the myristoyl pocket, leading to a kinase autoin-
hibition conformation.89 ABL001 was designed to inhibit BCR-ABL1 in
a non-ATP-competitive manner to maintain activity against BCR-ABL1
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452
mutations that confer resistance to TKIs. Preclinically, combined with
ATP-competitive TKIs, ABL001 eliminates early leukemic progenitors
and diminishes emergence of resistant clones.89 One hundred and one
patients with relapsed refractory CML and Philadelphia-positive acute
90
lymphoblastic leukemia were treated in a phase I trial. There were 5
dose limiting toxicities (DLTs): 2 Grade 3 lipase elevations (40 mg BID
and 200 mg QD), 1 Grade 2 arthralgia (80 mg BID), 1 acute coronary
syndrome (150 mg BID), and 1 Grade 3 bronchospasm (200 mg BID). A
dose of 40 mg BID was recommended for CML-CP patients. MMR was
achieved at 13% and 38% by 6 and 12 months of therapy, respectively.
Eighty percent (8/10) of patients with more than 35% Philadelphia-
positive metaphases achieved CCyR by 6 months. Further development
of the drug is ongoing.
4.2 | How to select a second or third line option
At the time of treatment failure, patients should undergo bone marrow
examination to allow proper determination of the CML phase and doc-
umentation of any clonal evolution. All patients should have CML cells
tested for BCR-ABL1 kinase domain mutations, as this will help guide
the selection of the TKI.91,92 When selecting between dasatinib, bosuti-
nib, and nilotinib, in vitro and in vivo data have identified distinct muta-
tions that exhibit decreased sensitivity to each of the agents.93,94
Physician may favor dasatinib or bosutinib if the patient has the follow-
ing mutations: Y253H, E255K/V, or F359C/V. Alternatively, nilotinib
may be favored in the presence of the V299L and F317L mutations.
For patients lacking these mutations, the choice should be on preexist-
ing conditions, toxicity profiles, and cost.
Bosutinib can be used for patients with most known mutations that
lead to imatinib failure.81 Like dasatinib and nilotinib, bosutinib is not
activie 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.95 Diarrhea was
documented in 82% of patients (n 5 570), most being grades 1/2 in
severity. Myelosuppression and liver function test abnormalities were
also common. With appropriate supportive care, monitoring, and dose
reductions for persistent diarrhea, most patients are able to continue
therapy with periodic dose interruptions or adjustment.
Ponatinib should be considered the agent of choice in patient with
CML and T315I mutation, and in instances where other TKIs are not
indicated (patients with resistance to at least one second generation
TKI). No other commercially available TKIs have activity against the
T315I mutation. The risk for serious toxicities (vaso-occlusive disease,
pancreatitis, hypertension, severe skin rashes) and of thrombotic events
with ponatinib is significant, but the benefits outweigh the risks for most
patients with a T315I mutation, as there are no other options for disease
control. These side effects are lower with ponatinib 15–30 mg daily.
Second and third generation TKIs have not been compared head-
to-head. Selection of one or the other is based on the side-effect pro-
files, mutations profile, drug interactions, compliance issues and the
JABBOUR AND KANTARJIAN
patient’s preexisting medical conditions. Mutational analysis are
required in patients who are failing imatinib or second generation TKIs,
or those who progress to AP/BP. Baseline mutational analysis on
patients with newly diagnosed CML-CP are not done, as this has not
proven to predict treatment outcome.
At MDACC, post imatinib failure, the choice of second or third
generation TKI is based on the disease phase, mutation profile, and
patient’s comorbidities. In advanced phases, we favor a combination of
chemotherapy and TKI (mainly ponatinib or dasatinib). In patients with
CML-CP with T315I mutation, ponatinib will be the first choice fol-
lowed by allo-SCT if a donor is available and an optimal response is not
achieved. Outside the context of T315I mutations, the type of muta-
tion will dictate the choice of therapy. Of note, patients with com-
pound mutations may not respond well to second generation TKI. A
close monitoring should be offered.96 If an optimal response is not
achieved, a switch of therapy to a third generation TKI and/or allo-SCT
is warranted. In patients with no mutation or a mutation sensitive to all
second generation TKIs, the choice will be based on comorbidities.
Patients with vascular risk factors and metabolic dysfunctions are not
candidates for nilotinib. Patients with lung injuries are not candidates
for dasatinib. Bosutinib may be the best choice for patients with car-
diac problems and arrhythmias.
4.3 | Allogeneic stem cell transplantation (allo-SCT)
The number of patients undergoing allo-SCT for CML-CP has decreased
significantly since TKIs were introduced, but will start to increase again
as the prevalence of CML increases, as about 2% of patients become
resistant to many TKIs every year and require allo-SCT. Allo-SCT has a
more important role when patients evolve into AP/BP (see below). Allo-
SCT remains an important therapeutic option for patients in CML-CP
whose CML has progressed after at least 2 TKIs, and those who poten-
tially harbore the T315I mutation (after a trial of ponatinib therapy).97
Prior exposure to TKIs does not impact transplant outcome negatively.
Patients referred to transplant may have a better outcome if entering
the transplant with a better response to TKIs (lower CML burden).98
Finally, allo-SCT cost versus TKIs cost and availability should be
considered. Allo-SCT, a curative one-time procedure costs $500 000 in
the United States, but only $20 000 in developing nations. Allo-SCT
should not be offered as frontline therapy unless the TKI prices are
prohibitive to a nation’s health care budget or not accessible to most.
In India, the annual price of generic imatinib is $400. Considering the
median age of patients with CML and the projected survival of 301
years ($400 3 30 years5 $12 000), imatinib therapy remains the best
frontline options. In nations where TKIs are not commonly accessible,
it may be better to perform allo-SCT on 100% of patients and cure
60%, rather than having TKIs available to 10% (and functional cure
10%). In contrast to the frontline setting, in the salvage setting the
value of allo-SCT versus second/third generation TKI is more pro-
nounced. Allo-SCT in first salvage as cure costs $20 000 versus $120
000–170 000/year for second-third generation TKIs. In these circum-
stances, allo-SCT could be offered as first salvage option in nations
with financial constraints.99,100

JABBOUR AND KANTARJIAN
5 | TREATMENT DURATION AND
DISCONTINUATION
Several studies have evaluated whether TKIs can be safely discontinued
in patients who have achieved long-term deep molecular responses. In
the Stop Imatinib (STIM) study, 100 patients who had achieved complete
molecular response (i.e., >5-log reduction in BCR-ABL1 and ABL1 levels
and undetectable transcripts on quantitative RT-PCR) after >2 years of
imatinib treatment discontinued TKI therapy and were followed prospec-
tively.101 Forty-two patients (61%) experienced molecular relapse, all but
2 within 6 months of TKI discontinuation. After reintroduction of imati-
nib, 26 patients again achieved CMR; the other 16 patients had
decreases in BCR-ABL1 levels. Similar results were observed in the com-
parably designed TWISTER study.102 Among the 40 patients enrolled,
the actuarial estimate of stable treatment-free remission (TFR) was 47%
at 2 years; all patients were sensitive to imatinib re-treatment.
Higher TFR rates can be achieved with second-generation TKIs
due to the relatively deeper and more sustained molecular responses
achieved with these agents compared to imaitnib.29,38 In the ENEST-
freedom study, TKI discontinuation was evaluated in patients with
chronic phase CML who had achieved at least MR4.5 after 2 years of
frontline nilotinib therapy, followed by 1 year of nilotinib consolidation.
Nilotinib was reinitiated in patients who lost MMR. Among 190
patients who entered the TFR phase, 98 patients (51.6%) remained in
MMR or better at 2 years after stopping nilotinib. Similar to the experi-
ence with imatinib, the vast majority of patients were able to regain a
deep molecular response after nilotinib reinitiation, although it is nota-
ble 11.6% of patients were unable to regain MR4.5 after resuming nilo-
tinib. In the STOP 2G-TKI study, patients receiving first-line or
subsequent dasatinib or nilotinib for 3 years and who were in MR4.5
with undetectable BCR-ABL1 transcripts for the preceding 2 years were
eligible for TKI discontinuation.103 The 2-year TFR rate was 53.6%, and
among patients who experienced molecular relapse and had to reinitia-
tion TKI therapy, all patients were able to achieve MR4.5 again.
Similar results were observed in the EURO-SKI trial, the largest
study to date of TKI discontinuation in CML.104 In this study of 821
patients with CML treated with frontline imatinib, nilotinib or dasatinib,
who had achieved at least MR4, and who subsequently stopped TKI
therapy, the molecular recurrence-free survival at 2 years was 52%.
Among 321 (86%) patients who lost their MMR and were restarted on
TKI, 81% regained a molecular response (MMR/MR4). In a multivariate
analysis, duration of MR4 for 31 years was the only significant factor
for persistent deep molecular response after stopping therapy. Addi-
tional factors include duration of TKI therapy for 61 years. 105
The relatively higher TFR rates observed with patients initially
treated with second-generation TKIs suggests that second-generation
TKIs may be preferred as initial therapy for patients in whom eventual
TKI discontinuation may be particularly valued (e.g., younger patients
106
expected to live more year benefitting from TKI discontinuation).
However, when factoring in the number of patients who achieve deep
enough molecular responses to be candidates for stopping TKI therapy,
the incidence of molecular cure remains relatively low, ranging from
approximately 15% with imatinib to 25%-30% with second-generation
A JH |
453
TKIs. Although the use of second-generation TKIs certainly increases
the likelihood of obtaining a sufficiently deep molecular response to
consider TKI discontinuation, the use of these second-generation
agents comes at significant financial cost. It has been estimated that
the use of frontline second-generation TKIs results in an increased cost
of $800 000 per quality-adjusted life-year, compared to generic imati-
nib.107,108 The financial burden associated with frontline use of
second-generation TKIs should therefore be carefully weighed against
the marginal improvement in cure fraction compared to imatinib.
Although it is encouraging that some patients may be functionally
cured with long-term TKI therapy, alternative strategies should be
explored to increase the cure fraction of patients with CML. These
approaches should focus on both inducing deeper molecular responses
and targeting the CML stem cell. Despite the presence of a constitutively
active BCR-ABL1 kinase, these leukemic stem cells may be quiescent,
which renders them relatively resistant to TKI therapy.109 The presence
of resistant leukemic stem cells, in part, explains why a substantial pro-
portion of patients rapidly relapse when TKI therapy is stopped. Future
TKI-independent therapeutic approaches that target the leukemic stem
cell will be imperative to increasing the number of patients with CML
who can be cured. The addition of pegylated interferon-a2b to imatinib
or dasatinib results in promising deep molecular responses that compare
favorably to those observed with either TKI alone, suggesting this may
be a useful approach to increase the potential for TFR.111,112 There are
also emerging data to suggest that the combination of Bcl-2 inhibitors
such as venetoclax in combination with TKIs can enhance cytotoxicity
and deplete CML stem cells.113,114 A study combining dasatinib 50 mg
daily with venetoclax in frontline CML-CP is currently ongoing. Studies
of several other agents in combination with TKIs are currently ongoing,
including hypomethylating agents,115 JAK2 inhibitors,116 and immune-
based therapies, including anti-PD-1 monoclonal antibodies and dendritic
cell vaccines.117 The hope is that these novel strategies will lead to
deeper and more durable responses than TKI therapy alone and will
therefore facilitate functional cure in a higher proportion of patients with
CML than does single-agent TKI therapy.
TKIs discontinuation studies in patients with durable CMR demon-
strate that stopping TKI therapy is feasible, and some patients may be
cured. At MDACC, therapy discontinuation is offered only for patients
in chronic phase with a quantifiable transcript, who have been on TKI
for at least 6 years, have achieved a sustained CMR for at least 3–4
years, and in whom a close follow-up can be performed (Table 8).
Going forward, it is important to continue to investigate the possibility
of safe treatment cessation. Measures of quality of life and adverse
event avoidance should be studied in subsequent trials. The economic
impact of long-term discontinuation of imatinib is substantial.
6 | ADVANCED STAGE CML
Patients with CML-AP or CML-BP may receive initial therapy with TKIs
(newer generation TKIs like dasatinib or ponatinib preferred over imati-
nib) to reduce the CML burden, and be considered for early allo-
SCT.118–122 Response rates with combinations of TKIs and
 |
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454
T AB LE 8 Requirements for TKI discontinuation in clinical practice
Discontinuation of TKI
Parameter Yes
Sokal risk Low-intermediate
BCR-ABL1 transcripts Quantifiable (e13a2 or e14a2)
CML stage Chronic
Response to first TKI Optimal
Duration of all TKIs therapy >6–8 years
Depth of molecular response CMR (MR4.5)
Duration of molecular response >31 years
Monitoring availability Ideal (every 2 months in years 1–2)
chemotherapy are 40% in nonlymphoid CML-BP and 70%-80% in
lymphoid CML-BP.123–125 Median survival times are 6 to 12 months,
and 12 to 24 months, respectively. The addition of TKIs to chemother-
apy has improved the response rates and prolonged the median sur-
vival time in CML-BP. We recently assessed outcome of 477 patients
with CML-BP who were treated with a TKI at some point during the
course of their CML.126 The median overall survival was 12 months
and the median failure-free survival was 5 months. The combination of
a TKI with intensive chemotherapy followed by stem cell transplanta-
126
tion appeared to confer the best outcome.
At present, allo-SCT is the only curative therapy for CML-AP and
CML-BP: overall cure rates are in the range of 15%-40% and 10%-
20%, respectively. Patients with cytogenetic clonal evolution as the
only accelerated phase criterion have a long-term event-free survival
rate of about 60%.127 Otherwise, TKIs provide hematologic responses
in 80% of patients and an estimated 4-year survival rates of 40%-55%
in CML-AP, but only a 40% response rate and a median survival of 9 to
12 months in CML-BP. Patients in the AP 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 frontline
TKI therapy than patients who evolve from CP to AP. The estimated
6–8 year survival rates with TKI therapy in de novo CML-AP are 60%-
127
80%. Such patients may continue on TKI therapy as their long-term
treatment if they achieve a complete cytogenetic response on TKI
therapy.
Allo-SCT should be considered early in patients in AP based on
response to TKI therapy. The only curative option for patients in BP
disease is allo-SCT. TKIs monotherapy or in combination with chemo-
therapy may serve as a good option for those who are not candidates
for transplant, or as a bridge to allo-SCT. The role of TKIs before and
after transplant is being evaluated. Accumulating data show that TKIs
do not increase transplant-related complications and when used after
low intensity conditioning regimens, may delay relapse rates and need
for donor lymphocyte infusions.
At MDACC, patients with CML-BP are treated with combination
of chemotherapy (type depends on the immunophenotype) and third
generation TKI followed by allo-SCT once a complete response is
achieved and placed on maintenance TKI therapy. Patients with de-
JABBOUR AND KANTARJIAN
No
High
Not quantifiable
Accelerated/blast phase
Failure
<3 years
Less than MR4
< 3 years
Poor; noncompliant
novo CML-AP are treated with frontline second generation TKI infin-
itely if an optimal response (CCyR; BCR-ABL1 transcripts [IS] <1%) is
achieved within 6 months of therapy All other patients in CML-AP are
treated with second/third generation TKI followed by allo-SCT.
7 | CONCLUSIONS AND FUTURE
DIRECTIONS
In 2018, CML experts and patients with CML have multiple treatment
options in the CML therapeutic armamentarium, including 5 TKIs (ima-
tinib, nilotinib, dasatinib, bosutinib, ponatinib), omacetaxine (protein
synthesis inhibitor), and several older agents (hydroxurea, interferon
alpha, busulfan, 6-mercaptopurine, cytarabine, decitabine, others).
Most patients with CML would be expected to have a normal life span,
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 allo-SCT before
CML progression. Future directions will focus on the potential molecu-
lar 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 of 35 times the inci-
dence. The prevalence is estimated to be close to 160 000 patients
with CML in the United States and about 3 million patients worldwide.
This may represent a considerable burden on patients and the health-
care systems in relation to drug availability, compliance, potential devel-
opment of long-term side effects, and costs. Therefore it is important
to continue research into therapies that increase the rates of durable
CMRs. This may be achievable with the current more potent new gen-
eration TKIs alone, or in combination with other available (Bcl-2 inhibi-
tors, peg-interferon alpha-2, omacetaxine, decitabine) or investigational
therapies (JAK2 inhibitors, hedgehog inhibitors, stem cell poisons, vac-
cines). 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

JABBOUR AND KANTARJIAN
BCR-ABL1 may help in the development of new strategies to target
them.
8 | MD ANDERSON CANCER CENTER
APPROACH
ALL patients suspected to have CML undergo bone marrow examina-
tion which will confirm the diagnosis and provide information needed
for staging. Baseline PCR is performed to identify the specific type of
rearrangement that can be appropriately followed when assessing for
response to TKI therapy.
Waiting for confirmation, patients are placed on transient cytore-
duction therapy with hydroxyurea. Tumor lysis syndrome prophylaxis is
implemented as well.
Patients are stratified into low-risk and intermediate/high-risk dis-
ease. Outside clinical trials, patients with low-risk disease are treated
with imatinib; patients with high-risk disease are treated with second
generation TKI. The choice of second generation TKI is based on
patients ’comorbidities.
Patients are monitored regularly every 3 months in the first year,
and later every 6 months. Monitoring by the use of peripheral blood
FISH and PCR are alternative to marrow examinations to determine
cytogenetic response. If a patient is responding optimally, and the FISH
study is negative at 6 or 12 months and or BCR-ABL1 transcripts [IS]
<1%, it may be reasonable to omit further marrow exams, as the
patient is likely to be in stable CCyR . The major treatment milestones
are at 6 and 12 months. Patients with lack of PCyR (BCR-ABL1 tran-
scripts [IS]  10%) at 6 months, lack of CCyR (BCR-ABL1 transcripts
[IS]  1%) at 12 months, and loss of response at any time are candi-
dates for a change of therapy. The choice of TKI is based on mutation
profile and patients’ comorbidities. We do not change therapy for
patients in CCyR but without MMR. Patients who meet all the relevant
benchmarks in the first 12 months are monitored periodically using
FISH and molecular testing (molecular testing only if BCR-ABL1 tran-
scripts consistently below 0.1% [IS]).
Post imatinib failure, patients should undergo a bone marrow
examination with cytogenetics and molecular testing, including analysis
for mutation. The choice of second or third generation TKIs is based on
disease phase, mutation profile, and patient’s comorbidities. In
advanced phases, we favor a combination of chemotherapy and TKI
(mainly ponatinib or dasatinib). In patients with CML-CP with T315I
mutation, ponatinib is the first choice treatment followed by allo-SCT if
a donor is available and an optimal response is not achieved. Outside
the context of a T315I mutation, the type of mutation dictates the
choice of therapy. Patients with compound mutations may not respond
well to second generation TKI, and a close monitoring is indicated. If an
optimal response is not achieved, a switch of therapy to a third genera-
tion TKI and/or allo-SCT is warranted. In patients with no mutation or
with mutations sensitive to all second generation TKIs, the choice is
based on comorbidities. Patients with vascular risk factors and meta-
bolic dysfunctions are not candidates for nilotinib therapy Patients
with lung injuries are not candidates for dasatinib therapy. Bosutinib
may be the best choice for patients with cardiac problems and
A JH |
455
arrhythmias. Allo-SCT remains an important therapeutic option for
patients in CML-CP in the following situations: patients who fail at
least 2 TKIs or potentially harbor the T315I mutation (after a trial of
ponatinib therapy).
Patients with CML-BP are treated with combination of chemother-
apy (type depends on the immunophenotype) and third generation TKI
followed by allo-SCT once a complete response is achieved and placed
on maintenance TKI therapy post allo-SCT. Patients with de-novo
CML-AP are treated with frontline second generation TKI infinitely if
an optimal response (CCyR; BCR-ABL1 transcripts [IS] <1%) is achieved
within 6 months of therapy. All other patients in CML-AP are treated
with second/third generation TKI followed by allo-SCT. Therapy dis-
continuation is offered only for patients with CML-CP with a quantifi-
able transcript, who have been on TKI for at least 6 years, have
achieved a sustained CMR for at least 3–4 years, and in whom a close
follow-up can be performed.
ORC ID
Elias Jabbour http://orcid.org/0000-0003-4465-6119
Hagop Kantarjian http://orcid.org/0000-0002-1908-3307
RE FE RE NC ES
[1] American Cancer Society. Cancer Facts & Figures 2017. Atlanta:
American Cancer Society; 2017.
[2] Huang X, Cortes J, Kantarjian H. Estimations of the increasing
prevalence and plateau prevalence of chronic myeloid leukemia in
the era of tyrosine kinase inhibitor therapy. Cancer. 2012;118(12):
3123–3127.
[3] Rowley JD. Letter: A new consistent chromosomal abnormality in
chronic myelogenous leukaemia identified by quinacrine fluores-
cence and Giemsa staining. Nature. 1973;243(5405):290–293.
[4] Mandanas RA, Leibowitz DS, Gharehbaghi K, et al. Role of p21
RAS in p210 bcr-abl transformation of murine myeloid cells. Blood.
1993;82(6):1838–1847.
[5] Okuda K, Matulonis U, Salgia R, Kanakura Y, Druker B, Griffin JD.
Factor independence of human myeloid leukemia cell lines is asso-
ciated with increased phosphorylation of the proto-oncogene Raf-
1. Exp Hematol. 1994;22(11):1111–1117.
[6] Raitano AB, Halpern JR, Hambuch TM, Sawyers CL. The Bcr-Abl
leukemia oncogene activates Jun kinase and requires Jun for trans-
formation. Proc Natl Acad Sci USA. 1995;92(25):11746–11750.
[7] Sawyers CL, Callahan W, Witte ON. Dominant negative MYC
blocks transformation by ABL oncogenes. Cell. 1992;70(6):901–
910.
[8] Shuai K, Halpern J, ten Hoeve J, Rao X, Sawyers CL. Constitutive
activation of STAT5 by the BCR-ABL oncogene in chronic myelog-
enous leukemia. Oncogene. 1996;13(2):247–254.
[9] Carlesso N, Frank DA, Griffin JD. Tyrosyl phosphorylation and
DNA binding activity of signal transducers and activators of tran-
scription (STAT) proteins in hematopoietic cell lines transformed by
Bcr/Abl. J Exp Med. 1996;183(3):811–820.
[10] Ilaria RL, Jr, Van Etten RA. P210 and P190 (BCR/ABL) induce the
tyrosine phosphorylation and DNA binding activity of multiple spe-
cific STAT family members. J Biol Chem. 1996;271(49):31704–
31710.
 |
A JH
456
[11] Silver RT, Woolf SH, Hehlmann R, et al. An evidence-based analy-
sis of the effect of busulfan, hydroxyurea, interferon, and alloge-
neic bone marrow transplantation in treating the chronic phase of
chronic myeloid leukemia: developed for the American Society of
Hematology. Blood. 1999;94(5):1517–1536.
[12] Deininger M, O’brien SG, Guilhot F. 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.
[13] Jabbour E, Cortes JE, Kantarjian HM. Molecular monitoring in
chronic myeloid leukemia: response to tyrosine kinase inhibitors
and prognostic implications. Cancer. 2008;112(10):2112–2118.
[14] Kantarjian H, Schiffer C, Jones D, Cortes J. Monitoring the
response and course of chronic myeloid leukemia in the modern
era of BCR-ABL tyrosine kinase inhibitors: practical advice on the
use and interpretation of monitoring methods. Blood. 2008;111(4):
1774–1780.
[15] Schoch C, Schnittger S, Bursch S, et al. Comparison of chromo-
some 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(1):53.
[16] Wang W, Cortes JE, Tang G, et al. Risk stratification of chromo-
somal abnormalities in chronic myelogenous leukemia in the era of
tyrosine kinase inhibitor therapy. Blood. 2016;127(22):2742–2750.
[17] Druker BJ, Lydon NB. Lessons learned from the development of
an abl tyrosine kinase inhibitor for chronic myelogenous leukemia.
J Clin Invest. 2000;105(1):3–7.
[18] O’Brien 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(11):994–
1004.
[19] Hochhaus A, Larson RA, Guilhot F, et al. Long-term outcomes of
imatinib treatment for chronic myeloid leukemia. N Engl J Med.
2017;376(10):917–927.
[20] Sacha T, Go ra-Tybor J, Szarejko M, et al. A multicenter prospective
study on efficacy and safety of imatinib generics: A report from
Polish Adult Leukemia Group imatinib generics registry. Am J Hem-
atol. 2017;92(7):E125–E128.
[21] Madhav D. India Generic imatinib in chronic myeloid leukemia: sur-
vival of the cheapest. Blood. 2016;128:abstract 630.
[22] Cortes JE, Baccarani M, Guilhot F, et al. Phase III, randomized,
open-label study of daily imatinib mesylate 400 mg versus 800 mg
in patients with newly diagnosed, previously untreated chronic
myeloid leukemia in chronic phase using molecular end points:
tyrosine kinase inhibitor optimization and selectivity study. J Clin
Oncol. 2010;28:424–430.
[23] Preudhomme C, Guilhot J, Nicolini FE, et al. Imatinib plus peginter-
feron alfa-2a in chronic myeloid leukemia. N Engl J Med. 2010;363
(26):2511–2521.
[24] Hehlmann R, Lauseker M, Saussele S, et al. Final evaluation of
randomized CML-study IV: 10-year survival and evolution of ter-
minal phase. Blood. 2017;130:abstract 897.
[25] Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-
methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methyl-
pyrimidin-4- ylamino)thiazole-5-carboxamide (BMS-354825), a dual
Src/Abl kinase inhibitor with potent antitumor activity in preclinical
assays. J Med Chem. 2004;47(27):6658–6661.
[26] O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-
Abl inhibitors AMN107 and BMS-354825 against clinically relevant
JABBOUR AND KANTARJIAN
imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65
(11):4500–4505.
[27] 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 imatinib-resistant ABL mutants. Can-
cer Res. 2006;66(11):5790–5797.
[28] Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with
a novel ABL kinase inhibitor. Science. 2004;305(5682):399–401.
[29] Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imati-
nib in newly diagnosed chronic-phase chronic myeloid leukemia. N
Engl J Med. 2010;362(24):2260–2270.
[30] Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-year study results
of DASISION: the dasatinib versus imatinib study in treatment-
naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34
(20):2333–2340.
[31] Radich JP, Kopecky KJ, Appelbaum FR, et al. A randomized trial of
dasatinib 100 mg versus imatinib 400 mg in newly diagnosed
chronic-phase chronic myeloid leukemia. Blood. 2012;120(19):
3898–3905.
[32] O’Brien SG, Hedgley C, Adams S, et al. Spiri6 2: An NCRI random-
ized study comparing dasatinib with imatinib in patients with
newly diagnosed CML. Blood (ASH Annual Meeting Abstracts).
2014;124:517.
[33] Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-
resistant Philadelphia chromosome-positive leukemias. N Engl J
Med. 2006;354(24):2531–2541.
[34] Shah NP, Rousselot P, Schiffer C, et al. Dasatinib in imatinib-
resistant or -intolerant chronic-phase, chronic myeloid leukemia
patients: 7-year follow-up of study CA180-034. Am J Hematol.
2016;91(9):869–874.
[35] Cortes J, Hochhaus A, Kantarjian H, et al. Impact of dose reduc-
tions on 5-year efficacy in newly diagnosed patients with chronic
myeloid leukemia in chronic phase (CML-CP) from DASISION. Am
Soc Clin Oncol. 2017;abstract 3036.
[36] Naqvi K, Cortes J, Skinner J, et al. Evaluating the role of lower
dose dasatinib in newly diagnosed early chronic phase-chronic
myeloid leukemia (CML-CP). Blood. 2017;130:abstract 1611.
[37] Weisberg E, Manley PW, Breitenstein W, et al. Characterization of
AMN107, a selective inhibitor of native and mutant Bcr-Abl. Can-
cer Cell. 2005;7(2):129–141.
[38] Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for
newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;
362(24):2251–2259.
[39] Hochhaus A, Saglio G, Hughes TP, et al. Long-term benefits and
risks of frontline nilotinib vs imatinib for chronic myeloid leukemia
in chronic phase: 5-year update of the randomized ENESTnd trial.
Leukemia. 2016;30(5):1044–1054.
[40] Wang J, Shen ZX, Saglio G, et al. Phase 3 study of nilotinib vs ima-
tinib in Chinese patients with newly diagnosed chronic myeloid
leukemia in chronic phase: ENESTchina. Blood. 2015;125(18):
2771–2778.
[41] Cortes JE, Gambacorti-Passerini C, Deininger MW, et al. Bosutinib
versus Iimatinib for newly diagnosed chronic myeloid leukemia:
results from the randomized BFORE Trial. J Clin Oncol. 2017.
[42] Jain P, Kantarjian H, Alattar ML, et al. Long-term molecular and
cytogenetic response and survival outcomes with imatinib 400 mg,
imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-
phase chronic myeloid leukaemia: retrospective analysis of patient
data from five clinical trials. Lancet Haematol. 2015;2(3):e118–
e128.

JABBOUR AND KANTARJIAN
[43] O’Brien S, Radich JP, Abboud CN, et al. Chronic myelogenous leu-
kemia, Version 1.2014. J Natl Compr Canc Netw. 2013;11:1327–
1340.
[44] Montani D, Bergot E, Gunther S, et al. Pulmonary arterial hyper-
tension in patients treated by dasatinib. Circulation. 2012;125(17):
2128–2137.
[45] Quintas-Cardama A, Han X, Kantarjian H, Cortes J. Tyrosine kinase
inhibitor-induced platelet dysfunction in patients with chronic
myeloid leukemia. Blood. 2009;114(2):261–263.
[46] Quintas-Cardama A, Kantarjian H, Ravandi F, et al. Bleeding diath-
esis in patients with chronic myeloid leukemia receiving dasatinib
therapy. Cancer. 2009;115(11):2482–2490.
[47] Aichberger KJ, Herndlhofer S, Schernthaner G, et al. Progressive
peripheral arterial occlusive disease and other vascular events dur-
ing nilotinib therapy in CML. Am J Hematol. 2011;86(7):533–539.
[48] Quintas-Cardama A, Kantarjian H, Cortes J. Nilotinib-Associated
Vascular Events. Clin Lymphoma Myeloma Leuk. 2012;12(5):337–
340.
[49] Tefferi A, Letendre L. Nilotinib treatment-associated peripheral
artery disease and sudden death: Yet another reason to stick to
imatinib as front-line therapy for chronic myelogenous leukemia.
Am J Hematol. 2011;86(7):610–611.
[50] Giles FJ, Mauro MJ, Hong F, et al. Rates of peripheral arterial
occlusive disease in patients with chronic myeloid leukemia in the
chronic phase treated with imatinib, nilotinib, or non-tyrosine
kinase therapy: a retrospective cohort analysis. Leukemia. 2013;27
(6):1310–1315.
[51] Smith TJ, Hillner BE. Bending the cost curve in cancer care. N Engl
J Med. 2011;364(21):2060–2065.
[52] Kantarjian HM, Fojo T, Mathisen M, Zwelling LA. Cancer drugs in
the United States: justum pretium—the just price. J Clin Oncol.
2013;31(28):3600–3604.
[53] 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;121:4439–4442.
[54] 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;103:553–
561.
[55] Larson RA, Conti R, Padula WV, et al. What is the most cost-
effective strategy for treating newly diagnosed chronic myeloid
leukemia (CML) after imatinib loses patent exclusivity? Blood (ASH
Annual Meeting Abstracts). 2014;124:738.
[56] Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in
“good-risk” chronic granulocytic leukemia. Blood. 1984;63(4):789–
799.
[57] Hasford J, Pfirrmann M, Hehlmann R, et al. A new prognostic
score for survival of patients with chronic myeloid leukemia
treated with interferon Alfa. J Natl Cancer Inst. 1998;90:850–858.
[58] Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet
recommendations for the management of chronic myeloid leuke-
mia: 2013. Blood. 2013;122(6):872–884.
[59] Testoni N, Marzocchi G, Luatti S, et al. Chronic myeloid leukemia:
a prospective comparison of interphase fluorescence in situ hybrid-
ization and chromosome banding analysis for the definition of
complete cytogenetic response: a study of the GIMEMA CML WP.
Blood. 2009;114(24):4939–4943.
[60] Kantarjian H, Cortes J. Considerations in the management of
patients with Philadelphia chromosome-positive chronic myeloid
A JH |
457
leukemia receiving tyrosine kinase inhibitors. J Clin Oncol. 2011;29:
1512–1516.
[61] 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.
[62] 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;27:3659–3663.
[63] 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;30:232–238.
[64] Jain P, Kantarjian H, Nazha A, et al. Early responses predict better
outcomes in patients with newly diagnosed chronic myeloid leuke-
mia: results with four tyrosine kinase inhibitor modalities. Blood.
2013;121(24):4867–4874.
[65] 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:
3739–3742.
[66] 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
(11):1686–1688.
[67] Branford S, Roberts N, Yeung DT, Altamura H, Parker WT, Hughes
TP. 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.
[68] Jabbour E, Kantarjian HM, O’brien 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;29:4260–4265.
[69] Branford S. Monitoring and defining early response: Where to
draw the line? Best Pract Res Heamtol. 2016;29:284–294.
[70] Cortes JE, De Souza CA, Ayala M, et al. Switching to nilotinib ver-
sus imatinib dose escalation in patients with chronic myeloid leu-
kaemia in chronic phase with suboptimal response to imatinib
(LASOR): a randomised, open-label trial. Lancet Haematol. 2016;3
(12):e581–e591.
[71] Hughes TP, Leber B, Cervantes F, et al. Sustained deep molecular
responses in patients switched to nilotinib due to persistent BCR-
ABL1 on imatinib: final ENESTcmr randomized trial results. Leuke-
mia. 2017;31(11):2529–2531.
[72] Marin D, Bazeos A, Mahon FX, et al. Adherence is the critical fac-
tor for achieving molecular responses in patients with chronic
myeloid leukemia who achieve complete cytogenetic responses on
imatinib. J Clin Oncol. 2010;28(14):2381–2388.
[73] 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(6):481–496.
[74] Noens L, van Lierde MA, De Bock R, et al. Prevalence, determi-
nants, and outcomes of nonadherence to imatinib therapy in
patients with chronic myeloid leukemia: the ADAGIO study. Blood.
2009;113(22):5401–5411.
[75] Bristol-Myers Squibb Company. Sprycel® (dasatinib) prescribing
information. Princeton, NJ; 2011.
 |
A JH
458
[76] Novartis Pharmaceuticals Corporation. Tasigna® (nilotinib) pre-
scribing information. East Hanover, NJ; 2011.
[77] Jabbour E, Kantarjian HM, Jones D, et al. Imatinib mesylate dose
escalation is associated with durable responses in patients with
chronic myeloid leukemia after cytogenetic failure on standard-
dose imatinib therapy. Blood. 2009;113(10):2154–2160.
[78] Kantarjian H, Pasquini R, Levy V, et al. Dasatinib or high-dose ima-
tinib for chronic-phase chronic myeloid leukemia resistant to imati-
nib at a dose of 400 to 600 milligrams daily: two-year follow-up of
a randomized phase 2 study (START-R). Cancer. 2009;115(18):
4136–4147.
[79] Garcia-Gutierrez JV, Herrera P, Abalo LL, Rey MD, Calbacho M.
Impact of second-generation tyrosine kinase inhibitors as second
line treatment for patients with chronic myeloid leukemia. Blood.
2011;118:632.
[80] Goh HG, Jootar S, Kim HJ, Sohn SK, Park JS, Kim SH. 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.
[81] Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and effi-
cacy of bosutinib (SKI-606) in chronic phase Philadelphia
chromosome-positive chronic myeloid leukemia patients with
resistance or intolerance to imatinib. Blood. 2011;118(17):4567–
4576.
[82] Yeung DT, Osborn M, White DL, Branford S, Kornhauser M, Slader
C. 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.
[83] Quintas-Cardama A, Cortes JE, O’brien S, et al. Dasatinib early
intervention after cytogenetic or hematologic resistance to imati-
nib in patients with chronic myeloid leukemia. Cancer. 2009;115
(13):2912–2921.
[84] O’Hare 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;16:401–412.
[85] Zhou T, Commodore L, Huang WS, et al. Structural mechanism of
the pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for over-
coming kinase inhibitor resistance. Chem Biol Drug Des. 2011;77:1–
11.
[86] Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A phase 2 trial of ponati-
nib in Philadelphia chromosome-positive leukemias. N Engl J Med.
2013;369(19):1783–1796.
[87] Kantarjian HM, Pinilla-Ibarz J, Le Coutre PD, et al. Five-year results
of the ponatinib phase II PACE trial in heavily pretreated CP-CML
patients. Am Soc Clin Oncol. 2017;abstract 7012.
[88] Iclusig (Ponatinib) [Prescribing Information]. Cambridge, MA: ARIAD
Pharmaceuticals, Inc; 2014.
[89] Wylie AA, Schoepfer J, Jahnke W, et al. The allosteric inhibitor
ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543
(7647):733–737.
[90] Hughes TP, Goh YT, Ottmann OG, et al. Expanded phase 1 study
of ABL001, a potent, allosteric inhibitor of BCR-ABL, reveals sig-
nificant and durable responses in patients with CML-chronic phase
with failure of prior TKI therapy. Blood. 2016;128:abstract 625.
[91] Cortes J, Jabbour E, Kantarjian H, et al. Dynamics of BCR-ABL
kinase domain mutations in chronic myeloid leukemia after
sequential treatment with multiple tyrosine kinase inhibitors. Blood.
2007;110(12):4005–4011.
JABBOUR AND KANTARJIAN
[92] Jabbour E, Branford S, Saglio G, Jones D, Cortes JE, Kantarjian
HM. Practical advice for determining the role of BCR-ABL muta-
tions in guiding tyrosine kinase inhibitor therapy in patients with
chronic myeloid leukemia. Cancer. 2011;117(9):1800–1811.
[93] Mu€ller MC, Cortes JE, Kim D-W, et al. Dasatinib treatment of chronic-
phase chronic myeloid leukemia: analysis of responses according to
preexisting BCR-ABL mutations. Blood. 2009;114(24):4944–4953.
[94] 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(25):4204–4210.
[95] 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.
2014;123(9):1309–1318.
[96] Jabbour E, Kantarjian H, Ghanem H, et al. The achievement of a
3-month complete cytogenetic response to second-generation
tyrosine kinase inhibitors predicts survival in patients with chronic
phase chronic myeloid leukemia after imatinib failure. Clin Lym-
phoma Myeloma Leuk. 2013;13(3):302–306.
[97] Jabbour E, Cortes J, Santos FP, et al. Results of allogeneic hemato-
poietic stem cell transplantation for chronic myelogenous leukemia
patients who failed tyrosine kinase inhibitors after developing BCR-
ABL1 kinase domain mutations. Blood. 2011;117(13):3641–3647.
[98] Lee SJ, Kukreja M, Wang T, et al. Impact of prior imatinib mesylate
on the outcome of hematopoietic cell transplantation for chronic
myeloid leukemia. Blood. 2008;112(8):3500–3507.
€elles GJ, Tarin-Arzaga LC, Gonzalez-Carrillo ML, et al.
[99] Ruiz-Argu
Therapeutic choices in patients with Ph-positive CML living in
Mexico in the tyrosine kinase inhibitor era: SCT or TKIs? Bone
Marrow Transplant. 2008;42(1):23–28.
[100] Jaime-Perez JC, Heredia-Salazar AC, Cantu-Rodríguez OG, et al.
Cost structure and clinical outcome of a stem cell transplantation
program in a developing country: the experience in northeast
Mexico. Oncologist. 2015;20(4):386–392.
[101] 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,
multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11(11):
1029–1035.
[102] Ross DM, Branford S, Seymour JF, et al. Safety and efficacy of
imatinib cessation for CML patients with stable undetectable mini-
mal residual disease: results from the TWISTER study. Blood.
2013;122(4):515–522.
[103] Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or
nilotinib in chronic myeloid leukemia: interim analysis of the STOP
2G-TKI study. Blood. 2017;129(7):846–854.
[104] Mahon FX, Richter J, Guilhot J, et al. Cessation of tyrosine kinase
inhibitors treatment in chronic myeloid leukemia patients with
deep molecular response: results of the euro-ski trial. Blood. 2016;
128(22):787–787.
[105] Duration of deep molecular response has most impact on the suc-
cess of cessation of tyrosine kinase inhibitor treatment in chronic
myeloid leukemia - results from the EURO-SKI trial. Blood. 2017;
130: abstract 313.
[106] Jabbour E. Chronic myeloid leukemia: First-line drug of choice. Am
J Hematol. 2016;91(1):59–66.
[107] Padula WV, Larson RA, Dusetzina SB, et al. Cost-effectiveness of
tyrosine kinase inhibitor treatment strategies for chronic myeloid
leukemia in chronic phase after generic entry of imatinib in the
United States. J Natl Cancer Inst. 2016;108(7).

JABBOUR AND KANTARJIAN
[108] Chhatwal J, Mathisen M, Kantarjian H. Are high drug prices for
hematologic malignancies justified? A critical analysis. Cancer.
2015;121(19):3372–3379.
[109] Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell:
stemming the tide of persistence. Blood. 2017;129(12):1595–1606.
[110] Holyoake TL, Vetrie D. The chronic myeloid leukemia stem cell:
stemming the tide of persistence. Blood. 2017;129(12):1595–1606.
[111] Simonsson B, Gedde-Dahl T, Markevarn B, et al. Combination of
pegylated IFN-alpha2b with imatinib increases molecular response
rates in patients with low- or intermediate-risk chronic myeloid
leukemia. Blood. 2011;118(12):3228–3235.
[112] Hjorth-Hansen H, Stentoft J, Richter J, et al. Safety and efficacy of
the combination of pegylated interferon-alpha2b and dasatinib in
newly diagnosed chronic-phase chronic myeloid leukemia patients.
Leukemia. 2016;30(9):1853–1860.
[113] Carter BZ, Mak PY, Mu H, et al. Combined targeting of BCL-2 and
BCR-ABL tyrosine kinase eradicates chronic myeloid leukemia
stem cells. Sci Transl Med. 2016;8(355):355ra117.
[114] Ko TK, Chuah CT, Huang JW, Ng KP, Ong ST. The BCL2 inhibitor
ABT-199 significantly enhances imatinib-induced cell death in
chronic myeloid leukemia progenitors. Oncotarget. 2014;5(19):
9033–9038.
[115] Schnekenburger M, Grandjenette C, Ghelfi J, et al. Sustained expo-
sure to the DNA demethylating agent, 2’-deoxy-5-azacytidine,
leads to apoptotic cell death in chronic myeloid leukemia by pro-
moting differentiation, senescence, and autophagy. Biochem Phar-
macol. 2011;81(3):364–378.
[116] Gallipoli P, Cook A, Rhodes S, et al. JAK2/STAT5 inhibition by
nilotinib with ruxolitinib contributes to the elimination of CML
CD341 cells in vitro and in vivo. Blood. 2014;124(9):1492–1501.
[117] Held SA, Heine A, Mayer KT, Kapelle M, Wolf DG, Brossart P.
Advances in immunotherapy of chronic myeloid leukemia CML.
Curr Cancer Drug Targets. 2013;13(7):768–774.
[118] 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;27:3472–3479.
[119] Oehler VG, Gooley T, Snyder DS, et al. The effects of imatinib
mesylate treatment before allogeneic transplantation for chronic
myeloid leukemia. Blood. 2007;109(4):1782–1789.
A JH |
459
[120] Carpenter PA, Snyder DS, Flowers ME, et al. Prophylactic adminis-
tration of imatinib after hematopoietic cell transplantation for
high-risk Philadelphia chromosome-positive leukemia. Blood. 2007;
109(7):2791–2793.
[121] 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(2):340–344.
[122] 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. Leu-
kemia. 2012;26(6):1189–1194.
[123] 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(12):4396–4407.
[124] Ravandi F, O’brien 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 lym-
phoblastic leukemia. Blood. 2010;116(12):2070–2077.
[125] Quintas-Cardama A, Kantarjian H, Garcia-Manero G, et al. A pilot
study of imatinib, low-dose cytarabine and idarubicin for patients
with chronic myeloid leukemia in myeloid blast phase. Leuk Lym-
phoma. 2007;48(2):283–289.
[126] Jain P, Kantarjian HM, Ghorab A, et al. Prognostic factors and sur-
vival outcomes in patients with chronic myeloid leukemia in blast
phase in the tyrosine kinase inhibitor era: Cohort study of 477
patients. Cancer. 2017;123(22):4391–4402.
[127] Ohanian M, Kantarjian HM, Quintas-Cardama A, et al. Tyrosine
kinase inhibitors as initial therapy for patients with chronic mye-
loid leukemia in accelerated phase. Clin Lymphoma Myeloma Leuk.
2014;14(2):155–162.
How to cite this article: Jabbour E, Kantarjian H. Chronic mye-
loid leukemia: 2018 update on diagnosis, therapy and monitor-
ing. Am J Hematol. 2018;93:442–459. https://doi.org/10.1002/
ajh.25011