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Class effects of tyrosine kinase inhibitors in the

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Article in Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K June
2009
DOI: 10.1038/leu.2009.111 Source: PubMed

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 Leukemia (2009) 23, 16981707
& 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00
www.nature.com/leu
SPOTLIGHT REVIEW
Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia
FJ Giles1, M ODwyer2 and R Swords1
1
Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center at San
Antonio, San Antonio, TX, USA and 2Department of Hematology, University College Hospital, Galway, Ireland
Tyrosine kinase inhibitors have revolutionized the treatment of
chronic myeloid leukemia (CML), offering patients several
targeted therapeutic options that provide the possibility of
sustained remissions and prolonged survival. With the avail-
ability of imatinib, nilotinib and dasatinib, physicians must
weigh the efficacy and safety profile of each agent when
choosing the best therapeutic option for individual patients.
Each agent targets tyrosine kinases within the cell uniquely to
SPOTLIGHT
cause the desired antiproliferative effect. In addition to inhibit-
ing the BCR-ABL kinase, imatinib and nilotinib target the same
array of other tyrosine kinases, including c-KIT and platelet-
derived growth factor receptor (PDGFR), albeit with differing
potencies. While targeting BCR-ABL with the highest potency
among approved agents in CML, dasatinib also targets a broad
array of off-target kinases, including SRC family members,
PDGFR and EPHB4. The differences in kinase inhibition profiles
among these agents in vitro probably account for the differing
clinical safety profiles of these agents. This paper reviews the
various kinases inhibited by imatinib, nilotinib and dasatinib,
and describes the potential impact of kinase inhibition on the
efficacy and safety of each agent.
Leukemia (2009) 23, 16981707; doi:10.1038/leu.2009.111;
published online 28 May 2009
Keywords: CML; imatinib; nilotinib; dasatinib; TKI; BCR-ABL
Introduction
The introduction of the small tyrosine kinase inhibitor (TKI),
imatinib, has revolutionized the treatment of chronic myeloid
leukemia (CML).1 Imatinib is a relatively specific inhibitor
of BCR-ABL, the gene product of the t(9;22) chromosomal
translocation event that forms the Philadelphia chromo-
some characteristic of CML and some acute lymphocytic
leukemias.2,3 The fusion of BCR-ABL results in the constitutive
activity of the ABL tyrosine kinase, which ultimately drives
transformation of hematopoietic progenitor cells.
Imatinib was approved by the US Food and Drug Adminis-
tration in 2002 for the first-line treatment of CML based on
its high cytogenetic and molecular response rates, long-term
efficacy and superior tolerability over interferon (IFN)-based
therapy.4,5 Imatinib is widely accepted as the standard therapy
for newly diagnosed chronic-phase CML patients in addition to
all CML patients who have failed stem cell transplant or IFN-a
therapy.6,7 Imatinib serves as a model for the utility of targeted
agents in the treatment of cancer. For a relatively few CML
patients, resistance to imatinib is present before, or develops
Correspondence: Dr FJ Giles, CTRC at The UT Health Science Center
at San Antonio, Institute for Drug Development, 7979 Wurzbach
Road, San Antonio, TX 78229, USA.
E-mail: frankgiles@aol.com
Received 19 March 2009; revised 6 April 2009; accepted 17 April
2009; published online 28 May 2009
during treatment.811 Several strategies are available to treat
imatinib-resistant patients, including imatinib dose escalation,
dose adjustment based on pharmacokinetic assessments and the
use of novel TKIs (Figure 1, Table 1).
Nilotinib and dasatinib are potent inhibitors of BCR-ABL that
are US Food and Drug Administration approved for the
treatment of patients resistant to, or intolerant of, prior therapy,
including imatinib. These second-generation TKIs have shown
efficacy in all imatinib-resistant or -intolerant CML patients.1214
Thus far, nilotinib and dasatinib appear to be similar with regard
to clinical efficacy,15 although they display differential safety
profiles.16 Other new kinase inhibitors are in early clinical
trials as alternatives to imatinib therapy, including bosutinib,
MK-0457 and INNO-406 (Figure 1, Table 1). Larger prospective,
randomized studies are needed to determine the place of these
new therapies in the treatment algorithm of CML. However, the
potential for increased potency of these drugs could eventually
lead to their replacement of imatinib as first-line CML therapy.
Although these new therapies are already changing the land-
scape of CML therapy, it is important to distinguish the
differences between these agents regarding target kinase profile,
safety and efficacy. This article will review the similarities and
differences in the kinase inhibition profiles of imatinib, nilotinib,
dasatinib and newer BCR-ABL kinase inhibitors, with a focus
on the safety of each agent. Although no randomized clinical
trials have been conducted comparing nilotinib and dasatinib
treatments, one must use the data from the available studies to
make an informed choice between the two agents for patients
who have become resistant or intolerant to imatinib therapy.
The following sections will highlight pre-clinical and clinical
data to assist in choosing between the currently available
second-generation agents.
Differential kinase inhibition profiles of TKIs in CML
treatment
Inhibition of the BCR-ABL tyrosine kinase is considered to be the
underlying mechanism of clinical activity of imatinib, nilotinib
and dasatinib in the treatment of CML. As the first-generation
TKI in this class of agents, imatinib inhibits BCR-ABL, albeit to a
lesser extent than nilotinib or dasatinib. Imatinib also inhibits
c-KIT and platelet-derived growth factor receptor (PDGFR) at
clinically relevant concentrations (Table 1). Nilotinib inhibits
most imatinib-resistant BCR-ABL forms, except T315I, in vitro at
concentrations approved for and tested in patients.17 Nilotinib
is 30-fold more potent than imatinib at inhibiting BCR-ABL
(Table 2).18,19 Early data on nilotinib in newly diagnosed CML
patients suggest clinical activity with the potential to exceed
first-line imatinib efficacy, pending longer follow-up data.20
Similar to imatinib, nilotinib inhibits c-KIT (IC50 90 nM)18,19
and PDGFR (IC50 72 nM).13,19 Nilotinib also inhibits the

ABL-related kinase ARG, DDR1 kinase, the oxidoreductase
NQO2,20,21 and has some activity against the ephrin receptor
EPHB4, but displays no activity against the Src family of
kinases.13,22 Similar to nilotinib, dasatinib also inhibits most
imatinib-resistant BCR-ABL forms, except T315I, in vitro.14,23
However, it displays greater inhibition, with approximately
Class effects of TKIs in the treatment of CML
FJ Giles et al
1699
325-fold more potency than imatinib at inhibiting BCR-ABL
(Table 2).14 Dasatinib also inhibits c-KIT and PDGFR with
greater potency, and has a broad range of inhibitory activity
against a number of other tyrosine kinases (Table 2), including
the ephrin receptor tyrosine kinase, Src and Src family kinases
(FGR, FYN, HCK, LCK, LYN and YES).22,24 Lack of selectivity in
binding Src family kinases probably derives from the fact that,
unlike imatinib and nilotinib, dasatinib binds to the active
conformation of the ABL kinase domain. In its active conforma-
tion, ABL bears remarkable structural resemblance to the
Src family kinases.25 Although both nilotinib and dasatinib
have shown activity against a range of BCR-ABL kinase
mutations, there exist a number of specific mutations that are
less sensitive to each of these agents. For nilotinib, these
mutations include E255K/V, Y253H, F359V and T315I, and for
dasatinib, these mutations include Q252H, E255K/V, F317L,
V299L and T315I.2628

SPOTLIGHT
The relationship of kinase inhibition profile with safety

Wild-type ABL inhibition: cardiac events

All currently approved TKIs for CML treatment inhibit wild-type
ABL kinase. ABL is a key mediator of normal cardiac function
and is expressed in the cardiac and other tissues (Figure 2). A
link between the imatinib inhibition of ABL and cardiac events
was first suggested by Kerkela et al.29 In this retrospective study,
10 subjects with normal baseline cardiac function developed
left ventricular dysfunction during imatinib therapy. Correlative
studies in mice and cell lines revealed that imatinib-induced
inhibition of ABL led to an endoplasmic reticulum stress
response, collapse of the mitochondrial membrane potential,

Table 2 IC50 values for bosutinib, imatinib, dasatinib and nilotinib

against BCR-ABL expressed in Ba/F3-transfected cells108

IC50 values (nM)

Bosutinib Imatinib Dasatinib Nilotinib

BCR-ABL 41.61 527 1.83 17.69

Figure 1 Structures of current and investigational tyrosine kinase
inhibitors for the treatment of CML.100 Adapted from Weisberg et al.106 Adapted from Redaelli et al. 108

Table 1 Novel tyrosine kinase inhibitors currently in clinical trials for the treatment of CML105

Tyrosine kinase inhibitor Kinase targets Drug Drug Company

administration development
status

Imatinib (STI571) ABL, PDGFR, c-KIT Oral Approved Novartis Pharmaceuticals,

San Carlos, CA, USA
Dasatinib (BMS-34825) ABL, PDGFR, c-KIT, FGR, FYN, HCK, LCK, Oral Approved Bristol-Myers Squibb,
LYN, SRC, YES, EPHB4 New York, NY, USA
Nilotinib (AMN 107) ABL, PDGFR, c-KIT, ARG, EPHB4 Oral Approved Novartis, San Carlos, CA, USA
Bosutinib (SKI-606) ABL, FGR, LYN, SRC Oral Phase II Wyeth, Madison, NJ, USA
INNO-406 (NS-187) ABL, LYN, PDGFR, c-KIT Oral Phase I Innovive Pharmaceuticals,
New York, NY, USA
AZD0530 Src family kinases Oral Phase II AstraZeneca, Washington, DC,
(solid tumors) USA
MK-0457 (VX-680) Aurora kinases, FLTE, JAK2, ABL, T315I ABL Intravenous Phase II Merck & Co., Inc., Whitehouse
Station, NJ, USA
PHA-739358 Aurora A, B and C Oral Phase II Nerviano Medical Sciences,
Nerviano, Italy
Abbreviation: CML, chronic myeloid leukemia.
Adapted from Weisberg et al.106

Leukemia
 Class effects of TKIs in the treatment of CML
FJ Giles et al
1700
SPOTLIGHT
Figure 2 ABL signaling and inhibition in cardiomyocytes.101 In cardiomyocytes, imatinib induces ER stress, leading to the activation of the PKR-
like ER kinase (PERK) and IRE1 pathways, and to the overexpression of protein kinase Cd (PKCd). PERK phosphorylates the eukaryotic translation
initiation factor 2a (EIF2a) as part of a protective response, and on sustained ER stress, IRE1 activates Jun N-terminal kinases (JNKs), leading to the
phosphorylation of 14-3-3 and release of BAX followed by mitochondrial depolarization, ATP depletion, cytochrome c (Cyt c) release, and features
of necrotic and apoptotic cell death. Adapted from Force et al.107
release of cytochrome c into the cytosol, reduction in cellular
ATP content and apoptosis.29 However, serious cardiac events
associated with imatinib therapy are rare. In fact, a retrospective
analysis of six imatinib monotherapy trials, comprising 2327
patients with 5595 years of patient exposure (median exposure
duration, 2.4 years), revealed a congestive heart failure
incidence of 0.2%.30 Furthermore, retrospective analysis of the
International Randomized Study of Interferon and STI571 (IRIS)
in Chronic Myeloid Leukemia trial, which compared
IFN cytarabine (Ara-C) with imatinib in 1106 newly diagnosed
patients with CML in chronic phase (CP), found that the incident
cases of cardiac failure and left ventricular dysfunction possibly
or probably related to study medication exposure was 0.04%
per year (1 case in 2309 years of patient exposure) for patients
receiving imatinib vs 0.75% per year (4 cases in 536 years of
patient exposure) in patients receiving IFN Ara-C.30 More
recently, a retrospective analysis of 219 patients with gastro-
intestinal stromal tumors or other sarcomas receiving imatinib
therapy showed rare occurrence of congestive heart failure,
observed in only one elderly patient with known prior cardiac
disease.31 Taken together, it appears that imatinib has little
clinical impact on cardiac function.
Cardiac adverse events (AEs), including congestive heart
failure, left ventricular dysfunction and QT prolongation, have
all been reported with dasatinib and nilotinib, with the rates of
left ventricular dysfunction highest with dasatinib.32,33 Further,
2% of patients in dasatinib clinical trials developed congestive
heart failure or cardiac dysfunction. Of these cases, half were
grade 3/4.34 A systematic literature review of clinical trials
using nilotinib 400 mg twice daily or dasatinib 70 mg twice
daily revealed that grade 3/4 nonhematologic AEs, including
arrhythmia, were more than 27 times higher for dasatinib
compared with nilotinib, though the events occurred in o5%
of the study population.16 Despite the cardiac concerns
for nilotinib and dasatinib, overall rates of QTcF interval
changes4500 ms were low for both agents (o1%).33,35 More-
over, although cardiac events were present, albeit uncommon,
in both dasatinib and nilotinib clinical trials, sudden death on
nilotinib or dasatinib because of cardiac events has rarely been
reported and can be further safeguarded against by performing
baseline electrocardiogram.36 Still, at this time, there is insuffi-
cient evidence to exclude a relationship between the rare
occurrence of sudden death in patients treated with either
nilotinib or dasatinib and cardiac AEs.
Leukemia
Src kinase inhibition: myelosuppression
Nilotinib does not inhibit the Src family of kinases at therapeutic
doses. However, owing to its less selective binding capacity,
dasatinib strongly inhibits Src and related kinases. These kinases
are key signaling members in normal hematopoiesis. Five Src
family members, HCK, LYN, FGR, LCK and BLK, are expressed
only in hematopoietic cells.37 HCK is critical for the develop-
ment and survival of myeloid cells and B lymphocytes. LYN is
expressed in all blood cell lineages except T cells and is
required for B-cell development.3840 LYN is also an important
modulator of erythropoiesis, as it positively modulates erythroid
progenitor cell expansion to promote erythrocyte survival.41 In
fact, LYN knockout mice are anemic.42 Although there is no
clear clinical link between Src inhibition by dasatinib and
myelosuppression, nilotinib, which does not inhibit the Src
family of kinases, has a more favorable myelosuppression
profile. Further, a review of clinical trial data reveals that rates
of grade 3/4 hematologic AEs for dasatinib treatment were
higher than those seen with nilotinib in both CML-CP and
CML-advanced phase (AP) patients.16,43 Specifically, CML-CP
patients displayed grade 3/4 neutropenia and thrombocytopenia
at respective rates of 50 and 49% with dasatinib therapy, and
30 and 28% with nilotinib therapy.44,45 Overall, rates of
myelosuppression are higher in CML-AP patients with both
agents. However, rates of grade 3/4 anemia, neutropenia and
thrombocytopenia were still higher in CML-AP patients receiv-
ing dasatinib: 70, 74 and 83%, respectively, compared with
CML-AP patients receiving nilotinib: 27, 41 and 36%, respec-
tively.43 It should be noted that rates of hematologic AEs on
dasatinib therapy improved with 100 mg once-daily dosing. In
the dasatinib phase II dose optimization study, 100 mg once-
daily dosing significantly reduced the incidence of grade 3/4
thrombocytopenia (22 vs 37%; P 0.004) and reduced the rates
of grade 3/4 anemia (10 vs 16%; P NS) and neutropenia (33 vs
42%; P NS).46 It is unclear what effects could develop because
of the long-term inhibition of Src in patients treated with
dasatinib for extended periods of time.
PDGF inhibition: altered bone metabolism and fluid
retention
Altered bone metabolism. Hypophosphatemia can occur
with imatinib and nilotinib therapy. Memorial Sloan-Kettering
investigators observed hypophosphatemia among a small

percentage of their CML patients enrolled in the IRIS trial
(described in detail above).47 In a subsequent casecontrol
study, 16 of 24 (67%) CML patients developed hypophos-
phatemia on imatinib. Grade 3/4 hypophosphatemia rates of
10% have been reported for patients receiving nilotinib.33
Patients with hypophosphatemia had elevated parathyroid
hormone levels, low-to-normal serum calcium levels, high
levels of phosphate excreted in the urine and decreased serum
levels of osteocalcin and N-telopeptide of collagen cross-links,
both of which are markers of bone resorption. It is hypothesized
that inhibition of bone turnover by imatinib leads to low serum
calcium and phosphate levels, which in turn causes increased
parathyroid secretion and phosphate excretion in an attempt to
maintain calcium homeostasis.
Platelet-derived growth factor receptor-a, a factor that
decreases osteoblast development and activity and may alter
bone metabolism, is known to be inhibited by imatinib and
nilotinib. PDGFRa is highly expressed in cultured osteoprogeni-
tors and osteoblasts, and plays a critical role in the development
of rat skeleton.48 The PDGF isoforms, PDGF-AA and PDGF-BB,
stimulate replication49 and migration50 of rat osteoblasts
in vitro. PDGF-BB also increases the number of rat osteoblasts
in vivo.51 In human and murine cells, osteoblast survival is
thought be stimulated by PDGF-BB through the phosphorylation
of Akt.52
Therefore, a decrease in osteoclast development and activity
may also result from imatinib and nilotinib therapy. In humans,
mature osteoclasts are derived from the monocytemacrophage
lineage.53 The maturation of macrophages into osteoclasts
requires the activity of macrophage colony-stimulating factor
secreted by stromal cells and osteoblasts, which binds to the
colony-stimulating factor 1 receptor on macrophages.54 In vitro
studies show that macrophage colony-stimulating factor activa-
tion of colony-stimulating factor 1 receptor is inhibited by
imatinib.55 Although data are limited, and no mechanistic
studies with nilotinib have been performed at this time, there
is some evidence that PDGF-BB stimulates bone resorption
by osteoclasts in humans directly through PDGFRb.56 Thus,
the inhibition of PRGFRb by imatinib may interfere with
osteoclast-stimulated bone resorption. In addition to the effects
of imatinib therapy described above, hypophosphatemia has
been observed in patients with renal cell carcinoma on
sunitinib47 and in approximately 11% of CML-CP patients in
clinical trials with dasatinib (Figure 3).16 Therefore, abnormal-
ities in bone metabolism may be a general class effect of TKIs
that inhibit PDGFR.
Fluid retention. Platelet-derived growth factor receptor
inhibition also affects fluid retention and serosal inflammation
(pleural effusions). PDGFRb is expressed in pericytes57 and lung
tissue, and is involved in the regulation of angiogenesis.58
Inhibition of PDGFR has been well documented to induce
changes in intratumoral interstitial pressures and fluid homeo-
stasis among the tumor compartment, vascular compartment
and extracellular space.59 These changes may explain why
patients who receive PDGFR inhibitors develop edema and third
spacing of fluid (mobilization of fluid to a location within the
body, rendering it unavailable to the circulatory system). By
contributing to edema and volume increase in patients, PDGFR
inhibition may also tax the cardiovascular system and induce
cardiotoxicity by indirectly straining the heart. Imatinib-asso-
ciated peripheral edema is primarily superficial.60 Serosal
inflammation resulting in anasarca, pleural or pericardial
effusion or ascites is rare with imatinib, occurring in 1% of
Class effects of TKIs in the treatment of CML
FJ Giles et al
1701
CML-CP and 3% of CML-blast phase (BP) patients.61 Nilotinib
inhibits PDGFR with a potency similar to that of imatinib and
the incidence of edema in nilotinib-treated patients is also
rare.33 An 11% rate of grade 1/2 peripheral edema was observed
in CML-CP patients enrolled in nilotinib phase II trials and
no patients had grade 3/4 peripheral edema. Occurrence of
anasarca, pleural or pericardial effusion and ascites was also
extremely rare. Serosal inflammation, specifically, pleural
effusion, is more common in CML patients treated with dasatinib
therapy, with rates of any grade pleural effusion ranging
between 14 and 35%. Rates of pleural effusion can be especially
high among patients with advanced CML. In patients who have
failed imatinib and received dasatinib therapy, rates of grade 3/4
pleural effusion were found to be as high as 19% in CML-CP
patients and 28% in CML-myeloid blast crisis patients.6264 All
of the aforementioned data are from dasatinib dosing at 70 mg
twice daily and it should be noted that the incidence of grade
3/4 pleural effusions, but not the overall incidence, was
significantly decreased with the widely used 100 mg once-daily
dosing of dasatinib (16 vs 7%; P 0.024).46 The high rates
SPOTLIGHT
of pleural effusion with dasatinib therapy may be related to its
potent inhibition of PDGFRb (IC50, 28 nmol/l).65,66 The lesser
degree of PDGFRb inhibition by imatinib and nilotinib may
explain the significantly lower incidence of pleural effusion with
these agents compared with dasatinib.67,68
Recent evidence suggests that the peripheral edema seen with
imatinib and the pulmonary edema associated with dasatinib
may be because of distinct mechanisms. In a recent cohort study
of 43 CML-CP patients, generalized fluid retention was not a
significant predictor of pulmonary edema.69 The only variables
found to be predictive of pulmonary edema in a multivariate
analysis were a history of autoimmune disease (relative risk, 13;
95% confidence interval, 1.6103) and dasatinib dose (relative
risk 7.4; 95% confidence interval, 1.244.3). These results
suggest that dasatinib-induced pulmonary edema does not
correlate with generalized fluid retention and may instead be
mediated by an immune mechanism. The findings also suggest
that the inhibition of PDGFR alone may not be sufficient to
cause serosal inflammation, but that the combined inhibition of
Src (affecting vascular permeability) and PDGFR (affecting
interstitial fluid pressure and vascular permeability) could be a
contributing factor to the high incidence of pleural effusions
with dasatinib. Notably, bosutinib, a dual Src and ABL inhibitor
with little activity against PDGFR, has not been associated with
pleural effusion.70,71 Src inhibition may also mediate fluid
retention. Vascular permeability mediated by vascular endo-
thelial growth factor is directly dependent on Src kinases that
are widely expressed in lung tissues.72,73 Src also regulates focal
adhesions and adherens junctions, which may be involved in
the stability of the pleural epithelium and pleural space
homeostasis.74,75 As Src kinases are inhibited by dasatinib with
an IC50 of 0.5 nM, it is reasonable to hypothesize that Src kinase
inhibition by dasatinib may contribute to fluid retention
observed in treated patients.37,65,66 Other risk factors for
pulmonary edema on dasatinib include prior cardiac history,
hypertension and twice-daily administration of dasatinib.62
Other risk factors include advanced disease (BP4AP4CP),
previous lung problems (smoking and infections) and in those
maintained on starting doses of dasatinib.76
c-KIT inhibition: dermatologic toxicity,
myelosuppression and other adverse events
The c-KIT receptor is an important target in the treatment of
various solid tumor types and hematologic malignancies. In
Leukemia
 Class effects of TKIs in the treatment of CML
FJ Giles et al
1702
SPOTLIGHT
Figure 3 Molecular determinants of hypophosphatemia in patients treated with PDGFR inhibitors.41 M-CSF, macrophage colony-stimulating
factor; PDGF, platelet-derived growth factor; RANK, receptor activator of NF-kB; RANKL, receptor activator of NF-kB ligand. Adapted
from Berman et al.47
these cancers, high levels of c-KIT result from overexpression of
the protein or mutations in the KIT gene. In most gastrointestinal
stromal tumor cases, c-KIT is constitutively activated.77
Activated forms of c-KIT have also been found in a number of
other malignancies, including mast cell disorders, seminomas
and acute myelogenous leukemia.78
Dermatologic toxicity. Cutaneous reactions, including
superficial edema and skin rash, are the most common
nonhematologic side effects found with imatinib therapy.5 In a
study of 118 CML patients on imatinib therapy, superficial
edema and rash were observed in 48 and 12.7% of patients,
respectively.79 There was also a high prevalence of pigmentary
changes, which included 40.9% depigmentation (localized or
generalized) and 3.6% hyperpigmentation. Pigmentary changes,
skin rash and related events are most likely due to imatinib
inhibition of c-KIT in the skin. c-KIT is normally expressed in
Leukemia
skin basal cells, melanocytes, epithelial cells of the breast, tissue
mast cells and other cells.80 Recent data suggest that c-KIT has a
major role in melanogenesis, melanocyte homeostasis and
ultraviolet B-induced pigmentation.81
Myelosuppression. c-KIT is essential for the development of
normal blood cells, melanocytes and mast cells.82,83 The degree
of c-KIT inhibition by imatinib, nilotinib and dasatinib seems to
correlate with the rates of myelosuppression seen with each
agent. With the identification of c-KIT as a potential target for
anticancer therapy, there were concerns that AEs might preclude
their utility in the anticancer armamentarium. Although it is still
unclear whether the inhibition of c-KIT plays a direct role in
some of the clinical AEs observed with c-KIT inhibitors, several
AEs reported with imatinib, nilotinib and dasatinib are
consistent with c-KIT inhibition, including myelosuppression.
Despite these safety concerns, the clinical activity of imatinib
 Class effects of TKIs in the treatment of CML
FJ Giles et al
1703
Table 3 Incidence of nonhematologic adverse events reported for Table 4 Incidence of hematologic adverse events reported for
nilotinib and dasatinib in STUDY 2101 and START-C trials, nilotinib and dasatinib in STUDY 2101 and START-C trials,
respectively respectively

Nonhematologic AEs Nilotinib107 (n 321)a Dasatinib62 (n 186)b Grade 3/4 hematologic AEs Nilotinib107 Dasatinib62
(n 321)a (n 186)b
Drug related (%) Any grade Grade 3/4 Any grade Grade 3/4
Neutropenia 30 49
Rash 30 2 22 0.5 Thrombocytopenia 28 47
Pruritus 25 o1 NR NR Anemia 10 22
Nausea 24 o1 19 1
Fatigue 20 1 28 1 Abbreviations: AEs, adverse events; START-C, SRC/ABL Tyrosine
Headache 18 2 34 1 Kinase Inhibitor Activity Research Trial.
a
Diarrhea 12 2 30 2 STUDY 2101, 14 months of follow-up.
b
Dyspnea NR NR 27 3 START-C, 8 months of follow-up.

Biochemical abnormalities (%)

Elevated total bilirubin 71 7 14 0 twice-daily dasatinib-treated patients compared with that in
Hyperglycemia 70 12 NR NR 400600 mg twice-daily nilotinib (18 vs 6%, respectively).
Elevated ALT 67 4 52 2
Elevated AST 54 2 60 2
Pleural effusions were also more frequently noted with dasatinib
Hypophosphatemia 52 15 NR NR treatment (19%) compared with nilotinib (1.2%) treatment.

Elevated lipase 45 16 NR NR
Fluid retention (%)
Peripheral edema 19 (6) 0 33 (18) 0 thrombocytopenia. Dasatinib treatment was also associated
Pleural effusion 4 (1.2) 2 (0.6) 35 (19) 6 (3)
Abbreviations: AEs, adverse events; ALT, alanine aminotransferase;
AST, aspartate aminotransferase; NR, not reported; START-C, SRC/
ABL Tyrosine Kinase Inhibitor Activity Research Trial.
a
STUDY 2101, 14 months of follow-up.
b
START-C, 8 months of follow-up.
and nilotinib in gastrointestinal stromal tumor has been
attributed to their inhibitory effects on the c-KIT receptor.84,85
Clinical implications of differential target kinase profiles
of imatinib, nilotinib and dasatinib
Imatinib has a favorable safety profile with an overall low
incidence of grade 3/4 AEs in newly diagnosed CML-CP
patients. Rash, fatigue, headache, nausea, diarrhea, and muscle
and joint pain are the most frequently reported drug-related
events. Less than 3% of patients report grade 3/4 events.5 Grade
3/4 superficial edema is also infrequent and occurs in less than
1% of patients. Imatinib treatment does result in myelo-
suppression, including grade 3/4 neutropenia (14.3%), thrombo-
cytopenia (7.8%) and anemia (3.1%). A longer-term follow-up
of the IRIS study (described above in detail) has not significantly
changed the safety profile of imatinib.86 Imatinib is overall well
tolerated. However, some patients require further treatment with
a second-generation TKI because of resistance to, or intolerance
of, imatinib.
Nilotinib and dasatinib are both highly active in CML-CP
patients who have failed imatinib because of resistance or
intolerance.44,45,64,87 However, their safety profiles differ sub-
stantially (Tables 3 and 4). The most common nonhematologic
grade 3/4 adverse events for patients with CML-CP treated with
nilotinib include lipase elevation (16%), bilirubin elevation (7%)
and hyperglycemia (12%). The increases in serum glucose were
not clinically significant and no patient discontinued study drug
because of hyperglycemia. Lipase elevations were transient and
asymptomatic; however, patients with an earlier history of
pancreatitis should have lipase checked periodically. Conver-
sely, headache and diarrhea related to study drug appear to be
more frequent in dasatinib-treated patients. Importantly, more
patients treated with dasatinib experience fluid retention. The
incidence of peripheral edema is threefold greater in 70 mg
SPOTLIGHT
Finally, hematologic AEs were more frequent in dasatinib-
treated patients, with nearly half the patients receiving 70 mg
twice-daily dasatinib experiencing grade 3/4 neutropenia and
with bleeding events, reported in 16% of all patients and in 4%
experiencing grade 3/4 AEs.44,88 In a separate study, 81% of all
bleeding episodes occurred in the gastrointestinal tract, with a
median time of 6 weeks to development of bleeding.89
Dasatinib treatment has also been shown to induce platelet-
aggregation effects when compared with imatinib, nilotinib or
bosutinib treatment.90 The low frequency of bleeding events
observed with nilotinib makes it a good choice for patients
with risk factors for bleeding complications. Overall, it is
important to consider that much of the current literature on
dasatinib-related AEs focuses on the 70 mg twice-daily dose, but
it is important to keep in mind that the 100 mg once-daily dose
is now widely used and significantly reduces the number
of several AEs, including grade 3/4 pleural effusion and
thrombocytopenia.46
A major therapeutic advantage of nilotinib is the absence
of any significant cross-intolerance with imatinib.91,92 Nilotinib
as subsequent treatment is very well tolerated by the majority
of patients with imatinib intolerance (Table 5). Recurrence
of similar grade 3/4 AEs during nilotinib therapy was observed
in less than 1% (1/71) and 18%, 7 of 38 patients with non-
hematologic and hematologic imatinib intolerance, respec-
tively. All the patients who experienced nonhematologic
imatinib intolerance were CML-CP patients experiencing
thrombocytopenia.91,92 During secondary dasatinib therapy,
approximately 4%, 9 of 225 patients with nonhematologic, and
13%, 6 of 46 patients with hematologic imatinib intolerance
experienced recurrence of similar grade 3/4 AEs.93,94 In this
study, reoccurrence of grade 3/4 hematologic toxicity was
observed in 86%, 37 of 43 patients. Cross-intolerance of
dasatinib treatment is most typically a result of neutro-
penia and/or thrombocytopenia.95100 Patients who switched
to dasatinib because of imatinib intolerance subsequently
discontinued dasatinib due to intolerance at similar levels to
nilotinib.
Taken together, nilotinib appears to have a greater overall
favorable safety profile with regard to fluid retention, myelo-
suppression and bleeding events, and shows little cross-
intolerance with imatinib in imatinib-intolerant patients. When
selecting a second-generation TKI for patients with imatinib
resistance or intolerance, the safety of the therapy should
help guide the treatment decision for each individual patient.

Leukemia
 Class effects of TKIs in the treatment of CML
FJ Giles et al
1704
Table 5 Comparison of nonhematologic adverse events observed in imatinib-intolerant patients treated with nilotinib90,91

Reason for imatinib Imatinib Grade 3/4 AE or persistent Grade 3/4 AE AE that led to dose D/C nilotinib
intolerance intolerant grade 2 AE on nilotinib on nilotinib reduction of nilotinib due to AE

Nonhematologic 57 4 1 0 0
Rash/skin 26 0 0 0 0
Fluid retention 17 0 0 0 0
GI 17 3 1 0 0
Diarrhea 12 3 1 0 0
Liver toxicity 9 1 0 0 0
ALT 3 1 0 0 0
AST 4 0 0 0 0
Myalgia/arthralgia 10 0 0 0 0
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; D/C, discontinued; GI, gastrointestinal.
SPOTLIGHT

However, other considerations are also important and must
be accounted for in the decision-making process, including the
patients mutation status, the differential pharmacokinetic
profile and dosing schedule of the therapy, concomitant
medications and likely adherence to therapy, among others.
as well as the most favorable safety profiles, and are excellent
therapeutic options for patients with CML. Future studies will
determine how the emerging therapies with varied target kinase
profiles will also fit into the CML treatment paradigm.

Emerging agents in the treatment of CML
Bosutinib (SKI-606) is an oral dual Src/Abl TKI capable of
200-fold greater BCR-ABL inhibition compared with imatinib
(Table 2). Unlike imatinib, bosutinib does not show any
appreciable activity against c-KIT or PDGFR.71 As bosutinib is
also an inhibitor of Src kinase, it may have a safety profile
similar to dasatinib. Interestingly, no patients in a phase I/II
bosutinib study experienced pleural effusion or pulmonary
edema.70 This could be because of the fact that bosutinib is a
weaker inhibitor of PDGFR.71 At the moment, the greatest safety
challenge with bosutinib appears to be the high level of grade
3/4 diarrhea that must be managed appropriately to ensure
treatment continuation. MK-0457 is a moderate-to-strong
inhibitor of ABL and JAK2, and a robust inhibitor of aurora
kinase and FLT3.101 Notably, MK-0457 is the only second-
generation TKI to show efficacy against the BCR-ABL T315I
mutation in vitro.102 In November 2007, patient enrollment into
phase I and II MK-0457 trials was suspended, pending a full
analysis of all efficacy and safety data after one patient displayed
QTc prolongation. INNO-406, which is structurally related to
imatinib and nilotinib, strongly inhibits both BCR-ABL and LYN.
This dual inhibition may be significant as acquired imatinib
resistance is thought to be mediated in part through LYN
overexpression. In vitro analysis of INNO-406 showed 20-fold
greater potency than imatinib and inhibited several imatinib-
resistant BCR-ABL mutants, but not T315I. In addition to
BCR-ABL, INNO-406 also inhibits PDGFR and c-KIT to a
similar degree as imatinib. INNO-406 has no effect on Src,24,103
and as a result, may have a safety advantage over dasatinib.
INNO-406 was well tolerated in phase I trials of heavily
pre-treated CML-AP patients who failed prior therapy, including
imatinib, because of resistance and intolerance.104106 More
clinical data are needed to determine if INNO-406 will
benefit CML patients. Overall, the prospects of combining
currently approved TKIs with emerging therapies that are active
against the T315I mutation are of particular interest, given
the potential for combination therapy of CML treatment in the
future.
Overall, there appears to be an emerging pattern of TKI kinase
selectivity profiles in the treatment of CML being closely linked
to their respective safety profiles. Currently, nilotinib and
imatinib exhibit the most selective kinase inhibition profiles,
Conflict of interest
FG received research support from Bristol-Myers Squibb, Merck,
Novartis and Wyeth; MOD received an honoraria from
Novartis; and RS has nothing to disclose.
Acknowledgements
Financial support for medical editorial assistance was provided by
Novartis Pharmaceuticals. We thank Michael Mandola, PhD
(Health Interactions), for medical editorial assistance with this
manuscript.
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