Dermatologic Therapy, Vol. 24, 2011, 386–395
Printed in the United States · All rights reserved
© 2011 Wiley Periodicals, Inc.
DERMATOLOGIC THERAPY
ISSN 1396-0296
dth_1431
386..395
Adverse cutaneous reactions
secondary to tyrosine kinase
inhibitors including imatinib
mesylate, nilotinib, and dasatinib
Iris Amitay-Laish*, Salomon M. Stemmer†‡ &
Mario E. Lacouture§
*Department of Dermatology, †Institute of Oncology, Davidoff Center, Rabin
Medical Center, Beilinson Hospital, Petah Tikva, ‡Sackler Faculty of
Medicine, Tel Aviv University, Tel Aviv, Israel and §Dermatology Service,
Rockefeller Outpatient Pavilion, Memorial Sloan-Kettering Cancer Center,
New York, New York
ABSTRACT: Imatinib mesylate is the first of a novel group of drugs that specifically target protein
tyrosine kinases, which are central to the pathogenesis of human cancer. It has been approved for the
treatment of chronic myeloid leukemia and gastrointestinal stromal tumor and has been found efficacious in other neoplastic diseases. Nilotinib and dasatinib, a second-generation of tyrosine kinase
inhibitors (TKIs), were developed in response to findings of emerging imatinib resistance or intolerance to the drug. Cutaneous reactions are the most common nonhematologic side effect of these
drugs, and their management is challenging especially in the absence of alternative anticancer
agents. The present review focuses on the clinical characteristics and the hypothesized molecular
pathogenesis of these first- and second-generation TKIs’ cutaneous side effects, and approaches to
their treatment. The wide range of adverse effects clarifies the difficulty in designing a truly antitumoral TKI.
KEYWORDS: cutaneous, dasatinib, imatinib mesylate, nilotinib, side effects, tyrosine kinase inhibitors
Introduction
Imatinib mesylate (Glivec/Gleevec; Novartis Pharmaceuticals, Basel, Switzerland; formerly known as
STI571), an oral anticancer agent, is the first of a
novel group of drugs, which are of small molecules
Address correspondence and reprint requests to: Iris
Amitay-Laish, MD, Department of Dermatology, Rabin
Medical Center, Beilinson Hospital, Petach Tikva, Israel, 4910,
or email: [email protected].
386
with specific cellular targets that inhibits several
protein tyrosine kinases. Imatinib inhibits tyrosine
kinases including bcr-abl, c-Kit, and plateletderived growth factor receptors (PDGFR), which
are central to the pathogenesis of human cancer
(1). The drug has been approved in the United
States (US) as the first-line therapy for chronic
myeloid leukemia (CML) and gastrointestinal
stromal tumor (GIST). It has also shown efficacy in
the treatment of metastatic dermatofibrosarcoma
protuberans, hypereosinophilic syndrome, other
Practical approach
chronic myeloproliferative diseases, a subset of
patients with systemic mastocytosis, and AIDSrelated Kaposi’s sarcoma (2). Recently, the efficacy
for systemic sclerosis (3,4) and nephrogenic systemic fibrosis (5) has also been reported.
Resistance to imatinib has developed, with point
mutations within the bcr-abl kinase domain or
increased levels of bcr-abl tyrosine kinase, being
the primary mechanisms (6,7). Dasatinib (Sprycel,
formerly BMS-354825; Bristol-Myers Squibb, New
York, NY, USA) and nilotinib (Tasigna, formerly
known as AMN107; Novartis) are secondgeneration bcr-abl tyrosine kinase inhibitors
(TKIs), which were manufactured to overcome
resistant cases. Dasatinib binds both active and
inactive bcr-abl, as well as the majority of abl
mutants. Nilotinib has greater binding affinity than
imatinib (8). Both drugs gained accelerated US
Food and Drug Administration approval for chronic
and accelerated phase of CML with resistance or
intolerance to previous therapy with imatinib.
Besides bcr-abl, dasatinib is a potent inhibitor of
the Src family kinases, c-Kit, PDGFR, and ephrin
A receptor kinase (8). Nilotinib can also inhibit
PDGFRb (which causes chronic myelomonocytic
leukemia), fip1-like-1- PDGFRa (which causes
hypereosinophilic syndrome), and c-Kit (9).
Given the necessity for these drugs, as they often
prolong life, and the long-term need for treatment,
increased attention is being addressed to their toxicity profiles. The present review focuses on the
cutaneous side effects of these first- and secondgeneration TKIs, as they are definitely not only
tumor-targeted agents.
Table 1. Cutaneous adverse effects
Drug
Imatinib
mesylate
(Glivec®)
Cutaneous adverse effects
(%/number of cases)
Superficial edema (48–65)
Maculopapular rash (~67)
Pigmentary changes
Hypo/depigmentation (41)
Hyperpigmentation (~4)
Lichenoid reaction (15 cases)
Psoriasiform rash/psoriasis (FC)
Pityriasis rosea-like eruption (FC)
AGEP (FC)
Stevens–Johnson syndrome (7 cases)
Urticaria
Neutrophilic dermatosis (FC)
Xerosis (17 cases)
Cheilitis (FC)
Case reports: photosensitivity, mycosis
fungoides-like, follicular mucinosis,
EBV-positive B-cell
lymphoproliferative disease,
porphyria, GVH-like, vasculitis,
panniculitis, hyaline cell syringoma,
malpighian epithelioma,
papuloerythroderma of Ofuji
AGEP, acute generalized exanthematous pustulosis; EBV,
Epstein–Barr virus; FC, few cases; GVH, graft-versus-host.
Imatinib mesylate
Cutaneous reactions are one of the most common
nonhematological side effects of imatinib
(Table 1), reported in 7% to 88.9% of patients in
different series. Their occurrence and severity are
dose dependent: studies noted a 7% incidence of
skin rash in patients treated with an almost noneffective dose of 25–140 mg/day of imatinib compared to a rate of 21–88% in patients treated with
400–800 mg/day (10–15). These findings, together
with the drug’s relatively low molecular weight,
suggest that the cutaneous adverse effects are not
immunogenic, but are rather due to a direct pharmacological effect of the drug (12).
Superficial edema
Two prospective studies of imatinib reported findings of superficial edema in 48% of 118 patients
FIG. 1. Periorbital superficial edema which appeared in
a patient with CML 2 months after imatinib treatment was
initiated.
(16) and 65% of 54 patients (12), sometimes
accompanied by weight gain (12), at an average of 6
weeks after drug initiation. Its occurrence was correlated with plasma levels of the drug, suggesting
dose dependency (10,12). The edema was of mild
to moderate severity and mainly localized to the
face, particularly the eyelids (FIG. 1); it was most
bothersome in the morning. In one case, periorbital edema with dark, purplish erythema mimicking heliotrope rash was described (17). Lower
extremity edema was also seen, but much less
often (1). Excessive central fluid retention (pleural
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Amitay-Laish et al.
effusion, congestive heart failure, etc.) has been
reported in 1–3% of imatinib-treated patients (18).
In most cases of superficial edema, imatinib
treatment need not be withdrawn, and no specific
therapy is required. Limiting salt intake or applying
topical phenylephrine 0.25% may be beneficial in
controlling periorbital edema. If the edema is
severe, diuretics may be indicated (10). Superficial
edema in imatinib-treated-patients has been
hypothesized to be secondary to an increase in
dermal interstitial fluid pressure (19) due to the
drug’s inhibition of PDGFR, which regulates interstitial fluid homeostasis by modulating the tension
between cells and extracellular matrix structures
(14).
Erythematous maculopapular rash
The majority of imatinib-related cutaneous reactions consist of generalized rashes, frequently
pruritic. They usually manifest as erythematous
maculopapular lesions on the forearms, trunk, or
less frequently, the face. The rash tends to be mild,
self-limiting, and easily manageable with antihistamines or topical steroids; a short course of oral
steroids can be used to treat more severe cases (10).
Imitanib should not be discontinued for as long
as the disease responds (1), although in severe/
life-threatening rash, dasatinib or nilotinib could
be considered as an alternative treatment option.
Valeyrie et al. (12) conducted a prospective
study of 54 patients treated with imatinib.
Erythematous macules and/or papules involving
the face, arms, or trunk occurred in 66.7% at an
average of 2 months after drug initiation. On
multivariate analysis, female sex and daily dose of
imatinib were independent risk factors for rash
(12). Five patients had extensive exanthematous,
maculopapular, or exfoliative dermatitis with or
without fever, which was classified as severe/lifethreatening (grade 3/4) according to the National
Cancer Institute’s Common Terminology Criteria
for Adverse Events (NCI CTCAE). Imatinib was
withdrawn in three of them.
41% of 118 imatinib-treated patients with CML.
Median time of onset from drug initiation was
4 weeks (range 2–14). One case report described
an increase in the extent of preexisting vitiligo
after initiation of imatinib therapy (20). Another
described hypopigmentation specifically targeting
lentigines in addition to generalized hypopigmentation in a patient with GIST. Immunohistochemical study of a hypopigmented lentigene using
hematoxylin-eosin and Melan-A stains showed
underactive melanocytes at the basal layer.
Fontana-Masson staining revealed only subtle
focal melanin pigmentation (21). It has been postulated that lentigines are part of familial GIST syndrome and therefore harbor the same mutation
that makes both interstitial cells of Cajal and melanocytes susceptible to imatinib therapy via the
c-Kit pathway. Hair depigmentation has been
reported as well (22).
Patchy hyperpigmentation may occur secondary to imatinib treatment, though less often than
hypopigmentation (16,23). In the study of Arora
et al. (16), 3.6% of the 118 patients with CML had
hyperpigmentation. FIG. 2 shows one example of
an asymptomatic grayish pigmentation that
appeared on the left shoulder blade of the patient
2 months after imatinib initiation (16). Histologic
evaluation demonstrated merely a delicate presence of dermal melanophages. Repigmentation or
darkening of hair color was observed in two series,
in 9 of 133 patients (24) and 8 of 54 patients (12).
The pathogenesis for these reactions is probably
related to changes in c-Kit, which is normally
expressed on melanocytes, epithelial cells of the
breast, dermal sweat glands, tissue mast cells, and
other cells (12). Together with its ligand, stem cell
factor (SCF), c-Kit regulates, among other things,
Pigmentary changes
Many reports have described pigmentary abnormalities secondary to treatment with imatinib.
They are generally characterized by localized,
patchy, or diffuse hypopigmentation and depigmentation, which is usually reversible with a dose
reduction or discontinuation of therapy (2,10–12).
Ethnically pigmented patients are most often
affected. Arora et al. (16) noted depigmentation in
388
FIG. 2. Grayish pigmentation appearing on the left scapula,
2 months after imatinib initiation.
Practical approach
the development, migration, and survival of melanocytes (25). Through a series of kinase activation
and phosphorylation reactions, the combination of
c-Kit and SCF activates the tyrosinase gene promoter, thereby initiating pigment production (25).
Specific hypopigmentary disorders, such as vitiligo
and piebaldism, are known to be associated with
c-Kit mutations (26). In vitro studies have shown
that the number of melanocytes with high tyrosinase activity decreases after imatinib treatment
(27). Parallel in vitro studies of fibroblasts have
shown a 50% decrease in melanocyte proliferation
after imatinib treatment. Because fibroblasts
secrete SCF, it is thus thought that imatinib may
inhibit pigment production through direct inhibition of c-Kit-mediated gene activation and indirect
inhibition of SCF production (27). The quantity
of the effect imatinib may inflict on the cellular
response may be specific to the c-Kit mutation in
the individual, and thus not all patients will experience pigmentary changes in response to imatinib,
and not all will experience it to the same degree (21).
reported three cases of psoriasiform palmoplantar
hyperkeratosis after long-term imatinib treatment
in patients with no history of psoriasis. Two of them
also had nail dystrophy. In all three, discontinuation or dose reduction of imatinib led to improvement in the lesions.
It is well known that T lymphocytes play a crucial
role in psoriasis. There is also evidence of the
pathogenetic involvement of PDGF and SCF in the
disease (31). Cytokine production and T cell proliferation are affected by imatinib. The drug inhibits
interferon-c secretion by T effector cells, but the
function of these cells is modulated rather than
suppressed (12). These effects, together with imatinib’s suppression of c-Kit and PDGFR, may help
to explain the exacerbation of psoriasis in some
patients.
Interestingly, however, Miyagawa et al. (33)
reported an imatinib-induced improvement in
psoriasis in one patient with GIST. Thus, more
studies are warranted to establish the effects of
imatinib on psoriasis.
Lichenoid reaction
Pityriasis rosea-like eruption
A mucosal/cutaneous lichenoid eruption has been
reported in about 15 imatinib-treated patients to
date (28,29). Three patients had mucosal lesions,
seven had cutaneous lesions, and five had both.
Biopsy study in some of the patients suggested a
diagnosis of lichen planus. The eruptions were considered dose related, as all affected patients (for
whom dosages were stated) were treated with
400 mg daily or more. The lesions developed 1–3
months after drug initiation in 10 patients and 4–12
months after drug initiation in four; in one patient,
the duration of treatment was not stated (11). In two
patients, systemic corticosteroids were required to
improve the skin symptoms. Ten patients were able
to continue or restart treatment with imatinib.
Dalmau et al. (30) described one case in which acitretin successfully alleviated a lichenoid reaction,
making it possible for the patient to continue taking
the effective imatinib dosage.
Konstantopoulos et al., in 2002, were the first to
report the occurrence of pityriasis rosea 4 weeks
after initiation of imatinib treatment in a woman
with a blast crisis of CML. It was not clear if the
exanthema was coincidental or an effect of the
drug (34). Three years later, Brazzelli et al. (35)
described three men who acquired an erythematous, slightly pruritic, macular skin eruption 3–4
weeks after starting treatment with imatinib. The
lesions were further characterized by a peripheral
collarette of desquamation with a vaguely parallel
distribution to Langer’s skin lines, and they were
confined to the trunk, and arms. These findings
suggested a clinical diagnosis of atypical pityriasis
rosea. The relationship of the rash to imatinib was
supported by its disappearance on suspension of
the drug and its reappearance in milder form when
the drug was restarted. The pathophysiology of this
cutaneous reaction is still unclear.
Psoriasiform rash/psoriasis
Acute generalized exanthematous pustulosis
Valeyrie et al. (12) described 4 of 54 imatinibtreated patients in whom a psoriasiform rash
appeared predominately on the scalp, arms, and
trunk 1–7 months after drug initiation. Two of them
had a history of psoriasis. Other studies described
similar findings (14,31). In all cases, the cutaneous
reaction subsided with discontinuation or reduction of imatinib therapy. Deguchi et al. (32)
In 2001, Brouard et al. (36) described a typical case
of imatinib-induced acute generalized exanthematous pustulosis (AGEP). Two additional cases were
reported 1 year later (37), and another case, 4 years
later (38). However, the latter three cases were
atypical because they appeared more than 3
months from treatment onset, the rash involved
mainly the face and trunk and spared the folds,
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Amitay-Laish et al.
and the lesions contained neutrophilic infiltrates
located in the superficial dermis, without involvement of the epidermis. AGEP has not been
described in patients receiving less than 600 mg/
day of imatinib, so it may be dose related. Some
authors postulated that imatinib induces AGEP via
a similar mechanism to mercury (36).
Stevens–Johnson syndrome
Some imatinib-treated patients acquire a severe
rash with desquamative components, including
Stevens–Johnson syndrome (SJS). Hsiao et al. (39)
described a 42-year-old patient with blast crisis of
CML in whom imatinib was stopped after 1 week
because of the development of SJS. Rechallenge
with a single dose of 600 mg was associated with a
reappearance of multiple pruritic vesicles and
bullae within 24 hours, pointing to the drug as the
probable cause of the rash. Six additional cases of
imatinib-induced SJS have since been reported
(40–45). In three of these patients, no reaction was
provoked on challenge with a lower dose after the
initial rash cleared (43,44). In one patient, initially
treated with 400 mg imatinib daily, a first challenge
with 200 mg daily provoked a similar reaction, but
rechallenge with 100 mg daily together with prednisolone 40 mg/day (1 mg/kg) was successful. The
prednisolone was tapered down over the next 6
weeks concomitant with a gradual increase in the
imitanib dose to 300 mg, with no further recurrence
of the rash (45). This approach should only be considered in patients for whom no treatment option
other than imatinib is available (10). Some authors
suggested a desensitization protocol in such cases
(46). In severe/life-threatening rash, dasatinib or
nilotinib could be considered as an alternative.
Urticaria
In the presence of the rare event of a high basophil
count (>20%) during imatinib treatment, urticarial
eruptions may develop, presumably because of
histamine release from basophils. This rash can be
managed by premedication with an antihistamine
and will usually resolve once the basophil counts
normalizes. The cause of the skin rashes is unclear.
However, inhibition of c-KIT, which is expressed on
skin basal cells, melanocytes, and mast cells, may
have a role (1,47).
Neutrophilic dermatosis
There are reports of a possible association of Sweet
syndrome (SS) with imatinib therapy in patients
390
with CML (48–50). In addition, Dib et al. (51)
described an imatinib-treated patient with neutrophilic eccrine hidradenitis, probably a variant of SS.
The hidradenitis appeared after complete hematologic and cytogenetic remission was achieved and
resolved shortly after imatinib was discontinued.
Breccia et al. (52) and Drummond et al. (53) each
described a case of erythema nodosum in a patient
using imatinib.
Other cutaneous reactions
Valeyrie et al. (12), in their study of 54 patients
treated with imatinib, documented cutaneous
dryness in 17 patients and cheilitis in four.
Increased photosensitivity was documented in
four white patients (12). Photosensitization was
also described by Rousselot et al. (54) in eight
patients treated with imatinib for CML. Six were in
the chronic phase and two in the accelerated
phase. All affected patients had been treated over a
long term, suggesting that the effect was secondary
to the cumulative dosage (regardless of the daily
dosage). It is postulated that imatinib impairs
melanogenesis via its inhibition of c-Kit activity,
thereby altering the skin’s protection against ultraviolet ray exposure.
Clark et al. (55) described an imitanib-treated
patient with a mycosis fungoides-like reaction,
and 1 year later, Yanagi et al. (56) reported a case
of follicular mucinosis associated with imatinib
treatment. One 70-year-old woman treated with
500 mg/day imatinib for CML presented with a
rapidly growing scalp tumor, which proved to be
Epstein–Barr virus-positive B-cell lymphoproliferative disease (57). The tumor resolved when the
dose of imanitib was lowered.
Another anecdotal side effect of imatinib
therapy is porphyria cutanea tarda, which was histopathologically and serologically confirmed (58).
On discontinuation of therapy, the photo-exposed
bullae resolved, and the serum porphyrin levels
returned to normal. Reintroduction of the drug led
to a reactivation of the cutaneous disease (58). Ho
et al. (59) suggested that imatinib itself may induce
porphyria.
Drummond et al. (53), in a prospective followup study of a large cohort of imatinib-treated
patients, were the first to report a graft-versus-hostdisease-like reaction and small-vessel vasculitis.
In addition, panniculitis was noted in one patient.
In the latter case, after excluding other possible
etiologies, the authors stopped imatinib and the
patient received corticosteroids, which led to rapid
improvement of all skin lesions. Thereafter,
Practical approach
imatinib therapy was reintroduced together with
glucocorticosteroids, with only a mild cutaneous
reaction and no general symptoms (60). Breccia
et al. (52) noted the development of a hyaline cell
syringoma, a rare benign cutaneous neoplasm, and
a malpighian epithelioma, 76 and 80 weeks, respectively, after imatinib was initiated. Others reported
a rash resembling papuloerythroderma of Ofuji
in a patient receiving imatinib therapy. Although
the drug was not discontinued, the rash resolved
with 4 months’ treatment with oral and topical
glucocorticoids (61).
Dasatinib and nilotinib
Dasatinib, a thiazole carboximide derivative, is
structurally related to imatinib. Dasatinib differs
from imatinib in its ability to bind to both active
and inactive conformations of the abl kinase
domain and also inhibit Src family kinase, c-Kit,
PDGFR, and ephtin A receptor kinases. In contrast
to imatinib, the affinity of dasatinib for c-Kit and
PDGFR is comparatively low (62,63). In vitro, dasatinib has 325-fold greater potency than imatinib
against cells expressing unmutated bcr-abl and is
effective against most imatinib-resistant kinase
domain mutation.
Nilotinib, a novel oral aminopyrimidine derivative, a second-generation TKI with structural similarity to imatinib. It does not affect Src family
kinases at therapeutic doses, but can also inhibit
PDGFRb, fip1-like-1- PDGFRa, and c-Kit (9,64).
Nilotinib is 20–50 times more potent than imatinib
in inhibiting bcr-abl, which may encourage its use
in patients who are refractory to imatinib (62).
Fewer side effects have been reported for the
newer drugs (Table 2). We assume this may be due
to the greater potency and specificity of the drugs
Table 2. Cutaneous adverse effects of nilotinib
and dasatinib (%)
Nilotinib
(Tasigna®)
Dasatinib
(Sprycel®)
Rash (specific morphologies not
stated) (10–28)
Pruritus (17–24)
Dry skin (13–17)
Alopecia (6)
Sweet’s syndrome
Rash (macular, papular, exfoliative)
(11–27)
Mucositis/stomatitis (16)
Pruritus (11)
Panniculitis
Vasculitis
to bcr-abl, as well as a reduced affinity for c-Kit and
PDGFR. It might also be explained by an incomplete data because of the relative shorter availability of the drugs (62–64).
Nilotinib
Kantarjian et al. (65), in a phase I study of nilotinib
in 119 patients with imatinib-resistant leukemia,
described the appearance of cutaneous grade 1–2
(NCI CTCAE version 3) adverse effects. These
included pruritus (17–20% of treated patients),
rash (10–17%; specific morphologies not stated),
and dry skin (13–17%). Cutaneous reactions were
the most frequent nonhematologic adverse effects
and appeared to be dose related. Alopecia was also
noted in 6% of study patients. In a subsequent
phase II study, “rash” was reported in 28% of
patients (severe in 3%) and pruritus was reported
in 24% (66).
Kaune et al. (50) described a 67-year-old patient
with a 6-year history of CML, which had been
stable on imatinib therapy for the last 4 years. The
patient presented with a blast crisis, and therapy
was switched to nilotinib. This shifted the disease
back to the chronic phase. After 10 months of nilotinib therapy, pneumonia with septic features
developed; 7 days later, bullous skin infiltrations
appeared on the arms and neck. A diagnosis of SS
was made. Treatment with prednisolone 1 mg/kg
daily combined with an adequate antibiotic led to
rapid resolution of the cutaneous bullous infiltrations. Nilotinib therapy was continued, with no
further skin lesions, and the patient remained in
the chronic phase of CML. The authors concluded
that skin infiltrations consistent with SS may be
associated not only with both the classic TKI imatinib (49–51) but also with the second-generation
TKI nilotinib. It should be remembered that SS can
occur in various phases of CML, and its potential
association with disease progression is still controversial. The patient described had no disease progression and showed no signs of a blast crisis in the
peripheral blood at the time of SS development
(50).
Dasatinib
Dasatinib was associated with a 35% risk of cutaneous side effects in one phase I trial and five phase
II trials including a total of 911 patients. There was
a lower incidence of skin rash in patients with
myeloid blast crisis (11–14%) or lymphoid blast
crisis (15–17%) than in patients with accelerated
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Amitay-Laish et al.
CML (22%) or chronic-phase CML (13–27%) (67–
70). Most of the reactions consisted of grade 1–2
localized and generalized erythema, macular and
papular eruptions, or “exfoliative rash.” Sixteen
percent of the study patients had mucositis and/or
stomatitis, and 11% had pruritus.
A rare presentation of painful panniculitis was
described in two dasatinib-treated patients with
imatinib-resistant chronic-phase CML (70). The
first, a 55-year-old woman in the fourth week of
dasatinib treatment, presented with fever (temperature, 38.1°C) and subcutaneous nodules with
overlying erythema on both thighs. The drug was
withheld, and the rash resolved within 1 week. On
rechallenge, the fever recurred together with the
rash, this time on the limbs and vulva. Biopsy of a
skin lesion revealed lobular panniculitis with
massive infiltration by polymorphonuclear leukocytes. The drug was again withdrawn and then
reintroduced together with prednisone (50 mg/
day), which successfully controlled the panniculitis. A minimum of 5 mg daily prednisone was
required to prevent recurrence. The second patient
was a 67-year-old woman in the 12th week of dasatinib treatment who presented with a similar rash.
A skin biopsy confirmed the diagnosis of panniculitis. The rash resolved when dasatinib was
stopped, but it recurred on rechallenge and was
not sensitive to steroid treatment. Since both
patients had tolerated imatinib without any cutaneous side effects, the toxic effects encountered
with dasatinib might have been related to a specific
tyrosine kinase it inhibits. It is also possible that
dasatinib caused panniculitis through more complete inhibition of a common target, such as abl.
A case of possible small-vessel vasculitis in the
setting of dasatinib-induced alveolitis has also been
described. However, a biopsy was not performed,
and the eruption as well as the alveolitis responded
to intravenous methylprednisone therapy (71).
It is noteworthy that the package insert of dasatinib warns against such dermatologic adverse
events as hyperhidrosis, alopecia, xerosis, acne,
skin ulcers, urticaria, dermatitis, photosensitivity
reaction, “nail disorder,” “pigmentation disorder,”
bullous conditions, and palmoplantar erythrodysesthesia syndrome (72).
Although beyond the scope of the present
review, a recent study demonstrated a beneficial
effect of imatinib in preventing skin thickening in
an experimental model of bleomycin-induced
dermal fibrosis and reduced myofibroblast differentiation and collagen production. A potent antifibrotic effect of imatinib was also observed in
animal models of pulmonary, renal, and liver fibro-
392
sis (73,74). Accordingly, experimental in vitro and
in vivo studies of dasatinib and nilotinib showed
evidence that they inhibited the synthesis of the
extracellular matrix proteins in systemic sclerosis
fibroblasts and prevented dermal fibrosis (75).
These drugs might therefore be potential promising additions to the arsenal of molecular-targeted
therapies in cutaneous and noncutaneous fibrotic
diseases.
Summary
For drug-related cutaneous eruptions in general,
the mainstays of management are early recognition of symptoms, withdrawal of the causative
agent, and prompt initiation of symptomatic treatment (76). However, when there are no alternative,
equally effective, anticancer drugs available, it may
be necessary to continue the treatment despite the
presence of cutaneous reactions (1). In these cases,
if type 1 hypersensitivity is suspected or the cutaneous reaction is severe, an oral desensitization
protocol consisting of incremental dosages of imatinib may be feasible (46). Some researchers found
that after resolution of the initial severe desquamative cutaneous reaction, anticancer treatment with
imatinib could be continued by gradually escalating the dose in combination with the administration of prednisone (1 mg/kg/day tapered down
over several weeks) to achieve long-term tolerance
(10,40). Moreover, considering that most severe
adverse cutaneous reactions to these drugs are
dose related, the mechanism could be pharmacologic rather than immunologic allergic (13,39).
Close monitoring for life-threatening cutaneous
reactions is important in patients treated with high
daily doses.
The recently developed molecular therapies
directed at specific cellular targets have enormously improved prognosis for many cancer
patients. However, the difficulty in designing a truly
antitumoral TKI is becoming clearer with time (77).
The data presented here suggest that tyrosine
kinase cell inhibitors have a wide range of adverse
cutaneous effects, reflecting the diverse mechanisms of action of the drugs. Our current understanding of the underlying mechanisms of these
effects is limited, and there are no known factors or
markers to identify patients at risk.
References
1. Guilhot F. Indications for imatinib mesylate therapy and
clinical management. Oncologist 2004: 9: 271–281.
Practical approach
2. Heidary N, Naik H, Burgin S. Chemotherapeutic agents
and the skin: an update. J Am Acad Dermatol 2008: 58:
545–570.
3. van Daele PL, Dik WA, Thio HB, et al. Is imatinib mesylate
a promising drug in systemic sclerosis? Arthritis Rheum
2008: 58: 2549–2552.
4. Sabnani I, Zucker MJ, Rosenstein ED, et al. A novel therapeutic approach to the treatment of sclerodermaassociated pulmonary complications: safety and efficacy of
combination therapy with imatinib and cyclophosphamide. Rheumatology (Oxford) 2009: 48: 49–52.
5. Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 2008: 58: 2543–
2548.
6. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity
of Bcr-Abl inhibitors AMN107 and BMS-354825 against
clinically relevant imatinib-resistant Abl kinase domain
mutants. Cancer Res 2005: 65: 4500–4505.
7. Burgess MR, Skaggs BJ, Shah NP, Lee FY, Sawyers CL. Comparative analysis of two clinically active BCR-ABL kinase
inhibitors reveals the role of conformation-specific binding
in resistance. Proc Natl Acad Sci U S A 2005: 102: 3395–
3400.
8. Piccaluga PP, Paolini S, Martinelli G. Tyrosine kinase
inhibitors for the treatment of Philadelphia chromosomepositive adult acute lymphoblastic leukemia. Cancer 2007:
110: 1178–1186.
9. Weisberg E, Manley P, Mestan J, Cowan-Jacob S,
Ray A, Griffin JD. (AMN107) Nnilotinib: a novel and selective inhibitor of BCR-ABL. Br J Cancer 2006: 94: 1765–
1769.
10. Deininger MWN, O’Brien SG, Ford JM, Druker BJ. Practical
management of patients with chronic myeloid leukemia
receiving imatinib. J Clin Oncol 2003: 21: 1637–1647.
11. Basso FG, Boer CC, Correa ME, et al. Skin and oral lesions
associated to imatinib mesylate therapy. Support Care
Cancer 2009: 17: 465–468.
12. Valeyrie L, Bastuji-Garin S, Revuz J, et al. Adverse cutaneous reactions to imatinib (STI-571) in Philadelphia chromosome positive leukemias: a prospective study of 54
patients. J Am Acad Dermatol 2003: 48: 201–206.
13. Brouard M, Saurat JH. Cutaneous reactions to STI571. N
Engl J Med 2001: 345: 618–619.
14. Scheinfeld N. Imatinib mesylate and dermatology, part 2: a
review of the cutaneous side effects of imatinib mesylate.
J Drugs Dermatol 2006: 5: 228–231.
15. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic
and cytogenetic responses to imatinib mesylate in chronic
myelogenous leukemia. N Engl J Med 2002: 346: 645–652.
16. Arora B, Kumar L, Sharma A, Wadhwa J, Kochupillai JWV.
Pigmentary changes in chronic myeloid leukemia patients
treated with imatinib mesylate. Ann Oncol 2004: 15: 358–
359.
17. Kuwano Y, Asahina A, Watanabe R, Fujimoto M, Ihn H,
Tamaki K. Heliotrope-like eruption mimicking dermatomyositis in a patient treated with imatinib mesylate for
chronic myeloid leukemia. Int J Dermatol 2006: 45: 1249–
1251.
18. Hensley ML, Ford JM. Imatinib treatment specific issues:
related to safety, fertility and pregnancy. Semin Hematol
2003: 40: 21–25.
19. Heuchel R, Berg A, Tallquist M, et al. Platelet-derived
growth factor beta receptor regulates interstitial fluid
homeostasis through phosphatidylinositol-3′ kinase signaling. Proc Natl Acad Sci U S A 1999: 96: 11410–11415.
20. Legros L, Cassuto JP, Ortonne JP. Imatinib mesilate
(Glivec): a systemic depigmenting agent for extensive vitiligo? Br J Dermatol 2005: 153: 691–692.
21. Campbell T, Felsten L, Moore J. Disappearance of lentigines in a patient receiving imatinib treatment for familial
gastrointestinal stromal tumor syndrome. Arch Dermatol
2009: 145: 1313–1316.
22. Huang X, Patel S, Ahmed N, Seiter K, Liu D. Severe toxicity
of skin rash, fever and diarrhea associated with imatinib:
case report and review of skin toxicities associated with
tyrosine kinase inhibitors. Drug Des Devel Ther 2009: 6:
215–219.
23. Mcpherson T, Sherman V, Turner R. Imatinib-associated
hyperpigmentation, a side effect that should be recognized.
J Eur Acad Dermatol Venereol 2009: 23: 82–83.
24. Etienne G, Cony-Makhoul P, Mahon FX. Imatinib mesylate
and grey hair. N Engl J Med 2000: 347: 446.
25. Tsao AS, Kantarjian H, Cortes J, O’Brien S, Talpaz M. Imatinib mesylate causes hypopigmentation in the skin.
Cancer 2003: 98: 2483–2487.
26. Dippel E, Haas N, Grabbe J, Schadendorf D, Hamann K,
Czarnetzki BM. Expression of the c-kit receptor in
hypomelanosis: a comparative study between piebaldism,
nevus depigmentosus and vitiligo. Br J Dermatol 1995: 132:
182–189.
27. Cario-Andre M, Ardilouze L, Pain C, Gauthier Y, Mahon FX,
Taieb A. Imatinib mesilate inhibits melanogenesis in vitro.
Br J Dermatol 2006: 155: 493–494.
28. Kuraishi N, Nagai Y, Hasegawa M, Ishikawa O. Lichenoid
drug eruption with palmoplantar hyperkeratosis due to
imatinib mesylate: a case report and a review of the literature. Acta Derm Venereol 2010: 90: 73–76.
29. Kawakami T, Kawanabe T, Soma Y. Cutaneous lichenoid
eruption caused by imatinib mesylate in a Japanese patient
with chronic myeloid leukaemia. Acta Derm Venereol 2009:
89: 325–326.
30. Dalmau J, Peramiquel L, Puig L, Fernandez-Figueras MT,
Roe E, Alomar A. Imatinib-associated lichenoid eruption:
acitretin treatment allows maintained antineoplastic effect.
Br J Dermatol 2006: 154: 1213–1216.
31. Dickens E, Lewis F, Bienz N. Imatinib: a designer drug,
another cutaneous complication. Clin Exp Dermatol 2009:
34: 603–604.
32. Deguchi N, Kawamura T, Shimizu A, et al. Imatinib mesylate causes palmoplantar hyperkeratosis and nail dystrophy in three patients with chronic myeloid leukemia. Br J
Dermatol 2006: 154: 1216–1218.
33. Miyagawa S, Fujimoto H, Ko S, Hirota S, Kitamura Y.
Improvement of psoriasis during imatinib therapy in a
patient with a metastatic tumour. Br J Dermatol 2002: 147:
406–407.
34. Konstantopoulos K, Papadogianni A, Dimopoulou M,
Kourelis C, Meletis J. Pityriasis rosea associated with
imatinib (STI571, Gleevec). Dermatology 2002: 205: 172–
173.
35. Brazzelli V, Prestinari F, Roveda E, et al. Pityriasis rosealike eruption during treatment with imatinib mesylate:
description of 3 cases. J Am Acad Dermatol 2005: 53: S240–
S243.
36. Brouard MC, Prins C, Mach-Pascual S, Saurat JH. Acute
generalized exanthematous pustulosis associated with
STI571 in a patient with chronic myeloid leukemia. Dermatology 2001: 203: 57–59.
37. Schwarz M, Kreuzer KA, Baskaynak G, Dorken B, le Coutre
P. Imatinib-induced acute generalized exanthematous
393
Amitay-Laish et al.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
pustulosis (AGEP) in two patients with chronic myeloid
leukemia. Eur J Haematol 2002: 69: 254–256.
Gambillara E, Laffitte E, Widmer N. Severe pustular eruption associated with imatinib and voriconazole in a patient
with chronic myeloid leukemia. Dermatology 2005: 211:
363–365.
Hsiao LT, Chung HM, Lin JT, et al. Stevens–Johnson
syndrome after treatment with STI571: a case report. Br J
Haematol 2002: 117: 620–622.
Rule SA, O’Brien SG, Crossman LC. Managing cutaneous
reactions to imatinib therapy. Blood 2002: 100: 3434–
3435.
Severino G, Chillotti C, De Lisa R, Del Zompo M, Ardau R.
Adverse reactions during imatinib and lansoprazole treatment in gastrointestinal stromal tumors. Ann Pharmacother 2005: 39: 162–164.
Vidal D, Puig L, Sureda A, Alomar A. Sti571-induced Stevense
Johnson syndrome. Br J Haematol 2002: 119: 274–275.
Pavithran K, Thomas M. Imatinib induced Stevens–
Johnson syndrome: lack of recurrence following
re-challenge with a lower dose. Indian J Dermatol Venereol
Leprol 2005: 71: 288–289.
Sanchez-Gonzalez B, Pascual-Ramirez JC, FernandezAbellan P, Belinchon-Romero I, Rivas C, Vegara-Aguilera G.
Severe skin reaction to imatinib in a case of Philadelphiapositive acute lymphoblastic leukemia. Blood 2003: 101:
2446.
Mahapatra M, Mishra P, Kumar R. Imatinib-induced
Stevens-Johnson syndrome: recurrence after re-challenge
with a lower dose. Ann Hematol 2007: 86: 537–538.
Nelson RP, Cornetta K, Ward KE, Ramanuja S, Fausel C,
Cripe LD. Desensitization to imatinib in patients with
leukemia. Ann Allergy Asthma Immunol 2006: 97: 216–
222.
Lammie A, Drobnjak M, Gerald W, et al. Expression of c-kit
and kit ligand proteins in normal human tissues. J Histochem Cytochem 1994: 42: 1417–1425.
Liu D, Seiter K, Mathews T, Madahar CJ, Ahmed T. Sweet’s
syndrome with CML cell infiltration of the skin in a patient
with chronic-phase CML while taking imatinib mesylate.
Leuk Res 2004: 28: S61–S63.
Ayirookuzhi SJ, Ma L, Ramshesh P, Mills G. Imatinibinduced sweet syndrome in a patient with chronic myeloid
leukemia. Arch Dermatol 2005: 141: 368–370.
Kaune KM, Baumgart M, Gesk S, et al. Bullous Sweet syndrome in a patient with t(9;22)(q34;q11)-positive chronic
myeloid leukemia treated with the tyrosine kinase inhibitor
nilotinib. Arch Dermatol 2008: 144: 361–364.
Dib EG, Ifthikharuddin JJ, Scott GA, Partilo SR. Neutrophilic
eccrine hidradenitis induced by imatinib mesylate
(Gleevec) therapy. Leuk Res 2005: 29: 233–234.
Breccia M, Carmosino I, Russo E, Morano SG, Latagliata R,
Alimena G. Early and tardive skin adverse events in chronic
myeloid leukaemia patients treated with imatinib. Eur J
Haematol 2005: 74: 121–123.
Drummond A, Micallef-Eynaud P, Douglas WS, et al. A
spectrum of skin reactions caused by the tyrosine kinase
inhibitor imatinib mesylate (STI571, Glivec). Br J Haematol
2003: 120: 911–913.
Rousselot P, Larghero J, Raffoux E, et al. Photosensitization
in chronic myelogenous leukemia patients treated with
imatinib mesylate. Br J Haematol 2003: 120: 1091–1092.
Clark SH, Duvic M, Prieto VG. Mycosis fungoides-like reaction in a patient treated with Gleevec. J Cutan Pathol 2003:
30: 279–281.
394
56. Yanagi T, Sawamura D, Shimizu H. Follicular mucinosis
associated with imatinib (STI571). Br J Dermatol 2004: 151:
1276–1278.
57. Bekkenk MW, Vermeer MH, Meijer CJLM, et al. EBVpositive cutaneous B-cell lymphoproliferative disease after
imatinib mesylate. Blood 2003: 102: 4243.
58. Breccia M, Latagliata R, Carmosino I, Mandelli F, Alimena
G. Reactivation of porphyria cutanea tarda as a possible
side effect of imatinib at high dosage in chronic myeloid
leukemia. Leukemia 2004: 18: 182.
59. Ho AYL, Deacon A, Osborne G, Mufti GJ. Precipitation of
porphyria cutanea tarda by imatinib mesylate? Br J Haematol 2003: 121: 375.
60. Ugurel S, Lahaye T, Hildenbrand R, et al. Panniculitis in a
patient with chronic myelogenous leukaemia treated with
imatinib. Br J Dermatol 2003: 149: 678–679.
61. Banka N, Aljurf M, Hamadah I. Imatinib (STI-571)-induced
exfoliative dermatitis in a Saudi patient with deck chair
sign. Dermatology 2003: 207: 329–330.
62. Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase
inhibitors – a review on pharmacology, metabolism and
side effects. Curr Drug Metab 2009: 10: 470–481.
63. Pavlu J, Marin D. Dasatinib and chronic myeloid leukemia:
two-year follow up in eight clinical trials. Clin Lymphoma
Myeloma 2009: 9: 417–424.
64. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with novel ABL kinase inhibitor. Science 2004: 305:
399–401.
65. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in
imatinib-resistant CML and Philadelphia chromosomepositive ALL. N Engl J Med 2006: 354: 2542–2551.
66. Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib
(formerly AMN107), a highly selective BCR-ABL tyrosine
kinase inhibitor, is effective in patients with Philadelphia
chromosome-positive chronic myelogenous leukemia in
chronic phase following imatinib resistance and intolerance. Blood 2007: 110: 3540–3546.
67. Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in
imatinib-resistant Philadelphia chromosome-positive
leukemias. N Engl J Med 2006: 354: 2531–2541.
68. Hochhaus A, Kantarjian HM, Baccarani M, et al.
Dasatinib induces notable hematologic and cytogenetic
responses in chronic-phase chronic myeloid leukemia
after failure of imatinib therapy. Blood 2007: 109: 2303–
2309.
69. Anon. 2006. Results from phase II studies of dasatinib in
patients with chronic myeloid leukaemia or Ph+ acute lymphocytic leukaemia with resistance or intolerance to imatinib. 11th Congress of European Hematology. Amsterdam,
The Netherlands.
70. Assouline S, Laneuville P, Gambacorti-Passerini C. Panniculitis during dasatinib therapy for imatinib-resistant
chronic myelogenous leukemia. N Engl J Med 2006: 354:
2623–2624.
71. Radaelli F, Bramanti S, Fantini NN, Fabio G, Greco I,
Lambertenghi-Deliliers G. Dasatinib-related alveolar
pneumonia responsive to corticosteroids. Leuk Lymphoma
2006: 47: 1180–1181.
72. Sprycel package insert. New York, NY: Bristol-Meyers
Squibb. http://www.fda.gov/cder/foi/label/2006/ 021986l
bl.pdf. Accessed January 6, 2008.
73. Danielsn CE, Wilkes MC, Edens M, et al. Imatinib mesylate
inhibits the profibrogenic activity of TGF-b and prevents
bleomycin- mediated lung fibrosis. J Clin Invest 2004: 114:
1308–1316.
Practical approach
74. Akhmetshina A, Dees C, Pileckyte M, et al. Dual inhibition
of c-abl and PDGF receptor signaling by dasatinib and nilotinib for the treatment of dermal fibrosis. FASEB J 2008: 22:
2214–2222.
75. Distler JH, Distler O. Intracellular tyrosine kinases as novel
targets for anti-fibrotic therapy in systemic sclerosis. Rheumatology (Oxford) 2008: 47: v10–v11.
76. Giles FJ. The toxicities of modern targeted therapies –
learning from the price of progress. Target Oncol 2009: 4:
65–66.
77. Roujeau JC, Stern RS. Severe adverse cutaneous reactions
to drugs. N Engl J Med 1994: 331: 1272–1285.
395