CME ARTICLE

A JH
CME Information: Chronic Myeloid Leukemia: 2016 update
on diagnosis, therapy and monitoring
CME Editor: Ayalew Tefferi, M.D.
Author: Elias Jabbour, M.D. and Hagop Kantarjian, M.D.

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Educational Objectives
Upon completion of this educational activity, participants will be better able to:

 Manage patients with newly diagnosed CML in CP

 Understand the milestones and indications for switch of therapy
 Manage patients with resistant disease
 Differentiate the TKIs available
 Manage patients with advanced phases, including the role of allogeneic stem cell transplantation

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CME Editor: Ayalew Tefferi, M.D. has no relevant financial relationships to disclose.
Author: Elias Jabbour, M.D. and Hagop Kantarjian, M.D. have no relevant financial relationships to disclose.
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252 American Journal of Hematology, Vol. 91, No. 2, February 2016

ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
AJH Educational Material A JH
Chronic myeloid leukemia: 2016 update on diagnosis,
therapy, and monitoring
Elias Jabbour* and Hagop Kantarjian

Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2
cases per 100,000 adults. 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 chromosome. The molecular
consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates
into a BCR-ABL oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and
dasatinib 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 2nd generation TKIs reported
significantly deeper and faster responses; their impact on long-term survival remains to be determined.
Salvage therapy: For patients who fail frontline therapy, second-line options include second and third
generation TKIs. Although second and third generation TKIs are potent and selective TKIs, they exhibit
unique pharmacological profiles and response patterns relative to different patient and disease
characteristics, 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 two TKIs, and for all patients in advanced phase disease.
Am. J. Hematol. 91:253265, 2016. V
C 2015 Wiley Periodicals, Inc.

Disease Overview
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one to two cases per 100,000 adults. It accounts for
approximately 15% of newly diagnosed cases of leukemia in adults [1]. In 2015, it is estimated about 7,000 new CML cases will be diagnosed in
the United States, and about 1,100 patients will die of CML. Since 2000, the year of introduction of imatinib, the annual mortality in CML has
decreased from 1020% down to 12% [1]. Consequently, the prevalence of CML in the United States, estimated at about 25-30,000 in 2000, has
increased to an estimated 801,00,0001 in 2015, and will reach a plateau of about 1,80,000 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 pathways such as RAS, RAF, JUN kinase, MYC and STAT [410] This
influences leukemogenesis by creating a cytokine-independent cell cycle with aberrant apoptotic signals in response to cytokine withdrawal.
Until a little more than a decade ago, drug therapy for CML was limited to nonspecific agents such as busulfan, hydroxyurea, and interferon-
alfa (INF-a) [11]. INF-a led to disease regression and improved survival but was hindered by its modest efficacy and a multitude of toxicities. Allo-
geneic stem cell transplantation (allo-SCT) is curative, but carries risks of morbidity and mortality. Further, allo-SCT is an option only for patients
with good performance status and organ functions, and who have an appropriate stem cell donor.
The CML therapeutic landscape changed dramatically with the development of small molecule tyrosine kinase inhibitors (TKIs) that potently inter-
fered with the interaction between the BCR-ABL1 oncoprotein and adenosine triphosphate (ATP), blocking cellular proliferation of the malignant
clone. This targeted approach altered the natural history of CML, improving the 10-year survival rate from approximately 20% to 8090% [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 in various cir-
cumstances and phases of the disease. Allo-SCT is an important treatment option in CML chronic phase (CP) post TKIs failure and in advanced
CML phases, and its role will be discussed. Cytogenetic and molecular benchmarks for patients on therapy will be discussed. Finally, appropriate
monitoring strategies for patients on various TKIs will be covered.

Department of Leukemia, the University of Texas M. D. Anderson Cancer Center, Houston, Texas
Conflict of interest: Nothing to report
*Correspondence to: Elias Jabbour, MD Anderson Cancer Center, Houston, Texas, USA, Box 428, 1515 Holcombe Blvd, Houston, TX 77030. E-mail: ejab-
bour@mdanderson.org
Received for publication: 7 December 2015; Accepted: 9 December 2015
Am. J. Hematol. 91:253265, 2016.
Published online: in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.24275

C 2015 Wiley Periodicals, Inc.

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doi:10.1002/ajh.24275 American Journal of Hematology, Vol. 91, No. 2, February 2016 253
Jabbour and Kantarjian
Manifestations and Staging
About 50% of patients with CML diagnosed in the United States
are asymptomatic. The disease is diagnosed often after a routine
physical examination or blood tests. CML can be classified into three
phases: CP, accelerated 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 quad-
rant fullness or pain. Rare manifestations include bleeding (associated
with a low platelet count and/or platelet dysfunction), thrombosis
(associated with thrombocytosis and/or marked leukocytosis), gouty
arthritis (from elevated uric acid levels), priapism (usually with
marked leukocytosis or thrombocytosis), retinal hemorrhages, and
upper gastrointestinal ulceration and bleeding (from elevated hista-
mine levels due to basophilia). Leukostatic symptoms (dyspnea,
drowsiness, loss of coordination, confusion) due to leukemic cells
sludging in the pulmonary or cerebral vessels, are uncommon in CP
despite white blood cell (WBC) counts exceeding 100 x 109/L. Spleno-
megaly is the most consistent physical sign detected in 4050% of
cases. Hepatomegaly is less common (less than 10%). Lymphadenopa-
thy 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% transit 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 (mye-
loid in 60%, lymphoid in 30%, megakaryocytic or undifferentiated in
10%) with worsening constitutional symptoms, bleeding, fever and
infections.
Diagnosis
The diagnosis of typical CML is simple and consists of document-
ing, in the setting of persistent unexplained leukocytosis (or occasion-
ally thrombocytosis), the presence of the Philadelphia (Ph)
chromosome abnormality, the t(9;22)(q34;q11), by routine cytogenet-
ics, or the Ph-related molecular BCR-ABL1 abnormalities by fluores-
cence in situ hybridization (FISH) or by molecular studies [1315].
A FISH analysis relies on the co-localization of large genomic
probes specific to the BCR and ABL genes. Comparison of simultane-
ous marrow and blood samples by FISH analysis shows high con-
cordance. FISH studies may have a false positive range of 15%
depending on the probes used.
Reverse transcriptase-polymerase chain reaction (RT-PCR) amplifies
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
0.51 log difference in some samples can occur depending on testing
procedures, sample handling, and laboratory experience [1315]. For
correlative 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 (62%) 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].
254 American Journal of Hematology, Vol. 91, No. 2, February 2016
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
The Ph chromosome is usually present in 100% of metaphases, often
as the sole abnormality. Ten to 15% of patients have additional chro-
mosomal 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 25% 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 ther-
apy 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 reverse transcriptase-polymerase
chain reaction is imperative to identify the specific type of rearrange-
ment that can be appropriately followed when assessing for response to
TKI therapy. About 2-5% of patients have b2a3 or b3a3 (not b2a2 or
b3a2) 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 may be in complete
molecular response on TKI.
Differential Diagnosis
CML must be differentiated from leukemoid reactions, which usu-
ally produce WBC counts, lower than 50 3 109/L, toxic granulocytic
vacuolation, Dohles bodies in the granulocytes, absence of basophilia,
and normal or increased LAP levels. The clinical history and physical
examination generally suggest the origin of the leukemoid reaction.
Corticosteroids can rarely cause extreme neutrophilia with a left shift,
but this abnormality is transient and of short duration.
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 3 109/L, and no Ph abnormality.
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 nor-
mal 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 hyperpla-
sia can be seen in essential thrombocythemia, with marked thrombocy-
tosis and splenomegaly. Some patients who present with clinical
characteristics of essential thrombocythemia (with marked thrombocyto-
sis 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.
Frontline Treatment Options
The three commercially available TKIs for the treatment of CML
include imatinib, dasatinib, and nilotinib. Current guidelines endorse
doi:10.1002/ajh.24275
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
TABLE I. Summary of Pivotal Phase III Trials of Approved Tyrosine Kinase Inhibitors for the Frontline Treatment of Chronic Myeloid Leukemia
Trial Treatment CCyR (%) MMR (%)
At 6 years
IRIS Imatinib (n 5 304) 83 86
At 2 years At 5 years
DASISION Dasatinib (n 5 259) 86 76
Imatinib (n 5 260) 82 64
At 2 years At 5 years
ENESTnd Nilotinib 300 mg (n 5 282) 87 77
Nilotinib 400 mg (n 5 281) 85 77
Imatinib (n 5 283) 77 60
NR5Not reported
all three as options for the initial management of CML in the chronic
phase (CML-CP) (Table I).
Imatinib
Imatinib mesylate was the first TKI to receive approval by the
Food and Drug Administration (FDA) 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
phosphorylation of proteins involved in cell signal transduction. It
efficiently inhibits the BCR-ABL1 kinase, but also blocks the platelet-
derived growth factor receptor (PGDFR) and the C-KIT tyrosine
kinase [16].
The International Randomized Study of Interferon and STI571
(IRIS) study is considered a landmark clinical trial for TKIs and
CML [17]. Investigators randomized 1,106 patients in CML-CP to
receive imatinib 400 mg/day or INF-a plus low-dose cytarabine. After
a median follow-up of 19 months, outcomes for patients receiving
imatinib were significantly better than in those treated with INF-a
plus cytarabine, notably the rates of CCyR rate (74% vs. 9%,
P < 0.001), and freedom-from-progression to AP or BP at 12 months
(99% vs. 93%, P < 0.001). Further highlighting the challenge of using
IFN-a was the high crossover rate to imatinib due to intolerance. The
responses to imatinib were also durable: in an 8-year follow-up of the
IRIS study [12], the estimated event-free survival rate was 81%, and
the overall survival (OS) rate was 93% when only CML-related deaths
were considered.
While the results using imatinib are impressive, only 55% of
patients enrolled in the IRIS study remained on therapy at the 8-year
follow-up time. This underscored the need for additional treatment
options for patients who had failed or were intolerant to imatinib.
This led to the rational development of second generation TKIs that
would effectively treat patients unable to continue on imatinib
therapy.
High-dose imatinib and imatinib-based combination
Other strategies for frontline therapy include using higher doses of
imatinib or combining a TKI with an additional agent, such as inter-
feron. In the Tyrosine Kinase Inhibitor Optimization and Selectivity
(TOPS) study, patients were randomized to receive imatinib 400 mg
once daily or twice daily (800 mg) [18]. Major molecular response
(MMR) rate at 12 months was the study primary endpoint. with cyto-
genetic response and time to such responses collected as secondary
outcomes. Patients in the high-dose group achieved faster CCyR and
MMR, but 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 fre-
quent administration and improved tolerability. In a phase III
randomized study, patients were assigned to one of four treatment
doi:10.1002/ajh.24275
Chronic myeloid leukemia
BCR-ABL < 10% Longest
at 3 months (%) EFS/PFS (%) OS (%) follow-up (years)
At 6 years
NR 81 85 8
At 5 years
84 85 91 5
64 86 90
At 5 years At 6 years
91 95 92 6
89 97 96
67 93 91
arms (imatinib 400 mg once daily, imatinib 600 mg once daily, imati-
nib 400 mg once daily plus peginterferon alfa-2a, or imatinib 400 mg
once daily plus subcutaneous cytarabine) [19]. 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 modified to 45 mcg once weekly. At 12 months, rates
of CCyR were similar among the four groups. The imatinib plus
peginterferon alfa-2a treated group obtained higher rates of MMR
and deeper molecular responses, but follow-up was not sufficient to
define the impact on long-term outcomes.
Dasatinib
Dasatinib is an oral, second generation TKI that is 350 times more
potent than imatinib in vitro [2022]. It also inhibits the Src family
of kinases, which may be important in blunting critical cell signaling
pathways [23]. Though initially evaluated in patients in the salvage
setting, it was later compared in frontline CML to imatinib to test the
possibility that frontline use of the more potent TKIs might improve
outcomes compared to imatinib.
The DASISION trial was a phase III randomized study comparing
imatinib 400 mg once daily to dasatinib 100 mg once daily in newly
diagnosed patients with CML [24]. The primary outcome was con-
firmed 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 on imatinib (77% vs. 66%,
P 5 0.007). 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 com-
pared to imatinib [25]. At 3 months, a higher proportion of patients
treated with dasatinib achieved BCR-ABL1 transcripts [IS]  10%
(84% vs. 64%, P < 0.0001). Meeting this threshold in either arm pre-
dicted for better progression-free survival and OS. Transformations to
CML-AP or CML-BP were fewer in patients treated with dasatinib
versus imatinib (4.6% vs. 7.3%).
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 [26]. Sim-
ilar to the results of the DASISION study, dasatinib treated patients
achieved higher rate of CCyR compared to patients receiving imatinib
(84% vs. 69%, P 5 0.04). There was more toxicity experienced in the
dasatinib armGrades 3 or 4 adverse events 58% with dasatinib and
35% imatinib), Mostly hematologic toxicity [26].
A third Phase 3 randomized study, SPIRIT 2, compared imatinib
400 mg daily with dasatinib 100 mg daily [27]. 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% versus 43% (P
<0.001). The 12-month CCyR rates were 51% and 40% (P <0.002),
American Journal of Hematology, Vol. 91, No. 2, February 2016 255
Jabbour and Kantarjian
TABLE II. Frontline TKIs Therapy: MDACC Experience
Imatinib Imatinib
% Cumulative 400 mg 800 Nilotinib Dasatinib
CCyR 85 90 99
MR4.5 56 74 80
respectively. Progression rate to CML-AP was 0.7% with imatinib and
0.5% with dasatinib. The progression rate to CML-BP was 1.7% ver-
sus 1%.
Pleural effusions occurred more frequently on dasatinib (19% vs.
<1%). Other side effects of dasatinib include myelosuppression
(20%), and rare pulmonary hypertension (12%).
Nilotinib
Nilotinib is a structural analog of imatinib. Its affinity for the ATP-
binding site on BCR-ABL1 is 30-50 times more in vitro [28]. Like
dasatinib, nilotinib initially demonstrated the ability to induce hemato-
logic and cytogenetic responses in patients who had failed imatinib.
Similar to the data with 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 imatinib 400 mg once daily [29]. The primary end-
point was the rate of MMR at 12 months. This endpoint was
achieved at statistically significantly higher rates for both doses of
nilotinib compared to imatinib (44% and 43% vs. 22%, P < 0.001).
The cumulative incidence of CCyR by 24 months was 87% with nilo-
tinib 300 mg twice daily, 85% with nilotinib 400 mg twice daily, and
77% with imatinib 400 mg daily (P < 0.001) [29].
With a minimum follow-up of 5 years, the two arms of nilotinib
demonstrated better early results compared with imatinib [30]. The
cumulative incidences of MMR by 60 months were 77%, 77%, and
60%, respectively (P <0.0001%). The incidences of BCR-ABL1 tran-
scripts [IS] < 0.0032% (roughly equivalent to a 4.5 log reduction of
disease) by 72 months were 56%, 55%, and 33%, respectively (P
<0.0001%). The incidences of transformation to AP or BP were 3.9%,
2.1%, and 7.4%, respectively (P 5 0.06 and 0.003, respectively). The
estimated 5-year EFS rates were 95%, 97%, and 93%, respectively.
The estimated 5-year survival rates were 94%, 96%, and 92%, respec-
tively. While nilotinib was superior to imatinib across all Sokal score
categories 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
transformations were 1% and 1% and 0% among patients with low-
Sokal risk treated with nilotinib 300 mg orally twice daily, nilotinib
400 mg orally 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 MMR rate was 52% at 12 months with nilotinib
compared with 28% with imatinib [31]. However, the rates of both
CCyR (84% vs. 87%) and progression-free survival (95% each) were
similar at 24 months. Overall, six patients in each arm progressed to
AP/BP. 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 [30].
Other notable side effects are headache and skin rashes (common
220-30%- but mild to moderate; alleviated by dose reduction), self-
256 American Journal of Hematology, Vol. 91, No. 2, February 2016
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
limited elevation of indirect bilirubin (10%), elevations of blood sugar
(1020%), and rare pancreatitis (12%).
The MD Anderson Cancer Center (MDACC)
experience
97
78 We recently published the long-term responses and outcomes of
patients with CML-CP and provided a comparison of four commonly
used TKI modalities (Table II) [32]. Unlike previous reports that
compared only imatinib 400 mg with either imatinib 800 mg, dasati-
nib, or nilotinib in randomised trials, our study provided a compara-
tive analysis of four TKI modalities after a long follow-up. The
analysis included 482 patients treated (July 2000 - September 2013)
in consecutive or parallel clinical trials, with imatinib 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 (i.e., dasatinib or nilotinib) achieved CCyR (58
[87%] of 67 for imatinib 400 mg vs. 180 [90%] of 199 for imatinib
800 mg, vs. 100 [96%] of 104 for dasatinib vs. 99 [93%] of 107 for
nilotinib), MMR (51 [76%] vs. 171 [86%] vs. 93 [90%] vs. 97 [91%]),
and 4
5 log or higher reduction in BCR-ABL1 transcripts (MR4.5
response 38 [57%] vs. 148 [74%] vs. 76 [71%] vs. 76 [71%]). This
finding was consistent over time (360 months); where at any time
point, imatinib induced lower rates of cytogenetic and molecular
responses. This landmark assessment contrasts with previous reports
where results are reported cumulatively (by not at) and can be
misleading. The 5-year event-free survival significantly differed
between the imatinib 400 mg group and the other TKI groups (imati-
nib 800 mg P 5 0
029, dasatinib P 5 0
003, nilotinib P 5 0.031). How-
ever, there was no significant difference in the 5-year failure-free
survival (P 5 0.32, P 5 0.075, P 5 0.332), transformation-free survival
(P 5 0.053, P 5 0.038, P 5 0.493), or OS (P 5 0.563, P 5 0.162,
P 5 0.981). We also compared event-free and OS 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 whether MMR or MR4.5 response was
achieved or not [32].
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 [33]. Second generation
TKIs produced higher rate of early optimal responses, but have so far
noimpact on long-term survival (probably because of available effective
salvage therapies). The main advantage of second generation TKI is
obtained in 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 various studies to date. These
strategies are also not benign interventions, as they add to the eco-
nomic and toxicity burden of the overall treatment plan. Allo-SCT or
other chemotherapy agents are not recommended as upfront treatments
for CML-CP given the excellent outcomes and long-term survival
achieved with the TKIs. An exception may be in emerging nations
where allo-SCT is a one-time procedure costing $14-20,000, accessible
to most patients. On the other hand generic imatinib in such geogra-
phies (e.g. India) costs only less than $400 per year of therapy. At
MDACC, patients with low-risk disease are offered frontline therapy
with imatinib. Patients with high-risk disease are candidates for
second-generation TKIs for the time being; this practice may change
once the generic formulation of imatinib is available in the United
States. Because of the higher rates of durable complete molecular
responses with second generation TKIs (which could lead to
doi:10.1002/ajh.24275
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
discontinuation of TKI therapy and potential molecular cures discussed
later), considerations of second generation TKIs in younger patients
with CML (e.g. age <50 years) vs. older patients, may be entertained.
Selecting a Frontline Therapy
Patients age and comorbidities and TKI toxicity profile. While
multiple TKIs are available for patients with newly diagnosed patient
with CML in 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 develop-
ing pleural effusions (existing lung injuries), TKI other than dasatinib
should be selected. This might be relevant for patients with a history of
lung disease (e.g., chronic obstructive pulmonary disease), cardiac disease
(e.g., congestive heart failure), or uncontrolled hypertension. Pulmonary
arterial hypertension (PAH) is also a rare important complication of
dasatinib [34], and patients with preexisting PAH may be considered for
alternative TKIs in the frontline setting. Dasatinib also inhibits platelets
function [35], and patients taking concomitant anticoagulants may be at
an increased risk of hemorrhagic complications [36].
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 dia-
betes or history of pancreatitis. During preclinical development, nilo-
tinib 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 patients QT interval. Patients should always be coun-
seled to take nilotinib 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 cerebrovas-
cular events, and peripheral artery occlusive disease (PAOD) [3740].
In the 6-year follow-up on the ENEST-nd trial [30], approximately
10% of patients experienced vascular events. Nilotinib use should be
limited in patients with risk factors such as diabetes mellitus or coro-
nary or cerebrovascular artery disease. Avoiding nilotinib in patients
with significant past vascular histories is warranted with the availabil-
ity of other viable options.
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 510% experience elevations in creatinine with long-term therapy.
Finally, patients age plays an important role in 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
elderly patients where the expected survival is shorter and discontinu-
ing therapy is less relevant.
Cost. The cost of cancer drugs has risen exponentially over the
past decade [41]. All anticancer agents approved in 2014 were priced
at over $120,000 annually [41]. Unlike TKIs in CML, most of these
therapies do not provide a substantial improvement in survival or
other objective measures to justify the cost. An international group of
CML experts called attention to the high prices of TKIs [42]. The
case of imatinib was used to illustrate the problem with the high can-
cer drug prices. When first approved, the annual price for imatinib
was less than $30,000 in the United States. This was the price set to
make the development and commercialization of imatinib profitable
when it was expected that most patients would be treated for perhaps
510 years. Patients now remain on imatinib and live a normal life-
span as long as they are compliant with the medication [43,44]. Para-
doxically, with a higher number of patients and a longer duration of
doi:10.1002/ajh.24275
Chronic myeloid leukemia
therapy, the annual price of imatinib in 2014 had quadrupled to
$132,000. This price is in the same range as dasatinib and nilotinib,
both priced above $130,000/year of therapy.
Today, the prices of TKIs are all fairly comparable. However, in
February 2016 imatinib will be available as a generic formulation.
The price will eventually fall dramatically below $5-8,000/year (as in
Canada; the annual price of generics in India is only $400). Physi-
cians will then have to assess the treatment value of second genera-
tion 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 imati-
nib and/or its generic formulation 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 [45]. They found that initiating
imatinib as frontline treatment and treating in a stepwise approach,
compared to physician choice, costs less and offered clinically equiva-
lent utility. In this analysis, the stepwise therapy was found to have
an incremental cost-effectiveness ratio (ICER) of $227,136/Quality-
adjusted life years (QALY). The ICER was favorable for stepwise ther-
apy for each Sokal risk group. Furthermore, the efficacy and safety of
generic imatinib was compared to the patented drug. In a series of
972 patients treated with either patented (n 5 671) or generic imati-
nib (n 5 237) at Tata Memorial Hospital in Mumbai, the rates of
CCyR were 72% and 75%, respectively; the 5-year survival rate was
86% [43,44].
Disease characteristics. For patients with CP-CML it is common to
use one of the available risk stratification scores, such as Sokal [47] or
Hasford [48] to help predict outcomes. Patients with low-risk disease
are expected to have optimal responses when imatinib, dasatinib, or
nilotinib. However, selecting a second generation TKI as frontline ther-
apy (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 DASISION and ENEST-nd trials [24,25,29,30].
Patients with higher risk disease have a lower likelihood of achieving
the early milestones of CCyR and MMR and, particularly, higher chan-
ces of disease transformation to AP-CML or BP-CML.
We recently reported that the expression of the b2a2 transcript
type correlates with an inferior response rate and long-term outcome,
and these associations are independent of other prognostic factors
[49]. Our analysis suggested that the inferior outcome observed for
patients with no major cytogenetic response (MCyR) at 3 months are
largely restricted to patients with b2a2 transcripts. The inferior out-
come for patients treated with standard-dose imatinib might be
mostly restricted to patients with b2a2. These observations merit pro-
spective validation, but they suggest that the transcript type might be
a biomarker that may help select therapy and course of action for
patients with CML treated with TKI [49].
Any of the thTKIs 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, patients age,
adverse event profile, risk stratification score, transcripts type, and
cost. Kinase domain mutation profile plays no role in selecting an ini-
tial TKI, but becomes relevant in the relapse setting.
Monitoring Treatment Response:
Surrogate Endpoints and Milestones
Because patients with CML on TKI therapy are expected to live for
a long period of time, surrogate markers of outcome are important.
American Journal of Hematology, Vol. 91, No. 2, February 2016 257
Jabbour and Kantarjian
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. Advances in tech-
nology have made available tests that avoid the need for traditional
bone marrow examinations for treatment monitoring (except when
changing TKI; or in unusual situations like unexpected myelosuppres-
sion in order to exclude transformation or the development of myelo-
dysplastic syndrome or other marrow conditions).
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 Phila-
delphia chromosome and to exclude clonal evolution. The current rec-
ommendation that patients have a follow-up bone marrow study at 3,
6, and 12 months after starting therapy may not be necessary anymore
[50]. An alternative method to determine cytogenetic response is with
the use of FISH and PCR on peripheral blood. If a patient is respond-
ing 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 mar-
row exams, as the patient is likely to be in CCyR [51,52]
For patients in durable CCyR receiving TKI therapy, periodic
molecular monitoring using RT-Q-PCR is acceptable and useful, but
may lead to erroneous changes in treatment due to discordant results
between laboratories or even within the same laboratory. This leads
to potentially discontinuing a useful therapy that the patient may
have been tolerating well. One strategy to minimize this is to use
interphase FISH as a complementary diagnostic test along with the
molecular test to detect possible false positive or negative results gen-
erated by either assay [52]. For patients in CCyR, the achievement
and maintenance of a MMR is of debatable significance. Several stud-
ies evaluating patients receiving imatinib or second generation TKIs
have found that patients in CCyR have similar survival whether they
achieved MMR or not [53,54].
Early molecular response has been shown in a number of studies
to have strong prognostic value (Table III). This has been shown with
each of the 3 TKIs used in the frontline setting. A BCR-ABL1 tran-
scripts [IS] < 10% at 3 months separates patients into high and low
risk categories for long-term outcomes (i.e., progression, survival)
TABLE III. Percentage of Survival by Early Molecular Response
Study Q-PCR<10%
UK (8-year) 93
MDACC (10-year) 98
ENEST-nd 97
DASISION 97
BELA 98
TABLE IV. Response Evaluation to TKIs Used as First-Line Therapy (ELN 2013)
Optimal
Baseline
3 months Ph1 < 35% And/or BCR-ABL  10%
6 months Ph1 0% And/or BCR-ABL < 1%
12 months BCR-ABL  0.1%
Any time BCR-ABL  0.1%
258 American Journal of Hematology, Vol. 91, No. 2, February 2016
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
[25,29,55,56]. The important question is what to advise a patient who
does not meet the 3-month benchmark? One option is to switch
TKIs early, but there are no data that this will alter long-term out-
come. Several experts suggested that a follow-up measurement at 6
months will help define patients clearly in need of a change in ther-
apy [49]. This strategy has been retrospectively analyzed by several
large groups with conflicting results [5759]. The results of two inde-
pendent study groups have suggested that all patients with BCR-ABL1
transcripts > 10% at 3 months do not necessarily have an inferior
outcome [58,59]. 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 BCR-
ABL1 transcripts [IS] >10% vs. <10% are 100% vs. 74%. Thus it may
be reasonable to change the TKI from imatinib to second generation
TKI for BCR-ABL1 transcripts [IS] >10% after 6 months [58]. How-
ever, a similar situation in a patient on second generation TKI (dasa-
tinib, nilotinib) does not necessarily imply consideration of allo-SCT.
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 for standard dose imatinib therapy. For second
generation TKIs, CCyR may need to be achieved sooner for an opti-
mal outcome, for example, within 6 months [60]. Patients who do
not achieve a complete hematologic response by 3 months should be
considered for a change in therapy (Tables IV and V).
One question is whether to change therapy at 3 months based on
the level of BCR-ABL1 transcripts [IS]. For patients on imatinib ther-
apy, if the 3-month transcript level is greater than 10%, we suggest
an approach similar to the ELN guidelines [49]: perform serial molec-
ular monitoring between 3 and 6 months to determine the response
precisely. 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% [61]. This
approach also applies to patients on second generation TKIs, because,
as mentioned earlier, very early switching has not yet shown to influ-
ence long-term outcome [62]. Another study randomized patients in
CCyR on imatinib for at least 2 years to continue imatinib or switch
to nilotinib [63]. Switching to nilotinib induced deeper molecular
responses, but did not translate into an improvement in progression-
Q-PCR>10%
free survival or in other meaningful outcomes.
54 Patients who meet all the relevant benchmarks in the first 12
94 months are monitored periodically using FISH and molecular testing
87 (molecular testing only if BCR-ABL1 [IS] transcripts consistently
86
86
below 0.1%). If there are clear signs of possible failure, patients
should undergo a bone marrow examination with cytogenetics, and
molecular testing including analysis for mutations. Any degree of
Warning Failure
CCA in Ph1 cells High-risk Sokal or
Hasford score
Ph1 36 95% And/or BCR-ABL > 10% Ph1 > 95% And/or No CHR
Ph1 1 35% And/or BCR-ABL 1 10% Ph1 > 35% And/or BCR-ABL > 10%
BCR-ABL 0.1 1% BCR-ABL > 1% And/or Ph1 > 0%
CCA in Ph- cells (27 or 7q-) Loss of CHR Loss or CCyR
Confirmed loss of MMR CCA in Ph1 cells
doi:10.1002/ajh.24275
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
TABLE V. MDACC Criteria for Response/Failure and Change of Therapy
Time (months) Imatinib Second generation TKIs
3-6 MCyR; PCR10% [IS] CCyR; PCR  1% [IS]
12 CCyR; PCR  1% [IS] CCyR; PCR  1% [IS]
Later CCyR; PCR  1% [IS] CCyR; PCR  1% [IS]
cytogenetic relapse calls for a change in therapy. Fluctuating molecu-
lar levels during continuous CCyR would only prompt closer moni-
toring 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 (non-measurable
BCR-ABL1 transcripts) offers the possibility of treatment discontinua-
tion in clinical trials only (Table VI). 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 (36 months) have shown better outcomes with achieve-
ment of a major cytogenetic response by 36 months on imatinib ther-
apy (Ph-positive metaphases  35%; BCR-ABL1 transcripts [IS]  10%).
While this is interpreted to mean that a change to second TKI therapy
may be considered if such outcome is not obtained, no studies have
shown that changing therapy from imatinib to second TKIs has
improved patients outcomes. When nilotinib or dasatinib are used in
front-line therapy, achievement of complete cytogenetic response by 36
months of TKIs therapy has been associated with improved outcomes.
At MDACC, our major treatment milestones are at 6 and 12
months. Patients with lack of PCyR (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 comorbidities. We do not consider a change of TKI ther-
apy in patients in CCyR but without MMR.
Management of TKI Resistance
A remaining problem with the widespread use of all commercially
available TKIs is increased drug resistance. A common mechanism of
resistance involves point mutations in the kinase domain of BCR-
ABL1, which impairs the activity of the available TKIs. Second gener-
ation 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 available 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 [6466]. In a study of 87 patients with CML-CP treated
with imatinib 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 <0.001) [64]. CMR rates were 0% vs. 44%
(P 5 0.002), and no molecular responses were observed when adher-
ence 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 [64].
doi:10.1002/ajh.24275
Chronic myeloid leukemia
TABLE VI. Important response categories in CML
Response Translates into:
BCR-ABL1  10% at Significantly improved survival
6 months; CCyR later
MMR Modest improvement in EFS;
possible longer duration
CCyR; no survival benefit
CMR Possibility of therapy
discontinuation (clinical trials only)
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 follow-
ing prior therapy including imatinib [67,68]. Clinical studies of
second-line and third line TKIs are summarized in Table VII. Based
on these studies, several noteworthy ideas have emerged. First,
second-line treatment with nilotinib, 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 [69], but switching to second-line
TKI can be more effective [70]. Several studies that evaluated second-
line nilotinib [71,72], dasatinib [70,72], or bosutinib [73], 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 [74]. In a retrospective pooled analysis of three clinical
studies of second-line dasatinib for patients resistant to or intolerant
of imatinib, patients who were switched to dasatinib after the loss of
MCyR (early intervention group) had higher rates of CHR, CCyR,
and MMR, as well as 24-month EFS, TFS, and OS, than patients who
were switched after the loss of both MCyR and CHR (late interven-
tion group) [75]. Although this analysis included studies with distinct
study designs and various dosing schedules of dasatinib, the essential
finding that earlier switch to dasatinib was associated with better
outcomes.
Bosutinib was initially studied in patients who had resistance to or
intolerance of imatinib [73]. 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 prespe-
cified 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 mutations that confer imatinib resistance, except for
T315I. Responses were independent of whether patients had resist-
ance 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 myelo-
suppression 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 [76]. It is 500 times
as potent than imatinib at inhibiting BCR-ABL1 [77]. The approval
of ponatinib was based on the phase II PACE trial, where 449
patients with heavily pretreated CML or Ph-positive acute
American Journal of Hematology, Vol. 91, No. 2, February 2016 259
Jabbour and Kantarjian ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES

lymphoblastic leukemia (ALL) were treated [78]. Patients were con-

CP: chronic phase; AP: accelerated phase; MyBP: myeloid blast phase; LyBP: lymphoid blast phase; BP: blast phase; MaHR: major hematologic response; CHR: complete hematologic response; NEL: no
Ma HR: 34
sidered for this trial if they had resistance to or intolerance of dasati-

N 5 94
nib or nilotinib, or if they had CML with T315I mutation. The dose

NR

NR
NR

NR
BP

36

36

9
-
of ponatinib was 45 mg once daily, and patients were stratified by
disease phase and presence or absence of a T315I mutation. Of the
267 patients who received ponatinib in CML-CP, 56% achieved a

At 3 years
Ponatinib

Ma HR: 57
MCyR by 12 months, which included 45/64 (70%) patients with a
N 5 79

NR

NR
NR

NR
AP

96
36

59
55
T315I mutation. Patients responded more favorably if they had
received fewer TKIs. After a median follow-up of 3.5 years, 59% of
patients achieved MCyR (primary endpoint) at any time; 83% of
those remained in MCyR at 3 years [79]. Furthermore, 39% of
N 5 270

patients achieved a MMR or better. The 3-years PFS and OS rates

NR
NR
CP

30
36

53
75

81
-
-
were 60% and 81%, respectively [79]. Arterial occlusive events
occurred in 28% of patients (23% serious). The most common all-
grade treatment-emergent adverse events occurring in  40% of CP-
N 5 38

NR

NR
NR
BP

50
36
36

35
18
CML patients were abdominal pain (46%), rash (46%), thrombocyto-
3

penia (45%), headache (43%), constipation (41%), and dry skin (41%)
[79]. Other notable toxicities include severe skin rashes (4-7%), pan-
At 4 years
Bosutinib

N 5 51

creatitis (7%), and severe hypertension (20%).

NR

NR

60
AP

20
54
54

27
0
6

As of early 2014, ponatinib labeling included a revised warning

regarding the risk of thrombotic events (13% per year), vascular
occlusions, heart failure, and hepatotoxicity, revised dosing informa-
N 5 200
CP

tion and indications limited to adults with T315I mutation and those
69

98
46
85
24

81

12

-

for whom no other TKI is indicated [80]. Vascular occlusion adverse

events were more frequent with increasing age and in patients with
Percent response

prior history of ischemia, hypertension, diabetes, or hyperlipidemia

N 5 31
LyBP

NR
82

32

42
19

16
13
0
3

[79]. Factors associated with increased risk of vascular occlusion

events include older age, higher dose, history of myocardial infarction
or prior vascular events, and longer duration of CML [79]. Studies
N 5 105
MyBP

assessing lower dose schedule of ponatinib are ongoing. In commu-

NR
82

29

42
22

10
11
3

nity practice, it may be safe to use ponatinib 30 mg daily (and lower

At 4 years
Nilotinib

the dose to 15 mg daily for toxicities) rather than use the FDA
TABLE VII. Summary of Important Phase II Trials of 2nd and 3rd Generation TKIs After Prior TKI Failure

approved dose of 45 mg daily.

N 5 137

NR
80
AP

20
56

67
31
12

12
9

How to select a second or third line option

At the time of treatment failure, patients should undergo bone mar-
row examination to allow proper determination of the CML phase and
N 5 321

NR
CP

48

94
70

45

87
76

14

documentation 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 [81,82]. When selecting between dasati-
N 5 48

nib, bosutinib, and nilotinib, in vitro and in vivo data have identified
LyBP

40

50
88

46
29

52
12

distinct mutations that exhibit decreased sensitivity to each of the

agents [83,84]. Physician may favor dasatinib or bosutinib if the patient
has the following mutations: Y253H, E255K/V, or F359C/V. Alterna-
N 5 109
MyBP

tively, nilotinib may be favored in the presence of the V299L and

50

50
36
26
27
91
12

7
At 6 years

F317L mutations. For patients lacking these mutations, the choice

Dasatinib

should be on preexisting conditions, toxicity profiles, and cost.

Bosutinib can be used for patients with most known mutations
N 5 174
AP

93

44

82
45

32
79

19
14

that lead to imatinib failure [73]. Like dasatinib and nilotinib, bosuti-
7

nib lacks activity against T315I. Bosutinib may be a reasonable choice

for patients who fail imatinib who are not good candidates for dasati-
N 5 167

nib or nilotinib. Bosutinib has a relatively distinct toxicity profile

evidence of leukemia; NR: not reported
CP

50
92
24
74

91
13

-

from the other TKIs, with the predominant problem being diarrhea
and other gastrointestinal complaints. Recently, an analysis was con-
ducted to closely characterize the toxicity of bosutinib and the man-
% Hematologic Response

% Cytogenetic Response

agement strategy [85]. Diarrhea was documented in 82% of patients

% Resistant to imatinib
Median follow-up (mo)

(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 diar-
rhea, most patients are able to continue therapy with periodic dose
% Survival
Complete

interruptions or adjustment.
Partial

Ponatinib should be considered the agent of choice in patient with

CHR
NEL

CML and T315I mutation, and in instances where other TKIs are not

260 American Journal of Hematology, Vol. 91, No. 2, February 2016 doi:10.1002/ajh.24275
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
indicated. No other commercially available TKIs have activity against
this 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 ponati-
nib 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 profiles,
mutations profile, drug interactions, compliance issues and the patients
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 pre-
dict treatment outcome.
At MDACC, post imatinib failure, the choice of second or third gen-
eration TKI is based on the disease phase, mutation profile, and
patients 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
followed by allo-SCT if a donor is available and an optimal response is
not achieved. Outside the context of T315I mutations, the type of
mutation will dictate the choice of therapy. Of note, patients with poor
response to imatinib and compound mutations may not respond well
to second generation TKI. A close monitoring should be offered [86]. If
an optimal response is not achieved, a switch of therapy to a third gen-
eration TKI and/or allo-SCT is warranted. In patients with no muta-
tion 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, while patients
with lung injuries are not candidates for dasatinib. Bosutinib may be
the best choice for patients with cardiac and rhythmic problems.
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 who fail at least 2 TKIs or are poten-
tially harboring the T315I mutation (after a trial of ponatinib ther-
apy) [87]. 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 (lower CML
burden) [88].
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 $12,000 to 20,000 in developing
nations. Allo-SCT should not be offered as frontline therapy unless
the TKI prices are prohibitive to a nations 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 pro-
jected survival of 301 years ($400 X 30 years 5 $12,000), imatinib
therapy remains better than performing allo-SCT. In nations where
TKIs are not commonly accessible, it is better to perform allo-SCT
on 100% and cure 60%, than having TKIs available to 10% (and func-
tional cure 10%). In contrast to the frontline setting, in the salvage
setting the value of allo-SCT versus second/third generation TKI is
more pronounced. Allo-SCT in first salvage as cure costs $20,000 vs.
$120,000-170,000/year for second-third generation TKIs. In these cir-
cumstances, allo-SCT could be offered as first salvage option in
nations with financial constraints [89,90].
doi:10.1002/ajh.24275
Chronic myeloid leukemia
Treatment Duration and
Discontinuation
The Stop Imatinib (STIM) trial investigated the risk of relapse in
patients on imatinib with ongoing complete molecular response
(CMR) for greater than two years who stopped treatment [91,92]. In
the most recent update, 100 patients had a median follow-up of 50
months and were monitored closely for evidence of molecular relapse.
Overall, 61% experienced a molecular relapse, with 95% of the events
occurring within 7 months of stopping imatinib. Almost all patients
were able to achieve CMR once imatinib therapy was restarted. Hav-
ing a low-risk Sokal score and duration of imatinib therapy greater
than 60 months predicted for continued CMR after therapy cessation.
These results were confirmed in other large studies of CML. The
TWISTER study followed 40 patients who stopped imatinib after
being without detectable minimal residual disease for greater than
two years [93]. Patients were followed for a minimum of 15 months
(median 43 months) from the time they stopped imatinib; 22 of 40
patients became molecularly positive; nearly 70% of the molecular
relapses occurred within the first 6 months of treatment cessation;
and patients who resumed TKIs were able to recapture deep molecu-
lar responses. Interestingly, highly sensitive patient-specific PCR was
able to detect the original CML clone in several patients who
remained off imatinib for several years. This indicates that it may not
be necessary to completely eradicate the disease to allow patients to
enjoy a functional cure.
The previous studies included heterogeneous groups of patients,
particularly ones exposed to interferon prior to the imatinib era. The
French group conducted a follow-up study to STIM enrolling patients
who have only been exposed to imatinib as CML therapy (STIM2)
[94]. The inclusion criteria were similar to those used in STIM1.
There were 124 patients identified who stopped imatinib therapy.
With a median follow-up of 12 months, 48 patients had molecular
relapse; 94% of relapses occurred within 6 months of TKI withdrawal.
All patients remained sensitive to imatinib or a second generation
TKI upon re-challenge. In this study and in others, patients with low
level positivity for BCR-ABL1 transcripts may be able to remain off
therapy with close monitoring. This was recently addressed systemati-
cally by the French investigators, who observed that is safe and effec-
tive to resume patients on TKI therapy if their transcript level
became greater than 0.1% (i.e., loss of MMR) [95].
A pan-European Stop Tyrosine Kinase Inhibitor trial (The EURO-
SKI study) aimed to define factors associated with durable deep
molecular response (MR) after stopping TKI. An interim analysis on
200 patients with 6-month follow-up of molecular events was
reported [96]. Adult CML patients in CML-CP on TKI treatment in
confirmed deep MR (MR4, BCR-ABL1 transcripts [IS] <0.01%) for
at least 1 year (>4 log reduction on TKI therapy for >12 months
confirmed by three consecutive PCR tests) and under TKI treatment
for at least 3 years were eligible. The duration of TKI treatment was
8 years (range, 312.6 years), and median duration of MR4 before
TKI cessation was 5.4 years (range, 111.7 years). Overall, 123 of the
200 patients remained without relapse in the first 6 months. Recur-
rence of CML, defined as loss of MMR, was observed in 47/114
patients (47%) treated for <8 years, compared to 27/86 patients
(27%) treated for >8 years (P 5 0.003). The duration of MR4 >5
years vs. <5 years was predictive factor for a lower relapse rate
(P 5 0.03).
TKIs discontinuation studies in patients with durable CMR demon-
strate that stopping TKI therapy is feasible, and some patients may be
cured. While the results thus far are encouraging, it is still recom-
mended that TKI therapy be stopped only under the auspices of a clini-
cal trial. Many laboratories are not able to produce precise and
reliable PCR results as those used in the above mentioned trials. Going
American Journal of Hematology, Vol. 91, No. 2, February 2016 261
Jabbour and Kantarjian
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.
At MDACC, therapy discontinuation is offered only for patients in
durable CMR and in the context of clinical trials.
Advanced Stage CML
Patients with CML-AP or CML-BP may receive initial therapy
with TKIs (newer generation TKIs like dasatinib or ponatinib pre-
ferred over imatinib) to reduce the CML burden, and be considered
for early allo-SCT [97101]. Response rates with combinations of
TKIs and chemotherapy are 40% in nonlymphoid CML-BP and 70-
80% in lymphoid CML-BP [102104]. Median survival times are 6
12 months, and 1224 months, respectively. The addition of TKIs to
chemotherapy has improved the response rates and prolonged the
median survival time in CML-BP.
At present, allo-SCT is the only curative therapy for AP and BP
CML: overall cure rates are in the range of 15 to 40% and 10 to 20%,
respectively [47,82]. Patients with cytogenetic clonal evolution as the
only AP criterion have a long-term event-free survival rate of about
60% [83]. Otherwise, TKIs provide hematologic responses in 80% of
patients and an estimated 4-year survival rates of 40 to 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
to 80% [105]. Such patients may continue on TKI therapy as their
long-term treatment if they achieve a CCyR 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 gen-
eration TKI followed by allo-SCT once a complete response is achieved
and placed on maintenance TKI therapy. 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.
Conclusions and Future Directions
In 2016, CML experts and patients with CML have multiple treat-
ment options in the CML therapeutic armamentarium, including 5
TKIs (imatinib, nilotinib, dasatinib, bosutinib, ponatinib), omacetax-
ine (protein synthesis inhibitor), and several older agents (hydrox-
urea, 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, in order to change therapy in a timely
manner and/or consider allo-SCT before CML progression. Future
directions will focus on the potential molecular cure of CML
262 American Journal of Hematology, Vol. 91, No. 2, February 2016
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES
(i.e. achievement of a durable CMR and its persistence after discon-
tinuation of TKI therapy). This is not a trivial issue since, with effec-
tive 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 2,030 to 2,040 at a rate of 35 times the incidence.
The prevalence is estimated to be close to 1,60,000 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
development 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 generation TKIs alone, or in combination with other
available (peg-interferon alpha-2, omacetaxine, decitabine) or investi-
gational therapies (JAK2 inhibitors, hedgehog inhibitors, stem cell
poisons, vaccines). Such strategies may improve the eradication of
minimal residual disease, potentially obviating the need for indefinite
therapy with TKIs. Further understanding of the pathophysiologic
events downstream of BCR-ABL1 may help in the development of
new strategies to target them.
MDACC Approach
ALL patients suspected to have CML undergo bone marrow exam-
ination which will confirm the diagnosis and provide information
needed for staging. Baseline PCR is performed in order 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. 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 tran-
scripts [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 transcripts [IS]  10%) at 6 months, lack of CCyR (BCR-ABL1
transcripts [IS]  1%) at 12 months, and loss of response at any time
are candidates for a change of therapy. The choice of TKI is based on
mutation profile and patients comorbidities. We do not change ther-
apy for patients in CCyR but without MMR. Patients who meet all
the relevant benchmarks in the first 12 months are monitored peri-
odically using FISH and molecular testing (molecular testing only if
BCR-ABL1 transcripts consistently below 0.1% [IS]).
Post imatinib failure, patients should undergo a bone marrow
examination with cytogenetics and molecular testing, including analy-
sis for mutation. The choice of second or third generation TKIs is
based on disease phase, mutation profile, and patients 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 muta-
tion dictates the choice of therapy. Patients with poor response to
imatinib and compound mutations may not respond well to second
generation TKI, and a close monitoring is indicated. If an optimal
doi:10.1002/ajh.24275
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES Chronic myeloid leukemia

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
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, while
patients with lung injuries are not candidates for dasatinib therapy.
Bosutinib may be the best choice for patients with cardiac and rhyth-
mic problems. Allo-SCT remains an important therapeutic option for
patients in CML-CP in the following situations: patients who fail at
least 2 TKIs or are potentially harboring 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 discontinuation is offered only for patients with
CML-CP in durable CMR (2 years) and in the context of clinical
trials.

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